WO2022256459A1 - Kras modulators and uses thereof - Google Patents

Kras modulators and uses thereof Download PDF

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WO2022256459A1
WO2022256459A1 PCT/US2022/031846 US2022031846W WO2022256459A1 WO 2022256459 A1 WO2022256459 A1 WO 2022256459A1 US 2022031846 W US2022031846 W US 2022031846W WO 2022256459 A1 WO2022256459 A1 WO 2022256459A1
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compound
alkyl
salt
heterocycle
optionally substituted
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PCT/US2022/031846
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French (fr)
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Hong Lin
Juan Luengo
Neil Johnson
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Quanta Therapeutics, Inc.
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Publication of WO2022256459A1 publication Critical patent/WO2022256459A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • KRAS MODULATORS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Applications Nos. 63/195,634 filed on June 1, 2021; 63/240,713 filed on September 03, 2021; and 63/297,617 filed on January 7, 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 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 (II) and a pharmaceutically acceptable excipient.
  • 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).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III) 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 (III).
  • 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.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (i.e., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl).
  • an alkyl comprises one to two carbon atoms (i.e., C 1 - C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl).
  • the alkyl group 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 –Cx-yalkylene- 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., C2-C12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C 2 -C 6 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., C2-C12 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., C2-C6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Cx-yalkenyl and Cx-yalkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term –C x- yalkenylene- 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 –Cx-yalkynylene- 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., C1-C8 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., C1-C5 alkylene).
  • an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1 -C 3 alkylene). 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., C5-C8 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., C3-C5 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., C2-C10 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., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkenylene).
  • an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkenylene).
  • Alkynylene 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., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). 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.
  • Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.
  • Alkoxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.
  • 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.
  • Heterocycle refers to a saturated or unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings.
  • Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • Bicyclic heterocycles may be fused, bridged or spiro-ring systems.
  • spiro-ring heterocycles have at least two molecular rings with only one common atom.
  • the spiro-ring heterocycle includes at least one heteroatom.
  • 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).
  • each heterocycle of R 9’ has only 1 nitrogen atom. In some cases, each heterocycle of R 9’ has only 1 nitrogen atom and is bound to Formula (I) via the 1 nitrogen atom.
  • Formula (I) is represented by Formula (X) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle optionally contains one or more additional heteroatoms selected from oxygen, boron, and sulfur; or Ring A is further selected from 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which optionally contain one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 12-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11- , and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , -SR 20 , - N(R 20 )S(O) 2 (R
  • Ring A is selected from a 5- to 12-membered monocyclic heterocycle, wherein the 5- to 12-membered monocyclic heterocycle optionally contains one or more additional heteroatoms selected from oxygen, boron, and sulfur; or Ring A is further selected from 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which optionally contain one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 12-membered monocyclic heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused monocyclic heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 )2, -OR 20 , -SR 20 , - N(R 20 )S(O)2(R 20 ).
  • Y is O. In some cases, Y is a bond. In some cases, R is -N(R 5 )-.
  • L is selected from C 1 -C 4 alkylene. In some cases, L is selected from Cl-C2 alkylene. In some cases, L is selected from C 1 alkylene.
  • L is selected from unsubstituted C 1 -C 4 alkylene.
  • L is selected from unsubstituted Cl-C2 alkylene. In some cases, L is selected from unsubstituted Cl alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [0069] In some embodiments, for a compound or salt of Formula (I) or Formula (X), 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-C 6 -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.
  • 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. In some cases, the heteroaryl or heterocycle has at least 1 nitrogen atom. In some cases, the heteroaryl or heterocycle has 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. In some cases, 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 heteroaryl of R 2 is a 5- to 12-membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12- membered heteroaryl, or 8- to 12-membered heteroaryl.
  • the heteroaryl of R 2 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl.
  • the heteroaryl of R 2 is a 6- to 11-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl. In some cases, the heteroaryl of R 2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl. In some cases, the heteroaryl of R 2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R 2 is an 8- to 9-membered heteroaryl.
  • the heteroaryl may be optionally substituted as described elsewhere herein.
  • the heterocycle portion is optionally substituted with one or more R 6 , wherein R 6 is independently selected from halogen, hydroxy, 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
  • R 2 is selected from optionally substituted -L-heterocycle.
  • the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms.
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted. In some cases, R 2 is selected from wherein the heterocycle portion is optionally substituted. In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from .
  • Y-R 2 is selected from
  • R 2 is selected optionally substituted heterocycle.
  • the heterocycle contains 1 nitrogen atom.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, - OC(O)N(R 5 )2, and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle.
  • Y-R 2 is from .
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, -OC(O)N(R 5 ) 2 , and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle.
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl. In some cases, R 2 is .
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, -OC(O)N(R 5 ) 2 , and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle.
  • Y-R 2 is selected from , , , .
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, - CH 2 OC(O)heterocycle, -CH 2 OC(O)N(R 5 ) 2 , and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from oxo and hydroxy.
  • Y- R 2 is selected from and [0076]
  • the heterocycle portion is optionally substituted with one or more R 6 .
  • the R 6 is independently selected from halogen, hydroxy, 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, the R 6 is independently selected from hydroxy, 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 .
  • the heteroaryl portion is optionally substituted with one or more R 6 .
  • R 6 is independently selected from halogen, hydroxy, 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 halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 - C3 alkoxy, -N(R 5 )2, and oxo. In some cases, the R 6 is independently selected from hydroxy, 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.
  • the R 6 is independently selected from halogen C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 . In some cases, the R 6 is independently selected from halogen or C 1 -C 3 alkyl. In some cases, R 6 is methyl or fluorine. [0078] In some embodiments, for a compound or salt of Formula (I) or Formula (X), Y-R 2 is selected from , , and . In some cases, R 2 is selected from , , and .
  • each R 20 is independently selected from hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl.
  • the heterocycle is a 4-membered heterocycle.
  • Y is a bond and Y-R 2 is .
  • 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. [0081] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R 3 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • the aryl of R 3 is selected from a C10-C14 aryl, C10-C13 aryl, C10-C12 aryl, C10-C11 aryl, C11-C14 aryl, C11- C13 aryl, C11-C12 aryl, C12-C14 aryl, C12-C13 aryl, C6-C13 aryl, and C6-C14 aryl.
  • R 3 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • the heteroaryl of R 3 is a 10- to 14-membered heteroaryl, 10- to 13-membered heteroaryl, 10- to 12- membered heteroaryl, 10- to 11-membered heteroaryl, 11- to 14-membered heteroaryl, 11- to 13- membered heteroaryl, 11- to 12-membered heteroaryl, 12- to 14-membered heteroaryl, 5- to 12- membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12-membered heteroaryl, or 8- to 12- membered heteroaryl.
  • the heteroaryl of R 3 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl.
  • the heteroaryl of R 2 is a 6- to 11-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl.
  • the heteroaryl of R 2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl.
  • the heteroaryl of R 2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R 2 is an 8- to 9-membered heteroaryl. In some cases, R 3 is selected from an optionally substituted heteroaryl.
  • R 3 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • the aryl is monocyclic. In some cases, the aryl is bicyclic. In some cases, the aryl is tricyclic. In some cases, the heteroaryl is monocyclic. In some cases, the heteroaryl is bicyclic.
  • the heteroaryl is tricyclic. In some cases, the aryl is bicyclic or tricyclic. In some cases, the heteroaryl is bicyclic or tricyclic. [0084] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R 3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl is a 10-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 10-to-12 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-to-13 membered tricyclic heteroaryl.
  • the heteroaryl is a 13-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-membered tricyclic heteroaryl. In some cases, the heteroaryl is a 13 membered tricyclic heteroaryl. [0085] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R 3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl includes 6 to 11 carbon atoms and at least one heteroatom selected from N, O, and S.
  • the heteroaryl includes 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, or 9 to 10 carbon atoms. In some cases, the heteroaryl includes at least one, two, or three heteroatoms. In some cases, the heteroaryl includes at most one, two, or three heteroatoms. In some cases, the heteroaryl includes at least one nitrogen atom. In some cases, the heteroaryl includes at least two or at least three nitrogen atoms. In some cases, the heteroaryl includes at least two nitrogen atoms. In some cases, the heteroaryl includes at least three nitrogen atoms.
  • the heteroaryl includes at most one nitrogen atom. In some cases, the heteroaryl includes at most two nitrogen atoms. In some cases, the heteroaryl includes at most three nitrogen atoms. In some cases, the heteroaryl has only nitrogen heteroatoms. In some cases, the heteroaryl has nitrogen and sulfur heteroatoms. In some cases, the heteroaryl includes at least one sulfur atom. [0086] In alternative embodiments, for a compound or salt of Formula (I) or Formula (X), 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.
  • R 3 is selected from an optionally substituted unsaturated 10-membered heterocycle.
  • the heterocycle is partially unsaturated.
  • the unsaturated heterocycle contains at least one nitrogen atom.
  • the unsaturated heterocycle contains at least one oxygen atom.
  • R 3 is selected from and which is optionally substituted.
  • R 3 is selected from [0087]
  • R 3 is selected from an optionally substituted heteroaryl.
  • R 3 is selected from an optionally substituted 10- to 15-memebered heteroaryl. In some cases, R 3 is selected from an optionally substituted 12- to 13-memebered heteroaryl. 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 , . , , each of which are optionally substituted.
  • R 3 is selected from In some cases, R 3 is selected from ,and In some cases, R 3 is selected from In some cases, R 3 is selected from [0088] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R 3 is selected from optionally substituted aryl. In some cases, the aryl is C10-C14 aryl.
  • the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -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 C 10 -C 14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 aminoalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and -N(R 5 )2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 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, hydroxy, -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 hydroxy, C 1-6 aminoalkyl, 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 hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl.
  • the C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl.
  • the C 6 -C 10 aryl is selected from phenyl and naphthalene.
  • R 3 is selected from indazole and naphthalene.
  • R 3 is naphthalene.
  • R 3 is selected from In some cases, R 3 is selected from . In some cases, R 3 is selected from . [0092] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R 3 is selected from an optionally substituted 9- to 15-memebered heteroaryl optionally substituted C 6 - C10 aryl.
  • R 3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents.
  • R 3 is selected from aryl, which is optionally substituted with one or more substituents.
  • the aryl is selected from a C6 aryl and C10 aryl.
  • the heteroaryl is selected from a 9- to 10-membered heteroaryl.
  • R 3 is selected from C 10 aryl and 9- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents.
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has two ntirgoen atoms and no further heteroatoms. In some cases, the heteroaryl has at least one oxygen atom. In some cases, the heteroaryl is bicyclic. In some cases, the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C 1-6 alkyl, C2-C4 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl. In some cases, R 3 is selected from , . In some cases, the aryl is substituted with at least one substituent selected from halogen and hydroxy.
  • R 3 is selected from In some cases, the aryl is substituted with at least two halogen atoms. In some cases, R 3 is selected from .
  • R 9’ is Ring A.
  • 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 C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, or C9-C12 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.
  • 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. [0097] In some embodiments, for a compound or salt of Formula (I), 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 heterocycle of R 9’ is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12- membered bridged heterocycle, or 8- to 12-membered bridged heterocycle.
  • the heterocycle of R 9’ is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8-membered bridged heterocycle.
  • the heterocycle of R 9’ is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle.
  • the heterocycle of R 9’ is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9-membered bridged heterocycle, or 7- to 8-membered bridged heterocycle.
  • the heterocycle of R 9’ is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridged heterocycle.
  • the heterocycle of R 9’ is an 8- to 9-membered bridged heterocycle.
  • the heterocycle of R 9’ is saturated.
  • the bridged heterocycle may be optionally substituted as described elsewhere herein.
  • the heterocycle of R 9’ is an unbridged heterocycle.
  • R 9’ is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom.
  • R 9’ is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted.
  • the heterocycle of R 9’ contains at most 1 nitrogen atom.
  • the heterocycle of R 9’ contains only 1 heteroatom atom.
  • the heteroatom is selected from nitrogen, oxygen, and sulfur.
  • the heterocycle is a monocyclic heterocycle or a bridged heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle is a bridged heterocycle.
  • the heterocycle is selected from .
  • the heterocycle is selected from In some cases, the heterocycle is selected from In some cases, the bridged heterocycle is selected from , , a d .
  • the bridged heterocycle has only 1 nitrogen atom. In some cases, the bridged heterocycle has only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom.
  • the heterocycle may be optionally substituted as described elsewhere herein.
  • the spiroheterocycle of R 9’ contains at most 1 nitrogen atom. In some cases, the spiroheterocycle of R 9’ contains only 1 nitrogen atom. In some cases, the spiroheterocycle of R 9’ contains at most 2 heteroatom atoms. In some cases, the spiroheterocycle of R 9’ contains at least 2 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the spiroheterocycle of R 9’ is bound to Formula (I) via the nitrogen atom.
  • the spiroheterocycle of R 9’ is selected from . In some embodiments, the spiroheterocycle of R 9’ is selected from The spiroheterocycle may be optionally substituted as described elsewhere herein. [00102] In some embodiments, for a compound or salt of Formula (I), R 9’ is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R 9’ is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R 9’ is selected from optionally substituted 8-membered spiroheterocycle.
  • the optionally substituted 7- to 8- membered spiroheterocycle contains only 1 nitrogen atom. In some cases, the optionally substituted 7- to 8-membered spiroheterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom.
  • 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 6-membered fused heterocycle.
  • the fused heterocycle has only 1 nitrogen atom. In some cases, the fused heterocycle has only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom.
  • the fused heterocycle may be optionally substituted as described elsewhere herein.
  • the fused heterocycle of R 9’ is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R 9’ is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R 9’ is selected from a 10- to 12-membered fused heterocycle.
  • the fused heterocycle may be optionally substituted with one or more substituents 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 fused heterocycle of R 9’ contains at most 1 nitrogen atom. In some embodiments, for a compound of Formula (I), the fused heterocycle of R 9’ contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle is . In some cases, the fused heterocycle is which is optionally substituted. In some cases, the fused heterocycle has only 1 nitrogen atom. The fused heterocycle may be optionally substituted as described elsewhere herein.
  • R 9’ is selected from C 6 - C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10- , 11-, and 12-membered fused heterocycle, each of which is optionally substituted.
  • R 9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and wherein each heterocycle contains only 1 nitrogen atom.
  • R 9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and wherein each heterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom.
  • R 9’ is selected from C 6 - C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents 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’ for a compound or salt of Formula (I), for R 9’ , R 20 of -OR 20 and -N(R 20 ) 2 , is selected hydrogen and C 1-6 alkyl.
  • R 9’ is selected from C 6 - C7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted.
  • the heterocycle contains at most 1 nitrogen atom.
  • the heterocycle contains only 1 nitrogen atom.
  • the heterocycle is bound to Formula (I) via the only 1 nitrogen atom.
  • R 9’ is selected from C6-C7 carbocycle, each of which is optionally substituted.
  • 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, -N(R 20 )C(O)N(R 20 )2, and C 1-6 alkyl.
  • 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. 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 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’ is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, wherein the C3-C12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -
  • the 5- to 12-membered heterocycle is a monocyclic 5- to 12-membered heterocycle.
  • R 9’ is selected from C 3 - C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C 3 -C 12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -
  • each heterocycle contains only 1 nitrogen atom. In some cases, each heterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom.
  • R 9’ is selected from C3- C 12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen,
  • R 9’ is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR 20 , -N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , and -B(OR 20 ) 2 .
  • R 9’ is selected from , , , , and , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , and -B(OR 20 )2.
  • R 9’ is selected from , , , , and , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , and -B(OR 20 )2.
  • R 9’ is
  • R 9’ is selected from 5- to 10- membered heterocycle, wherein the 5- to 10-membered heterocycle contains 1 nitrogen atom, and wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C 1-6 cyanoalkyl, -CN, -OR 20 , -N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aminoalkyl.
  • the 5- to 10-membered heterocycle is a monocyclic heterocycle.
  • the 5- to 10-membered heterocycle is an unsaturated 5- to 10-membered heterocycle.
  • the 5- to 10-membered heterocycle contains at least 1 double bond. In some cases, the 5- to 10-membered heterocycle contains at least 2 double bonds. In some cases, the 5- to 10-membered heterocycle which contains 1 nitrogen atom, is bound to Formula (I) through the nitrogen atom.
  • R 9’ is selected from , , , , , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 cyanoalkyl, -CN, -OR 20 , - N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aminoalkyl.
  • R 9’ is selected from , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 cyanoalkyl, - CN, -OR 20 , C 1-6 alkyl, and C 1-6 hydroxyalkyl.
  • the optional one or more substituents are independently selected from halogen, C 1-6 cyanoalkyl, -CN, -OR 20 , C 1-6 alkyl, and C 1-6 hydroxyalkyl.
  • each R 20 is independently selected from hydrogen and C 1-6 alkyl.
  • R 9’ is selected from In some cases, R 9’ is selected from [00119] In some embodiments, for a compound of Formula (I), R 9’ is selected unsaturated 7- membered monocyclic heterocycle, which is optionally substituted with one or more substituents independently selected from C 1-6 cyanoalkyl, and -CN. In some cases, R 9’ is selected from , which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 cyanoalkyl, -CN, -OR 20 , C 1-6 alkyl, and C 1-6 hydroxyalkyl.
  • R 9’ is selected from , which is optionally substituted with one or more substituents independently selected from C 1-6 cyanoalkyl, and -CN. In some cases, R 9’ is selected from , which is substituted with one or more substituents independently selected from C 1-6 cyanoalkyl, hydroxy and -CN. In some cases, R 9’ is selected from , which is optionally substituted with one or more substituents independently selected from C 1-6 cyanoalkyl, hydroxy and -CN. In some cases, R 9’ is selected from , , and . In some cases, R 9’ is selected from , and . In some cases, R 9’ is . In some cases, R 9’ is . In some cases, R 9’ is .
  • R 9’ is .
  • R 9’ is selected unsaturated 7- membered monocyclic heterocycle, which is optionally substituted with one or more substituents independently selected from -OH, and C 1-6 hydroxyalkyl.
  • R 9’ is selected from , which is optionally substituted with one or more substituents independently selected from -OH, and C 1-6 hydroxyalkyl.
  • R 9’ is .
  • R 9’ is selected from , which is substituted with at least one -OH.
  • R 9’ is , , , and .
  • R 9’ is , and .
  • R 9’ is selected from 5- to 10- membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -N(R 20 )2, -OR 20 , and C 1-6 alkyl.
  • the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl.
  • the 5- to 10-membered heterocycle is a monocyclic 5- to 10- membered heterocycle.
  • R 9’ is selected from and , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl. In some cases, R 9’ is selected from , , and .In some cases, R 9’ is selected from , , , , , , , , . , , , , , , , , , , , , , and , each of which are optionally substituted. [00122] In some embodiments, for a compound or salt of Formula (I), R 9’ is selected from , , and , each of which are optionally substituted.
  • R 9’ is selected from , , , , and , each of which are optionally substituted.
  • R 9’ is selected from , , . , , , , , , , , , , and , each of which are optionally substituted.
  • R 9’ is which is optionally substituted.
  • R 9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 9’ is selected from a heterocycle as drawn in Table 1.
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • 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. In some cases, R 9’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds.
  • R 9’ is selected from , , , , and wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, 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, -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, -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 n some cas 9’ es, R is selected from .
  • R 9’ is selected from In some cases, R 9’ is .
  • R 9’ is selected from , , and , wherein each is substituted with one or more substituents independently selected from halogen.
  • R 9’ is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R 9’ is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen.
  • R 9’ is selected from an unsaturated 7-membered heterocycle, substituted with at least one halogen. In some cases, R 9’ is selected from , , , In so 9’ me cases, R is selected from . In some cases, R 9’ is selected from , , a d . In some cases, R 9’ is selected from and . In some cases, R 9’ is . In some cases, R 9’ is . In some cases, R 9’ is . [00132] In some embodiments, for a compound or salt of Formula (I), R 9’ is selected from an optionally substituted 6-membered unsaturated heterocycle and optionally substituted 6- membered saturated heterocycle.
  • R 9’ is selected from and , 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 and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl.
  • R 9’ is selected from , , and .
  • R 9’ is selected from and , wherein each is optionally substituted two 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 two substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 9’ is , which is substituted with two substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 9’ is .
  • R 9’ is selected from C 3 - C12 carbocycle; 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the C3-C12 carbocycle; 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted.
  • R 9’ is selected from 5- to 8-membered monocyclic heterocycle, 7- to 8-membered bridged heterocycle, 7-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and each of which is bond to Formula (I) via the 1 nitrogen atom.
  • R 9’ is selected from 5- to 8-membered monocyclic heterocycle, each of which contains at only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 8-membered monocyclic heterocycle, which is optionally substituted, and each of which is bound to Formula (I) via the 1 nitrogen atom.
  • R 9’ is selected from 5- to 8-membered monocyclic heterocycle, each of which contains at only 1 nitrogen atom; wherein the 5- to 8-membered monocyclic heterocycle is optionally substituted, and wherein the 5- to 8-membered monocyclic heterocycle is bound to Formula (I) via the 1 nitrogen atom.
  • R 9’ is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains only 1 nitrogen atom, or R 9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11- , and 12-membered fused heterocycle, wherein the 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle each contain only 1 nitrogen atom; and wherein the 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted.
  • R 9’ is selected from 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or R 9’ is further selected from 8-, 10, 11-membered spiro heterocycle and 10-membered fused heterocycle, wherein the 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle each contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle, are each optionally substituted; and wherein the, 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle, of R 9’ are each bound to Formula (I) via the only 1 nitrogen atom.
  • the 5- to 8-membered heterocycle is unsaturated. In some cases, the 5- to 8-membered heterocycle is a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a monocyclic 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a bicyclic 5- to 8-membered heterocycle. In some cases, R 9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 9’ is selected from 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or R 9’ is further selected from 8-membered spiro heterocycle, wherein the 8-membered spiro heterocycle contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, and 8- membered spiro heterocycle, are each optionally substituted; and wherein the 5- to 8-membered heterocycle, and 8-membered spiro heterocycle of R 9’ are each bound to Formula (I) via the only 1 nitrogen atom.
  • the 5- to 8-membered heterocycle is a partially unsaturated 5- to 8-membered heterocycle or a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is partially unsaturated.
  • the 5- to 8-membered heterocycle is a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8- membered heterocycle is a monocyclic 5- to 8-membered heterocycle. In some cases, R 9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 9’ is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle, is optionally substituted; and wherein the 6- to 7-membered heterocycle of R 9’ is bound to Formula (I) via the only 1 nitrogen atom.
  • the heterocycle contains only 1 nitrogen atom and no further heteroatoms.
  • R 9’ is selected from , , , , , , and , any of which is optionally substituted.
  • R 9’ is selected from , , , , and , any of which is optionally substituted.
  • R 9’ is selected from , , , , and , any of which is optionally substituted.
  • the 6- to 7-membered heterocycle is a partially unsaturated 6- to 7-membered heterocycle or a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is partially unsaturated. In some cases, the 6- to 7-membered heterocycle is a saturated 6- to 7- membered heterocycle.
  • the 6- to 7-membered heterocycle is a monocyclic 6- to 7- membered heterocycle.
  • R 9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • R 9’ is selected from , and .
  • R 9’ is .
  • Ring A is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle, is optionally substituted. In some cases, the 6- to 7-membered heterocycle contains 1 nitrogen atom and no further heteroatoms. In some cases, Ring A is selected from , , , , , , and , any of which is optionally substituted. In some cases, Ring A is selected from , , , , and , any of which is optionally substituted.
  • Ring A is selected from , , , , and , any of which is optionally substituted.
  • the 6- to 7-membered heterocycle is a partially unsaturated 6- to 7-membered heterocycle or a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is partially unsaturated. In some cases, the 6- to 7-membered heterocycle is a saturated 6- to 7- membered heterocycle.
  • the 6- to 7-membered heterocycle is a monocyclic 6- to 7- membered heterocycle.
  • Ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and .ovi [00143]
  • R 9’ is selected from 6- membered heterocycle, wherein the 6-membered heterocycle contains only 1 nitrogen atom, and wherein the 6-membered heterocycle, is optionally substituted; and wherein the 6-membered heterocycle of R 9’ is bound to Formula (I) via the only 1 nitrogen atom.
  • R 9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 9’ is selected from 6- membered heterocycle, wherein the 6-membered heterocycle contains only 1 nitrogen atom, and wherein the 6-membered heterocycle, is optionally substituted; and wherein the 6-membered heterocycle of R 9’ is bound to Formula (I) via the only 1 nitrogen atom.
  • R 9’ is selected from , and , any of which is optionally substituted.
  • the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6- membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6- membered heterocycle is not a bridged heterocycle. In some cases, R 9’ is selected from , , , , , , , , , , and . [00145] In some embodiments, for a compound or salt of Formula (I), R 9’ is not .
  • R 9’ is not . In some cases, R 9’ is not . In some cases, R 9’ is not . In some cases, R 9’ is not . In some cases, R 9’ is not . [00146] In some embodiments, for a compound or salt of Formula (X), Ring A is not . In some cases, Ring A is not . [00147] In some embodiments, for a compound or salt of Formula (I), R 9’ is not a bridged heterocycle. [00148] In some embodiments, for a compound or salt of Formula (X), Ring A is not a bridged heterocycle.
  • Ring A is selected from a 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or Ring A is further selected from 8-membered spiro heterocycle, wherein the 8- membered spiro heterocycle contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, and 8-membered spiro heterocycle, are each optionally substituted.
  • the 5- to 8-membered heterocycle is an unsaturated 5- to 8-membered heterocycle or a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is unsaturated.
  • the 5- to 8-membered heterocycle is a saturated 5- to 8- membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a monocyclic 5- to 8- membered heterocycle. In some cases, Ring A is selected from , , , , , , , , , , , , , , , , , , , , , , and , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • 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, is optionally substituted; and wherein the 6- to 7-membered heterocycle of R 9’ is bound to Formula (I) via the only 1 nitrogen atom.
  • 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.
  • the 6- to 7-membered heterocycle contains one sulfur atom.
  • the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle. 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, R 9’ is selected from , , , and , each of which is optionally substituted. In some cases, 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. In some cases, the one or more optional substituents of R 9’ are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R 9’ are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  • R 9’ is selected from , , , , , In some cases, R 9’ is selected from [00151] In some embodiments, for a compound or salt of Formula (I), R 9’ is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and one sulfur atom. [00152] In some embodiments, for a compound or salt of Formula (X), Ring A 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, is optionally substituted.
  • 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.
  • the 6- to 7-membered heterocycle contains one sulfur atom.
  • the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle.
  • the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle.
  • Ring A is selected from , , , , , and , each of which is optionally substituted. In some cases, Ring A is selected from , , , and , each of which is optionally substituted.
  • Ring A is selected from , , , , , each of which is optionally substituted.
  • the one or more optional substituents of Ring A are each independently selected from halogen, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  • the one or more optional substituents of Ring A are each independently selected from halogen, -OH, and -CN.
  • the one or more optional substituents of Ring A are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  • each R 20 is independently selected from hydrogen, C 1-6 alkoxy, and cyano; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, -NO2, -NH 2 , 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.
  • each R 20 is independently selected from hydrogen, and cyano; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, -NO2, -NH2, C1-10 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.
  • the optional substituents of R 9’ do not include -N(R 20 )2. In some cases, the optional substituents of R 9’ do not include - NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , and -NH 2 . In some cases, the optional substituents of R 9’ do not include any primary or secondary amines. [00155] In some embodiments, for a compound or salt of Formula (X), the optional substituents of Ring A do not include -N(R 20 ) 2 .
  • the optional substituents of Ring A do not include -NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , and -NH 2 . In some cases, the optional substituents of Ring A do not include any primary or secondary amines. [00156] In some embodiments, for a compound or salt of Formula (I) or Formula (X), wherein the compound is not a Michael acceptor. [00157] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the compound or salt 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 inhibitor for KRAS G12D and/or other G12 mutants.
  • Y is O. In some cases, Y is a bond. In some cases, Y is NR 5 .
  • L is selected from unsubstituted C 1 -C 4 alkylene. In some cases, L is selected from Cl-C2 alkylene. In some cases, L is selected from C 1 alkylene.
  • L is selected from unsubstituted C 1 -C 4 alkylene. In some cases, L is selected from unsubstituted Cl-C2 alkylene.
  • L is selected from unsubstituted Cl alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [00165] In some embodiments, for a compound or salt of Formula (II), 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-C 6 -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 (II), the heterocycle of R 2 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00167] In some embodiments, for a compound or salt of Formula (II), the heteroaryl of R 2 is a 5- to 12-membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12-membered heteroaryl, or 8- to 12-membered heteroaryl.
  • the heteroaryl of R 2 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl. In some cases, the heteroaryl of R 2 is a 6- to 11-membered heteroaryl, 6- to 10- membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl. In some cases, the heteroaryl of R 2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl.
  • the heteroaryl of R 2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R 2 is an 8- to 9-membered heteroaryl. In some embodiments, for a compound of Formula (II), the heteroaryl of R 2 is saturated. The heteroaryl may be optionally substituted as described elsewhere herein. [00168] In some embodiments, for a compound or salt of Formula (II), R 2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom.
  • the heterocycle has only 1 nitrogen atom and no other heteroatoms.
  • R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • substituents selected from heterocycle, oxo, and hydroxy selected from halogen, hydroxy, C 1 -C 3 alkyl, -N(R 5 )S(O) 2 (R 5 ), -OC(O)N(R 5 ) 2 , oxo,
  • Y-R 2 is selected from , , , , , , , , , and .
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • the heterocycle portion is optionally substituted with one or more R 6 .
  • the R 6 is independently selected from halogen, hydroxy, 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, the R 6 is independently selected from hydroxy, 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.
  • the R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 )2.
  • Y-R 2 is selected from , , and .
  • the carbocycle of R 19’ is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, and C3- C6 carbocycle.
  • the carbocycle of R 19’ is selected from C3-C12 carbocycle, C4-C12 carbocycle, C 5 -C 12 carbocycle, C 6 -C 12 carbocycle, C 7 -C 12 carbocycle, C 8 -C 12 carbocycle, and C 9 - C12 carbocycle.
  • the spiroheterocycle of R 19’ is a 6- to 12-membered spiroheterocycle, 6- to 12-membered spiroheterocycle, 7- to 12- membered spiroheterocycle, or 8- to 12-membered spiroheterocycle.
  • the spiroheterocycle of R 19’ is a 6- to 11-membered spiroheterocycle, 6- to 10-membered spiroheterocycle, 6- to 9-membered spiroheterocycle, or 6- to 8-membered spiroheterocycle.
  • the spiroheterocycle of R 19’ is a 7- to 11-membered spiroheterocycle, 7- to 10- membered spiroheterocycle, 7- to 9-membered spiroheterocycle, or 7- to 8-membered spiroheterocycle.
  • the spiroheterocycle of R 19’ is an 8- to 11-membered spiroheterocycle.
  • the spiroheterocycle may be optionally substituted as described elsewhere herein.
  • the fused heterocycle of R 19’ 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 19’ 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 19’ 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 19’ is an 8- to 11-membered fused heterocycle.
  • the fused heterocycle of R 19’ is a 6-membered fused heterocycle.
  • the fused heterocycle of R 19’ is a 7-membered fused heterocycle.
  • the fused heterocycle may be optionally substituted as described elsewhere herein.
  • the heterocycle of R 19’ 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 19’ 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 19’ 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 19’ 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 19’ is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle.
  • the heterocycle of R 19’ is an 8- to 9-membered heterocycle.
  • the heterocycle of R 19’ is saturated.
  • the heterocycle may be optionally substituted as described elsewhere herein.
  • R 19’ is selected from an optionally substituted C3-C7 carbocycle and optionally substituted 5- to 11-membered heterocycle.
  • R 19’ is selected from an optionally substituted C 3- C 7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
  • R 19’ is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle. In some cases, R 19’ is selected from an optionally substituted 5- to 11-membered saturated heterocycle. [00179] In some embodiments, for a compound or salt of Formula (II), for R 19’ , the 5- to 11- membered saturated heterocycle contains at most 2 nitrogen atoms. In some embodiments, for a compound of Formula (II), for R 19’ , the 5- to 11-membered saturated heterocycle contains at most 1 nitrogen atom.
  • the 5- to 11- membered saturated heterocycle contains at least 1 oxygen atom.
  • R 19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 19’ 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 , -N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , and -B(OR 20 )2.
  • R 19’ is selected from , , , , and , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , -N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , and -B(OR 20 )2.
  • R 19’ is selected from , , , , , , , , , , , and .
  • R 19’ is selected from 5- to 10-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -N(R 20 )2, -OR 20 , and C 1-6 alkyl. In some cases, the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl. In some embodiments, for a compound of Formula (II), R 19’ is selected from and , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl.
  • R 19’ is selected from , , and .
  • R 19’ is selected from, , , , , , , , . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • the one or more substituents are independently selected from -OR 20 , - N(R 20 ) 2 , C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl.
  • the one or more substituents 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 substituents are independently selected from -OR 20 , and C 1-6 hydroxyalkyl. In some cases, the one or more substituents are independently selected from -N(R 20 )2, and C 1-6 aminoalkyl. In some cases, the one or more substituents are independently selected from -N(R 20 )C(O)N(R 20 ) 2 .
  • R 20 of R 19’ is selected from hydrogen and C1-3 alkyl. In some cases, R 20 of R 19’ is hydrogen. [00188] In some embodiments, for a compound or salt of Formula (II), R 19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 19’ is selected from , , , , , and . In some cases, R 19’ is . In some cases, R 19’ is . [00190] In some embodiments, for a compound or salt of Formula (II), R 19’ is selected from an optionally substituted 5- to 10-membered heterocycle. In some cases, the 5- to 10-membered heterocycle contains only 1 nitrogen atom. In some cases, the 5- to 10-membered heterocycle is unsaturated.
  • the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 )2, C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aminoalkyl.
  • the 5- to 10-membered heterocycle is an unsaturated 5- to 10-membered heterocycle.
  • the 5- to 10-membered heterocycle contains at least 1 double bond.
  • the 5- to 10-membered heterocycle contains at least 2 double bonds.
  • the 5- to 10-membered heterocycle which contains 1 nitrogen atom is bound to Formula (II) through the nitrogen atom.
  • R 19’ is selected from , , , , , , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aminoalkyl.
  • the optional one or more substituents are independently selected from halogen, C 1-6 cyanoalkyl, -CN, -OH, C 1-6 alkyl, and C 1-6 hydroxyalkyl.
  • each R 20 is independently selected from hydrogen and C 1-6 alkyl.
  • R 19’ is selected from , , , , , , , , , , , , , , , , , , , , , and . In some cases, R 19’ is selected from , , , , , , , , , , , , and . [00191] In some embodiments, for a compound or salt of Formula (II), R 19’ is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is selected from a spiroheterocycle, fused heterocycle, and a monocyclic heterocycle.
  • the heterocycle is not a bridged heterocycle.
  • the heterocycle is a spiroheterocycle.
  • the heterocycle is a fused heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle is selected from a 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10, 11-membered spiro heterocycle, 6-, 7-, 9-, 10-, 11-, and 12-membered fused heterocycle.
  • the 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10-, 11- membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle each contain only 1 nitrogen atom; and wherein the 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10-, 11- membered spiro heterocycle, and 6-, 7-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted.
  • R 19’ is selected from 5- to 8-membered monocyclic heterocycle, 8-, 10-, 11-membered spiroheterocycle, and 7-, 10- membered fused heterocycle, are each optionally substituted; and wherein the, 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 7-, 10-membered fused heterocycle, of R 19’ are each bound to Formula (II) via the only 1 nitrogen atom.
  • the 5- to 8-membered heterocycle is a monocyclic 5- to 8-membered heterocycle.
  • R 19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 19’ is selected from an optionally substituted 6- to 12-membered fused heterocycle. In some cases, R 19’ is selected from an optionally substituted 6- to 10-membered fused heterocycle. In some cases, R 19’ is an optionally substituted 7-membered fused heterocycle. In some cases, the fused heterocycle has only 1 nitrogen atom. In some cases, the fused heterocycle has only 1 nitrogen atom and 1 oxygen atom. In some cases, the heterocycle has at least 1 oxygen atom. In some cases, the fused heterocycle has at most 1 nitrogen atom. In some cases, the fused heterocycle is bound to Formula (II) via the 1 nitrogen atom.
  • the fused heterocycle is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, hydroxy, and oxo.
  • the fused heterocycle is substituted with one or more substituents selected from halogen, C 1-6 alkyl, hydroxy, and oxo.
  • R 19’ is selected , and .
  • R 19’ is selected , which is substituted with one or more substituents selected from halogen, and C 1-6 haloalkyl.
  • R 19’ is selected and .
  • R 19’ is selected .
  • R 19’ is selected .
  • R 3 is selected from an optionally substituted heteroaryl.
  • R 3 is selected from an optionally substituted 10- to 15-memebered heteroaryl.
  • R 3 is selected from an optionally substituted 12- to 13-memebered heteroaryl.
  • R 3 is selected from , . , and , each of which are optionally substituted.
  • R 3 is selected from , , , , , , , , and .
  • R 3 is selected from , , , , , , , and .
  • R 3 is selected from an unsubstituted heteroaryl.
  • the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, 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 20 ) 2 .
  • the C 10 -C 14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 aminoalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and - N(R 20 )2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl.
  • R 3 is selected from optionally substituted C 6 -C 10 aryl.
  • the C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, 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 C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 aminoalkyl, 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 hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl. In some cases, the C 6 - C 10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [00197] In some embodiments, for a compound or salt of Formula (II), R 3 is selected from indazole and naphthalene.
  • R 3 is naphthalene.
  • R 3 is selected from , , , , , and . In some cases, R 3 is selected from . In some cases, R 3 is selected from . [00199] In some embodiments, for a compound or salt of Formula (II), R 3 is selected from , , , , , , , , , , , , , , , , , , , , , , , and . [00200] In some embodiments, for a compound or salt of Formula (II), R 3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents.
  • R 3 is selected from aryl, which is optionally substituted with one or more substituents.
  • the aryl is selected from a C6 aryl and C10 aryl.
  • the heteroaryl is selected from a 9- to 10-membered heteroaryl.
  • R 3 is selected from C 10 aryl and 9- to 10- membered heteroaryl, each of which is optionally substituted with one or more substituents.
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms.
  • the heteroaryl has two ntirgoen atoms and no further heteroatoms.
  • the heteroaryl has at least one oxygen atom.
  • the heteroaryl is bicyclic.
  • the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C 1-6 alkyl, C2-C4 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.
  • R 3 is selected from , , , , , , , , , , , and .
  • the aryl is substituted with at least one substituent selected from halogen and hydroxy.
  • R 3 is selected from , , , , , and .
  • R 19’ is selected from an optionally substituted 6- to 7-membered heterocycle.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom.
  • the 6- to 7-membered heterocycle of R 19’ is bound to Formula (II) via the only 1 nitrogen atom.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further heteroatoms.
  • R 19’ is selected from , , , , , , and , any of which is optionally substituted.
  • the 6- to 7-membered heterocycle is a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle.
  • R 19’ is selected from , , , , , , , , , , , , , , and . [00202] [00203] In some embodiments, for a compound or salt of Formula (II), R 19’ is not . In some cases, R 19’ is not . In some cases, R 19’ is not . In some cases, R 19’ is not . In some cases, R 19’ is not . In some cases, R 19’ is not . In some cases, R 19’ is not .
  • R 19’ is not a bridged heterocycle.
  • R 19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
  • R 19’ is selected from an optionally substituted unsaturated 6- to 7-membered heterocycle.
  • R 19’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • R 19’ is selected from an optionally substituted unsaturated 6-membered heterocycle.
  • R 19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 19’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • R 19’ is selected from , and , 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. In some cases, R 19’ is selected from , , , , and .
  • R 19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl.
  • R 19’ is selected from , , and .
  • R 19’ is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 19’ is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C 1-6 haloalkyl.
  • 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 13 is selected from optionally substituted C 6 -C 10 aryl.
  • the C6- C 10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 )2, -NO2, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  • the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  • R20 is hydrogen.
  • R 20 is selected from hydrogen and C 1-6 alkyl.
  • R 20 of R 13 is selected from hydrogen and C1-3 alkyl.
  • R 13 is optionally substituted naphthalene.
  • the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from - OH and C 1-6 hydroxyalkyl.
  • R 13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, and C1-3 alkyl.
  • R 13 is selected from , , , and .
  • R 13 is selected from indazole and naphthalene.
  • R 13 is naphthalene.
  • R 13 is selected from , , , , and . In some cases, R 13 is selected from . [00224] In some embodiments, for a compound or salt of Formula (II), wherein the compound is not a Michael acceptor. [00225] In some embodiments, for a compound or salt of Formula (II), wherein the compound does not include an electrophilic substituent. [00226] In some embodiments, for a compound or salt of Formula (II), the compound or salt does not include an electrophilic substituent. [00227] In some embodiments, for a compound or salt of Formula (II), 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 inhibitor for KRAS G12D and/or other G12 mutants.
  • the unsaturated 5- to 12- membered heterocycle of R 29’ contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains at least 1 nitrogen atom. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains only 1 nitrogen atom.
  • the unsaturated 5- to 12- membered heterocycle of R 29’ contains at least 1 double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains at most 1 double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains at least 1 carbon-carbon double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R 29’ contains at most 1 carbon-carbon double bond. [00233] In some embodiments, for a compound of Formula (III), R 29’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
  • R 29’ is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R 29’ is selected from an optionally substituted unsaturated 6-membered heterocycle. [00234]
  • R 29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen and C 1-6 haloalkyl.
  • R 29’ is selected from , , , and .
  • R 29’ is selected from and .
  • R 29’ is selected from , and .
  • R 29’ is selected from , , and , 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 29’ is selected from and is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In somec cases, R 29’ is selected from , and . [00238] In some embodiments, for a compound of Formula (III), R 29’ is selected from unsaturated 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle, is optionally substituted.
  • the unsaturated 6- to 7-membered heterocycle contains only 1 nitrogen atom. In some cases, the unsaturated 6- to 7-membered heterocycle of R 29’ is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R 29’ is selected from , , , , and , any of which is optionally substituted. In some cases, R 29’ is selected from , , and , any of which is optionally substituted. In some cases, R 29’ is selected from , , , , and , any of which is optionally substituted.
  • the unsaturated 6- to 7-membered heterocycle is an unsaturated monocyclic 6- to 7-membered heterocycle.
  • R 29’ is selected from , , , , and , any of which is substituted with one or more substituents selected from halogen.
  • R 29’ is selected from, , , , , , , and .
  • R 3 is selected from an optionally substituted heteroaryl.
  • the heteroaryl includes 6 to 11 carbon atoms and at least one heteroatom selected from N, O, and S.
  • the heteroaryl includes 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, or 9 to 10 carbon atoms. In some cases, the heteroaryl includes at least one, two, or three heteroatoms. In some cases, the heteroaryl includes at most one, two, or three heteroatoms. In some cases, the heteroaryl includes at least one nitrogen atom. In some cases, the heteroaryl includes at least two or at least three nitrogen atoms. In some cases, the heteroaryl includes at least two nitrogen atoms. In some cases, the heteroaryl includes at least three nitrogen atoms.
  • the heteroaryl includes at most one nitrogen atom. In some cases, the heteroaryl includes at most two nitrogen atoms. In some cases, the heteroaryl includes at most three nitrogen atoms. In some cases, the heteroaryl has only nitrogen heteroatoms. In some cases, the heteroaryl has nitrogen and sulfur heteroatoms. In some cases, the heteroaryl includes at least one sulfur atom. [00240] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from an optionally substituted heteroaryl. In some cases, R 3 is selected from an optionally substituted 10- to 15-memebered heteroaryl. In some cases, R 3 is selected from an optionally substituted 12- to 13-memebered heteroaryl.
  • R 3 is selected from , . , and , each of which are optionally substituted.
  • R 3 is selected from , , , , , , , , and .
  • R 3 is selected from , , , , , , , and .
  • R 3 is selected from an unsubstituted heteroaryl.
  • R 3 is selected from . In some cases, R 3 is selected from . [00241] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from optionally substituted aryl. In some cases, the aryl is C 10 -C 14 aryl.
  • the C 10 - C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, 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 C 10 -C 14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 aminoalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and -N(R 5 )2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl. In some cases, the C 10 -C 14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl.
  • R 3 is selected from optionally substituted C 6 -C 10 aryl.
  • the C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, 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 C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 aminoalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and -N(R 5 ) 2 . In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl.
  • the C 6 - C 10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [00243] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from indazole and naphthalene. In some cases, R 3 is naphthalene.
  • R 3 is selected from , , , , , and . In some cases, R 3 is selected from . In some cases, R 3 is selected from . [00245] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from , , , , , , , , , , , , , , , , , , , , , , , and . [00246] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents.
  • R 3 is selected from aryl, which is optionally substituted with one or more substituents.
  • the aryl is selected from a C6 aryl and C10 aryl.
  • the heteroaryl is selected from a 9- to 10-membered heteroaryl.
  • R 3 is selected from C10 aryl and 9- to 10- membered heteroaryl, each of which is optionally substituted with one or more substituents.
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms.
  • the heteroaryl has two ntirgoen atoms and no further heteroatoms.
  • the heteroaryl has at least one oxygen atom.
  • the heteroaryl is bicyclic.
  • the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C 1-6 alkyl, C2-C4 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.
  • R 3 is selected from , , , , , , , , , , , and .
  • the aryl is substituted with at least one substituent selected from halogen and hydroxy.
  • R 3 is selected from , , , , , and .
  • the aryl is substituted with at least two halogen atoms.
  • R 3 is selected from .
  • Y is O.
  • L is selected from unsubstituted C 1 -C 4 alkylene.
  • 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- heterocycle and -L-N(R 5 )2. In some cases, R 2 is selected from optionally substituted -L- heterocycle. [00250] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • Y-R 2 is selected from , , and .
  • Y-R 2 is selected from , , , , , , , , , ,
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, -OC(O)N(R 5 )2, and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle.
  • Y-R 2 is selected from , , , , , , and .
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CH 2 OC(O)heterocycle, - CH2OC(O)N(R 5 )2, and -O-C 1 -C 3 alkyl, wherein the alkyl of -O-C 1 -C 3 alkyl is optionally substituted with substituents selected from oxo and hydroxy.
  • Y-R 2 is selected from , , , , and .
  • the heterocycle portion is optionally substituted with one or more R 6 .
  • the R 6 is independently selected from halogen, hydroxy, 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, the R 6 is independently selected from hydroxy, 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.
  • the heteroaryl portion is optionally substituted with one or more R 6 .
  • R 6 is independently selected from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 - C3 alkoxy, -N(R 5 )2, and oxo.
  • the R 6 is independently selected from halogen, hydroxy, 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, the R 6 is independently selected from hydroxy, 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.
  • the R 6 is independently selected from halogen C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 )2. In some cases, the R 6 is independently selected from halogen or C 1 -C 3 alkyl. In some cases, R 6 is methyl or fluorine. [00254] In some embodiments, for a compound of Formula (III), Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted. [00255] In some embodiments, for a compound of Formula (III), R 2 is selected from and , wherein the heterocycle portion is optionally substituted.
  • the heterocycle portion is optionally substituted with one or more R 6 , wherein R 6 is independently selected from halogen, hydroxy, 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.
  • R 6 is independently selected from halogen, hydroxy, 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.
  • Y-R 2 is selected from , , and .
  • R 4 is selected from halogen and hydrogen. In some cases, R 4 is selected from halogen.
  • R 4 is fluorine. In some cases, R 4 is hydrogen.
  • R 3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, C2-C4 alkynyl, and C1-3 alkyl. In some cases, R 3 is selected from , , , , and . [00261] In some embodiments, for a compound or salt of Formula (III), R 3 is selected from and .
  • each R 20 is independently selected from hydrogen and -CN; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, - C1-10 haloalkyl, -O-C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • the compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • 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.
  • 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 disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • 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).
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds 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. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • 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 are preferred prodrugs of the present disclosure.
  • 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.
  • 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.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
  • compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (II), and (III) (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. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • 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 is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers 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 [00305]
  • the present disclosure provides compounds that inhibit KRas G12 mutants, KRAS G12D, G12D alleles, or alleles.
  • the method may inhibit KRas G12 mutants activity in a cell.
  • inhibiting 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 Formula (I), Formula (II), Formula (III), Formula (X), 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 Formula (I) or Formula (II) or Formula (III) or Formula (X) or a pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • a compound of Formula (I) or Formula (II) or Formula (III) or Formula (X) or a 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.
  • compositions and methods of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • the compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one 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 G12D alleles-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
  • compositions and methods provided herein may be used for the treatment of an alleles-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
  • the KRas G12D, other G12 mutants, G12D alleles, or alleles associated cancer is lung cancer.
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.
  • 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 (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy is also provided herein.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of KRas G12D and/or other G12 mutants is also provided herein.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of G12D alleles is also provided herein.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of alleles is also provided herein.
  • a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12D and/or other G12 mutants -associated disease or disorder is also provided herein.
  • Also provided herein is a use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) 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.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder.
  • Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a G12D allele-associated disease or disorder.
  • Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an allele-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 (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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 compounds described herein display selectivity towards inhibiting KRAS vs NRAS.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • the 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.
  • 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. Alternatively, 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 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • 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.
  • the following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope Preparation of Compounds [00338]
  • 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. [00339] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES [00340] The following synthetic schemes are provided for purposes of illustration, not limitation.
  • Step 2 Synthesis of 7-(3-(benzyloxy)naphthalen-1-yl)-2,4-dichloro-8- fluoropyrido[4,3-d]pyrimidine (2d): To a mixture of 7-(3-benzyloxy-1-naphthyl)-8-fluoro- pyrido[4,3-d]pyrimidine-2,4-diol (2c, 350 mg, 0.850 mmol, 1.0 eq) in POCl 3 (5 mL) was added DIEA (0.7 mL, 4.23 mmol, 5.0 eq). The mixture was stirred at 100 o C for 6 h under N2.
  • Step 4 Synthesis of tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)carbamate (2h): A mixture of tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-2- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2f, 100 mg, 0.160 mmol, 1.0
  • reaction mixture was concentrated and purified by Prep- HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% TFA) / MeOH at flow rate : 50 mL / min to afford tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)carbamate (2h, 32.0 mg, 0.0445 mmol, 28.5% yield) as a yellow solid.
  • Step 1 Synthesis of tert-butyl N-[[1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)pyrrolidin-3-yl]methyl]carbamate (6c): To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3- d]pyrimidine (6a, 385 mg, 1.52 mmol, 1.0 eq) and DIEA (5.08 mL, 30.7 mmol, 20.2 eq) in DCM (10 mL) was added tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate (6b, 366 mg, 1.83 mmol, 1.2 eq) at -50 °C and the mixture was stirred for 1.5 h.
  • Example 3 Exemplary synthesis of compound 11 [00352] Step 1. Synthesis of 4-(2-chloro-8-fluoro-4-((1R,3r,5S)-3-hydroxy-8- azabicyclo[3.2.1]octan- 8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl pivalate (11b): To a solution of compound 11a (prepared similarly to that of compound 2d) (110.0 mg, 0.250 mmol) in DCM (3.0 mL) was added DIEA (174.48 mg, 1.35 mmol) and (1R,5S)-8- azabicyclo[3.2.1]octan-3-ol (31.49 mg, 0.2500 mmol) at 0 o C.
  • Step 2 tert-butyl N-[[(2S)-1-[7-(3-benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2- yl]methyl]carbamate (19b).
  • Step 3 tert-butyl N-[[(2S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4- yl]pyrrolidin-2-yl]methyl]carbamate (19c).
  • Step 4 4-[4-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (19).
  • reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCO3) / MeOH at flow rate : 35 mL / min to afford 4-[4-[(2S)-2- (aminomethyl)pyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (1.22 mg, 0.00220 mmol, 12.0% yield) as a white solid.
  • reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% TFA) / ACN at flow rate : 30 mL / min to afford tert-butyl N-[anti-3-[7-(3- benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate (150 mg, 0.196 mmol, 62.9 % yield) as a yellow solid.
  • Step 2 tert-butyl (anti-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)carbamate (22c).
  • Step 3 4-(4-(anti-8--amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (22d).
  • reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H 2 O (0.1% NH 4 HCCO 3 ) /ACN at flow rate : 30 mL / min to afford 4-(4-(8-anti-amino-3- azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (27.1 mg, 0.0473 mmol, 51.0% yield) as a yellow solid.
  • Step 4 3-(anti-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-1,1-dimethylurea (22).
  • Example 6 Exemplary synthesis of compound 24 [00362]
  • Compound 26 was prepared using procedures analogous to those described for example 5, with (S)-(1-methylpyrrolidin-2-yl)methanol replacing ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol in step 4.
  • LCMS calculated for C 33 H 39 FN 7 O 3 (M+H) + m/z 600.3; found: 600.2.
  • Example 9 Exemplary synthesis of compound 5 [00363] Step 1: To a solution of benzyl 4-oxoazepane-1-carboxylate (250.0 mg, 1.01 mmol) in anhydrous THF (15 mL) was added chloro(methyl)magnesium (0.51mL, 1.52 mmol, 3 mol/L in THF) dropwise. After addition the mixture was stirred at 0 o C to rt. for 16 h under Ar. LCMS showed the reaction worked. The reaction was quenched with sat. ammonium chloride (1 mL) and extracted with EtOAc (3x15 mL).
  • Step 2 A solution of benzyl 4-hydroxy-4-methyl-azepane-1-carboxylate (250.mg, 0.9500mmol) in THF (5mL) and Ethanol (5mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (50.0 mg, 20% w/w) at 25 o C for 16 h.
  • Step 3 A mixture of compound 5c (120.68 mg, 0.93 mmol), DIPEA (0.46mL, 2.8mmol) and compound 1 (415.0 mg, 0.930 mmol) in DMA (20 mL) was stirred at 0 o C for 2 h under Ar.
  • Step 4 To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (51.5 mg, 0.450 mmol) in DMF (3 mL) was added NaH (10.7 mg, 0.450 mmol) at 0 o C under Ar. The mixture was stirred for 30 min, followed by addition of compound 5a (60.0 mg, 0.110 mmol) in DMF (3 mL). The resulted mixture was stirred at 0 o C for 1 h under Ar. LCMS showed the reaction worked. The reaction mixture was quenched by addition of sat.
  • Example 10 Exemplary synthesis of compound 3 [00367]
  • Compound 3 was prepared using procedures analogous to those described for example 3.1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol.
  • Example 11 Exemplary synthesis of compound 4 [00368]
  • Compound 4 was prepared using procedures analogous to those described for example 3..1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol.
  • Example 12 Exemplary synthesis of compound 1 [00369]
  • Compound 1 was prepared using procedures analogous to those described for example 3 starting from tert-butyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate.4-(4- ((1R,3S,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol.
  • Example 13 Exemplary synthesis of compound 2 [00370]
  • Compound 2 was prepared using procedures analogous to those described for example 3 starting from tert-butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate).4-(4- ((1R,3R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol.
  • Example 14 Exemplary synthesis of compound 7 [00371]
  • Compound 7 was prepared using procedures analogous to those described for example 3.
  • Example 17 Exemplary synthesis of compound 15 [00374]
  • Compound 15 was prepared using procedures analogous to those described for example 3.4-(4-(4-aminoazepan-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (16).
  • Example 18 Exemplary synthesis of compound 14 [00375]
  • Compound 14 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-4-methyl-azepan-4-ol (14).
  • Example 19 Synthesis of compound 16 [00376]
  • Compound 16 was prepared using procedures analogous to those described for example 3.4-[4-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-8-fluoro-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (16).
  • Example 20 Synthesis of compound 17 [00377]
  • Compound 17 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (17).
  • Example 21 Exemplary synthesis of compound 18 [00378]
  • Compound 18 was prepared using procedures analogous to those described for example 3.4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- [3-(hydroxymethyl)pyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (18).
  • Example 22 Exemplary synthesis of compound 20 [00379]
  • Compound 20 was prepared using procedures analogous to those described for example 3.4-[4-[(3S)-3-aminopyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (20).
  • Example 23 Exemplary synthesis of compound 26 [00380]
  • Compound 26 was prepared using procedures analogous to those described for example 3.4-[4-[(3R)-3-aminopyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (26).
  • Example 24 Exemplary synthesis of compound 27 [00381]
  • Compound 27 was prepared using procedures analogous to those described for example 3.4-[4-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol (27).
  • Example 25 Exemplary synthesis of compound 5 [00382]
  • Compound 5 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4-methyl-azepan-4-ol (5).
  • Example 26 Exemplary synthesis of compound 21 [00383]
  • Compound 21 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]azepan-4-ol (21).
  • Step 1 To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (500 mg, 1.98 mmol, 1.0 eq) in DCM (8 mL) were added piperidin-4-one;hydrochloride (268 mg, 1.98 mmol, 1.0 eq) and DIEA (1.38 mL, 7.92 mmol, 4.0 eq) at -60 o C. The mixture was stirred at -60 o C for 1 h. The reaction mixture was quenched with aqueous saturated NH4Cl, and extracted with DCM (40 mL ⁇ 3).
  • Step 2 To a mixture of 1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)piperidin-4-one (180 mg, 0.571 mmol 1.0 eq) in 1,4-dioxane (4 mL) were added [(8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (273 mg, 1.71 mmol, 3.0 eq) and DIEA (295 mg, 2.28 mmol, 4.0 eq). The mixture was stirred at 80 o C for 36 h.
  • Step 3 To a mixture of 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-one (250 mg, 0.571 mmol, 1.0 eq) in Methanol (5 mL) was added NaBH4 (64.8 mg, 1.71 mmol, 3.0 eq) at 0 °C. The mixture was stirred at room temperature overnight.
  • Step 4 To a mixture of 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (75.0 mg, 0.171 mmol, 1.0 eq) in 1,4-dioxane/water (2.5 mL/0.5 mL) were added triisopropyl-[2-[8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane (111 mg, 0.260 mmol, 1.5 eq), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27.9 mg, 0.0
  • Step 5 To a mixture of 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]piperidin-4-ol (20.0 mg, 0.0280 mmol, 1.0 eq) in DMF (1.5 mL) was added CsF (21.3 mg, 0.141 mmol, 5.0 eq).
  • the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCO3) / MeOH at flow rate : 50 mL / min to afford 1-[7-(8- ethynyl-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (6.82 mg, 0.0120 mmol, 42.5% yield) as a light yellow solid.
  • Example 29 Exemplary synthesis of compound 30 [00390]
  • Step 1 To a stirred solution of KOH (2754.82 mg, 12.13 mmol) in dry methanol (15 mL) at 0 °C under nitrogen was added a solution of benzyl 4-oxoazepane-1-carboxylate (1000.0 mg, 4.04 mmol) in dry methanol (15 mL) dropwise over 10 min. The reaction mixture was stirred at 0 °C for another 10 min, and PhI(AcO)2 (1563.02 mg, 4.85 mmol) was added portionwise over 10 min. The reaction mixture was warmed to room temperature, with stirring overnight.
  • Step 2 To a solution of benzyl 3-hydroxy-4-oxo-azepane-1-carboxylate (1064.0 mg, 4.04 mmol) in THF (15mL)/ methanol (15mL) was added slowly NaBH4 (152.88 mg, 4.04 mmol) portionwise at 0 °C. The mixture was warmed up to 25 °C and stirred for additional 1.5 h. EtOAc (10 mL) and sat.
  • Step 3 A solution of benzyl 3,4-dihydroxyazepane-1-carboxylate (450.0 mg, 1.7 mmol) in THF (15 mL)/Ethanol (15 mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (195.06 mg, 0.17 mmol) at 25 o C for 16 h. The reaction mixture was filtered and evaporated to give the crude product azepane-3,4-diol (222 mg,1.69 mmol, 99% yield) as a light-yellow solid which was used for next step without further purification.
  • Step 4 Compound 30 was prepared using procedures analogous to those described for example 3.To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (41.35 mg, 0.26 mmol) in DMF (2 mL) was added NaH (10.39 mg, 0.26 mmol) at 0 o C under Ar .
  • Example 30 Exemplary synthesis of compound 31 Synthesis of 4-(hydroxymethyl)azepan-4-ol (compound 31c) [00394]
  • Step 1 The t-BuOK (544.52 mg, 4.85 mmol) was added slowly to a stirred suspension of methyl(triphenyl)phosphonium bromide (1733.45 mg, 4.85 mmol) in anhydrous THF (5 mL) at -78 °C. The mixture was warmed up to -40° C and stirred for additional 45 min.
  • Step 2 To a solution of benzyl 4-methyleneazepane-1-carboxylate (200.0 mg, 0.82 mmol) in acetone (6 mL) and water (2mL) was added K2OsO4.2H2O (30.04 mg, 0.08 mmol) and NMO (286.52 mg, 2.45 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated, and the residue was partitioned between 20% citric acid and ethyl acetate.
  • Step 3 A solution of benzyl 4-hydroxy-4-(hydroxymethyl)azepane-1-carboxylate (160.0 mg, 0.57 mmol) in THF (10 mL)/ethanol (10 mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (65.87 mg, 0.06 mmol) at 25 o C for 16 h. The reaction mixture was filtered and evaporated to give the crude product 4-(hydroxymethyl)azepan-4-ol (83 mg, 0.57 mmol, 99% yield) as a light yellow solid which was used for next step without further purification.
  • Step 4 A mixture of 4-(hydroxymethyl)azepan-4-ol (49.02 mg, 0.34 mmol) and DIPEA (0.17 mL, 1.01 mmol) in DCM (3 mL) was added dropwise slowly to a solution of [4- (2,4-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl)-2-naphthyl] 2,2-dimethylpropanoate (150.0 mg, 0.34 mmol) in DCM (15 mL) at 0 o C. The reaction mixture was stirred at 0 o C for 2 h under Ar.
  • Step 5 To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (115.15 mg, 0.72 mmol) in DMF (3 mL) was added NaH (28.93 mg, 0.72 mmol) at 0 o C under Ar.
  • Example 31 Exemplary synthesis of compound 32 [00399] Synthesis of 1-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)- 7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-4-(3- hydroxypropyl)piperidin-4-ol [00400] The suspension of LiAlH4 (32.53 mg, 0.04 mmol) in THF (0.5 ml) was dropwise added into the solution of compound 45 (20. mg, 0.03 mmol) in THF (5 mL) at 0 o C.
  • Example 32 Exemplary synthesis of compound 33 [00401]
  • Compound 33 was prepared using procedures analogous to those described for example 2.
  • Example 33 Exemplary synthesis of compound 34: Synthesized from compound 31 [00402] To a solution of 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl] methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-4-(hydroxymethyl)azepan- 4-ol;2,2,2-trifluoroacetic acid (20.0 mg, 0.02mmol) and CDI (19.78 mg, 0.12 mmol) in THF (30 mL) was added DIPEA (0.06 mL, 0.37 mmol) at rt. under Ar.
  • Example 34 Exemplary synthesis of compound 35: [00403] Synthesis of 2-(azepan-4-yl)acetonitrile (compound 35c) [00404] Step 1: The sodium hydride (146.29 mg, 6.1 mmol) was put into the solution of 2- diethoxyphosphorylacetonitrile (0.91 g, 5.16 mmol) in THF (10 ml) at 25 o C. The mixture was stirred for 10 min, then tert-butyl 4-oxoazepane-1-carboxylate (1.0 g, 4.69 mmol) was added and the mixture was stirred at rt for 18 h. The solvent was removed and water (20 ml) was added.
  • Step 2 The solution of tert-butyl (4Z)-4-(cyanomethylene)azepane-1-carboxylate (150.0 mg, 0.63 mmol) and Pd (6.76 mg, 0.06 mmol, 10% over carbon) in methanol (5 mL) was stirred at rt under H 2 for 18h. The mixture was filtered and the solvent was evaporated to get tert-butyl 4-(cyanomethyl)azepane-1-carboxylate (120 mg, 0.50 mmol, 79% yield) as colorless oil.
  • Step 3 The solution of tert-butyl 4-(cyanomethyl)azepane-1-carboxylate (120.0 mg, 0.5 mmol) and trifluoroacetic acid (574.09 mg, 5.04 mmol) in DCM (5 mL) was stirred at rt for 1h. The solvent was removed to get 2-(azepan-4-yl)acetonitrile (60 mg, 0.43 mmol, 86% yield) as crude colorless oil.
  • Compound 35 was prepared using procedures analogous to those described for example 3.2-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)acetonitrile (compound 35).
  • Example 35 Exemplary synthesis of compound 36.
  • Compound 36 was prepared using procedures analogous to those described for example 3. (3R,5S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-5-(hydroxymethyl)pyrrolidin- 3-ol (Compound 36).
  • Example 36 Exemplary synthesis of compound 37.
  • [00409] Synthesis of (5S)-5-(hydroxymethyl)-3-methylpyrrolidin-3-ol (compound 37d)
  • PE: EtOAc 4:1
  • PE:EtOAc 1:1
  • PE: EtOAc 4:1 to 1:1
  • Step 4 The solution of compound 37c (130.0 mg, 0.38mmol) and trifluoroacetic acid (428.88 mg, 3.76 mmol) in DCM (5 mL) was stirred at 25 o C for 1h. The reaction was monitored by LCMS.
  • Example 37 Exemplary synthesis of compound 38.
  • Compound 38 was prepared using procedures analogous to those described for example 3.. (3S,4R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3,4-diol.
  • Example 39 Exemplary synthesis of compound 40: [00417]
  • Compound 40 was prepared using procedures analogous to those described for example 5. Methyl (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)carbamate (compound 40).
  • Example 41 Exemplary synthesis of compound 42: [00419] Compound 42 was prepared using procedures analogous to those described for example 3.2-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-ol (compound 42).
  • Example 43 Exemplary synthesis of compound 44 [00421]
  • Compound 44 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-5-(hydroxymethyl)azepan-4-ol (compound 44, synthesized according to procedure A).
  • Example 44 Exemplary synthesis of compound 45 [00422]
  • Compound 44 was prepared using procedures analogous to those described for example 3. 8-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]decan-2-one (compound 45).
  • Example 45 Exemplary synthesis of compound 46 [00423]
  • Compound 46 was prepared using procedures analogous to those described for example 3.
  • Example 46 Exemplary synthesis of compound 47 [00424]
  • Compound 47 was prepared using procedures analogous to those described for example 3. (5R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-5- (hydroxymethyl)pyrrolidin-3-ol (compound 47).
  • Example 47 Exemplary synthesis of compound 48 [00425]
  • Compound 48 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-2-methyl-piperidin-4-ol (compound 48).
  • Example 48 Exemplary synthesis of compound 49 [00426]
  • Compound 49 was prepared using procedures analogous to those described for example 3. 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (4-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (compound 49).
  • Example 49 Exemplary synthesis of compound 50 [00427]
  • Compound 50 was prepared using procedures analogous to those described for example 3. 8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-1-oxa-8-azaspiro[4.5]decan-3-one (compound 50).
  • Example 50 Exemplary synthesis of compound 51 [00428]
  • Compound 51 was prepared using procedures analogous to those described for example 3.3,3-difluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (compound 51).
  • Example 51 Exemplary synthesis of compound 52 [00429]
  • Compound 52 was prepared using procedures analogous to those described for example 3. (3R,4R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3,4-diol (compound 52).
  • Compound 53 was prepared using procedures analogous to those described for example 3.1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperidin-4-ol (compound 53).
  • Compound 55 was prepared using procedures analogous to those described for example 3. (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (compound 55).
  • Example 55 Exemplary synthesis of compound 56 [00433]
  • Compound 56 was prepared using procedures analogous to those described for example 5 from compound 15. Methyl N-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)azepan-4-yl)methanesulfonamide (compound 56).
  • Example 57 Exemplary synthesis of compound 58
  • Compound 58 was prepared using procedures analogous to those described for example 3.
  • LCMS calculated for C 31 H 34 F 2 N 5 O 4 (M+H) + m/z 578.3; found: 578.2.
  • Example 58 Exemplary synthesis of compound 59.
  • Example 59 Exemplary synthesis of compound 60.
  • Example 60 Exemplary synthesis of compound 61.
  • Example 61 Exemplary synthesis of compound 62.
  • Step 1 To a solution of 2,3,6,7-tetrahydro-1H-azepine (492 mg, 5.06 mmol, 1.0 eq) in DCM (9 mL) were added 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.28 g, 5.06 mmol, 1.0 eq) and DIEA (1.96 mg, 15.2 mmol, 3 eq) at -70 °C under N2. Then the mixture was stirred at -70 °C for 1h.
  • Example 62 Exemplary synthesis of compound 63.
  • Example 64 Exemplary synthesis of compound 65 [00446]
  • Compound 65 was prepared using procedures analogous to those described for example 61.
  • Example 65 Exemplary synthesis of compound 66.
  • Step 1 Synthesis of tert-butyl 3-fluoro-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 3,3-difluoropiperidine-1-carboxylate (compound 66a and 67a)
  • Step 2 Synthesis of tert-butyl 3-fluoro-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 3,3-difluoropiperidine-1-carboxylate (compound 66a and 67a)
  • DAST 970.72 mg, 6.02 mmol
  • Step 2 Synthesis of 5-fluoro-1,2,3,6-tetrahydropyridine and 3,3-difluoropiperidine (compound 66b and 67b). To a solution of tert-butyl 5-fluoro-3,6-dihydro-2H-pyridine-1- carboxylate (200.0 mg, 0.99 mmol) in DCM (10 mL) was added TFA (3.0 mL, 0.41mmol) at r.t.
  • Example 66 Exemplary synthesis of compound 67.
  • Step 8 To a solution of 2-[8-[4-(3,3-difluoro-1-piperidyl)-8-fluoro-2-[[(2R,8S)-2- fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (compound 66130.0 mg, 0.16 mmol) in DCM (4 mL) was added 4M HCl in dioxane (2.0 mL, 0.41 mmol) at r.t.
  • Compound 68 was prepared using procedures analogous to those described for example 61.4-[4-(3,6-Dihydro-2H-pyridin-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen- 2-ol;2,2,2-trifluoroacetic acid (compound 68, 104.1 mg, 0.1250 mmol, 65 % yield) as yellow solid.
  • Example 68 Exemplary synthesis of compound 72.
  • [00459] Synthesis of 7,7-difluoro-3-azabicyclo[4.1.0]heptane compound 72a
  • Compound 72 was prepared using procedures analogous to those described for example 3 using example 72c.4-[4-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]- 5-ethynyl-6-fluoro-naphthalen-2-ol.
  • Compound 80 was prepared using procedures analogous to those described for example 3 using example 80a.5-ethynyl-6-fluoro-4-[8-fluoro-4-(4-fluoro-3,6-dihydro-2H- pyridin-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol.
  • Example 70 Exemplary synthesis of compound 87.
  • [00467] Synthesis of 2-(5-fluoro-1,2,3,6-tetrahydropyridin-3-yl)acetonitrile 87a: [00468] Step 1: The mixture of 2-(5-fluoro-3-pyridyl)acetonitrile (200.0 mg, 1.469 mmol, 1.0 eq) and bromomethylbenzene (753.82 mg, 4.408 mmol, 3.0 eq) in Acetone (2 mL) was stirred at 60 °C overnight under N 2 .
  • Step 2 To the solution of 2-(1-benzyl-5-fluoro-pyridin-1-ium-3- yl)acetonitrile;bromide (520.0 mg, 1.693 mmol, 1.0 eq) in Methanol (8 mL) / DCM (8 mL) was added CERIUM(III) CHLORIDE HEPTAHYDRATE (630.75 mg, 1.693 mmol, 1.0 eq) followed by NaBH4 (1286.63 mg, 33.859 mmol, 20.0 eq) at 0 °C. A distinct bright color was observed upon addition.
  • Step 3 To a solution of 2-(1-benzyl-5-fluoro-3,6-dihydro-2H-pyridin-3- yl)acetonitrile (20.0 mg, 0.087 mmol) in DCE (1.5 mL) was added 1-chloroethyl carbonochloridate (37.25 mg, 0.261 mmol) and the reaction was stirred at 100 °C for 6 h. Then the mixture was concentrated. The residue was dissolved in Methanol (1.5 mL) and stirred at 70 °C for 1 h.
  • Example 71 Exemplary synthesis of compound 96.
  • Synthesis of ((4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol 96a [00474] Step 1: To a solution of O1-tert-butyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (10.0 g, 40.8 mmol, 1.0 eq) in DMF (100 mL) was added NaH (1.96 g, 48.9 mmol, 1.2 eq) ⁇ at 0 °C under N2.
  • Step 2 To a solution of 1-(tert-butyl) 2-methyl (4R)-4-methoxypyrrolidine-1,2- dicarboxylate (10.5 g, 40.5 mmol, 1.0 eq) in THF (80 mL) was added LAH (121 mL, 121 mmol, 1M in THF, 3.0 eq) ⁇ dropwise at 0 °C under N 2 . Then the mixture was stirred at 80 o C for 3h. ⁇ The reaction mixture was quenched with Na 2 SO 4 -10H 2 O, filtered.
  • Example 72 Exemplary synthesis of compound 99.
  • [00477] Synthesis of 4-fluoro-2,3,6,7-tetrahydro-1H-azepine 99a
  • Step 1 To a solution of 4-methylbenzenesulfonamide (5000.0 mg, 29.2mmol) and 4- bromobut-1-ene (5.93 mL, 58.4 mmol) in DMF (50 mL) was added K 2 CO 3 (2.01 g, 146.01 mmol) at r.t. The mixture was stirred at 100 o C for 18 h under argon.
  • Step 2 To solution of N,N-bis(but-3-enyl)-4-methyl-benzenesulfonamide (2100.0 mg, 7.52 mmol) in DCM (20 mL) was added Et3N.3HF (4.9 mL, 30.06 mmol). The mixture was cooled down to 0 o C and protected from the light. Then NBS (2006.57 mg, 11.27 mmol) was added into the mixture at 0 o C under argon atmosphere. The mixture was warmed up to r.t., and stirred at r.t. for 16 h. The mixture was concentrated to afford a crude product.
  • Step 3 To solution of N-(4-bromo-3-fluoro-butyl)-N-but-3-enyl-4-methyl- benzenesulfonamide (800.0 mg, 2.11mmol) in PhMe (10 mL) was added a solution of t-BuOK (711.94mg, 6.34mmol) in THF (4 mL). The mixture was stirred at 100 o C for 16 h. The mixture was filtered over celite and concentrated. The crude product of N-but-3-enyl-N-(3-fluorobut-3- enyl)-4-methyl- benzenesulfonamide (650 mg, crude) was obtained as a yellow oil.
  • Step 5 The mixture of Mg (89.11 mg, 3.71 mmol) and 4-fluoro-1-(p-tolylsulfonyl)- 2,3,6,7-tetrahydroazepine (100.0 mg, 0.37mmol) in methanol (3 mL) was sonicated at r.t.
  • Example 73 Exemplary synthesis of compound 103.
  • Synthesis of compound 103a [00485] Step1: The mixture of 2,7-dichloro-8-fluoro-4-(2,3,6,7-tetrahydroazepin-1- yl)pyrido[4,3-d]pyrimidine (200 mg, 0.640 mmol, 1.0 eq), [rac-(2R,8S)-2-[tert- butyl(diphenyl)silyl]oxy-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (666 mg, 1.68 mmol, 2.6 eq) and DIEA (0.320 mL, 1.92 mmol, 3.0 eq) ⁇ in ⁇ 1,4-Dioxane (4 mL) was heated to 85 °C under N2 for ⁇ 60 h.
  • Step 2 To a solution of tert-butyl-diphenyl-[[rac-(2R,8S)-8-[[7-chloro-8-fluoro-4- (2,3,6,7-tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]silane (150 mg, 0.220 mmol, 1.0 eq) in ⁇ THF (2 mL) was added ⁇ TBAF (0.670 mL, 0.670 mmol, 3.0 eq, 1M in THF).
  • Step 3 To a solution of ⁇ rac-(2R,8S)-8-[[7-chloro-8-fluoro-4-(2,3,6,7- tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin- 2-ol (120 mg, 0.280 mmol, 1.0 eq) in ⁇ THF (5 mL) at ⁇ 0 o C, NaH (110 mg, 2.77 mmol, 10.0 eq) was added and the solution was stirred at 20 o C for 30 min.
  • Example 74 Exemplary synthesis of compound 104.
  • Step 1 To a solution of 2-bromoaniline (5.0 g, 29.1 mmol, 1.0 eq) in water (125 mL) and concentrated HCl (12.5 mL) was added dropwise an aqueous (25 mL) solution of Sodium nitrite (2306.08 mg, 33.426 mmol, 1.15 eq). The reaction mixture was stirred at 0 °C for 1 h and then Sodium azide (2267.53 mg, 34.880 mmol, 1.2 eq) dissolved in water (25 mL) was added dropwise.
  • Step 2 To a mixture of 1-azido-2-bromo-benzene (5600.0 mg, 28.28 mmol, 1.0 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (15732.71 mg, 56.560 mmol, 2.0 eq) and sodium carbonate (7194.42 mg, 67.872 mmo, 2.4 eq) in 1,4-Dioxane (100 mL) / Water (10 mL) was added Pd(PPh 3 ) 4 (1633.99 mg, 1.414 mmol), and then flushed with N 2 for three times.
  • 1-azido-2-bromo-benzene 5600.0 mg, 28.28 mmol, 1.0 eq
  • Step 3 A solution of 5-(2-azidophenyl)-1-tetrahydropyran-2-yl-pyrazole (1000.0 mg, 3.713 mmol, 1.0 eq) in Phenyl ether (5 mL) was heated to 170 °C for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography, eluting with FC (eluting with EtOAc in Pet.ether 0 to 60%) to give the 1-tetrahydropyran-2-yl-4H-pyrazolo[4,3- b]indole (290.0 mg, 1.202 mmol, 32.4% yield) as white solid.
  • Step 4 Under Ar atmosphere, to a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1- yl)pyrido[4,3-d]pyrimidine (50.0 mg, 0.115 mmol, 1.90 eq) in Toluene (1 mL) were added 1- tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole (33.21 mg, 0.138 mmol, 1.2 eq), Pd2(dba)3 (21.01 mg, 0.023 mmol, 0.2 eq), Cesium carbonate (111.84 mg, 0.344 mmol, 3.0 eq) and RuPhos (21.41 mg, 0.046 mmol, 0.4 e
  • Example 75 Exemplary synthesis of compound 105.
  • Step 1 The mixture of 4-nitrobenzoic acid (39.94 mg, 0.239mmol, 3.0 eq), Ph3P (62.68 mg, 0.239 mmol, 3.0 eq), (2R,7aS)-7a-(((4-(cyclohept-4-en-1-yl)-7-(8-ethynyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (50.0 mg, 0.080 mmol) and 4A Molecular sieve (150.0 mg) in THF (1mL) was cooled to 0 °C.
  • Step 2 To a solution of (2S,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl 4-nitrobenzoate (28.0 mg, 0.036 mmol, 1.0 eq) in Methanol (2mL) was added K2CO3 (2.49 mg, 0.018 mmol, 0.5 eq) at 20°C.
  • Example 76 Exemplary synthesis of compound 108.
  • Compound 108 was prepared using procedures analogous to those described for example 66 using compound 107.
  • Example 77 Exemplary synthesis of compound 109.
  • [00497] Synthesis of 5-chloro-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole 109a
  • Step 1 To a solution of 2-bromo-6-chloro-aniline (5.00 g, 24.2 mmol, 1.0 eq) in water (125 mL) and concentrated HCl (5 mL) was added an aqueous (25 mL) solution of Sodium nitrite (1.92 g, 27.8 mmol, 1.2 eq) dropwise at 0 °C.
  • Step 2 The mixture of 2-azido-1-bromo-3-chloro-benzene (5.04 g, 21.7 mmol, 1.0 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (7.24 g, 26.0 mmol, 1.2 eq), Pd(PPh 3 ) 4 (1.25 g, 1.08 mmol, 0.05 eq) and ⁇ sodium carbonate (5.52 g, 52.0 mmol, 2.4 eq) in 1,4-Dioxane (80 mL) / Water (20 mL) was purged with N2 for three times and then stirred at 90 °C overnight.
  • Step 3 A solution of 5-(2-azido-3-chloro-phenyl)-1-tetrahydropyran-2-yl-pyrazole (1.20 g, 3.95 mmoll, 1.0 eq) in Phenyl ether (5.00 ml) was heated to 170 o C for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography (eluting with 10-30% ethyl acetate in PE) to give the 5-chloro-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3- b]indole (130 mg, 0.472 mmol, 11.9% yield) as a light yellow oil.
  • Example 78 Exemplary synthesis of compound 110 and 111.
  • Step 1 A solution of (S)-7a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)tetrahydro-1H-pyrrolizin-2(3H)-one (23.0 mg, 0.037 mmol, 1.0 eq) and Titannium(IV) isopropoxide (41.79 mg, 0.147 mmol, 4.0 eq) in NH3-MeOH (7M,3 mL).
  • Example 79 Exemplary synthesis of compound 113.
  • [00506] Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydropyrazolo[4,3-b]indole-3- carbonitrile 113a
  • Step 1 To a solution of 1-tettrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole (730.0 mg, 3.025 mmol, 1.0 eq) in THF (2 mL) was added DMAP (739.2 mg, 6.051 mmol, 2.0 eq), followed by Di-tert-butyl dicarbonate (990.44 mg, 4.538 mmol, 1.5 eq) at 0 °C.
  • Step 2 To a solution of tert-butyl 1-tetrahydropyran-2-ylpyrazolo[4,3-b]indole-4- carboxylate (900.0 mg, 2.636 mmol, 1.90 eq) in MeCN (1.5 mL) was added NBS (516 mg, 2.90 mmol, 1.1 eq) and the reaction was stirred at room temperature overnight. Then the reaction was quenched with Na 2 S 2 O 3 solution and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4.
  • Step 3 The mixture of tert-butyl 3-bromo-1-tetrahydropyran-2-yl-pyrazolo[4,3- b]indole-4-carboxylate (100.0 mg, 0.238 mmol, 1.0 eq), Zn(CN) 2 (111.75 mg, 0.952 mmol, 4.0 eq), Pd 2 (dba) 3 (8.72mg, 0.010 mmol, 0.04 eq), Pd(dppf)Cl 2 (10.44 mg, 0.014 mmol, 0.06 eq) and Zn powder (3.89 mg, 0.060 mmol, 0.25 eq) in DMA (2 mL) was bubbled with Ar for 2 min.
  • Example 80 Nucleotide Exchange Assay: [00510] 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
  • GST-tagged KRAS G12D (2-169) and anti-GST MAb Tb Cryptate Gold were diluted into assay buffer (20 mM HEPES, pH 7.3, 150 mM NaCl, 5 mM MgCl 2 , 0.05% BSA 0.0025% NP40, 1 mM DTT) to prepare a 2.5X donor solution.5X compound was added to the protein mixture and incubated for 1 h at RT.2.5X acceptor solution containing SOS1cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY-647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 5 nM GST-tagged KRAS G12D (2-169), 20 nM SOScat, and 150 nM GTP.
  • assay buffer 20 mM HEPES, pH 7.3, 150 mM NaCl, 5 mM MgCl 2 , 0.05% BSA 0.0025% NP40, 1 mM DTT
  • Example 80 Protein Constructs for Protein-Protein Interaction: Table 2: Assay, Protein construct, and protein construct sequences Example 81. Recombinant Protein Production: [00512] Biotinylated KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020).
  • 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.
  • NEA KRAS G12D IC 50 (uM) values of selected compounds are depicted in Table 4 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 82 Protein-Protein Interaction (PPI) Assay: [00514] 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).
  • HTRF Homogenous time resolved fluorescence
  • 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 IC50 (uM) values of selected compounds are depicted in Table 4 and Table 5 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.
  • Compounds described herein are active against KRAS G12 mutant and other alleles representative by PPI-G12D, PPI-G12V and PPI-w.t.KRAS potency for broad activity against mutant KRAS and wtKRAS amplification driven malignancies. Compounds described herein are selective for the KRAS isoform representative by lack of activity in the PPI-NRAS assay. Example 83.
  • Phospho-ERK cellular HTRF assay measures ERK protein phosphorylated at Thr202/Tyr204 as a readout of MAPK pathway activation (Cisbio 64ERKPEH).
  • PANC-1 cells ATCC CRL-1469
  • AGS cells ATCC CRL-1739
  • PANC-1 cells high glucose DMEM 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 (PANC-1: 20,000 cells/well; AGS: 30,000 cells/well).
  • the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO.
  • the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit. Then, the cell lysates are treated with the detection reagents overnight at 4 o C in darkness.
  • PANC1 pERK IC 50 (uM) values of selected compounds are depicted in Table 3 with compounds having a value between 0.1 uM to 2 uM as ++++; 2 uM to 12 uM as +++; 12 uM to 20 uM as ++; and > 20 uM as +.
  • AGS pERK HTRF Method A
  • IC50 (uM) values of selected compounds are depicted in Table 4 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.
  • 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
  • DMEM and RPMI medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin.
  • Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20).
  • Cells were seeded into 384-well plate (Greiner 781091) at density of 5,000 cells/well for AGS, and allowed to grow overnight in a 37 ⁇ C CO2 incubator. The next day, compounds were dispensed into wells with a 1 ⁇ 2 log, 10-point serial dilution and top concentration of 10 ⁇ M using Tecan D300e dispenser and incubated for 3 hours in a 37 ⁇ C CO2 incubator.
  • IC 50 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) IC50 (uM) values of selected compounds are depicted in Table 4 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 4 includes NEA KRAS G12D IC50 (uM) values ( ⁇ 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC 50 (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 5 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.

Abstract

Provided herein are KRAS modulating compounds, such as compounds of Formula (I), (II), (III), or (X), or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any of the foregoing, useful for modulating KRAS GD12 and/or other G12 mutants. Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.

Description

KRAS MODULATORS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Applications Nos. 63/195,634 filed on June 1, 2021; 63/240,713 filed on September 03, 2021; and 63/297,617 filed on January 7, 2022; the entire contents of each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008.133(7): p.1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression. [0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification. [0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind selectively to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p.1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS-mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. Thus, there is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signals via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state. SUMMARY OF THE INVENTION [0005] The present disclosure relates to Formula (I), Formula (II), Formula (III), or Formula (X) including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and to uses thereof in, for example, inhibiting KRas G12D and/or other G12 mutants. [0006] In an aspect, the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl- , (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7- , 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; and wherein the C3-C12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen, C1-6 alkoxy, and cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [0007] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0008] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0009] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0010] In an aspect, the present disclosure provides a compound represented by the structure of Formula (II): Formula (II); or a pharmaceutically acceptable salt thereof, wherein: R13 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, - C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R19’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -B(OR20)2, -N(R20) S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; Y is selected from a bond, O and NR5; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; Q is selected from a bond and O; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-Cl-C6 haloalkyl, - L-O-R5, -L-NR5C(O)-aryl, -L-COOH, and -L-C(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; and each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [0011] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0012] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0013] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0014] In an aspect, the present disclosure provides a compound represented by the structure of Formula (III): Formula (III); or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, Cl-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- Cl-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OCl-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents are selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl,C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R29’ is selected from an unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [0015] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0016] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0017] 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. INCORPORATION BY REFERENCE [0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION [0019] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments. [0020] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions [0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1- C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. [0023] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0024] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. [0026] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. [0027] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx- yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2- 6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain. [0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). [0029] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene). [0030] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). [0031] "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. [0032] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. [0033] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. [0034] “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. [0035] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. [0036] "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. [0037] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. [0038] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rc is an alkylene chain as described above. [0039] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-cycloalkyl where Rc is an alkylene chain as described above. [0040] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents. [0041] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane. [0042] "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. [0043] "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. [0044] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like. [0045] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like. [0046] "Cyanoalkyl" as used herein 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. [0047] “Heterocycle” refers to a saturated or unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring heterocycles have at least two molecular rings with only one common atom. The spiro-ring heterocycle includes at least one heteroatom. [0048] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group. [0049] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine. An “X- membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc. [0050] 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. [0051] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. [0052] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb -N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. [0053] As used in the specification and claims, the singular form“a”,“an”and“the”includes plural references unless the context clearly dictates otherwise. [0054] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. [0055] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0056] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0057] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0058] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. [0059] 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. [0060] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X). Compounds of the disclosure [0061] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. [0062] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- Cl-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OCl-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl- , (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7- , 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; and wherein the C3-C12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen, C1-6 alkoxy, and cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [0063] In some embodiments, for a compound or salt of Formula (I), each heterocycle of R9’ has only 1 nitrogen atom. In some cases, each heterocycle of R9’ has only 1 nitrogen atom and is bound to Formula (I) via the 1 nitrogen atom. [0064] In some embodiments, Formula (I) is represented by Formula (X) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle optionally contains one or more additional heteroatoms selected from oxygen, boron, and sulfur; or Ring A is further selected from 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which optionally contain one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 12-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11- , and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)OR20, - OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [0065] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a 5- to 12-membered monocyclic heterocycle, wherein the 5- to 12-membered monocyclic heterocycle optionally contains one or more additional heteroatoms selected from oxygen, boron, and sulfur; or Ring A is further selected from 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which optionally contain one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 12-membered monocyclic heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused monocyclic heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)OR20, - OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [0066] In some embodiments, for a compound or salt of Formula (I) or Formula (X), Y is O. In some cases, Y is a bond. In some cases, R is -N(R5)-. [0067] In some embodiments, for a compound or salt of Formula (I) or Formula (X), L is selected from C1-C4 alkylene. In some cases, L is selected from Cl-C2 alkylene. In some cases, L is selected from C1 alkylene. [0068] In some embodiments, for a compound or salt of Formula (I) or Formula (X), L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from unsubstituted Cl-C2 alkylene. In some cases, L is selected from unsubstituted Cl alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [0069] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L-5- to 12- membered heteroaryl, optionally substituted -L-C6-C12aryl, -L-N(R5)2, and -L-O-R5. In some cases, R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L- heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12- membered heterocycle, optionally substituted -L-5-to-12-membered heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle. In some cases, R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azocane, and azonane. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, piperidine, piperazine, azocane, and azonane. In some cases, the heteroaryl is selected from pyrrole, pyrazole, furan, thiohene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyrazine, and triazine. In some cases, the heteroaryl or heterocycle has at most 1 nitrogen atom. In some cases, the heteroaryl or heterocycle has at least 1 nitrogen atom. In some cases, the heteroaryl or heterocycle has 1 nitrogen atom. [0070] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the heterocycle of R2 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12- membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 7- to 11-membered heterocycle, 7- to 10- membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R2 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R2 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [0071] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the heteroaryl of R2 is a 5- to 12-membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12- membered heteroaryl, or 8- to 12-membered heteroaryl. In some cases, the heteroaryl of R2 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 6- to 11-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R2 is an 8- to 9-membered heteroaryl. The heteroaryl may be optionally substituted as described elsewhere herein. [0072] In some embodiments, for a compound or salt of Formula (I) or Formula (X), for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo [0073] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2 is selected from wherein the heterocycle portion is optionally substituted. In some cases, R2 is selected from wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, Y-R2 is selected from . In some cases, Y-R2 is selected from
[0074] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R2 is selected optionally substituted heterocycle. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, - OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle. In some cases, Y-R2 is from . In some cases, R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, -OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle. In some cases, R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl. In some cases, R2 is . [0075] In some embodiments, for a compound or salt of Formula (I) or Formula (X), Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, -OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle. In some cases, Y-R2 is selected from , , , . In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, - CH2OC(O)heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from oxo and hydroxy. In some cases, Y- R2 is selected from and [0076] In some embodiments, for a compound of Formula (I), for R2, the heterocycle portion is optionally substituted with one or more R6. In some cases, the R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen, hydroxy, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. [0077] In some embodiments, for a compound or salt of Formula (I) or Formula (X), for R2, the heteroaryl portion is optionally substituted with one or more R6. In some cases, R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1- C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen or C1-C3 alkyl. In some cases, R6 is methyl or fluorine. [0078] In some embodiments, for a compound or salt of Formula (I) or Formula (X), Y-R2 is selected from , , and . In some cases, R2 is selected from , , and . [0079] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R2 is selected from a heterocycle, wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, each R20 is independently selected from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl. In some cases, the heterocycle is a 4-membered heterocycle. In some cases, Y is a bond and Y-R2 is . [0080] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R4 is selected from halogen and hydrogen. In some cases, R4 is selected from halogen. In some cases, R4 is selected from chloride and fluorine. In some cases, R4 is fluorine. In some cases, R4 is hydrogen. [0081] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from optionally substituted aryl and optionally substituted heteroaryl. In some cases, the aryl of R3 is selected from a C10-C14 aryl, C10-C13 aryl, C10-C12 aryl, C10-C11 aryl, C11-C14 aryl, C11- C13 aryl, C11-C12 aryl, C12-C14 aryl, C12-C13 aryl, C6-C13 aryl, and C6-C14 aryl. [0082] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from optionally substituted aryl and optionally substituted heteroaryl. In some cases, the heteroaryl of R3 is a 10- to 14-membered heteroaryl, 10- to 13-membered heteroaryl, 10- to 12- membered heteroaryl, 10- to 11-membered heteroaryl, 11- to 14-membered heteroaryl, 11- to 13- membered heteroaryl, 11- to 12-membered heteroaryl, 12- to 14-membered heteroaryl, 5- to 12- membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12-membered heteroaryl, or 8- to 12- membered heteroaryl. In some cases, the heteroaryl of R3 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 6- to 11-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R2 is an 8- to 9-membered heteroaryl. In some cases, R3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the heteroaryl is optionally substituted with one or more substituents selected from cyano, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, the heteroaryl is unsubstituted. [0083] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from optionally substituted aryl and optionally substituted heteroaryl. In some cases, the aryl is monocyclic. In some cases, the aryl is bicyclic. In some cases, the aryl is tricyclic. In some cases, the heteroaryl is monocyclic. In some cases, the heteroaryl is bicyclic. In some cases, the heteroaryl is tricyclic. In some cases, the aryl is bicyclic or tricyclic. In some cases, the heteroaryl is bicyclic or tricyclic. [0084] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl is a 10-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 10-to-12 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-to-13 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 13-to-14 membered tricyclic heteroaryl. In some cases, the heteroaryl is a 12-membered tricyclic heteroaryl. In some cases, the heteroaryl is a 13 membered tricyclic heteroaryl. [0085] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl includes 6 to 11 carbon atoms and at least one heteroatom selected from N, O, and S. In some cases, the heteroaryl includes 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, or 9 to 10 carbon atoms. In some cases, the heteroaryl includes at least one, two, or three heteroatoms. In some cases, the heteroaryl includes at most one, two, or three heteroatoms. In some cases, the heteroaryl includes at least one nitrogen atom. In some cases, the heteroaryl includes at least two or at least three nitrogen atoms. In some cases, the heteroaryl includes at least two nitrogen atoms. In some cases, the heteroaryl includes at least three nitrogen atoms. In some cases, the heteroaryl includes at most one nitrogen atom. In some cases, the heteroaryl includes at most two nitrogen atoms. In some cases, the heteroaryl includes at most three nitrogen atoms. In some cases, the heteroaryl has only nitrogen heteroatoms. In some cases, the heteroaryl has nitrogen and sulfur heteroatoms. In some cases, the heteroaryl includes at least one sulfur atom. [0086] In alternative embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from an optionally substituted heterocycle. In some cases, the heterocycle is an 8- to 12-membered heterocycle. In some cases, R3 is selected from an optionally substituted unsaturated 8- to 12- membered heterocycle. In some cases, R3 is selected from an optionally substituted unsaturated 10-membered heterocycle. In some cases, the heterocycle is partially unsaturated. In some cases, the unsaturated heterocycle contains at least one nitrogen atom. In some cases, the unsaturated heterocycle contains at least one oxygen atom. In some cases, R3 is selected from and which is optionally substituted. In some cases, the optional substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from [0087] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from an optionally substituted heteroaryl. In some cases, R3 is selected from an optionally substituted 10- to 15-memebered heteroaryl. In some cases, R3 is selected from an optionally substituted 12- to 13-memebered heteroaryl. In some cases, heteroaryl of R3 is substituted with at least one substituent. In some cases, heteroaryl of R3 is substituted with at least two substituents. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, R3 is selected from , . , , each of which are optionally substituted. In some cases, R3 is selected from each of which are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1- C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from
. In some cases, R3 is selected from an unsubstituted heteroaryl. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from . In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from chlorine and fluorine. In some cases, R3 is selected from In some cases, R3 is selected from ,and In some cases, R3 is selected from In some cases, R3 is selected from [0088] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from optionally substituted aryl. In some cases, the aryl is C10-C14 aryl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. [0089] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and - N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and - N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [0090] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from indazole and naphthalene. In some cases, R3 is naphthalene. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C2-6 alkynyl, -OH, and C1-3 alkyl. [0091] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from and . In some cases, R3 is selected from . In some cases, R3 is selected from In some cases, R3 is selected from . In some cases, R3 is selected from . [0092] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from an optionally substituted 9- to 15-memebered heteroaryl optionally substituted C6- C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1- C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2; and the 9- to 15-memebered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from ,
[0093] In some embodiments, for a compound or salt of Formula (I) or Formula (X), R3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, R3 is selected from aryl, which is optionally substituted with one or more substituents. In some cases, the aryl is selected from a C6 aryl and C10 aryl. In some cases, the heteroaryl is selected from a 9- to 10-membered heteroaryl. In some cases, R3 is selected from C10 aryl and 9- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has two ntirgoen atoms and no further heteroatoms. In some cases, the heteroaryl has at least one oxygen atom. In some cases, the heteroaryl is bicyclic. In some cases, the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C1-6 alkyl, C2-C4 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl. In some cases, R3 is selected from , . In some cases, the aryl is substituted with at least one substituent selected from halogen and hydroxy. In some cases, R3 is selected from In some cases, the aryl is substituted with at least two halogen atoms. In some cases, R3 is selected from . [0094] In some embodiments, for a compound or salt of Formula (I), R9’ is Ring A. [0095] In some embodiments, for a compound or salt of Formula (I), the carbocycle of R9’ is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, or C3-C6 carbocycle. In some cases, the carbocycle of R9’ is selected from C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle. [0096] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R9’ is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R9’ is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R9’ is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R9’ is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R9’ is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R9’ is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R9’ is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [0097] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R9’ is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is an 8- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R9’ is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein. [0098] In some embodiments, for a compound or salt of Formula (I)), the heterocycle of R9’ is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12- membered bridged heterocycle, or 8- to 12-membered bridged heterocycle. In some cases, the heterocycle of R9’ is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8-membered bridged heterocycle. In some cases, the heterocycle of R9’ is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle. In some cases, the heterocycle of R9’ is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9-membered bridged heterocycle, or 7- to 8-membered bridged heterocycle. In some cases, the heterocycle of R9’ is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridged heterocycle. In some cases, the heterocycle of R9’ is an 8- to 9-membered bridged heterocycle. In some cases, the heterocycle of R9’ is saturated. The bridged heterocycle may be optionally substituted as described elsewhere herein. In some cases, the heterocycle of R9’ is an unbridged heterocycle. [0099] In some embodiments, for a compound or salt of Formula (I), R9’ is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom. In some embodiments, for a compound of Formula (I), R9’ is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted. In some cases, [00100] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R9’ contains at most 1 nitrogen atom. In some cases, the heterocycle of R9’ contains only 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected from . In some cases, the heterocycle is selected from In some cases, the heterocycle is selected from In some cases, the bridged heterocycle is selected from , , a d . In some cases, the bridged heterocycle has only 1 nitrogen atom. In some cases, the bridged heterocycle has only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom. The heterocycle may be optionally substituted as described elsewhere herein. [00101] In some embodiments, for a compound or salt of Formula (I), the spiroheterocycle of R9’ contains at most 1 nitrogen atom. In some cases, the spiroheterocycle of R9’ contains only 1 nitrogen atom. In some cases, the spiroheterocycle of R9’ contains at most 2 heteroatom atoms. In some cases, the spiroheterocycle of R9’ contains at least 2 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the spiroheterocycle of R9’ is bound to Formula (I) via the nitrogen atom. In some embodiments, the spiroheterocycle of R9’ is selected from . In some embodiments, the spiroheterocycle of R9’ is selected from The spiroheterocycle may be optionally substituted as described elsewhere herein. [00102] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R9’ is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R9’ is selected from optionally substituted 8-membered spiroheterocycle. In some cases, the optionally substituted 7- to 8- membered spiroheterocycle contains only 1 nitrogen atom. In some cases, the optionally substituted 7- to 8-membered spiroheterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom. [00103] In some embodiments, for a compound or salt of Formula (I), the fused heterocycle of R9’ is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12- membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is a 7- to 11-membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is a 6-membered fused heterocycle. In some cases, the fused heterocycle has only 1 nitrogen atom. In some cases, the fused heterocycle has only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom. The fused heterocycle may be optionally substituted as described elsewhere herein. [00104] In some embodiments, for a compound or salt of Formula (I), the fused heterocycle of R9’ is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R9’ is selected from a 10- to 12-membered fused heterocycle. The fused heterocycle may be optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. The fused heterocycle may be optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00105] In some embodiments, for a compound or salt of Formula (I), the fused heterocycle of R9’ contains at most 1 nitrogen atom. In some embodiments, for a compound of Formula (I), the fused heterocycle of R9’ contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle is . In some cases, the fused heterocycle is which is optionally substituted. In some cases, the fused heterocycle has only 1 nitrogen atom. The fused heterocycle may be optionally substituted as described elsewhere herein. [00106] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C6- C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10- , 11-, and 12-membered fused heterocycle, each of which is optionally substituted. In some cases, R9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and wherein each heterocycle contains only 1 nitrogen atom. In some cases, R9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and wherein each heterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom. [00107] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C6- C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6 aminoalkyl, C1- 6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00108] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C6- C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00109] In some embodiments, for a compound or salt of Formula (I), for R9’, R20 of -OR20 and -N(R20)2, is selected hydrogen and C1-6 alkyl. [00110] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C6- C7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains only 1 nitrogen atom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R9’ is selected from C6-C7 carbocycle, each of which is optionally substituted. [00111] In some embodiments, for a compound of Formula (I), the one or more optional substituents of R9’ are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, -N(R20)C(O)N(R20)2, and C1-6 alkyl. [00112] In some embodiments, for a compound or salt of Formula (I), the one or more optional substituents of R9’ are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R9’ are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R9’ are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9’ are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9’ are independently selected from -OR20, -N(R20)2, and C1-6 alkyl. In some cases, the one or more optional substituents of R9’ are independently selected from -N(R20)C(O)N(R20)2. [00113] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, wherein the C3-C12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the 5- to 12-membered heterocycle is a monocyclic 5- to 12-membered heterocycle. [00114] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, each heterocycle contains only 1 nitrogen atom. In some cases, each heterocycle contains only 1 nitrogen atom and is bound to Formula (I) via the only 1 nitrogen atom. [00115] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12 carbocycle, 5- to 12- membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12- membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20) S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00116] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, R9’ is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -N(R20)2, C1-6 alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, - N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1- 6 aminoalkyl. In some cases, R9’ is selected from , , , , , , wherein each is optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, [00117] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, -N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. In some embodiments, for a compound of Formula (I), R9’ is selected from , , , , and , each of which is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, -N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. In some embodiments, for a compound of Formula (I), R9’ is
[00118] In some embodiments, for a compound of Formula (I), R9’ is selected from 5- to 10- membered heterocycle, wherein the 5- to 10-membered heterocycle contains 1 nitrogen atom, and wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 cyanoalkyl, -CN, -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 aminoalkyl. In some cases, the 5- to 10-membered heterocycle is a monocyclic heterocycle. In some cases, the 5- to 10-membered heterocycle is an unsaturated 5- to 10-membered heterocycle. In some cases, the 5- to 10-membered heterocycle contains at least 1 double bond. In some cases, the 5- to 10-membered heterocycle contains at least 2 double bonds. In some cases, the 5- to 10-membered heterocycle which contains 1 nitrogen atom, is bound to Formula (I) through the nitrogen atom. In some cases, R9’ is selected from , , , , , , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 cyanoalkyl, -CN, -OR20, - N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 aminoalkyl. In some cases, R9’ is selected from , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 cyanoalkyl, - CN, -OR20, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, the optional one or more substituents are independently selected from halogen, C1-6 cyanoalkyl, -CN, -OR20, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, each R20 is independently selected from hydrogen and C1-6 alkyl. In some cases, R9’ is selected from In some cases, R9’ is selected from [00119] In some embodiments, for a compound of Formula (I), R9’ is selected unsaturated 7- membered monocyclic heterocycle, which is optionally substituted with one or more substituents independently selected from C1-6 cyanoalkyl, and -CN. In some cases, R9’ is selected from , which is optionally substituted with one or more substituents independently selected from halogen, C1-6 cyanoalkyl, -CN, -OR20, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, R9’ is selected from , which is optionally substituted with one or more substituents independently selected from C1-6 cyanoalkyl, and -CN. In some cases, R9’ is selected from , which is substituted with one or more substituents independently selected from C1-6 cyanoalkyl, hydroxy and -CN. In some cases, R9’ is selected from , which is optionally substituted with one or more substituents independently selected from C1-6 cyanoalkyl, hydroxy and -CN. In some cases, R9’ is selected from , , and . In some cases, R9’ is selected from , and . In some cases, R9’ is . In some cases, R9’ is . In some cases, R9’ is . [00120] In some embodiments, for a compound of Formula (I), R9’ is selected unsaturated 7- membered monocyclic heterocycle, which is optionally substituted with one or more substituents independently selected from -OH, and C1-6 hydroxyalkyl. In some cases, R9’ is selected from , which is optionally substituted with one or more substituents independently selected from -OH, and C1-6 hydroxyalkyl. In some cases, R9’ is . In some cases, R9’ is selected from , which is substituted with at least one -OH. In some cases, R9’ is , , , and . In some cases, R9’ is , and . [00121] In some embodiments, for a compound of Formula (I), R9’ is selected from 5- to 10- membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -N(R20)2, -OR20, and C1-6 alkyl. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some cases, the 5- to 10-membered heterocycle is a monocyclic 5- to 10- membered heterocycle. In some embodiments, for a compound of Formula (I), R9’ is selected from and , each of which is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some cases, R9’ is selected from , , and .In some cases, R9’ is selected from , , , , , , , , , , , . , , , , , , , , , , , , and , each of which are optionally substituted. [00122] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , and , each of which are optionally substituted. [00123] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , , , and , each of which are optionally substituted. [00124] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , . , , , , , , , , , , , , and , each of which are optionally substituted. [00125] In some embodiments, for a compound or salt of Formula (I), R9’ is which is optionally substituted. [00126] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00127] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , , , , and . In some cases, R9’ is . In some cases, R9’ is . [00128] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from a heterocycle as drawn in Table 1. [00129] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl; R3 is naphthalene, wherein naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R4 is selected from hydrogen, halogen or C1-C3 alkyl; Y is O; L is independently a C1-C4 alkylene; R2 is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2. In some cases, Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. [00130] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R9’ is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R9’ is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds. In some cases, R9’ is selected from , , , , and wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9’ is selected from , , , and wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9’ is selected from , , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9’ is selected from
Figure imgf000052_0001
n some cas 9’
Figure imgf000052_0002
es, R is selected from
Figure imgf000052_0003
. In some cases, R9’ is selected from
Figure imgf000052_0004
Figure imgf000052_0005
In some cases, R9’ is . In some cases, R9’ is selected from , , and , wherein each is substituted with one or more substituents independently selected from halogen. [00131] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R9’ is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R9’ is selected from an unsaturated 7-membered heterocycle, substituted with at least one halogen. In some cases, R9’ is selected from , , , In so 9’
Figure imgf000053_0001
me cases, R is selected from
Figure imgf000053_0002
. In some cases, R9’ is selected from
Figure imgf000053_0003
, , a d . In some cases, R9’ is selected from and . In some cases, R9’ is . In some cases, R9’ is . In some cases, R9’ is . [00132] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from an optionally substituted 6-membered unsaturated heterocycle and optionally substituted 6- membered saturated heterocycle. [00133] In some embodiments, for a compound of Formula (I), R9’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00134] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. [00135] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from , , and . [00136] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00137] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R9’ is , which is substituted with two substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R9’ is . [00138] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from C3- C12 carbocycle; 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the C3-C12 carbocycle; 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted. In some cases, R9’ is selected from 5- to 8-membered monocyclic heterocycle, 7- to 8-membered bridged heterocycle, 7-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted, and each of which is bond to Formula (I) via the 1 nitrogen atom. In some cases, R9’ is selected from 5- to 8-membered monocyclic heterocycle, each of which contains at only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; wherein the 5- to 8-membered monocyclic heterocycle, which is optionally substituted, and each of which is bound to Formula (I) via the 1 nitrogen atom. In some cases, R9’ is selected from 5- to 8-membered monocyclic heterocycle, each of which contains at only 1 nitrogen atom; wherein the 5- to 8-membered monocyclic heterocycle is optionally substituted, and wherein the 5- to 8-membered monocyclic heterocycle is bound to Formula (I) via the 1 nitrogen atom. [00139] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains only 1 nitrogen atom, or R9’ is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11- , and 12-membered fused heterocycle, wherein the 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle each contain only 1 nitrogen atom; and wherein the 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted. In some cases, R9’ is selected from 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or R9’ is further selected from 8-, 10, 11-membered spiro heterocycle and 10-membered fused heterocycle, wherein the 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle each contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle, are each optionally substituted; and wherein the, 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle, of R9’ are each bound to Formula (I) via the only 1 nitrogen atom. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -B(OR20)2, -OR20, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -B(OR20)2, -OR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -B(OR20)2, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -B(OH)2, -OH, -NH-S(O)2C1-6 alkyl, -C(O)NH2, -NH-C(O)- (C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -NH-C(O)N(C1-6 alkyl)2, -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the 5- to 8-membered heterocycle is unsaturated. In some cases, the 5- to 8-membered heterocycle is a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a monocyclic 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a bicyclic 5- to 8-membered heterocycle. In some cases, R9’ is selected from , , , , , , , , , , , , , , , , , , ,
Figure imgf000057_0001
Figure imgf000058_0001
[00140] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or R9’ is further selected from 8-membered spiro heterocycle, wherein the 8-membered spiro heterocycle contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, and 8- membered spiro heterocycle, are each optionally substituted; and wherein the 5- to 8-membered heterocycle, and 8-membered spiro heterocycle of R9’ are each bound to Formula (I) via the only 1 nitrogen atom. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)- (C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 5- to 8-membered heterocycle is a partially unsaturated 5- to 8-membered heterocycle or a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is partially unsaturated. In some cases, the 5- to 8-membered heterocycle is a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8- membered heterocycle is a monocyclic 5- to 8-membered heterocycle. In some cases, R9’ is selected from
Figure imgf000059_0001
, , , , , , , ,
Figure imgf000059_0002
, , , , , , , , , , , , , , , , , , , , , , , , and . [00141] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle, is optionally substituted; and wherein the 6- to 7-membered heterocycle of R9’ is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the heterocycle contains only 1 nitrogen atom and no further heteroatoms. In some cases, R9’ is selected from , , , , , , and , any of which is optionally substituted. In some cases, R9’ is selected from , , , , and , any of which is optionally substituted. In some cases, R9’ is selected from , , , , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -OH, -NH2, - NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 6- to 7-membered heterocycle is a partially unsaturated 6- to 7-membered heterocycle or a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is partially unsaturated. In some cases, the 6- to 7-membered heterocycle is a saturated 6- to 7- membered heterocycle. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7- membered heterocycle. In some cases, R9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some cases, R9’ is selected from , and . In some cases, R9’ is . In In some cases, R9’ is [00142] In some embodiments, for a compound or salt of Formula (X), Ring A is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle, is optionally substituted. In some cases, the 6- to 7-membered heterocycle contains 1 nitrogen atom and no further heteroatoms. In some cases, Ring A is selected from , , , , , , and , any of which is optionally substituted. In some cases, Ring A is selected from , , , , and , any of which is optionally substituted. In some cases, Ring A is selected from , , , , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OR20, - N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -OH, - NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 6- to 7-membered heterocycle is a partially unsaturated 6- to 7-membered heterocycle or a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is partially unsaturated. In some cases, the 6- to 7-membered heterocycle is a saturated 6- to 7- membered heterocycle. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7- membered heterocycle. In some cases, Ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and .ovi [00143] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 6- membered heterocycle, wherein the 6-membered heterocycle contains only 1 nitrogen atom, and wherein the 6-membered heterocycle, is optionally substituted; and wherein the 6-membered heterocycle of R9’ is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -B(OR20)2, -OR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -B(OH)2, -OH, - NH-S(O)2C1-6 alkyl, -C(O)NH2, -NH-C(O)-(C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -NH- C(O)N(C1-6 alkyl)2, -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2- 6 alkenyl, and C2-6 alkynyl. In some cases, R9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00144] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 6- membered heterocycle, wherein the 6-membered heterocycle contains only 1 nitrogen atom, and wherein the 6-membered heterocycle, is optionally substituted; and wherein the 6-membered heterocycle of R9’ is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R9’ is selected from , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -OH, -NH2, - NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6- membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6- membered heterocycle is not a bridged heterocycle. In some cases, R9’ is selected from , , , , , , , , , , , , and . [00145] In some embodiments, for a compound or salt of Formula (I), R9’ is not . In some cases, R9’ is not . In some cases, R9’ is not . In some cases, R9’ is not . In some cases, R9’ is not . [00146] In some embodiments, for a compound or salt of Formula (X), Ring A is not . In some cases, Ring A is not . [00147] In some embodiments, for a compound or salt of Formula (I), R9’ is not a bridged heterocycle. [00148] In some embodiments, for a compound or salt of Formula (X), Ring A is not a bridged heterocycle. [00149] In some embodiments, for a compound or salt of Formula (X), Ring A is selected from a 5- to 8-membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or Ring A is further selected from 8-membered spiro heterocycle, wherein the 8- membered spiro heterocycle contain only 1 nitrogen atom; wherein the 5- to 8-membered heterocycle, and 8-membered spiro heterocycle, are each optionally substituted. In some cases, the one or more optional substituents of Ring A are each independently selected from halogen, - OR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1- 6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring A are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2- 6 alkynyl. In some cases, the 5- to 8-membered heterocycle is an unsaturated 5- to 8-membered heterocycle or a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is unsaturated. In some cases, the 5- to 8-membered heterocycle is a saturated 5- to 8- membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a monocyclic 5- to 8- membered heterocycle. In some cases, Ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00150] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur, wherein the 6- to 7-membered heterocycle, is optionally substituted; and wherein the 6- to 7-membered heterocycle of R9’ is bound to Formula (I) via the only 1 nitrogen atom. 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 contains one sulfur atom. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. In some cases, R9’ is selected from , , , , , and , each of which is optionally substituted. In some cases, R9’ is selected from , , , and , each of which is optionally substituted. In some cases, R9’ is selected from , , , , each of which is optionally substituted. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R9’ are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, R9’ is selected from
Figure imgf000068_0001
, , , ,
Figure imgf000068_0002
In some cases, R9’ is selected
Figure imgf000068_0003
from
Figure imgf000069_0001
[00151] In some embodiments, for a compound or salt of Formula (I), R9’ is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and one sulfur atom. [00152] In some embodiments, for a compound or salt of Formula (X), Ring A 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, is optionally substituted. 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 contains one sulfur atom. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. In some cases, Ring A is selected from , , , , , and , each of which is optionally substituted. In some cases, Ring A is selected from , , , and , each of which is optionally substituted. In some cases, Ring A is selected from , , , , each of which is optionally substituted. In some cases, the one or more optional substituents of Ring A are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring A are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of Ring A are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, Ring A is selected from
Figure imgf000070_0001
, , ,
Figure imgf000070_0002
In some cases, Ring A is selected from
Figure imgf000071_0001
,
Figure imgf000071_0002
[00153] In some embodiments, for a compound or salt of Formula (I) or Formula (X), each R20 is independently selected from hydrogen, C1-6 alkoxy, and cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen, and cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, - C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [00154] In some embodiments, for a compound or salt of Formula (I), the optional substituents of R9’ do not include -N(R20)2. In some cases, the optional substituents of R9’ do not include - NH(C1-10 alkyl), -N(C1-10 alkyl)2, and -NH2. In some cases, the optional substituents of R9’ do not include any primary or secondary amines. [00155] In some embodiments, for a compound or salt of Formula (X), the optional substituents of Ring A do not include -N(R20)2. In some cases, the optional substituents of Ring A do not include -NH(C1-10 alkyl), -N(C1-10 alkyl)2, and -NH2. In some cases, the optional substituents of Ring A do not include any primary or secondary amines. [00156] In some embodiments, for a compound or salt of Formula (I) or Formula (X), wherein the compound is not a Michael acceptor. [00157] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the compound or salt does not include an electrophilic substituent. [00158] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the compound or salt does not form a covalent bond with any of the KRAS G12D and/or other G12 mutants. [00159] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants. [00160] In some embodiments, for a compound or salt of Formula (I) or Formula (X), the compound or salt is not a covalent inhibitor for KRAS G12D and/or other G12 mutants. [00161] In another aspect, the present disclosure provides a compound of Formula (II): Formula (II); or a pharmaceutically acceptable salt thereof, wherein: R13 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, - C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R19’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -B(OR20)2, -N(R20) S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; Y is selected from a bond, O and NR5; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; Q is selected from a bond and O; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, heterocycle, Cl-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, - L-O-R5, -L-NR5C(O)-aryl, -L-COOH, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; and each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [00162] In some embodiments, for a compound or salt of Formula (II), Y is O. In some cases, Y is a bond. In some cases, Y is NR5. [00163] In some embodiments, for a compound or salt of Formula (II), L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from Cl-C2 alkylene. In some cases, L is selected from C1 alkylene. [00164] In some embodiments, for a compound or salt of Formula (II), L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from unsubstituted Cl-C2 alkylene. In some cases, L is selected from unsubstituted Cl alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [00165] In some embodiments, for a compound or salt of Formula (II), R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5. In some embodiments, for a compound of Formula (I), R2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L- 5- to 12-membered heteroaryl, optionally substituted -L-C6-C12aryl, -L-N(R5)2, and -L-O-R5. In some cases, R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L- heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12- membered heterocycle, optionally substituted -L-5- to 12-membered heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle. In some cases, R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azocane, and azonane. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, piperidine, piperazine, azocane, and azonane. In some cases, the heteroaryl is selected from pyrrole, pyrazole, furan, thiohene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyrazine, and triazine. In some cases, the heteroaryl or heterocycle has at most 1 nitrogen atom. In some cases, the heteroaryl or heterocycle has at least 1 nitrogen atom. [00166] In some embodiments, for a compound or salt of Formula (II), the heterocycle of R2 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R2 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (II), the heterocycle of R2 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00167] In some embodiments, for a compound or salt of Formula (II), the heteroaryl of R2 is a 5- to 12-membered heteroaryl, 6- to 12-membered heteroaryl, 7- to 12-membered heteroaryl, or 8- to 12-membered heteroaryl. In some cases, the heteroaryl of R2 is a 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 6- to 11-membered heteroaryl, 6- to 10- membered heteroaryl, 6- to 9-membered heteroaryl, or 6- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 7- to 11-membered heteroaryl, 7- to 10-membered heteroaryl, 7- to 9-membered heteroaryl, or 7- to 8-membered heteroaryl. In some cases, the heteroaryl of R2 is a 5- to 6-membered heteroaryl or 5- to 9-membered heteroaryl. In some cases, the heteroaryl of R2 is an 8- to 9-membered heteroaryl. In some embodiments, for a compound of Formula (II), the heteroaryl of R2 is saturated. The heteroaryl may be optionally substituted as described elsewhere herein. [00168] In some embodiments, for a compound or salt of Formula (II), R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, R2 is selected from and , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, Y-R2 is selected from , ,
Figure imgf000076_0001
, , , , , , , , , , and . [00169] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. [00170] In some embodiments, for a compound or salt of Formula (II), for R2, the heterocycle portion is optionally substituted with one or more R6. In some cases, the R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00171] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from , , and . [00172] In some embodiments, for a compound or salt of Formula (II), the carbocycle of R19’ is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, and C3- C6 carbocycle. In some cases, the carbocycle of R19’ is selected from C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, and C9- C12 carbocycle. [00173] In some embodiments, for a compound or salt of Formula (II), the spiroheterocycle of R19’ is a 6- to 12-membered spiroheterocycle, 6- to 12-membered spiroheterocycle, 7- to 12- membered spiroheterocycle, or 8- to 12-membered spiroheterocycle. In some cases, the spiroheterocycle of R19’ is a 6- to 11-membered spiroheterocycle, 6- to 10-membered spiroheterocycle, 6- to 9-membered spiroheterocycle, or 6- to 8-membered spiroheterocycle. In some cases, the spiroheterocycle of R19’ is a 7- to 11-membered spiroheterocycle, 7- to 10- membered spiroheterocycle, 7- to 9-membered spiroheterocycle, or 7- to 8-membered spiroheterocycle. In some cases, the spiroheterocycle of R19’ is an 8- to 11-membered spiroheterocycle. The spiroheterocycle may be optionally substituted as described elsewhere herein. [00174] In some embodiments, for a compound or salt of Formula (II), the fused heterocycle of R19’ is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12- membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R19’ is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R19’ is a 7- to 11-membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R19’ is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R19’ is a 6-membered fused heterocycle. In some cases, the fused heterocycle of R19’ is a 7-membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein. [00175] In some embodiments, for a compound or salt of Formula (II), the heterocycle of R19’ is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R19’ is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R19’ is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R19’ 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 R19’ is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R19’ is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (II), the heterocycle of R19’ is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00176] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted C3-C7 carbocycle and optionally substituted 5- to 11-membered heterocycle. [00177] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted C3-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle. [00178] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle. In some cases, R19’ is selected from an optionally substituted 5- to 11-membered saturated heterocycle. [00179] In some embodiments, for a compound or salt of Formula (II), for R19’, the 5- to 11- membered saturated heterocycle contains at most 2 nitrogen atoms. In some embodiments, for a compound of Formula (II), for R19’, the 5- to 11-membered saturated heterocycle contains at most 1 nitrogen atom. [00180] In some embodiments, for a compound or salt of Formula (II), for R19’, the 5- to 11- membered saturated heterocycle contains at least 1 oxygen atom. R19’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; [00181] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2,-N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, - N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, R19’ is selected from , , , , , , , , , , , , , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, - N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, R19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00182] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, -N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. In some embodiments, for a compound of Formula (II), R19’ is selected from , , , , and , each of which is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, -N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. In some embodiments, for a compound of Formula (II), R19’ is selected from , , , , , , , , , , , , and . [00183] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from 5- to 10-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -N(R20)2, -OR20, and C1-6 alkyl. In some cases, the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some embodiments, for a compound of Formula (II), R19’ is selected from and , each of which is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some cases, R19’ is selected from , , and . [00184] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from, , , , , , , , . , , , , , , , , , , , , , , , , , , , , , , , , , and , each of which are optionally substituted. [00185] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from C6 saturated or partially saturated carbocycle and 5- to 11-membered saturated heterocycle, each of which are optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, -NO2, =O, C1-6 alkyl, -N(R20)C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the one or more substituents are independently selected from -OR20, - N(R20)2, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R19’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00186] In some cases, for a compound or salt of Formula (II), for R19’, the one or more substituents are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, and C1-6 hydroxyalkyl. In some cases, the one or more substituents are independently selected from -OR20, and C1-6 hydroxyalkyl. In some cases, the one or more substituents are independently selected from -N(R20)2, and C1-6 aminoalkyl. In some cases, the one or more substituents are independently selected from -N(R20)C(O)N(R20)2. [00187] In some embodiments, for a compound or salt of Formula (II), for R20 of R19’ is selected from hydrogen and C1-3 alkyl. In some cases, R20 of R19’ is hydrogen. [00188] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00189] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from , , , , , and . In some cases, R19’ is . In some cases, R19’ is . [00190] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted 5- to 10-membered heterocycle. In some cases, the 5- to 10-membered heterocycle contains only 1 nitrogen atom. In some cases, the 5- to 10-membered heterocycle is unsaturated. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 aminoalkyl. In some cases, the 5- to 10-membered heterocycle is an unsaturated 5- to 10-membered heterocycle. In some cases, the 5- to 10-membered heterocycle contains at least 1 double bond. In some cases, the 5- to 10-membered heterocycle contains at least 2 double bonds. In some cases, the 5- to 10-membered heterocycle which contains 1 nitrogen atom, is bound to Formula (II) through the nitrogen atom. In some cases, R19’ is selected from , , , , , , , and , each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 aminoalkyl. In some cases, the optional one or more substituents are independently selected from halogen, C1-6 cyanoalkyl, -CN, -OH, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, each R20 is independently selected from hydrogen and C1-6 alkyl. In some cases, R19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , and . In some cases, R19’ is selected from , , , , , , , , , , , , , , , , , , , , and . [00191] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is selected from a spiroheterocycle, fused heterocycle, and a monocyclic heterocycle. In some cases, the heterocycle is not a bridged heterocycle. In some cases, the heterocycle is a spiroheterocycle. In some cases, the heterocycle is a fused heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is selected from a 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10, 11-membered spiro heterocycle, 6-, 7-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10-, 11- membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle each contain only 1 nitrogen atom; and wherein the 5- to 12-membered monocyclic heterocycle, 7-, 8-, 10-, 11- membered spiro heterocycle, and 6-, 7-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted. [00192] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from 5- to 8-membered monocyclic heterocycle, 8-, 10-, 11-membered spiroheterocycle, and 7-, 10- membered fused heterocycle, are each optionally substituted; and wherein the, 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 7-, 10-membered fused heterocycle, of R19’ are each bound to Formula (II) via the only 1 nitrogen atom. In some cases, the one or more optional substituents of R19’ are each independently selected from from halogen, -OR20, -N(R20)2, -C(O)R20, -B(OR20)2, -N(R20)S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the one or more optional substituents of R19’ are each independently selected from halogen, -B(OR20)2, -OR20, -N(R20)2, =O, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R19’ are each independently selected from halogen, -B(OH)2, -OH, -N(R20)2, =O, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the 5- to 8-membered heterocycle is partially unsaturated. In some cases, the 5- to 8-membered heterocycle is a saturated 5- to 8-membered heterocycle. In some cases, the 5- to 8-membered heterocycle is a monocyclic 5- to 8-membered heterocycle. In some cases, R19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , OH N , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [00193] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted 6- to 12-membered fused heterocycle. In some cases, R19’ is selected from an optionally substituted 6- to 10-membered fused heterocycle. In some cases, R19’ is an optionally substituted 7-membered fused heterocycle. In some cases, the fused heterocycle has only 1 nitrogen atom. In some cases, the fused heterocycle has only 1 nitrogen atom and 1 oxygen atom. In some cases, the heterocycle has at least 1 oxygen atom. In some cases, the fused heterocycle has at most 1 nitrogen atom. In some cases, the fused heterocycle is bound to Formula (II) via the 1 nitrogen atom. In some cases, the fused heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -N(R20)S(O)2(R20), -N(R20)C(O)N(R20)2, =O, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the fused heterocycle is optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, hydroxy, and oxo. In some cases, the fused heterocycle is substituted with one or more substituents selected from halogen, -OR20, -N(R20)2, -C(O)R20, -B(OR20)2, -N(R20) S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the fused heterocycle is substituted with one or more substituents selected from halogen, -OR20, - C(O)R20, -N(R20)S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the fused heterocycle is substituted with one or more substituents selected from halogen, C1-6 alkyl, hydroxy, and oxo. In some cases, R19’ is selected , and . In some cases, R19’ is selected and each of which i 20
Figure imgf000088_0001
s optionally with one or more substituents selected from halogen, -OR , - N(R20)S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R19’ is selected , which is optionally with one or more substituents selected from halogen, -OR20, -N(R20)S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R19’ is selected , which is substituted with one or more substituents selected from halogen, and C1-6 haloalkyl. In some cases, R19’ is selected and . In some cases, R19’ is selected . In some cases, R19’ is selected . [00194] In some embodiments, for a compound or salt of Formula (II), R3 is selected from an optionally substituted heteroaryl. In some cases, the one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from an optionally substituted 10- to 15-memebered heteroaryl. In some cases, R3 is selected from an optionally substituted 12- to 13-memebered heteroaryl. In some cases, heteroaryl of R3 is substituted with at least one substituent. In some cases, heteroaryl of R3 is substituted with at least two substituents. In some cases, the substituents are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, and -N(R20)2. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, the substituents are selected from halogen, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, R3 is selected from , . , and , each of which are optionally substituted. In some cases, R3 is selected from , , , and , each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. In some cases, R3 is selected from , , and , each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from , , , , , , , , , , and . In some cases, R3 is selected from , , , , , , , , , and . In some cases, R3 is selected from an unsubstituted heteroaryl. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from . In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from chlorine and fluorine. In some cases, R3 is selected from , , and . In some cases, R3 is selected from ,and . In some cases, R3 is selected from . In some cases, R3 is selected from . [00195] In some embodiments, for a compound or salt of Formula (II), R3 is selected from optionally substituted aryl. In some cases, the aryl is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the aryl is C10-C14 aryl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and - N(R20)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and - N(R20)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. [00196] In some embodiments, for a compound or salt of Formula (II), R3 is selected from optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C6- C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [00197] In some embodiments, for a compound or salt of Formula (II), R3 is selected from indazole and naphthalene. In some cases, R3 is naphthalene. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C2-6 alkynyl, -OH, and C1-3 alkyl. [00198] In some embodiments, for a compound or salt of Formula (II), R3 is selected from , , , and . In some cases, R3 is selected from , , , , and . In some cases, R3 is selected from , , , , , and . In some cases, R3 is selected from . In some cases, R3 is selected from . [00199] In some embodiments, for a compound or salt of Formula (II), R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , and . [00200] In some embodiments, for a compound or salt of Formula (II), R3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, R3 is selected from aryl, which is optionally substituted with one or more substituents. In some cases, the aryl is selected from a C6 aryl and C10 aryl. In some cases, the heteroaryl is selected from a 9- to 10-membered heteroaryl. In some cases, R3 is selected from C10 aryl and 9- to 10- membered heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has two ntirgoen atoms and no further heteroatoms. In some cases, the heteroaryl has at least one oxygen atom. In some cases, the heteroaryl is bicyclic. In some cases, the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C1-6 alkyl, C2-C4 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl. In some cases, R3 is selected from , , , , , , , , , , , , , and . In some cases, the aryl is substituted with at least one substituent selected from halogen and hydroxy. In some cases, R3 is selected from , , , , , and . In some cases, the aryl is substituted with at least two halogen atoms. In some cases, R3 is selected from . [00201] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R19’ is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further heteroatoms. In some cases, R19’ is selected from , , , , , , and , any of which is optionally substituted. In some cases, R19’ is selected from , , , , and , any of which is optionally substituted. In some cases, R19’ is selected from , , , , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R19’ are each independently selected from halogen, -OR20, =O, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle or a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is unsaturated. In some cases, the 6- to 7-membered heterocycle is a saturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is a monocyclic 6- to 7-membered heterocycle. In some cases, R19’ is selected from , , , , , , , , , , , , , , , , , , , , , and . [00202] [00203] In some embodiments, for a compound or salt of Formula (II), R19’ is not . In some cases, R19’ is not . In some cases, R19’ is not . In some cases, R19’ is not . In some cases, R19’ is not . [00204] In some embodiments, for a compound or salt of Formula (II), R19’ is not a bridged heterocycle. [00205] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. [00206] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted unsaturated 6- to 7-membered heterocycle. [00207] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted unsaturated 7-membered heterocycle. [00208] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted unsaturated 6-membered heterocycle. [00209] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R19’ is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R19’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R19’ is selected from , , , , and . [00210] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00211] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. [00212] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from , , and . [00213] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00214] In some embodiments, for a compound or salt of Formula (II), R19’ is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl. [00215] In some embodiments, for a compound or salt of Formula (II), R4 is selected from halogen and hydrogen. In some cases, R4 is selected from halogen. In some cases, R4 is selected from chloride and fluorine. In some cases, R4 is fluorine. In some cases, R4 is hydrogen. [00216] In some embodiments, for a compound or salt of Formula (II), R13 is selected from optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the C6- C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, R20 is hydrogen. In some cases, R20 is selected from hydrogen and C1-6 alkyl. [00217] In some embodiments, for a compound or salt of Formula (II), R13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00218] In some embodiments, for a compound or salt of Formula (II), R20 of R13 is selected from hydrogen and C1-3 alkyl. [00219] In some embodiments, for a compound or salt of Formula (II), R13 is optionally substituted naphthalene. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from - OH and C1-6 hydroxyalkyl. [00220] In some embodiments, for a compound or salt of Formula (II), R13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, and C1-3 alkyl. [00221] In some embodiments, for a compound or salt of Formula (II), R13 is selected from , , , and . [00222] In some embodiments, for a compound or salt of Formula (II), R13 is selected from indazole and naphthalene. In some embodiments, for a compound of Formula (II), R13 is naphthalene. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, and C1-3 alkyl. [00223] In some embodiments, for a compound or salt of Formula (II), R13 is selected from , , , and . In some cases, R13 is selected from , , , and . In some cases, R13 is selected from , , , , and . In some cases, R13 is selected from . [00224] In some embodiments, for a compound or salt of Formula (II), wherein the compound is not a Michael acceptor. [00225] In some embodiments, for a compound or salt of Formula (II), wherein the compound does not include an electrophilic substituent. [00226] In some embodiments, for a compound or salt of Formula (II), the compound or salt does not include an electrophilic substituent. [00227] In some embodiments, for a compound or salt of Formula (II), the compound or salt does not form a covalent bond with any of the KRAS G12D and/or other G12 mutants. [00228] In some embodiments, for a compound or salt of Formula (II), the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants. [00229] In some embodiments, for a compound or salt of Formula (II), the compound or salt is not a covalent inhibitor for KRAS G12D and/or other G12 mutants. [00230] In another aspect, the present disclosure provides a compound of Formula (III): Formula (III); or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, Cl-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- Cl-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OCl-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents are selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo;; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R29’ is selected from an unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [00231] In some embodiments, for a compound of Formula (III), the unsaturated 5- to 12- membered heterocycle of R29’ contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains at least 1 nitrogen atom. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains only 1 nitrogen atom. [00232] In some embodiments, for a compound of Formula (III), the unsaturated 5- to 12- membered heterocycle of R29’ contains at least 1 double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains at most 1 double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains at least 1 carbon-carbon double bond. In some cases, the unsaturated 5- to 12-membered heterocycle of R29’ contains at most 1 carbon-carbon double bond. [00233] In some embodiments, for a compound of Formula (III), R29’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R29’ is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R29’ is selected from an optionally substituted unsaturated 6-membered heterocycle. [00234] In some embodiments, for a compound of Formula (III), for R29’, the one or more optional substituents are independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -N(R20)S(O)2(R20), -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, for R29’, the one or more optional substituents are independently selected from halogen, -OH, -NH2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, for R29’, the one or more optional substituents are independently selected from halogen, - OH, -NH2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, for R29’, the one or more optional substituents are independently selected from halogen and C1-6 haloalkyl. [00235] In some embodiments, for a compound of Formula (III), for R29’, the one or more optional substituents are independently selected from halogen. In some cases, R29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen and C1-6 haloalkyl. In some cases, R29’ is selected from , , , and . In some cases, R29’ is selected from and . In some cases, R29’ is selected from , and . [00236] In some embodiments, for a compound of Formula (III), R29’ is selected from , , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00237] In some embodiments, for a compound of Formula (III), R29’ is selected from and is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In somec cases, R29’ is selected from , and . [00238] In some embodiments, for a compound of Formula (III), R29’ is selected from unsaturated 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle, is optionally substituted. In some cases, the unsaturated 6- to 7-membered heterocycle contains only 1 nitrogen atom. In some cases, the unsaturated 6- to 7-membered heterocycle of R29’ is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R29’ is selected from , , , , and , any of which is optionally substituted. In some cases, R29’ is selected from , , and , any of which is optionally substituted. In some cases, R29’ is selected from , , , , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R29’ are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R29’ are each independently selected from fluorine, -OH, -NH2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R29’ are each independently selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is an unsaturated monocyclic 6- to 7-membered heterocycle. In some cases, R29’ is selected from , , , , and , any of which is substituted with one or more substituents selected from halogen. In some cases, R29’ is selected from, , , , , , , and . [00239] In some embodiments, for a compound or salt of Formula (III), R3 is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl includes 6 to 11 carbon atoms and at least one heteroatom selected from N, O, and S. In some cases, the heteroaryl includes 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, or 9 to 10 carbon atoms. In some cases, the heteroaryl includes at least one, two, or three heteroatoms. In some cases, the heteroaryl includes at most one, two, or three heteroatoms. In some cases, the heteroaryl includes at least one nitrogen atom. In some cases, the heteroaryl includes at least two or at least three nitrogen atoms. In some cases, the heteroaryl includes at least two nitrogen atoms. In some cases, the heteroaryl includes at least three nitrogen atoms. In some cases, the heteroaryl includes at most one nitrogen atom. In some cases, the heteroaryl includes at most two nitrogen atoms. In some cases, the heteroaryl includes at most three nitrogen atoms. In some cases, the heteroaryl has only nitrogen heteroatoms. In some cases, the heteroaryl has nitrogen and sulfur heteroatoms. In some cases, the heteroaryl includes at least one sulfur atom. [00240] In some embodiments, for a compound or salt of Formula (III), R3 is selected from an optionally substituted heteroaryl. In some cases, R3 is selected from an optionally substituted 10- to 15-memebered heteroaryl. In some cases, R3 is selected from an optionally substituted 12- to 13-memebered heteroaryl. In some cases, heteroaryl of R3 is substituted with at least one substituent. In some cases, heteroaryl of R3 is substituted with at least two substituents. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, R3 is selected from , . , and , each of which are optionally substituted. In some cases, R3 is selected from , , , and , each of which are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, Cl- C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from , , and , each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from , , , , , , , , , , and . In some cases, R3 is selected from , , , , , , , , , and . In some cases, R3 is selected from an unsubstituted heteroaryl. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from . In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from chlorine and fluorine. In some cases, R3 is selected from , , and . In some cases, R3 is selected from ,and . In some cases, R3 is selected from . In some cases, R3 is selected from . [00241] In some embodiments, for a compound or salt of Formula (III), R3 is selected from optionally substituted aryl. In some cases, the aryl is C10-C14 aryl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1- C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the C10- C14 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C10-C14 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. [00242] In some embodiments, for a compound or salt of Formula (III), R3 is selected from optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C6- C10 aryl is optionally substituted with one or more substituents independently selected from hydroxy, C2-6 alkynyl, fluorine, and C1-C4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [00243] In some embodiments, for a compound or salt of Formula (III), R3 is selected from indazole and naphthalene. In some cases, R3 is naphthalene. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C2-6 alkynyl, -OH, and C1-3 alkyl. [00244] In some embodiments, for a compound or salt of Formula (III), R3 is selected from , , , and . In some cases, R3 is selected from , , , , and . In some cases, R3 is selected from , , , , , and . In some cases, R3 is selected from . In some cases, R3 is selected from . [00245] In some embodiments, for a compound or salt of Formula (III), R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , and . [00246] In some embodiments, for a compound or salt of Formula (III), R3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, R3 is selected from aryl, which is optionally substituted with one or more substituents. In some cases, the aryl is selected from a C6 aryl and C10 aryl. In some cases, the heteroaryl is selected from a 9- to 10-membered heteroaryl. In some cases, R3 is selected from C10 aryl and 9- to 10- membered heteroaryl, each of which is optionally substituted with one or more substituents. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has two ntirgoen atoms and no further heteroatoms. In some cases, the heteroaryl has at least one oxygen atom. In some cases, the heteroaryl is bicyclic. In some cases, the aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, C1-6 alkyl, C2-C4 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl. In some cases, R3 is selected from , , , , , , , , , , , , , and . In some cases, the aryl is substituted with at least one substituent selected from halogen and hydroxy. In some cases, R3 is selected from , , , , , and . In some cases, the aryl is substituted with at least two halogen atoms. In some cases, R3 is selected from . [00247] In some embodiments, for a compound or salt of Formula (III), Y is O. [00248] In some embodiments, for a compound or salt of Formula (III), L is selected from unsubstituted C1-C4 alkylene. [00249] In some embodiments, for a compound or salt of Formula (III), R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5. In some cases, R2 is selected from optionally substituted -L- heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L- heterocycle. [00250] In some embodiments, for a compound or salt of Formula (III), R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, Y-R2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some cases, Y-R2 is selected from , , and . In some cases, Y-R2 is selected from , , , , , , , , , , , , , , , , , , , , , , , and . [00251] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, -OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle. In some cases, Y-R2 is selected from , , , , , , and . In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CH2OC(O)heterocycle, - CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from oxo and hydroxy. In some cases, Y-R2 is selected from , , , , and . [00252] In some embodiments, for a compound or salt of Formula (III), for R2, the heterocycle portion is optionally substituted with one or more R6. In some cases, the R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen, hydroxy, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. [00253] In some embodiments, for a compound or salt of Formula (III) for R2, the heteroaryl portion is optionally substituted with one or more R6. In some cases, R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1- C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, - N(R5)2, and oxo. In some cases, the R6 is independently selected from hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from halogen or C1-C3 alkyl. In some cases, R6 is methyl or fluorine. [00254] In some embodiments, for a compound of Formula (III), Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted. [00255] In some embodiments, for a compound of Formula (III), R2 is selected from and , wherein the heterocycle portion is optionally substituted. [00256] In some embodiments, for a compound or salt of Formula (III), for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, Y-R2 is selected from , , and . [00257] In some embodiments, for a compound or salt of Formula (III), R4 is selected from halogen and hydrogen. In some cases, R4 is selected from halogen. In some cases, R4 is fluorine. In some cases, R4 is hydrogen. [00258] In some embodiments, for a compound or salt of Formula (III), R3 is selected from C6- C10 aryl, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1- C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. [00259] In some embodiments, for a compound or salt of Formula (III), R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C2- C4 alkynyl, and C1-6 haloalkyl. [00260] In some embodiments, for a compound or salt of Formula (III), R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, C2-C4 alkynyl, and C1-3 alkyl. In some cases, R3 is selected from , , , , and . [00261] In some embodiments, for a compound or salt of Formula (III), R3 is selected from and . [00262] In some embodiments, for a compound or salt of Formula (III), each R20 is independently selected from hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, - C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [00263] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [00264] 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. [00265] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000117_0001
[00266] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [00267] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [00268] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [00269] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [00270] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [00271] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [00272] 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. [00273] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. [00274] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00275] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure. [00276] 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. [00277] 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. [00278] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [00279] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations [00280] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (II), and (III) (also referred to herein as “a pharmaceutical agent”). [00281] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999). [00282] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. [00283] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. [00284] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. [00285] 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. [00286] 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. [00287] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen. [00288] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion. [00289] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art. [00290] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally. [00291] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating. [00292] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented. [00293] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof. [00294] 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. [00295] 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. [00296] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. [00297] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects. [00298] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ^ range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb ^ ^ and AeroDose ^ ^ ^vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC ^ and Pari LC Star ^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ^ ^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. [00299] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination. [00300] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross- linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound. [00301] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients. [00302] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert. [00303] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art. [00304] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. Methods of Treatment [00305] In an aspect, the present disclosure provides compounds that inhibit KRas G12 mutants, KRAS G12D, G12D alleles, or alleles. In some cases, the method may inhibit KRas G12 mutants activity in a cell. In some cases, inhibiting 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 Formula (I), Formula (II), Formula (III), Formula (X), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants. In some cases, a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound of Formula (I) or Formula (II) or Formula (III) or Formula (X) or a pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and/or other G12 mutants, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants. The ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods. [00306] In some embodiments, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and/or other G12 mutants activity of the amount of phosphorylated ERK. [00307] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. The compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. [00308] The compositions and methods provided herein may be used for the treatment of a G12D alleles-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof. [00309] The compositions and methods provided herein may be used for the treatment of an alleles-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof. [00310] In some cases, the KRas G12D, other G12 mutants, G12D alleles, or alleles associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co- administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. [00311] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [00312] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. [00313] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of KRas G12D and/or other G12 mutants. [00314] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of G12D alleles. [00315] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of alleles. [00316] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12D and/or other G12 mutants -associated disease or disorder. [00317] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a G12D allele associated disease or disorder. [00318] Also provided herein is a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of an allele -associated disease or disorder. [00319] Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. [00320] Also provided herein is a use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) 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. [00321] Also provided herein is a use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of G12D allele. [00322] Also provided herein is a use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of an allele. [00323] Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder. [00324] Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a G12D allele-associated disease or disorder. [00325] Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an allele-associated disease or disorder. [00326] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and/or other G12 mutants (e.g., a KRas G12D and/or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (X) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [00327] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject. [00328] The compounds described herein display selectivity towards inhibiting KRAS vs NRAS. [00329] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. [00330] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. [00331] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [00332] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. [00333] 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. [00334] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. [00335] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. [00336] In certain embodiments, the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. [00337] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope Preparation of Compounds [00338] 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. [00339] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES [00340] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [00341] The present disclosure provides processes for preparing compounds the compounds described herein (described in greater detail below). Example 1. Exemplary synthesis of compound 2 [00342] Step 1. Synthesis of 7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidine-2,4-diol (2c): A microwave vial was charged with 7-chloro-8-fluoro-pyrido[4,3- d]pyrimidine-2,4-diol (2a, 330 mg, 1.53 mmol, 1.0 eq), 2-(3-benzyloxy-1-naphthyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2b, 551 mg, 1.53 mmol, 1.0 eq), Pd(dppf)Cl2.DCM (62.5 mg, 0.0800 mmol, 0.5 eq), potassium carbonate (634 mg, 4.59 mmol, 3.0 eq) and water/1,4-dioxane (0.5 mL/5 mL) under N2. The sealed vial was heated for 2 h in a Biotage Initiator Eight Microwave Reactor at a constant temperature of 100 oC. The resulting solution was filtered, and then the filtrate was concentrated and purified by flash column chromatography (silica gel, eluting with 2% to 5% MeOH/DCM) to afford 7-(3-benzyloxy-1-naphthyl)-8-fluoro-pyrido[4,3- d]pyrimidine-2,4-diol (2c, 350 mg, 0.847 mmol, 55.3% yield) as a yellow solid. LCMS calculated for C24H17FN3O3 (M+H)+ m/z =414.1; found: 414.2. [00343] Step 2. Synthesis of 7-(3-(benzyloxy)naphthalen-1-yl)-2,4-dichloro-8- fluoropyrido[4,3-d]pyrimidine (2d): To a mixture of 7-(3-benzyloxy-1-naphthyl)-8-fluoro- pyrido[4,3-d]pyrimidine-2,4-diol (2c, 350 mg, 0.850 mmol, 1.0 eq) in POCl3 (5 mL) was added DIEA (0.7 mL, 4.23 mmol, 5.0 eq). The mixture was stirred at 100 oC for 6 h under N2. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 5% THF/DCM) to afford 7-(3-benzyloxy-1-naphthyl)-2,4-dichloro-8-fluoro- pyrido[4,3-d]pyrimidine (2d, 255 mg, 0.570 mmol, 67.3% yield) as a yellow solid. LCMS calculated for C24H15Cl2FN3O (M+H)+ m/z =450.0; found: 450.1/452.1. [00344] Step 3. tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2f): To a mixture of 7-(3-benzyloxy-1-naphthyl)-2,4-dichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2d, 100 mg, 0.220 mmol, 1.0 eq) in DCM (5 mL) were added tert-butyl N-[(8-syn)-3-azabicyclo[3.2.1]octan- 8-yl]carbamate (2e, 50.3 mg, 0.220 mmol, 1.0 eq) (CAS: 847795-98-6) and DIEA (0.11 mL, 0.670 mmol, 3.0 eq) in dioxane (1 mL) at -60 oC . The mixture was stirred at -60 oC for 1 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 25% EA/PE) to afford tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-2- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2f, 100 mg, 0.156 mmol, 71.0% yield) as a white solid. LCMS calculated for C36H36ClFN5O3 (M+H)+ m/z = 640.2; found: 640.3/642.3. [00345] Step 4. Synthesis of tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)carbamate (2h): A mixture of tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-2- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2f, 100 mg, 0.160 mmol, 1.0 eq), [(2S)-1-methylpyrrolidin-2-yl]methanol (2g, 36.0 mg, 0.310 mmol, 1.9 eq) and t-BuOK (35.0 mg, 0.310 mmol, 1.9 eq) in 1,4-dioxane (10 mL) was stirred at room temperature for 1 h under N2. The reaction mixture was concentrated and purified by Prep- HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% TFA) / MeOH at flow rate : 50 mL / min to afford tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)carbamate (2h, 32.0 mg, 0.0445 mmol, 28.5% yield) as a yellow solid. LCMS calculated for C42H48FN6O4 (M+H)+ m/z = 719.4; found: 719.6. [00346] Step 5. Synthesis of (syn-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8- yl)carbamate (2i): A mixture of tert-butyl (syn-3-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)carbamate (2h, 32.0 mg, 0.0400 mmol, 1.0 eq) and Pd(OH)2/C (53.3 mg, 0.380 mmol, 10.0 eq) in THF (1 mL) was stirred at room temperature for 1 h under H2. The resulting mixture was filtered, and then the filtrate was concentrated to afford crude product tert-butyl (syn-3-(8- fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2i, 30.0 mg) as yellow solid, which was used in next step. LCMS calculated for C35H42FN6O4 (M+H)+ m/z = 629.3; found: 629.4. [00347] Step 6.4-(4-(8-syn-amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (2): To a mixture of tert-butyl (syn-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (2i, 30.0 mg, 0.0400 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% TFA) / MeOH at flow rate : 50 mL / min to afford 4-(4-(8-syn-amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (13.0 mg, 0.0157 mmol, 37.7% yield). LCMS calculated for C30H34FN6O2 (M+H)+ m/z = 529.3; found: 529.4.1H NMR (400 MHz, CD3OD) δ 9.22 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 7.22 - 7.27 (m, 2 H), 4.91 (dd, J = 12.8, 2.8 Hz, 1 H), 4.66 - 4.79 (m, 3 H), 3.90 (d, J = 10.4 Hz, 3 H), 3.69 - 3.81(m, 1 H), 3.55 (t, J = 4.4 Hz, 1 H), 3.20 - 3.28 (m, 1 H), 3.18 (s, 3 H), 2.54 - 2.58 (m, 2 H), 2.35 - 2.47 (m, 1 H), 2.18 - 2.27 (m, 1 H), 2.08 - 2.14 (m, 2 H), 1.91 - 1.99 (m, 2 H), 1.71 - 1.80 (m, 2 H). Example 2. Exemplary synthesis of compound 6
[00348] Step 1. Synthesis of tert-butyl N-[[1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)pyrrolidin-3-yl]methyl]carbamate (6c): To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3- d]pyrimidine (6a, 385 mg, 1.52 mmol, 1.0 eq) and DIEA (5.08 mL, 30.7 mmol, 20.2 eq) in DCM (10 mL) was added tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate (6b, 366 mg, 1.83 mmol, 1.2 eq) at -50 °C and the mixture was stirred for 1.5 h. The resulting mixture was diluted with water (100 mL), and extracted with dichloromethane (2 × 100 mL). The combined organic layers was washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 5% MeOH / DCM) to afford tert-butyl N- [[1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]methyl]carbamate (6c, 394 mg, 0.946 mmol, 62.1% yield) as a yellow solid. LCMS calculated for C17H21Cl2FN5O2 (M+H)+ m/z = 416.1; found: 416.2/418.2. [00349] Step 2. Tert-butyl N-[[1-[7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]carbamate (6d): A mixture of tert-butyl N-[[1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3- yl]methyl]carbamate (6c, 166 mg, 0.400 mmol, 1.0 eq), [(2S)-1-methylpyrrolidin-2-yl]methanol (2g, 184 mg, 1.59 mmol, 4.0 eq) and DIEA (155 mg, 1.20 mmol, 3.0 eq) in 1,4-dioxane (2.5 mL) was stirred at 80 °C for 6 hours. The resulting mixture was filtered. The filtrate was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% formic acid) / MeOH at flow rate : 50 mL / min to give tert-butyl N-[[1-[7-chloro-8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-3- yl]methyl]carbamate (6d, 124 mg, 0.250 mmol, 62.8% yield) as a yellow solid. LCMS calculated for C23H33ClFN6O3 (M+H)+ m/z = 495.2; found: 495.3/497.3. [00350] Step 3. Tert-butyl N-[[1-[8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]carbamate (6f): To a mixture of tert-butyl N-[[1-[7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]carbamate (6d, 66.0 mg, 0.133 mmol, 1.0 eq) in 1,4-dioxan/water (1.5 mL/0.15 mL) were added 2-[3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6e, 54.5 mg, 0.173 mmol, 1.3 eq), cesium carbonate (86.7 mg, 0.267 mmol, 2.0 eq) and Pd(dppf)Cl2 (9.75 mg, 0.0133 mmol, 0.1 eq). The mixture was degassed and refilled with N2 for three times. Then the reaction was stirred at 90 °C for 10 h. The resulting mixture was filtered, and then the filtrate was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% formic acid) / MeOH at flow rate : 50 mL / min to afford tert-butyl N-[[1-[8-fluoro-7-[3- (methoxymethoxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]carbamate (6f, 22.0 mg, 0.0340 mmol, 25.5% yield) as a white solid. LCMS calculated for C35H44FN6O5 (M+H)+ m/z = 647.3; Found: 647.5. [00351] Step 4.4-[4-[3-(aminomethyl)pyrrolidin-1-yl]-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (6): To a solution of tert-butyl N-[[1- [8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]carbamate (6f, 22.0 mg, 0.0340 mmol, 1.0 eq) in MeCN (20 mL) was added HCl in dioxane(4 M) (0.250 mL, 1.02 mmol, 30 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The resulting mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% TFA) / MeOH at flow rate: 50 mL / min to afford 4-[4-[3-(aminomethyl)pyrrolidin-1-yl]- 8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (6, 10.1 mg, 0.0198 mmol, 58.2% yield) as a yellow solid. LCMS calculated for C28H32FN6O2 (M+H)+ m/z = 503.3; Found: 503.4.1H NMR (400 MHz, CD3OD) δ 9.47 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 7.39 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.28 - 7.33 (m, 1 H), 4.91 - 5.05 (m, 1 H), 4.43 - 4.55 (m, 3 H), 4.09 - 4.18 (m, 1 H), 3.95 - 4.05 (m, 2 H), 3.76 - 3.82 (m, 1 H), 3.18 - 3.27 (m, 3 H), 3.12 (s, 3 H), 2.85 - 2.94 (m, 1 H), 2.40 - 2.52 (m, 2 H), 1.96 - 2.28 (m, 4 H). Example 3. Exemplary synthesis of compound 11 [00352] Step 1. Synthesis of 4-(2-chloro-8-fluoro-4-((1R,3r,5S)-3-hydroxy-8- azabicyclo[3.2.1]octan- 8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl pivalate (11b): To a solution of compound 11a (prepared similarly to that of compound 2d) (110.0 mg, 0.250 mmol) in DCM (3.0 mL) was added DIEA (174.48 mg, 1.35 mmol) and (1R,5S)-8- azabicyclo[3.2.1]octan-3-ol (31.49 mg, 0.2500 mmol) at 0 oC. Then the mixture was stirred at 0 oC for 1 hour. The reaction was monitored by LCMS. The mixture was concentrated to afford a crude product which was triturated in DCM/MeOH (5 mL, 10:1) and filtered. The compound 11b (100.0 mg, 0.187 mmol, 75% yield) was obtained as a yellow solid. LCMS (ESI): m/z calcd for C29H28ClFN4O3+H: 535.2, found: 535.3. [00353] Step 2. Synthesis of (1R,3S,5S)-8-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2- (((S)-1- methylpyrrolidin- 2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3- ol;2,2,2-trifluoroacetic acid (11): To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (2g, 43.05 mg, 0.370 mmol) in DMF (3 mL) was added NaH (17.94 mg, 0.750 mmol) at 25 oC under argon atmosphere，and the mixture was stirred at 25 oC for 0.5 hour. Then compound 11b (50.0 mg, 0.090 mmol) was added into the mixture which was stirred at 0 oC for 1 hour. The reaction was monitored by LCMS. After the reaction was complete, the mixture was filtered, and the filtrate was purified by prep-HPLC (H2O:CH3CN = 90:10 to 50:50, 0.1% TFA as additive) to give compound 11 (31.4 mg, 0.0464mmol, 49.7% yield) as white solid. LCMS (ESI): m/z calcd for C30H32FN5O3+H: 530.2, found: 530.2.1H NMR (400 MHz, MeOD) δ 9.19 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.25 (q, J = 6.0 Hz, 2H), 5.29 (s, 2H), 4.90 (dd, J = 13.0, 2.7 Hz, 1H), 4.68 (dd, J = 12.9, 6.6 Hz, 1H), 4.20 (s, 1H), 3.91 (s, 1H), 3.74 (s, 1H), 3.29 – 3.20 (m, 1H), 3.09 (s, 3H), 2.52 (d, J = 7.1 Hz, 2H), 2.38 (d, J = 14.4 Hz, 3H), 2.25 – 1.97 (m, 7H). Example 4. Exemplary synthesis of compound 19 [00354] Step 1: tert-butyl N-[[(2S)-1-[7-(3-benzyloxy-1-naphthyl)-2-chloro-8-fluoro- pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2-yl]methyl]carbamate (19a). To a mixture of 7-(3- benzyloxy-1-naphthyl)-2,4-dichloro-8-fluoro-pyrido[4,3-d]pyrimidine (60.0 mg, 0.130 mmol, 1.0 eq) in DCM (3 mL) were added tert-butyl N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (28.0 mg, 0.140 mmol, 1.05 eq) and DIEA (68.9 mg, 0.530 mmol, 4.0 eq) at -60 oC. The mixture was stirred at -60 oC for 0.5 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 30% EA/PE) to afford tert-butyl N-[[(2S)-1-[7-(3- benzyloxy-1-naphthyl)-2-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2- yl]methyl]carbamate (65.0 mg, 0.106 mmol, 79.4% yield) as a white solid. LCMS calculated for C34H34ClFN5O3 (M+H)+ m/z = 614.2; found: 614.4. [00355] Step 2: tert-butyl N-[[(2S)-1-[7-(3-benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2- yl]methyl]carbamate (19b). A mixture of tert-butyl N-[[(2S)-1-[7-(3-benzyloxy-1-naphthyl)-2- chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2-yl]methyl]carbamate (35.0 mg, 0.0600 mmol, 1.0 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (36.3 mg, 0.230 mmol, 4.0 eq) and DIEA (22.1 mg, 0.170 mmol, 3.0 eq) in 1,4-dioxane (1 mL) was stirred at 80 oC for 24h. The mixture was diluted with EA (15 mL), washed with water (3 x 10 mL) and brine (10 mL), dried over Na2SO4, concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% FA) / MeOH at flow rate : 35 mL / min to afford tert- butyl N-[[(2S)-1-[7-(3-benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2- yl]methyl]carbamate (12.0 mg, 0.0163 mmol, 28.6% yield) as an oil. LCMS calculated for C42H47F2N6O4 (M+H)+ m/z = 737.4; found:737.4. [00356] Step 3: tert-butyl N-[[(2S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4- yl]pyrrolidin-2-yl]methyl]carbamate (19c). A mixture of tert-butyl N-[[(2S)-1-[7-(3-benzyloxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]pyrrolidin-2-yl]methyl]carbamate (12.0 mg, 0.0200 mmol, 1.0 eq) and Pd(OH)2/C (10%, 9.36 mg) in THF (0.5 mL) was stirred at room temperature for 6 h under H2. The resulting mixture was filtered, and then the filtrate was concentrated to afford crude product tert-butyl N-[[(2S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3- d]pyrimidin-4-yl]pyrrolidin-2-yl]methyl]carbamate (12.0 mg) as an oil. LCMS calculated for C35H41F2N6O4 (M+H)+ m/z = 647.3; found: 647.2. [00357] Step 4: 4-[4-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (19). To a mixture of tert-butyl N-[[(2S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4- yl]pyrrolidin-2-yl]methyl]carbamate (12.0 mg, 0.0200 mmol, 1.0 eq) in DCM (1.5 mL) was added TFA (0.5 mL) . The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCO3) / MeOH at flow rate : 35 mL / min to afford 4-[4-[(2S)-2- (aminomethyl)pyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (1.22 mg, 0.00220 mmol, 12.0% yield) as a white solid. LCMS calculated for C30H33F2N6O2 (M+H)+ m/z = 547.3; found: 547.2.1H NMR (400 MHz, CD3OD) δ 9.30 (s, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.39 - 7.53 (m, 2 H), 7.20 - 7.30 (m, 3 H), 5.30 (d, J = 54.4 Hz, 1 H), 4.35 (d, J = 10.4 Hz, 1 H), 4.10 - 4.29 (m, 3 H), 3.56 - 3.84 (m, 1 H), 3.22 - 3.27 (m, 2 H), 3.17 - 3.22 (m, 2 H), 2.93 - 3.06 (m, 2 H), 1.81 - 2.39 (m, 11 H). Example 5. Exemplary synthesis of compound 22 [00358] Step 1: tert-butyl N-[(anti-3-[7-(3-benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]carbamate (22b). A mixture of tert-butyl N-[anti-3-[7-(3-benzyloxy- 1-naphthyl)-2-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8- yl]carbamate (200 mg, 0.310 mmol, 1.0 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methanol (74.6 mg, 0.470 mmol, 1.5 eq) and t-BuOK (35.0 mg, 0.310 mmol, 2.2 eq) in 1,4- Dioxane (3 mL) was stirred at room temperature for 10 h under N2. The reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% TFA) / ACN at flow rate : 30 mL / min to afford tert-butyl N-[anti-3-[7-(3- benzyloxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate (150 mg, 0.196 mmol, 62.9 % yield) as a yellow solid. LCMS calculated for C44H49F2N6O4 (M+H)+ m/z =763.4; found:763.6. [00359] Step 2: tert-butyl (anti-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)carbamate (22c). A solution of tert-butyl N-[anti-3-[7-(3-benzyloxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1] octan-8-yl]carbamate (155 mg, 0.203 mmol, 1.0 eq) and Pd(OH)2/C (10%, 100 mg) in THF (3 mL) was stirred at room temperature for 1 h under H2. The resulting mixture was filtered, and then the filtrate was concentrated to afford crude tert-butyl N-[anti-3-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]carbamate (100 mg, 0.149 mmol, 73.2 % yield) as yellow solid. LCMS calculated for C37H43F2N6O4 (M+H)+m/z =673.3; found:673.4. [00360] Step 3: 4-(4-(anti-8--amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (22d). To a mixture of tert-butyl N-[anti-3-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]carbamate (60.0 mg, 0.0892 mmol, 1.0 eq) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCCO3) /ACN at flow rate : 30 mL / min to afford 4-(4-(8-anti-amino-3- azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (27.1 mg, 0.0473 mmol, 51.0% yield) as a yellow solid. LCMS calculated for C32H35F2N6O2 (M+H)+m/z =573.3; found: 573.2; 1H NMR (400 MHz, CD3OD) δ 9.09 (d, J = 4.0 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.21 - 7.26 (m, 2 H), 5.30 (d, J = 53.6 Hz, 1 H), 4.74 (s, 2 H), 4.27 (dd, J = 31.6, 10.4 Hz, 2 H), 3.59 - 3.68 (m, 2 H), 3.26 - 3.29 (s, 2 H), 3.18 - 3.25 (m, 2 H), 2.97 - 3.04 (m, 1 H), 2.19 - 2.37 (m, 4 H), 2.09 - 2.16 (m, 1 H), 1.87 - 2.02 (m, 5 H), 1.52 - 1.62 (m, 2 H). [00361] Step 4: 3-(anti-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-1,1-dimethylurea (22). To a solution of 4-(4-(anti-8-amino-3- azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (15.0 mg, 0.0262 mmol, 1.0 eq) and DIEA (0.01 mL, 0.0786 mmol, 3.0 eq) in DCM (0.5 mL) was added N,N-dimethylcarbamoyl chloride (4.23 mg, 0.0393 mmol, 1.5 eq). The solution was stirred at room temperature for 10 h. The reaction mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCO3) / MeOH at flow rate : 30 mL / min to afford 3-[anti-3-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3- hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-1,1-dimethyl- urea (6.07 mg, 0.00943 mmol, 36.0% yield) as yellow solid. LCMS calculated for C35H40F2N7O3 (M+H)+m/z =644.3; found: 644.2; 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1 H), 9.18 (s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.43 (t, J = 6.8 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.22 - 7.26 (m, 2 H), 5.69 (d, J = 4.0 Hz, 1 H), 5.28 (d, J = 53.6 Hz, 1 H), 4.60 (d, J = 10.4 Hz, 2 H), 4.04 - 4.16 (m, 2 H), 3.82 (d, J = 4.8 Hz, 1 H), 3.63 (d, J = 12.4 Hz, 2 H), 2.96 - 3.10 (m, 3 H), 2.79 - 2.84 (m, 7 H), 2.42 (s, 2 H), 2.13 - 2.18 (m, 1 H), 1.99 - 2.06 (m, 2 H), 1.77 - 1.87 (m, 5 H), 1.41 - 1.46 (m, 2 H). Example 6: Exemplary synthesis of compound 24 [00362] Compound 26 was prepared using procedures analogous to those described for example 5, with (S)-(1-methylpyrrolidin-2-yl)methanol replacing ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol in step 4. LCMS calculated for C33H39FN7O3 (M+H)+ m/z = 600.3; found: 600.2.1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 7.75 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.22 - 7.26 (m, 2 H), 4.77 (d, J = 12.4 Hz, 2 H), 4.45 - 4.55 (m, 2 H), 3.97 (s, 1 H), 3.73 (d, J = 12.8 Hz, 2 H), 3.07 - 3.14 (m, 1 H), 2.91 (s, 6 H), 2.81 - 2.88 (m, 1 H), 2.55 (s, 3 H), 2.50 (s, 2 H), 2.36 - 2.43 (m, 1 H), 2.10 - 2.18 (m, 1 H), 1.90 - 1.96 (m, 2 H), 1.75 - 1.88 (m, 3 H), 1.58 - 1.63 (m, 2 H).
Example 9: Exemplary synthesis of compound 5 [00363] Step 1: To a solution of benzyl 4-oxoazepane-1-carboxylate (250.0 mg, 1.01 mmol) in anhydrous THF (15 mL) was added chloro(methyl)magnesium (0.51mL, 1.52 mmol, 3 mol/L in THF) dropwise. After addition the mixture was stirred at 0 oC to rt. for 16 h under Ar. LCMS showed the reaction worked. The reaction was quenched with sat. ammonium chloride (1 mL) and extracted with EtOAc (3x15 mL). The organic layer was washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude product compound 5b (260 mg,0.98 mmol, 98% yield) as an oil which was used for next step without further purification. LCMS (ESI): m/z calcd for C15H21NO3+H: 264.1, found: 264.2. [00364] Step 2: A solution of benzyl 4-hydroxy-4-methyl-azepane-1-carboxylate (250.mg, 0.9500mmol) in THF (5mL) and Ethanol (5mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (50.0 mg, 20% w/w) at 25 oC for 16 h. LCMS showed the reaction worked. The reaction mixture was filtered and evaporated to give the crude product benzyl 4-hydroxy-4- methyl-azepane-1-carboxylate (122 mg, 100% yield) as an oil which was used for next step without further purification. LCMS (ESI): m/z calcd for C7H15NO +H: 130.1, found: 130.2. [00365] Step 3: A mixture of compound 5c (120.68 mg, 0.93 mmol), DIPEA (0.46mL, 2.8mmol) and compound 1 (415.0 mg, 0.930 mmol) in DMA (20 mL) was stirred at 0 o C for 2 h under Ar. LCMS&TLC (PE:EtOAc = 1:1, Rf = 0.50) showed the reaction worked. The mixture was diluted with EtOAc (150 mL), washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuo. The residue was purified by flash chromatography eluting with 0-60% EtOAc/hexanes as eluent to give compound 5b (300.0 mg , 0.56 mmol, 60 % yield) as a sticky brown solid. LCMS (ESI): m/z calcd for C29H30ClFN4O3+H: 537.1, found: 537.1. [00366] Step 4: To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (51.5 mg, 0.450 mmol) in DMF (3 mL) was added NaH (10.7 mg, 0.450 mmol) at 0 oC under Ar. The mixture was stirred for 30 min, followed by addition of compound 5a (60.0 mg, 0.110 mmol) in DMF (3 mL). The resulted mixture was stirred at 0 oC for 1 h under Ar. LCMS showed the reaction worked. The reaction mixture was quenched by addition of sat. NH4Cl solution, filtered and purified by prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA ) from 5.0% to 95% ) to give 5 (30.0 mg , 0.0391mmol, 35 % yield) as a light yellow solid. LCMS (ESI): m/z calcd for C30H34FN5O3+H: 532.2, found: 532.2.1H NMR (400 MHz, MeOD) δ 9.26 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.31 (s, 1H), 7.25 (q, J = 6.0 Hz, 2H), 4.69 (ddd, J = 12.9, 6.6, 2.7 Hz, 1H), 4.23 (d, J = 13.5 Hz, 2H), 4.14 – 3.97 (m, 2H), 3.91 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 3.27 (s, 1H), 3.09 (s, 3H), 2.41 (d, J = 8.1 Hz, 2H), 2.27 – 1.75 (m, 9H), 1.72 – 1.54 (m, 1H), 1.29 (s, 3H). Example 10: Exemplary synthesis of compound 3 [00367] Compound 3 was prepared using procedures analogous to those described for example 3.1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol. LCMS (ESI): m/z calcd for C29H32FN5O3+H: 518.2; found: 518.3.1H NMR (400 MHz, MeOD) δ 9.22(s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.31 (d, J = 2.4 Hz,1H), 7.26-7.22 (m, 2H), 4.91 (d, J = 2.8Hz, 1H), 4.73-4.68 (m, 1H), 4.22-4.10 (m, 3H), 4.05-3.91 (m, 3H), 3.76- 3.70 (m, 1H), 3.26-3.21 (m, 1H), 3.09 (s, 3H), 2.46-2.36 (m, 1H), 2.26-2.02 (m, 6H), 1.97-1.42 (m, 3H). Example 11: Exemplary synthesis of compound 4 [00368] Compound 4 was prepared using procedures analogous to those described for example 3..1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol. LCMS (ESI): m/z calcd for C31H34FN5O3+H: 544.3; found: 544.4.1H NMR (400 MHz, MeOD) δ 9.24 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m,1H), 7.31 (d, J = 2.0 Hz, 1H), 7.27-7.23 (m, 2H), 4.68 (s, 2H), 4.23-4.12 (m, 3H), 4.06-3.97 (m, 2H), 3.74-3.68 (m, 2H), 3.30-3.26 (m, 2H), 2.36-2.03 (m, 11H), 1.99-1.75 (m, 3H). Example 12: Exemplary synthesis of compound 1 [00369] Compound 1 was prepared using procedures analogous to those described for example 3 starting from tert-butyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate.4-(4- ((1R,3S,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. LCMS (ESI): m/z calcd for C31H34FN5O3+H: 544.3; found: 544.4.1H NMR (400 MHz, MeOD) δ9.21 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.28 – 7.16 (m, 2H), 5.32 (s, 2H), 5.05 – 4.85 (m, 1H), 4.71 (dd, J = 12.9, 6.7 Hz, 1H), 3.89 (d, J = 4.9 Hz, 1H), 3.80 – 3.66 (m, 1H), 3.63 – 3.48 (m, 1H), 3.28 – 3.17 (m, 1H), 3.10 (s, 3H), 2.83 (dt, J = 14.1, 6.9 Hz, 2H), 2.41 (dd, J = 14.8, 7.2 Hz, 1H), 2.32 – 2.16 (m, 2H), 2.14 – 1.99 (m, 5H), 1.95 (dd, J = 14.5, 5.1 Hz, 2H). Example 13: Exemplary synthesis of compound 2 [00370] Compound 2 was prepared using procedures analogous to those described for example 3 starting from tert-butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate).4-(4- ((1R,3R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. LCMS (ESI): m/z calcd for C31H34FN5O3+H: 544.3; found: 544.4.1H NMR (400 MHz, MeOD) δ9.24 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.57 – 7.38 (m, 2H), 7.27 (dt, J = 13.3, 6.4 Hz, 3H), 5.38 (s, 2H), 5.04 – 4.90 (m, 1H), 4.71 (dd, J = 12.9, 6.7 Hz, 1H), 3.90 (d, J = 5.8 Hz, 2H), 3.76 (d, J = 5.5 Hz, 1H), 3.27 – 3.17 (m, 1H), 3.10 (s, 3H), 2.44 – 1.93 (m, 12H). Example 14: Exemplary synthesis of compound 7 [00371] Compound 7 was prepared using procedures analogous to those described for example 3. (S)-4-(8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6- yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (TM-1653,). LCMS (ESI): m/z calcd for C29H31FN6O2+H: 515.2, found: 515.3.1H NMR (400 MHz, MeOD) δ 9.35 (s, 1H), 7.81-7.73 (m, 1H), 7.54-7.38 (m, 2H), 7.34-7.19 (m, 3H), 4.93-4.85 (m, 2H), 4.77-4.66 (m, 1H), 4.40-4.10 (m, 7H), 3.94-3.84 (m, 1H), 3.80-3.69 (m, 1H), 3.30-3.20 (m, 1H), 3.17-3.07 (m, 3H), 2.54-2.33 (m, 3H), 2.30-2.02 (m, 3H). Example 15: Exemplary synthesis of compound 8 [00372] Compound 8was prepared using procedures analogous to those described for example 3. (S)-4-(8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-2- yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (8). LCMS (ESI): m/z calcd for C29H31FN6O2+H: 515.2, found: 515.1.1H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.81-7.73 (m, 1H), 7.54-7.19 (m, 5H), 5.04-4.85 (m, 3H), 4.77-4.40 (m, 3H), 3.93-3.85 (m, 1H), 3.80-3.60 (m, 3H), 3.50-3.39 (m, 2H), 3.30-3.20 (m, 1H), 3.15-3.02 (m, 3H), 2.52-2.30 (m, 3H), 2.28-2.00 (m, 3H). Example 16: Exemplary synthesis of compound 9 [00373] Compound 9 was prepared using procedures analogous to those described for example 3. (S)-4-(4-(1,4-diazepan-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (9). LCMS (ESI): m/z calcd for C28H31FN6O2+H: 503.2, found: 503.3.1H NMR (400 MHz, MeOD) δ 9.26 (s, 1H), 7.81-7.73 (m, 1H), 7.54-7.38 (m, 2H), 7.34-7.18 (m, 3H), 4.95-4.85 (m, 1H), 4.77-4.66 (m, 1H), 4.42-4.25 (m, 4H), 3.94-3.84 (m, 1H), 3.80-3.60 (m, 3H), 3.45-3.35 (m, 2H), 3.30-3.20 (m, 1H), 3.18-3.08 (m, 3H), 2.50-2.30 (m, 3H), 2.28-2.03 (m, 3H). Example 17: Exemplary synthesis of compound 15 [00374] Compound 15 was prepared using procedures analogous to those described for example 3.4-(4-(4-aminoazepan-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (16). LCMS (ESI): m/z calcd for C29H33FN6O2+H: 517.3; found: 517.4.1H NMR (400 MHz, MeOD) δ 9.23 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.8 Hz,1H),7.44 (t, J = 7.2 Hz, 1H), 7.31(s,1H), 7.26-7.22 (m, 2H), 5.13-5.04 (m, 1H), 4.74-4.69 (m, 1H), 4.42(d, J = 14.4 Hz, 1H), 4.32 (d, J = 13.6 Hz, 1H), 4.05 (t, J = 10.8 Hz, 1H), 3.92 (t, J = 12.8 Hz, 2H), 3.78-3.72 (m, 1H), 3.45-3.37 (m, 1H), 3.27-3.20 (m, 1H), 3.10 (s, 3H), 2.42-2.38 (m, 2H), 2.22-2.10 (m, 7H), 1.75-1.66 (m, 1H). Example 18: Exemplary synthesis of compound 14 [00375] Compound 14 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-4-methyl-azepan-4-ol (14). LCMS (ESI): m/z calcd for C32H35F2N5O3+H: 576.2, found: 576.2.1H NMR (400 MHz, MeOD) δ 9.17 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 7.1 Hz, 1H), 7.31 – 7.13 (m, 3H), 5.30 (d, J = 53.3 Hz, 1H), 4.25 (ddd, J = 40.2, 24.2, 12.0 Hz, 4H), 4.09 – 3.89 (m, 2H), 3.29 – 3.06 (m, 3H), 3.06 – 2.93 (m, 1H), 2.48 – 1.73 (m, 11H), 1.71 – 1.52 (m, 1H), 1.27 (s, 3H). Example 19: Synthesis of compound 16 [00376] Compound 16 was prepared using procedures analogous to those described for example 3.4-[4-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-8-fluoro-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (16). LCMS (ESI): m/z calcd for C28H29FN6O2+H: 501.2, found: 501.1.1H NMR (400 MHz, MeOD) δ 9.34 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.53-7.39 (m, 2H), 7.33-7.19 (m, 3H), 4.95-4.84 (m, 1H), 4.75-4.65 (m, 1H), 4.53-4.44 (m, 2H), 4.31-4.22 (m, 2H), 3.94-3.84 (m, 1H), 3.77-3.67 (m, 1H), 3.31-3.21 (m, 1H), 3.09 (s, 3H), 2.58-2.51 (m, 1H), 2.47-2.34 (m, 3H), 2.24-2.02 (m, 3H). Example 20: Synthesis of compound 17 [00377] Compound 17 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (17). LCMS (ESI): m/z calcd for C23H26ClN5O2+H: 547.2; found: 548.4.1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 9.14 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.0 Hz, 1H), 7.34 – 7.18 (m, 3H), 5.28 (d, J = 54.0 Hz, 1H), 4.89 (d, J = 3.9 Hz, 1H), 4.33 – 4.20 (m, 2H), 4.14 (d, J = 10.4 Hz, 1H), 4.05 (d, J = 10.4 Hz, 1H), 3.97 – 3.84 (m, 1H), 3.76 – 3.63 (m, 2H), 3.17 – 3.04 (m, 2H), 3.01 (s, 1H), 2.83 (dd, J = 15.2, 9.0 Hz, 1H), 2.18 – 2.10 (m, 1H), 2.10 – 2.04 (m, 1H), 2.03 – 1.90 (m, 3H), 1.90 – 1.71 (m, 3H), 1.69 – 1.55 (m, 2H). Example 21: Exemplary synthesis of compound 18 [00378] Compound 18 was prepared using procedures analogous to those described for example 3.4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- [3-(hydroxymethyl)pyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (18). LCMS (ESI): m/z calcd for C23H26ClN5O2+H: 547.2; found: 548.4.1H NMR (400 MHz, MeOD) δ 9.32 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.29 – 7.18 (m, 3H), 5.30 (d, J = 54.1 Hz, 1H), 4.33 (dd, J = 10.6, 2.8 Hz, 1H), 4.26 (dd, J = 10.5, 2.5 Hz, 1H), 4.22 – 4.07 (m, 2H), 4.07 – 3.74 (m, 2H), 3.76 – 3.57 (m, 2H), 3.27 – 3.11 (m, 3H), 3.05 – 2.97 (m, 1H), 2.72 – 2.56 (m, 1H), 2.40 – 2.10 (m, 4H), 2.04 – 1.83 (m, 4H). Example 22: Exemplary synthesis of compound 20 [00379] Compound 20 was prepared using procedures analogous to those described for example 3.4-[4-[(3S)-3-aminopyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (20). LCMS (ESI): m/z calcd for C29H30F2N6O2: 533.2, found: 533.3.1H NMR (400 MHz, MeOD) δ 9.37 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.27 – 7.18 (m, 2H), 5.58 (dt, J = 6.3, 3.5 Hz, 1H), 4.75 (d, J = 12.4 Hz, 1H), 4.70 (d, J = 12.4 Hz, 1H), 4.51 – 4.25 (m, 3H), 4.24 – 4.16 (m, 2H), 4.09 – 3.83 (m, 3H), 3.55 – 3.43 (m, 1H), 2.79 – 2.53 (m, 3H), 2.48 – 2.30 (m, 4H), 2.25 – 2.10 (m, 1H). Example 23: Exemplary synthesis of compound 26 [00380] Compound 26 was prepared using procedures analogous to those described for example 3.4-[4-[(3R)-3-aminopyrrolidin-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (26). LCMS (ESI): m/z calcd for C29H30F2N6O2: 533.2, found: 533.11H NMR (400 MHz, MeOD) δ 9.36 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.27 – 7.20 (m, 2H), 5.58 (d, J = 51.9 Hz, 1H), 4.72 (d, J = 2.9 Hz, 2H), 4.35 (d, J = 11.4 Hz, 3H), 4.15 (dd, J = 29.0, 16.0 Hz, 2H), 4.05 – 3.80 (m, 3H), 3.53 – 3.43 (m, 1H), 2.74 – 2.53 (m, 3H), 2.38 (dd, J = 12.0, 6.1 Hz, 4H), 2.20 (s, 1H). Example 24: Exemplary synthesis of compound 27 [00381] Compound 27was prepared using procedures analogous to those described for example 3.4-[4-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol (27). LCMS (ESI): m/z calcd for C30H30F2N6O2: 545.2, found: 545.0.1H NMR (400 MHz, MeOD) δ 9.34 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.52-7.39 (m, 2H), 7.33-7.18 (m, 3H), 5.67-5.46 (m, 1H), 4.76-4.64 (m, 2H), 4.56-4.44 (m, 2H), 4.31-4.22 (m, 2H), 4.17-3.80 (m, 3H), 3.52-3.41 (m, 1H), 2.79-2.50 (m, 3H), 2.49-2.27 (m, 1H), 2.26-2.13 (m, 1H). Example 25: Exemplary synthesis of compound 5 [00382] Compound 5 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4-methyl-azepan-4-ol (5). LCMS (ESI): m/z calcd for C30H34FN5O3: 531.26, found: 532.2.1H NMR (400 MHz, MeOD) δ 9.26 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.31 (s, 1H), 7.25 (q, J = 6.0 Hz, 2H), 4.69 (ddd, J = 12.9, 6.6, 2.7 Hz, 1H), 4.23 (d, J = 13.5 Hz, 2H), 4.14 – 3.97 (m, 2H), 3.91 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 3.27 (s, 1H), 3.09 (s, 3H), 2.41 (d, J = 8.1 Hz, 2H), 2.27 – 1.75 (m, 9H), 1.72 – 1.54 (m, 1H), 1.29 (s, 3H). Example 26: Exemplary synthesis of compound 21 [00383] Compound 21 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]azepan-4-ol (21). LCMS (ESI): m/z calcd for C31H33F2N5O3+H+: 562.3; found: 562.4.1H NMR (400 MHz, MeOD-d4) δ 9.20 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.44-7.40 (m, 1H), 7.28-7.22 (m, 3H),5.31 (d, J = 54.4 Hz, 1H), 4.34-4.31 (m, 1H), 4.27-4.24 (m, 1H), 4.21-3.98 (m, 5H), 3.28-3.13 (m, 3H), 3.05-2.99 (m, 1H), 2.38-2.21 (m, 4H), 2.20-1.86 (m, 7H), 1.80-1.74 (m, 1H). Example 27: Exemplary synthesis of compound 28
[00384] Step 1: To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (500 mg, 1.98 mmol, 1.0 eq) in DCM (8 mL) were added piperidin-4-one;hydrochloride (268 mg, 1.98 mmol, 1.0 eq) and DIEA (1.38 mL, 7.92 mmol, 4.0 eq) at -60 oC. The mixture was stirred at -60 oC for 1 h. The reaction mixture was quenched with aqueous saturated NH4Cl, and extracted with DCM (40 mL × 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 40% to 60% EA/PE) to afford 1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (180 mg, 0.571 mmol, 28.8% yield) as a white solid. LCMS calculated for C12H10Cl2FN4O (M+H)+ m/z =315.0; found: 315.0/317.0. [00385] Step 2: To a mixture of 1-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)piperidin-4-one (180 mg, 0.571 mmol 1.0 eq) in 1,4-dioxane (4 mL) were added [(8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (273 mg, 1.71 mmol, 3.0 eq) and DIEA (295 mg, 2.28 mmol, 4.0 eq). The mixture was stirred at 80 oC for 36 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 6% to 10% MeOH/DCM) to afford 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-one (250 mg, 0.571 mmol, 99.9% yield) as a light yellow oil. LCMS calculated for C20H23ClF2N5O2 (M+H)+m/z =438.2; found: 438.0/440.0. [00386] Step 3: To a mixture of 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-one (250 mg, 0.571 mmol, 1.0 eq) in Methanol (5 mL) was added NaBH4 (64.8 mg, 1.71 mmol, 3.0 eq) at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with ice water, concentrated and purified by flash column chromatography (silica gel, eluting with 7% to 10% MeOH/DCM) to afford 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (175 mg, 0.398 mmol, 69.7% yield) as a white solid. LCMS calculated for C20H25ClF2N5O2 (M+H)+m/z =440.2; found: 440.0/442.0.1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1 H), 5.30 (d, J = 54.0 Hz, 1 H), 4.88 (d, J = 4.0 Hz, 1 H), 4.01 - 4.25 (m, 4 H), 3.80 - 3.91 (m, 1 H), 3.60 - 3.74 (m, 2 H), 3.17 (d, J = 5.2 Hz, 1 H), 3.07 - 3.16 (m, 3 H), 2.80 - 2.89 (m, 1 H), 2.07 - 2.16 (m, 2 H), 1.95 - 2.06 (m, 1 H), 1.76 - 1.94 (m, 5 H), 1.48 - 1.64 (m, 2 H). [00387] Step 4: To a mixture of 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (75.0 mg, 0.171 mmol, 1.0 eq) in 1,4-dioxane/water (2.5 mL/0.5 mL) were added triisopropyl-[2-[8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane (111 mg, 0.260 mmol, 1.5 eq), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27.9 mg, 0.0340 mmol, 0.2 eq) and cesium carbonate (166 mg, 0.512 mmol, 3.0 eq) under N2. The sealed vial was heated for 6 h in a Biotage Initiator Eight Microwave Reactor at a constant temperature of 100oC. The resulting mixture was filtered, and then the filtrate was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% TFA) / MeOH at flow rate : 50 mL / min to afford 1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (51.0 mg, 0.0720 mmol, 42.0% yield) as a yellow oil. LCMS calculated for C41H52F2N5O2Si (M+H)+ m/z = 712.4; found: 712.5. [00388] Step 5: To a mixture of 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]piperidin-4-ol (20.0 mg, 0.0280 mmol, 1.0 eq) in DMF (1.5 mL) was added CsF (21.3 mg, 0.141 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% NH4HCO3) / MeOH at flow rate : 50 mL / min to afford 1-[7-(8- ethynyl-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (6.82 mg, 0.0120 mmol, 42.5% yield) as a light yellow solid. LCMS calculated for C32H32F2N5O2 (M+H)+m/z = 556.2; found: 556.2.1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1 H), 8.04 - 8.11 (m, 2 H), 7.74 (dd, J = 7.2, 1.2 Hz, 1 H), 7.63 - 7.71 (m, 1 H), 7.60 (dd, J = 7.2, 1.2 Hz, 1 H), 7.52 (dd, J = 8.0, 7.2 Hz, 1 H), 5.30 (d, J = 54.0 Hz, 1 H), 4.35 - 4.44 (m, 2 H), 4.22 - 4.33 (m, 2 H), 4.02 - 4.09 (m, 1 H), 3.71 - 3.87 (m, 2 H), 3.30 - 3.35 (m, 1 H), 3.16 - 3.25 (m, 2 H), 3.14 (d, J = 5.6 Hz, 1 H), 2.97 - 3.05 (m, 1 H), 2.17 - 2.40 (m, 2 H), 1.95 - 2.15 (m, 5 H), 1.71 - 1.94 (m, 3 H). Example 28: Exemplary synthesis of compound 29: [00389] Compound 29 was prepared using procedures analogous to those described for example 27 with azepan-4-one replacing piperidin-4-one in step 1. LCMS calculated for C33H34F2N5O2 (M+H)+ m/z = 570.3; found: 570.5.1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1 H), 8.03 - 8.12 (m, 2 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.59 (d, J = 6.8 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 5.30 (d, J = 54.4 Hz, 1 H), 4.27 - 4.34 (m, 1 H), 3.92 - 4.27 (m, 6 H), 3.17 - 3.27 (m, 3 H), 3.15 (d, J = 7.6 Hz, 1 H), 2.96 - 3.06 (m, 1 H), 1.69 - 2.39 (m, 12 H). Example 29: Exemplary synthesis of compound 30 [00390] Step 1: To a stirred solution of KOH (2754.82 mg, 12.13 mmol) in dry methanol (15 mL) at 0 °C under nitrogen was added a solution of benzyl 4-oxoazepane-1-carboxylate (1000.0 mg, 4.04 mmol) in dry methanol (15 mL) dropwise over 10 min. The reaction mixture was stirred at 0 °C for another 10 min, and PhI(AcO)2 (1563.02 mg, 4.85 mmol) was added portionwise over 10 min. The reaction mixture was warmed to room temperature, with stirring overnight. After the starting material disappeared as monitored by TLC, MeOH was removed under reduced pressure and the residue was cooled to 0 °C and 30 ml of 2N HCI was added carefully. The mixture was stirred at room temperature for 2 hours, and then ethyl acetate and water (50 mL, 1: 1) were added. The aqueous layer was separated and was extracted with ethyl acetate (30 mL) three times, the combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated under vacuo to give crude benzyl 3-hydroxy-4-oxo-azepane- 1-carboxylate (1064 mg, 4.041 mmol, 99.9% yield) as a light-yellow oil which was used for next step without further purification. LCMS (ESI): m/z calcd for C14H17NO4+H+: 263.12, found: 264.2. [00391] Step 2: To a solution of benzyl 3-hydroxy-4-oxo-azepane-1-carboxylate (1064.0 mg, 4.04 mmol) in THF (15mL)/ methanol (15mL) was added slowly NaBH4 (152.88 mg, 4.04 mmol) portionwise at 0 °C. The mixture was warmed up to 25 °C and stirred for additional 1.5 h. EtOAc (10 mL) and sat. NH4Cl aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate twice, dried over anhydrous Na2SO4, filtered and concentrated under vacuo to give crude product which was purified by prep-HPLC (eluted with CH3CN in H2O (0.1% TFA) from 5.0% to 95%) to give benzyl 3,4-dihydroxyazepane-1-carboxylate (270 mg, 1.012mmol, 25% yield) as a sticky colorless oil. LCMS (ESI): m/z calcd for C14H19NO4+H+: 265.1, found: 266.1. [00392] Step 3: A solution of benzyl 3,4-dihydroxyazepane-1-carboxylate (450.0 mg, 1.7 mmol) in THF (15 mL)/Ethanol (15 mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (195.06 mg, 0.17 mmol) at 25 oC for 16 h. The reaction mixture was filtered and evaporated to give the crude product azepane-3,4-diol (222 mg,1.69 mmol, 99% yield) as a light-yellow solid which was used for next step without further purification. LCMS (ESI): m/z calcd for C6H13NO2+H+: 131.1, found: 132.4. [00393] Step 4: Compound 30 was prepared using procedures analogous to those described for example 3.To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (41.35 mg, 0.26 mmol) in DMF (2 mL) was added NaH (10.39 mg, 0.26 mmol) at 0 oC under Ar . After 30 min, [4-[2-chloro-4-(3,4-dihydroxyazepan-1-yl)-8-fluoro-pyrido[4,3-d]pyrimidin-7- yl]-2-naphthyl] 2,2-dimethylpropanoate (35.0 mg, 0.06 mmol) in DMF (2 mL) was added. The mixture was stirred at rt. for 3 h under Ar. The mixture was quenched by addition of sat. NH4Cl solution and diluted with EtOAc (50 mL), washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (eluted with CH3CN in H2O (0.1% NH4OH) from 5.0% to 95%) to give 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy- 1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]azepane-3,4-diol (compound 30) (15 mg, 0.025 mmol, 38.5% yield) as a white solid . LCMS (ESI): m/z calcd for C31H33F2N5O4+H+: 578.2, found: 578.1.1H NMR (400 MHz, MeOD) δ 9.29 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.48 – 7.35 (m, 1H), 7.37 – 7.10 (m, 3H), 5.31 (d, J = 53.8 Hz, 2H), 4.31 (ddd, J = 26.5, 10.5, 6.0 Hz, 3H), 4.10 (s, 2H), 4.00 – 3.81 (m, 1H), 3.72 (dd, J = 14.4, 9.4 Hz, 1H), 3.64 – 3.45 (m, 1H), 3.27 – 3.10 (m, 2H), 3.02 (d, J = 5.2 Hz, 1H), 2.44 – 1.73 (m, 9H), 1.62 – 0.74 (m, 4H). Example 30: Exemplary synthesis of compound 31 Synthesis of 4-(hydroxymethyl)azepan-4-ol (compound 31c) [00394] Step 1: The t-BuOK (544.52 mg, 4.85 mmol) was added slowly to a stirred suspension of methyl(triphenyl)phosphonium bromide (1733.45 mg, 4.85 mmol) in anhydrous THF (5 mL) at -78 °C. The mixture was warmed up to -40° C and stirred for additional 45 min. A solution of benzyl 4-oxoazepane-1-carboxylate (1000.0 mg, 4.04 mmol) in anhydrous THF (5 mL) was added via syringe and stirring was continued at -40° C for 2 h. Then, EtOAc (10 mL) and sat. NH4Cl aqueous solution (10 mL) was added. The mixture was extracted with ethyl acetate twice, dried over anhydrous Na2SO4, filtered and concentrated under vacuo to give crude product which was purified by silica gel column chromatography (PE:EtOAc from 20:1 to 10:1) to give benzyl 4-methyleneazepane-1-carboxylate (450 mg, 1.83 mmol, 45% yield) as a light yellow oil . LCMS (ESI): m/z calcd for C14H17NO4+H+: 246.1, found:246.1.1H NMR (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 5.13 (s, 2H), 4.74 (dd, J = 31.4, 4.5 Hz, 2H), 3.47 (dt, J = 11.9, 5.8 Hz, 4H), 2.43 (dt, J = 18.1, 6.0 Hz, 2H), 2.30 – 2.19 (m, 2H), 1.80 – 1.64 (m, 2H). [00395] Step 2: To a solution of benzyl 4-methyleneazepane-1-carboxylate (200.0 mg, 0.82 mmol) in acetone (6 mL) and water (2mL) was added K2OsO4.2H2O (30.04 mg, 0.08 mmol) and NMO (286.52 mg, 2.45 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated, and the residue was partitioned between 20% citric acid and ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated to give benzyl 4-hydroxy-4-(hydroxymethyl)azepane-1-carboxylate (227 mg, 0.81 mmol, 99% yield) which was used for next step without further purification. LCMS (ESI): m/z calcd for C15H21NO4+H+: 280.2, found: 280.1. [00396] Step 3: A solution of benzyl 4-hydroxy-4-(hydroxymethyl)azepane-1-carboxylate (160.0 mg, 0.57 mmol) in THF (10 mL)/ethanol (10 mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (65.87 mg, 0.06 mmol) at 25 oC for 16 h. The reaction mixture was filtered and evaporated to give the crude product 4-(hydroxymethyl)azepan-4-ol (83 mg, 0.57 mmol, 99% yield) as a light yellow solid which was used for next step without further purification. LCMS (ESI): m/z calcd for C7H15NO2+H+: 146.2, found: 146.2. [00397] Step 4: A mixture of 4-(hydroxymethyl)azepan-4-ol (49.02 mg, 0.34 mmol) and DIPEA (0.17 mL, 1.01 mmol) in DCM (3 mL) was added dropwise slowly to a solution of [4- (2,4-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl)-2-naphthyl] 2,2-dimethylpropanoate (150.0 mg, 0.34 mmol) in DCM (15 mL) at 0 oC. The reaction mixture was stirred at 0 oC for 2 h under Ar. The mixture was diluted with DCM (50 mL), washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to give crude product which was purified on SGC (PE:EtOAc form 1:1 to 0:1) to give [4-[2-chloro-8-fluoro-4- [4-hydroxy-4-(hydroxymethyl)azepan-1-yl]pyrido[4,3-d]pyrimidin-7-yl]-2-naphthyl] 2,2- dimethylpropanoate (180 mg, 0.33 mmol, 96% yield) as a sticky colorless oil. LCMS (ESI): m/z calcd for C29H30ClFN4O4+H+: 553.2, found: 553.1. [00398] Step 5: To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (115.15 mg, 0.72 mmol) in DMF (3 mL) was added NaH (28.93 mg, 0.72 mmol) at 0 oC under Ar. After 30 min, [4-[2-chloro-8-fluoro-4-[4-hydroxy-4-(hydroxymethyl)azepan-1- yl]pyrido[4,3-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate (100.0 mg, 0.18 mmol) in DMF (3 mL) was added. The resulted mixture was stirred at 0 oC for 2 h under Ar. The mixture was quenched by addition of sat. NH4Cl solution, and extracted with EtOAc (50 mL), washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1% NH4OH) from 5.0% to 95%) to give 1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3- d]pyrimidin-4-yl]-4-(hydroxymethyl)azepan-4-ol (compound 31) (10 mg, 0.015 mmol, 8.5% yield) as a white solid. LCMS (ESI): m/z calcd for C32H35F2N5O4+H+: 592.2, found: 592.1.1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 7.79 (s, 1H), 7.49 (d, J = 38.8 Hz, 2H), 7.23 (s, 3H), 5.30 (d, J = 55.4 Hz, 1H), 4.05 (m, 7H), 3.08 (m, 8H), 1.92 (m, 12H). Example 31: Exemplary synthesis of compound 32 [00399] Synthesis of 1-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)- 7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-4-(3- hydroxypropyl)piperidin-4-ol [00400] The suspension of LiAlH4 (32.53 mg, 0.04 mmol) in THF (0.5 ml) was dropwise added into the solution of compound 45 (20. mg, 0.03 mmol) in THF (5 mL) at 0 oC. And the mixture was stirred for 0.5 h. Then, water (0.5 ml) and NaOH (15%, 0.5 ml) were added. The mixture was filtered. The filtrate was concentrated, and purified by silica gel chromatography (DCM:MeOH= 10:1) to get compound 32 (8.27 mg, 0.013 mmol, 45% yield) as yellow solid. LCMS (ESI): m/z calcd for C33H37F2N5O4+H+: 606.1, found: 606.1.1H NMR (400 MHz, MeOD) δ 9.13 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.23 (q, J = 5.9 Hz, 2H), 5.51 (d, J = 52.1 Hz, 1H), 4.57 (dt, J = 17.7, 12.5 Hz, 4H), 3.99 – 3.68 (m, 5H), 3.59 (t, J = 6.1 Hz, 2H), 3.45 – 3.33 (m, 1H), 2.70 – 2.02 (m, 6H), 1.83 (d, J = 3.3 Hz, 4H), 1.75 – 1.55 (m, 4H). Example 32: Exemplary synthesis of compound 33 [00401] Compound 33 was prepared using procedures analogous to those described for example 2. 1-[8-fluoro -2-[[(2R,8S) -2-fluoro-1,2,3,5,6,7 –hexahydropyrrolizin -8-yl]methoxy] -7-(1H- indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl]azepan-4-ol. LCMS (ESI): m/z calcd for C28H31F2N7O2+H+: 536.3; found: 536.4.1H NMR (400 MHz, MeOD) δ 9.19(s, 1H), 8.31(s, 1H), 7.70-7.65(m, 2H), 7.54(t, J=8.0 Hz, 1H), 5.31(d, J=54.8 Hz, 1H), 4.59(s, 1H), 4.31-4.20(m, 2H), 4.14-3.92(m, 5H), 3.26-3.15(m, 2H), 3.05-2.98(m, 1H), 2.37-1.86(m, 11H), 1.77-1.69(m, 1H). Example 33: Exemplary synthesis of compound 34: Synthesized from compound 31 [00402] To a solution of 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl] methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-4-(hydroxymethyl)azepan- 4-ol;2,2,2-trifluoroacetic acid (20.0 mg, 0.02mmol) and CDI (19.78 mg, 0.12 mmol) in THF (30 mL) was added DIPEA (0.06 mL, 0.37 mmol) at rt. under Ar. The reaction mixture was stirred for 5 h at 70 oC under Ar. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1% TFA) from 5.0% to 95%) to give 9- [8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxy-1- naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-1,3-dioxa-9-azaspiro[4.6]undecan-2-one;2,2,2- trifluoroacetic acid (compound 34) (17 mg, 0.020 mmol, 80% yield) as a light yellow solid . LCMS (ESI): m/z calcd for C33H33F2N5O5+H+: 617.24, found: 618.1.1H NMR (400 MHz, MeOD) δ 9.33 – 8.87 (m, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.65 – 7.36 (m, 2H), 7.27 (d, J = 25.6 Hz, 2H), 5.57 (d, J = 51.6 Hz, 1H), 4.70 (s, 1H), 4.47 – 4.18 (m, 2H), 4.18 (s, 5H), 3.46 (s, 1H), 3.27 – 3.11 (m, 1H), 2.86 – 1.82 (m, 8H), 1.34 (t, J = 19.0 Hz, 8H). Example 34: Exemplary synthesis of compound 35: [00403] Synthesis of 2-(azepan-4-yl)acetonitrile (compound 35c) [00404] Step 1: The sodium hydride (146.29 mg, 6.1 mmol) was put into the solution of 2- diethoxyphosphorylacetonitrile (0.91 g, 5.16 mmol) in THF (10 ml) at 25 oC. The mixture was stirred for 10 min, then tert-butyl 4-oxoazepane-1-carboxylate (1.0 g, 4.69 mmol) was added and the mixture was stirred at rt for 18 h. The solvent was removed and water (20 ml) was added. The mixture was extracted with EtOAc (20 mLx2), dried over Na2SO4, concentrated and purified by silica gel chromatography (PE: EtOAc from 10:1 to 3:1) to get tert-butyl (4Z)-4- (cyanomethylene)azepane-1-carboxylate (1 g, 4.2 mmol, 90% yield) as colorless oil. LCMS (ESI): m/z calcd for C9H12N2O2+H+ [M-C4H7]: 181.1, found: 181.1. [00405] Step 2: The solution of tert-butyl (4Z)-4-(cyanomethylene)azepane-1-carboxylate (150.0 mg, 0.63 mmol) and Pd (6.76 mg, 0.06 mmol, 10% over carbon) in methanol (5 mL) was stirred at rt under H2 for 18h. The mixture was filtered and the solvent was evaporated to get tert-butyl 4-(cyanomethyl)azepane-1-carboxylate (120 mg, 0.50 mmol, 79% yield) as colorless oil. LCMS (ESI): m/z calcd for C8H14N2+H+ [M-Boc+H]: 139.1, found: 139.1. [00406] Step 3: The solution of tert-butyl 4-(cyanomethyl)azepane-1-carboxylate (120.0 mg, 0.5 mmol) and trifluoroacetic acid (574.09 mg, 5.04 mmol) in DCM (5 mL) was stirred at rt for 1h. The solvent was removed to get 2-(azepan-4-yl)acetonitrile (60 mg, 0.43 mmol, 86% yield) as crude colorless oil. LCMS (ESI): m/z calcd for C8H14N2+H+: 139.1, found: 139.1. [00407] Compound 35 was prepared using procedures analogous to those described for example 3.2-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)acetonitrile (compound 35). LCMS (ESI): m/z calcd for C33H34F2N6O2+H+: 585.1, found: 585.2.1H NMR (400 MHz, MeOD) δ 9.17 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.25 (dd, J = 21.0, 2.1 Hz, 3H), 5.31 (d, J = 53.7 Hz, 1H), 4.45 – 4.19 (m, 4H), 4.10 – 3.81 (m, 2H), 3.28 – 3.12 (m, 2H), 3.08 – 2.97 (m, 1H), 2.48 (d, J = 6.2 Hz, 2H), 2.39 – 1.82 (m, 13H), 1.42 (dd, J = 23.2, 11.8 Hz, 1H). Example 35: Exemplary synthesis of compound 36. [00408] Compound 36 was prepared using procedures analogous to those described for example 3. (3R,5S)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-5-(hydroxymethyl)pyrrolidin- 3-ol (Compound 36). LCMS (ESI)：m/z calcld for C30H31F2N5O4+H+: 564.2, found: 564.4.1H NMR (400 MHz, MeOD) δ 9.19 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.26 (d, J = 18.4 Hz, 3H), 5.42 – 5.20 (m, 1H), 4.63 (dd, J = 3.8, 2.0 Hz, 2H), 4.43 – 4.14 (m, 4H), 4.05 (dd, J = 12.6, 2.0 Hz, 1H), 3.83 (d, J = 8.6 Hz, 1H), 3.21 (dd, J = 3.8, 1.6 Hz, 2H), 3.04 (dd, J = 9.4, 5.6 Hz, 1H), 2.37 – 2.13 (m, 5H), 2.02 – 1.83 (m, 3H). Example 36: Exemplary synthesis of compound 37. [00409] Synthesis of (5S)-5-(hydroxymethyl)-3-methylpyrrolidin-3-ol (compound 37d) [00410] Step 1: The solution of compound 37a (1.0 g, 4.6 mmol), TBSCl (0.76 g, 5.06 mmol) and imidazole (0.34 g, 5.06 mmol) in DCM (30 mL) was stirred at 25 oC for 1 h. The mixture was extracted with DCM and water, dried over Na2SO4, concentrated. The mixture was purified by silica gel chromatography (PE: EtOAc = 4:1) to get compound 37b(1) (920 mg, 2.75 mmol, 60% yield) as colorless oil.1H NMR (400 MHz, MeOD) δ 4.34 (s, 1H), 3.95 – 3.72 (m, 2H), 3.56 (dd, J = 27.3, 9.1 Hz, 1H), 3.41 – 3.26 (m, 2H), 2.21 – 2.06 (m, 1H), 1.96 – 1.80 (m, 1H), 1.41 (d, J = 4.8 Hz, 9H), 0.84 (s, 9H), 0.01 (dd, J = 12.3, 7.8 Hz, 6H). [00411] Step 2: The solution of compound 37b(1) (0.92 g, 2.78 mmol) and Dess-Martin periodinate (2.35 g, 5.55 mmol) in DCM (30 mL) was stirred at 25 oC for 1h. The mixture was extracted with DCM and water, dried over Na2SO4, concentracted. The mixture was purified by silica gel chromatography (PE:EtOAc = 1:1) to get compound 37b (700 mg, 2.12 mmol, 77% yield) as colorless oil.1H NMR (400 MHz, DMSO) δ 4.29 – 4.18 (m, 1H), 3.88 (dd, J = 29.9, 9.5 Hz, 1H), 3.77 (d, J = 18.1 Hz, 1H), 3.52 (ddd, J = 28.5, 19.9, 10.3 Hz, 2H), 2.87 (td, J = 18.8, 9.6 Hz, 1H), 2.26 (d, J = 17.7 Hz, 1H), 1.43 (d, J = 5.2 Hz, 9H), 0.84 (d, J = 13.2 Hz, 9H), -0.01 (t, J = 6.3 Hz, 6H). [00412] Step 3: To a solution of compound 37b (300.0 mg, 0.91 mmol) in THF (10 mL) was added CH3MgCl (1.37 mL, 1.37 mmol, 1 mol/L in THF) at -65 oC. The mixture was stirred at - 65 oC for 3 h. The mixture was quenched with NH4Cl (aq., 3 mL), extracted with EtOAc (30 ml*3), dried over Na2SO4, and concentrated. The mixture was purified by silica gel chromatography (PE: EtOAc = 4:1 to 1:1) to get compound 37c (270 mg, 0.78 mmol, 86% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ 4.77 (s, 1H), 3.78 – 3.59 (m, 3H), 3.19 – 3.00 (m, 2H), 1.85 (t, J = 15.8 Hz, 2H), 1.35 (d, J = 2.9 Hz, 9H), 1.17 (s, 9H), 0.83 (s, 11H), 0.00 (s, 6H). [00413] Step 4: The solution of compound 37c (130.0 mg, 0.38mmol) and trifluoroacetic acid (428.88 mg, 3.76 mmol) in DCM (5 mL) was stirred at 25 oC for 1h. The reaction was monitored by LCMS. The solvent was removed to get compound 37d (50 mg, 0.38 mmol, crude) as colorless oil. LCMS (ESI): m/z calcd for C6H13NO2+H+: 132.1, found: 132.1. [00414] Compound 37 was prepared using procedures analogous to those described for example 3. (5S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7- (3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-5-(hydroxymethyl)-3- methylpyrrolidin-3-ol (compound 37). LCMS (ESI): m/z calcd for C31H33F2N5O4+H+: 578.1, found: 578.1.1H NMR (400 MHz, MeOD) δ 9.25 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 – 7.04 (m, 3H), 5.30 (d, J = 53.1 Hz, 1H), 4.34 (d, J = 10.4 Hz, 1H), 4.31 – 4.14 (m, 3H), 4.07 (d, J = 10.7 Hz, 1H), 3.89 (dd, J = 11.2, 2.7 Hz, 1H), 3.21 (d, J = 21.4 Hz, 3H), 3.01 (d, J = 5.6 Hz, 1H), 2.43 – 1.80 (m, 9H), 1.42 (s, 3H). Example 37: Exemplary synthesis of compound 38. [00415] Compound 38 was prepared using procedures analogous to those described for example 3.. (3S,4R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3,4-diol. LCMS (ESI): m/z calcd for C29H29F2N5O4+H+: 550.2; found: 550.0.1H NMR (400 MHz, MeOD) δ 9.31 (s, 1H), 7.79-7.71 (m, 1H), 7.55-7.36 (m, 2H), 7.32-7.19 (m, 3H), 5.41-5.21 (m, 1H), 4.42-4.23 (m, 5H), 4.15-3.90 (m, 3H), 3.30-3.18 (m, 3H), 3.10-2.96 (m, 1H), 2.44-2.09 (m, 3H), 2.07-1.84 (m, 3H). Example 38: Exemplary synthesis of compound 39: [00416] Compound 39 was prepared using procedures analogous to those described for example 3. Synthesized according to example 1. (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy) -7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 2,5-dihydro-1H-pyrrol-3-yl)boronic acid (compound 39). LCMS (ESI): m/z calcd for C29H28BF2N5O4+H+: 476.1; found: 476.3.1H NMR (400 MHz, DMSO) δ 10.86-10.80 (m, 1H), 10.05-9.99 (m, 1H), 9.57-9.43 (m, 1H), 8.22-8.14 (m, 1H), 7.85-7.79 (m, 1H), 7.56-7.41 (m, 2H), 7.35-7.21 (m, 3H), 6.67 (s, 1H), 5.67-5.47 (m, 1H), 5.11-4.96 (m, 2H), 4.78-4.58 (m, 4H), 3.95-3.73 (m, 3H), 3.38-3.24 (m, 1H), 2.67-2.52 (m, 3H), 2.40-2.02 (m, 5H). Example 39: Exemplary synthesis of compound 40: [00417] Compound 40 was prepared using procedures analogous to those described for example 5. Methyl (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)carbamate (compound 40). LCMS (ESI): m/z calcd for C33H36F2N6O4+H+: 619.3; found: 619.1.1H NMR (400 MHz, MeOD) δ 9.19 (s, 1H), 7.79-7.71 (m, 1H), 7.56-7.48 (m, 1H), 7.47-7.39 (m, 1H), 7.32-7.18 (m, 3H), 5.41-5.22 (m, 1H), 4.38-4.18 (m, 4H), 4.10-3.85 (m, 2H), 3.75-3.59 (m, 4H), 3.38-3.17 (m, 3H), 3.09-2.96 (m, 1H), 2.39-1.82 (m, 11H), 1.66-1.51 (m, 1H). Example 40: Exemplary synthesis of compound 41:
[00418] Compound 41 was prepared using procedures analogous to those described for example 5. Methyl 3-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)-1,1- dimethylurea (compound 41). LCMS (ESI): m/z calcd for C34H39F2N7O3+H+: 632.3; found: 632.1.1H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 7.78-7.71 (m, 1H), 7.56-7.48 (m, 1H), 7.47- 7.39 (m, 1H), 7.32-7.19 (m, 3H), 5.40-5.21 (m, 1H), 4.39-4.19 (m, 4H), 4.09-3.74 (m, 3H), 3.30- 3.13 (m, 3H), 3.08-2.97 (m, 1H), 2.87 (s, 6H), 2.42-1.84 (m, 11H), 1.67-1.52 (m, 1H). Example 41: Exemplary synthesis of compound 42: [00419] Compound 42 was prepared using procedures analogous to those described for example 3.2-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-ol (compound 42). LCMS (ESI): m/z calcd for C31H31F2N5O3+H+: 559.24; found: 560.1.1H NMR (400 MHz, MeOD) δ 9.38 (s, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.28 – 7.21 (m, 3H), 5.37 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.82 – 4.23 (m, 5H), 3.30 – 3.17 (m, 5H), 2.26 – 1.83 (m, 10H). Example 42: Exemplary synthesis of compound 43 [00420] Compound 43 was prepared using procedures analogous to those described for example 3. (3R,4R)-4-amino-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (compound 43). LCMS (ESI): m/z calcd for C29H30F2N6O3+H+: 549.2; found: 549.3.1H NMR (400 MHz, MeOD) δ 9.36(s, 1H), 7.77(d, J=8.0 Hz, 1H), 7.51-7.42(m, 2H), 7.31-7.22(m, 3H), 5.58(d, J=52 Hz, 1H), 4.73-4.63(m, 2H), 4.58-4.51(m, 1H), 4.49-4.46(m, 2H), 4.24-4.01(m, 3H), 3.96-3.84(m, 3H), 3.50-3.42(m, 1H), 2.77-2.59(m, 2H), 2.59-2.39(m, 3H), 2.38-2.03(m, 1H). Example 43: Exemplary synthesis of compound 44 [00421] Compound 44 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-5-(hydroxymethyl)azepan-4-ol (compound 44, synthesized according to procedure A). LCMS (ESI): m/z calcd for C32H35F2N5O4+H+: 592.3, found 592.5.1H NMR (400 MHz, MeOD) δ 9.26 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.34 – 7.11 (m, 3H), 5.57 (d, J = 54.8 Hz, 1H), 4.83 – 4.73 (m, 3H), 4.68 (s, 1H), 4.38 – 4.15 (m, 2H), 4.12 – 3.78 (m, 3H), 3.79 – 3.39 (m, 4H), 2.66 (dd, J = 50.3, 21.0 Hz, 1H), 2.50 – 2.28 (m, 2H), 2.19 (s, 2H), 2.05 – 1.64 (m, 3H). Example 44: Exemplary synthesis of compound 45 [00422] Compound 44 was prepared using procedures analogous to those described for example 3. 8-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]decan-2-one (compound 45). LCMS (ESI): m/z calcd for C33H33F2N5O4+H+: 602.1; found: 602.2.1H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.22 – 7.03 (m, 3H), 5.21 (d, J = 54.1 Hz, 1H), 4.50 (s, 2H), 4.35 (dd, J = 10.9, 6.4 Hz, 2H), 4.20 (dd, J = 27.8, 10.6 Hz, 2H), 3.86 – 3.64 (m, 2H), 3.15 (dd, J = 20.0, 4.0 Hz, 2H), 2.93 (dd, J = 15.1, 9.7 Hz, 1H), 2.61 (t, J = 8.3 Hz, 2H), 2.30 – 1.75 (m, 11H). Example 45: Exemplary synthesis of compound 46 [00423] Compound 46 was prepared using procedures analogous to those described for example 3. 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl]azepan-4-ol;2,2,2-trifluoroacetic acid (compound 46). LCMS (ESI): m/z calcd for C29H33F2N7O2+H+: 550.3; found: 550.2.1H NMR (400 MHz, MeOD) δ 9.30 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 5.58 (d, J = 52.0 Hz, 1H), 4.71 (d, J = 9.6 Hz, 2H), 4.18 (d, J = 15.6 Hz, 3H), 4.04 – 3.88 (m, 4H), 3.47 (s, 1H), 2.77 – 2.41 (m, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.02 (dd, J = 54.8, 15.8 Hz, 3H), 1.96 – 1.68 (m, 3H). Example 46: Exemplary synthesis of compound 47 [00424] Compound 47 was prepared using procedures analogous to those described for example 3. (5R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-5- (hydroxymethyl)pyrrolidin-3-ol (compound 47). LCMS (ESI): m/z calcd for C30H31F2N5O4+H+: 564.2; found: 564.4.1H NMR (400 MHz, MeOD) δ 9.30(s, 1H), 7.75(d, J=8.4 Hz, 1H), 7.51- 7.40(m, 2H), 7.28-7.23(m, 3H), 5.31(d, J=54.0 Hz, 1H), 4.55-4.53(m, 2H), 4.35-4.29(m, 3H), 4.20-4.16(m, 1H), 4.05-4.02(m, 1H), 3.91(d, J=11.2 Hz, 1H), 3.36-3.31(m, 1H), 3.27-3.22 (m, 2H), 3.06-3.00(m, 1H), 2.38-2.13(m, 5H), 2.03-1.90(m, 3H). Example 47: Exemplary synthesis of compound 48 [00425] Compound 48 was prepared using procedures analogous to those described for example 3.1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-2-methyl-piperidin-4-ol (compound 48). LCMS (ESI): m/z calcd for C31H33F2N5O3+H+: 562.3, found 562.4.1H NMR (400 MHz, MeOD) δ 9.04 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.25 (dd, J = 13.7, 5.4 Hz, 3H), 4.31 (ddd, J = 36.4, 25.9, 15.3 Hz, 4H), 3.97 (t, J = 12.1 Hz, 1H), 3.22 (d, J = 19.5 Hz, 3H), 3.03 (s, 1H), 2.27 (dd, J = 33.2, 18.9 Hz, 2H), 2.18 (d, J = 29.0 Hz, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.72 (d, J = 6.9 Hz, 3H), 1.28 (s, 1H). Example 48: Exemplary synthesis of compound 49 [00426] Compound 49 was prepared using procedures analogous to those described for example 3. 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (4-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (compound 49). LCMS (ESI): m/z calcd for C31H33F2N5O3+H+: 562.3; found: 562.1.1H NMR (400 MHz, MeOD) δ 9.09 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.31 – 7.17 (m, 3H), 5.30 (d, J = 54.7 Hz, 1H), 4.75 (d, J = 13.1 Hz, 2H), 4.57 (s, 1H), 4.29 (dd, J = 30.4, 10.5 Hz, 2H), 3.53 – 3.40 (m, 4H), 3.26 – 3.16 (m, 2H), 3.01 (d, J = 5.8 Hz, 1H), 2.23 (ddd, J = 47.6, 33.0, 6.4 Hz, 3H), 1.97 (d, J = 10.8 Hz, 6H), 1.50 (d, J = 10.2 Hz, 2H). Example 49: Exemplary synthesis of compound 50 [00427] Compound 50 was prepared using procedures analogous to those described for example 3. 8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- (3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-1-oxa-8-azaspiro[4.5]decan-3-one (compound 50). LCMS (ESI): m/z calcd for C33H33F2N5O4+H+: 602.3; found: 602.1.1H NMR (400 MHz, MeOD): δ 9.11 (d, J = 10.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.27 – 7.20 (m, 2H), 5.31 (d, J = 53.2 Hz, 1H), 4.58 (s, 2H), 4.44 – 4.35 (m, 2H), 4.33 (s, 1H), 4.27 (d, J = 10.6 Hz, 1H), 4.09 (s, 2H), 3.99 (t, J = 10.0 Hz, 2H), 3.25 (d, J = 15.6 Hz, 3H), 3.04 (d, J = 5.4 Hz, 1H), 2.51 (d, J = 8.8 Hz, 1H), 2.40 – 2.27 (m, 1H), 2.27 – 2.21 (m, 1H), 2.14 (d, J = 8.0 Hz, 1H), 2.05 (d, J = 4.4 Hz, 3H), 2.03 (s, 3H). Example 50: Exemplary synthesis of compound 51 [00428] Compound 51 was prepared using procedures analogous to those described for example 3.3,3-difluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-ol (compound 51). LCMS (ESI): m/z calcd for C30H29F4N5O3+H+: 584.2; found: 584.1.1H NMR (400 MHz, MeOD): δ 9.15 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.27 – 7.19 (m, 2H), 5.31 (d, J = 54.4 Hz, 1H), 4.41 – 4.27 (m, 4H), 4.19 – 4.03 (m, 3H), 3.27 (s, 2H), 3.22 (s, 1H), 3.08 – 2.98 (m, 1H), 2.41 – 2.27 (m, 1H), 2.27 – 2.19 (m, 2H), 2.15 (d, J = 8.4 Hz, 1H), 2.00 (dd, J = 17.0, 6.0 Hz, 3H), 1.96 – 1.84 (m, 1H). Example 51: Exemplary synthesis of compound 52 [00429] Compound 52 was prepared using procedures analogous to those described for example 3. (3R,4R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3,4-diol (compound 52). LCMS (ESI): m/z calcd for C29H29F2N5O4+H+: 550.2, found: 550.0.1H NMR (400 MHz, MeOD) δ 9.40 (s, 1H), 7.81-7.73 (m, 1H), 7.56-7.39 (m, 2H), 7.34-7.19 (m, 3H), 5.66-5.47 (m, 1H), 4.81-4.62 (m, 2H), 4.55-4.11 (m, 4H), 4.09-3.80 (m, 5H), 3.52-3.40 (m, 1H), 2.80-2.51 (m, 2H), 2.49-2.30 (m, 3H), 2.24-2.12 (m, 1H). Example 52: Exemplary synthesis of compound 53
[00430] Compound 53 was prepared using procedures analogous to those described for example 3.1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperidin-4-ol (compound 53). LCMS (ESI): m/z calcd for C32H35F2N5O3+H+: 576.3, found: 576.0.1H NMR (400 MHz, MeOD) δ 9.08 (s, 1H), 7.79-7.72 (m, 1H), 7.56-7.38 (m, 2H), 7.33-7.19 (m, 3H), 5.41-5.21 (m, 1H), 4.63-4.53 (m, 3H), 4.42-4.26 (m, 2H), 4.20-4.01 (m, 2H), 3.30-3.26 (m, 2H), 3.04-2.96 (m, 1H), 2.39-1.78 (m, 10H), 1.63-1.51 (m, 3H), 1.45-1.37 (m, 3H). Example 53: Exemplary synthesis of compound 54 [00431] Compound 54 was prepared using procedures analogous to those described for example 5 from compound 15. N-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)-2- hydroxyacetamide (compound 54). LCMS (ESI): m/z calcd for C33H36F2N6O4+H+: 619.3, found: 619.0.1H NMR (400 MHz, MeOD) δ 9.23-9.15 (m, 1H), 7.79-7.71 (m, 1H), 7.57-7.37 (m, 2H), 7.31-7.18 (m, 3H), 5.40-5.21 (m, 1H), 4.38-4.21 (m, 4H), 4.08-3.91 (m, 5H), 3.30-3.10 (m, 3H), 3.08-2.96 (m, 1H), 2.41-1.82 (m, 11H), 1.74-1.60 (m, 1H). Example 54: Exemplary synthesis of compound 55
[00432] Compound 55 was prepared using procedures analogous to those described for example 3. (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (compound 55). LCMS (ESI): m/z calcd for C30H30BF2N5O4+H+: 574.24; found: 574.1.1H NMR (400 MHz, DMSO) δ 10.91-10.84 (m, 1H), 10.10-9.98 (m, 1H), 9.27 (s, 1H), 7.85-7.77 (m, 1H), 7.58-7.40 (m, 2H), 7.35-7.21 (m, 3H), 6.48 (s, 1H), 5.68-5.48 (m, 1H), 4.70-4.57 (m, 4H), 4.12-4.00 (m, 2H), 3.95-3.70 (m, 4H), 3.37-3.28 (m, 2H), 2.63-2.42 (m, 3H), 2.40-2.00 (m, 5H). Example 55: Exemplary synthesis of compound 56 [00433] Compound 56 was prepared using procedures analogous to those described for example 5 from compound 15. Methyl N-(1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)azepan-4-yl)methanesulfonamide (compound 56). LCMS (ESI): m/z calcd for C32H36F2N6O4S+H+: 639.2; found: 639.0.1H NMR (400 MHz, MeOD) δ 9.29-9.22 (m, 1H), 7.81-7.73 (m, 1H), 7.57-7.38 (m, 2H), 7.34-7.19 (m, 3H), 5.67-5.48 (m, 1H), 4.79-4.63 (m, 2H), 4.35-3.78 (m, 7H), 3.65-3.40 (m, 2H), 2.97 (s, 3H), 2.80-2.55 (m, 2H), 2.47-2.30 (m, 4H), 2.28- 2.00 (m, 5H), 1.77-1.65 (m, 1H). Example 56: Exemplary synthesis of compound 57 [00434] Compound 57 was prepared using procedures analogous to those described for example 5 from compound 15. Methyl (1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)azepan-4-yl)carbamate. LCMS calculated for C33H42FN6O4 (M+H)+ m/z = 605.3; found: 605.5.1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.4, 4.4 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.24 (s, 1 H), 6.88 (s, 1 H), 6.69 (s, 1 H), 5.34 (d, J = 53.2 Hz, 1 H), 4.84 - 4.92 (m, 1 H), 4.17 - 4.47 (m, 4 H), 3.72 - 3.81 (m, 1 H), 3.66 - 3.71 (m, 5 H), 3.19 - 3.55 (m, 5 H), 3.00 - 3.11 (m, 1 H), 2.71 - 2.79 (m, 1 H), 2.62 - 2.66 (m, 1 H), 1.37 - 2.55 (m, 15 H). Example 57: Exemplary synthesis of compound 58 [00435] Compound 58 was prepared using procedures analogous to those described for example 3. Cis-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-3-ol: LCMS calculated for C31H34F2N5O4 (M+H)+ m/z =578.3; found: 578.2.1H NMR (400 MHz, CD3OD) δ 9.29 (d, J = 1.2 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.47 - 7.35 (m, 1 H), 7.15 - 7.31 (m, 3 H), 5.31 (d, J = 54.0 Hz, 1 H), 4.74 - 4.85 (m, 2 H), 4.24 - 4.38 (m, 2 H), 4.15 (s, 1 H), 3.50 - 3.74 (m, 3 H), 3.18 - 3.38 (m, 4 H), 2.99 - 3.07 (m, 1 H), 2.09 - 2.44 (m, 3 H), 1.67 - 2.07 (m, 6 H). Example 58: Exemplary synthesis of compound 59. [00436] Compound 59 was prepared using procedures analogous to those described for example 3. Trans-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-4- (hydroxymethyl)piperidin-3-ol: LCMS calculated for C31H34F2N5O4 (M+H)+ m/z =578.3; found: 578.2.1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.17 - 7.32 (m, 3 H), 5.30 (d, J = 54.0 Hz, 1 H), 4.56 - 4.75 (m, 2 H), 4.30 (dd, J = 28.0, 10.8 Hz, 2 H), 3.82 (dd, J = 10.8, 4.4 Hz, 1 H), 3.62 - 3.79 (m, 2 H), 3.48 (t, J = 12.0 Hz, 1 H), 3.17 - 3.31 (m, 4 H), 2.97 - 3.07 (m, 1 H), 2.08 - 2.40 (m, 3 H), 1.52 - 2.08 (m, 6 H). Example 59: Exemplary synthesis of compound 60. [00437] Compound 60 was prepared using procedures analogous to those described for example 3. (4S,5R)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]azepane-4,5-diol: LCMS calculated for C31H34F2N5O4 (M+H)+ m/z =578.3; found: 578.2.1H NMR (400 MHz, CD3OD) δ 9.22 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.20 - 7.30 (m, 3 H), 5.34 (d, J = 53.6 Hz, 1 H), 4.34 (dd, J = 29.6, 10.8 Hz, 2 H), 4.01 - 4.22 (m, 4 H), 3.93 (d, J = 7.2 Hz, 2 H), 3.32 - 3.50 (m, 3 H), 3.00 - 3.16 (m, 1 H), 2.24 - 2.46 (m, 4 H), 1.93 - 2.24 (m, 6 H). Example 60: Exemplary synthesis of compound 61.
Figure imgf000175_0001
[00438] Compound 61 was prepared using procedures analogous to those described for example 3. (3R,4S)-1-(7-(3-(benzyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidine-3,4-diol: LCMS calculated for C31H34F2N5O4 (M+H)+m/z =578.3; found:578.2.1H NMR (400 MHz, CD3OD) δ 9.30 (d, J = 1.6 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.39 - 7.46 (m, 1 H), 7.20 - 7.31(m, 3 H), 4.24 - 4.47 (m, 4 H), 3.56 - 3.69 (m, 2 H), 3.36 - 3.51 (m, 2 H), 2.99 - 3.09 (m, 1 H), 1.89 - 2.37 (m, 9 H), 1.28 - 1.34 (m, 5 H).
[00439] Example 61: Exemplary synthesis of compound 62. [00440] Step 1. To a solution of 2,3,6,7-tetrahydro-1H-azepine (492 mg, 5.06 mmol, 1.0 eq) in DCM (9 mL) were added 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.28 g, 5.06 mmol, 1.0 eq) and DIEA (1.96 mg, 15.2 mmol, 3 eq) at -70 °C under N2. Then the mixture was stirred at -70 °C for 1h. The resulting mixture was quenched with saturated aqueous NH4Cl (60 mL), and then extracted with EtOAc (60 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 20% to 30% EA/PE) to afford the 2,7-dichloro-8-fluoro-4-(2,3,6,7-tetrahydro -1H- azepin-1-yl)pyrido[4,3-d]pyrimidine (Compound 62a, 1.18 g, 3.77 mmol, 74.4% yield) as a light yellow solid. LCMS calculated for C13H12C12FN4 (M+H)+ m/z = 313.04; found: 313.1/3151. [00441] Step 2. The mixture of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (1.50 g, 9.42 mmol, 2.5 eq), DIEA (1.95 g, 15.1 mmol, 4.0 eq) and 2,7-dichloro-8- fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidine (1.18 g, 3.77 mmol, 1.0 eq) in 1,4-Dioxane (5 mL) was stirred at 80 °C for 24 h. The mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 5% to 7% MeOH/DCM) to afford 7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,3,6,7- tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidine (Compound 62b, 1.43 g, 3.27 mmol, 86.9% yield) as a light yellow solid. LCMS calculated for C21H25ClF2N5O (M+H)+ m/z = 436.17; found: 436.2/438.2. [00442] Step 3. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H - pyrrolizin-7a-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidine (30.0 mg, 0.0688 mmol, 1.0 eq) in 1,4-Dioxane (2 mL)/Water (0.1 mL) were added 2-[7,8-difluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (31.3 mg, 0.0895 mmol, 1.3 eq) , Cs2CO3 (56.1 mg, 0.172 mmol, 2.5 eq), CsF (8.27 mg, 0.138 mmol, 2.0 eq), CataCXium A Pd G3 (7.52 mg, 0.0103 mmol, 0.15 eq), and then flushed with N2 for three times. The system was stirred at 95 °C for 10 h. The mixture was concentrated and purified by Prep- HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% FA) / MeOH at flow rate: 50 mL / min to afford 7-[7,8-difluoro-3-(methoxymethoxy) -1-naphthyl]-8-fluoro-2- [[(2R,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,3,6,7-tetrahydroazepin- 1-yl)pyrido[4,3-d]pyrimidine (Compound 62c, 36.0 mg, 0.0577 mmol, 83.9% yield) as a yellow solid. LCMS calculated for C33H34F4N5O3 (M+H)+ m/z = 624.3; found: 624.3. [00443] Step 4. To a solution of 7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,3,6,7- tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidine (36.0 mg, 0.0577 mmol, 1.0 eq) in EA (4 mL) was added 4M HCl in dioxane (0.433 mL, 1.73 mmol, 30 eq) at 25 °C. The mixture was stirred at 25 °C for 3.5 hours. The mixture was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase : H2O (0.1% FA) / MeOH at flow rate: 45 mL / min to afford 5,6- difluoro-4-[8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (2,3,6,7-tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol as formic acid salt (Compound 62, 22.9 mg, 0.0357 mmol, white solid, 61.9% yield). LCMS calculated for C31H30F4N5O2 (M+H)+ m/z = 580.2; found: 580.3.1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1 H), 7.57 - 7.65 (m, 1 H), 7.36 - 7.44 (m, 1 H), 7.34 (t, J = 2.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 5.79 (s, 2 H), 5.48 (dt, J = 52.0, 6.4 Hz, 1 H), 4.50 - 4.62 (m, 2 H), 4.29 (t, J = 5.2 Hz, 4 H), 3.60 - 3.88 (m, 3 H), 3.32 - 3.40 (m, 1 H), 2.41 - 2.77 (m, 6 H), 2.30 - 2.39 (m, 1 H), 2.20 - 2.27 (m, 2 H), 2.03 - 2.13 (m, 1 H). Example 62: Exemplary synthesis of compound 63. [00444] Compound 63 was prepared using procedures analogous to those described for example 61.7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidine, Compound 63: LCMS calculated for C33H31F3N5O (M+H)+ m/z =570.25; found: 570.2.1H NMR (400 MHz, DMSO- d6) δ 9.12 (s, 1 H), 8.10 - 8.28 (m, 2 H), 7.52 - 7.74 (m, 3 H), 5.74 (s, 2 H), 5.28 (d, J = 54.0 Hz, 1 H), 4.08 - 4.27 (m, 5 H), 3.97 - 4.07 (m, 2 H), 2.98 - 3.14 (m, 3 H), 2.77 - 2.87 (m, 1 H), 2.55 - 2.69 (m, 4 H), 1.95 - 2.17 (m, 3 H), 1.70 - 1.90 (m, 3 H). Example 63: Exemplary synthesis of compound 64. [00445] Compound 64 was prepared using procedures analogous to those described for example 61.5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol, Compound 64: LCMS calculated for C33H31F3N5O2 (M+H)+ m/z =586.24; found: 586.3.1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1 H), 7.85 (dd, J = 9.2, 5.6 Hz, 1 H), 7.32 (dd, J = 16.0, 5.6 Hz, 2 H), 7.21 (d, J = 2.4 Hz, 1 H), 5.79 (t, J = 2.8 Hz, 2 H), 5.30 (d, J = 54.0 Hz, 1 H), 4.18 - 4.36 (m, 6 H), 3.38 (dd, J = 6.0, 0.8 Hz, 1 H), 3.16 - 3.26 (m, 3 H), 2.96 - 3.05 (m, 1 H), 2.65 - 2.78 (m, 4 H), 2.09 - 2.39 (m, 3 H), 1.83 - 2.05 (m, 3 H). Example 64: Exemplary synthesis of compound 65 [00446] Compound 65 was prepared using procedures analogous to those described for example 61. 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,3,4,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (compound 65): LCMS calculated for C33H31F3N5O2 (M+H)+ m/z =586.24; found: 586.2. 1H NMR (400 MHz, CD3OD) δ 9.01 (s, 1 H), 7.84 (dd, J = 9.2, 5.6 Hz, 1 H), 7.33 (d, J = 2.8 Hz, 1 H), 7.29 (dd, J = 9.2 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 5.94 - 6.05 (m, 2 H), 5.30 (d, J = 54.4 Hz, 1 H), 4.51 (s, 2 H), 4.22 - 4.33 (m, 3 H), 4.10 - 4.15 (m, 1 H), 3.39 (dd, J = 6.4, 0.4 Hz, 1 H), 3.17 - 3.29 (m, 3 H), 2.97 - 3.03 (m, 1 H), 2.19 - 2.36 (m, 6 H), 2.10 - 2.15 (m, 1 H), 1.94 - 2.01 (m, 2 H), 1.86 - 1.90 (m, 1 H).
Example 65: Exemplary synthesis of compound 66.
Figure imgf000180_0001
[00447] Step 1. Synthesis of tert-butyl 3-fluoro-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 3,3-difluoropiperidine-1-carboxylate (compound 66a and 67a) [00448] To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (400.0 mg, 2.01 mmol) in THF (10 mL) was added DAST (970.72 mg, 6.02 mmol) at 0 oC. The mixture was stirred at 60 oC for 6 h, then allowed to cool to r.t. overnight. The reaction mixture was poured into ice water (10 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford yellow crude product (450 mg) which was used without purification. [00449] Step 2. Synthesis of 5-fluoro-1,2,3,6-tetrahydropyridine and 3,3-difluoropiperidine (compound 66b and 67b). To a solution of tert-butyl 5-fluoro-3,6-dihydro-2H-pyridine-1- carboxylate (200.0 mg, 0.99 mmol) in DCM (10 mL) was added TFA (3.0 mL, 0.41mmol) at r.t. The reaction mixture was then stirred at 25 oC for 30 min. The mixture was concentrated to afford a crude product as brown oil. [00450] 1.3 Synthesis of 2,7-dichloro-8-fluoro-4-(3-fluoro-5,6-dihydropyridin-1(2H)- yl)pyrido[4,3-d] pyrimidine and 2,7-dichloro-4-(3,3-difluoropiperidin-1-yl)-8-fluoropyrido[4,3- d]pyrimidine (compound 66b and 67b respectively). [00451] Step 3. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (600.0 mg, 2.38 mmol) and 5-fluoro-1,2,3,6-tetrahydropyridine (120.16 mg, 1.19 mmol; mixture with 3,3- difluoropiperidine) in DCM (20 mL) was added DIPEA (1.18 mL, 7.13 mmol) at 0 oC. The reaction mixture was stirred at 0 oC to 25 oC for 2 h under Ar. The mixture was concentrated and purified on flash chromatography column (H2O:CH3CN = 70:30) to obtain a mixture of 2,7- dichloro-8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)pyrido[4,3-d]pyrimidine (compound 66c) and 2,7-dichloro-4-(3,3-difluoro-1-piperidyl)-8-fluoro-pyrido[4,3-d]pyrimidine (compound 67c) (total 440 mg, 56% yield) as yellow solid. LCMS (ESI)：m/z calcd for C12H8Cl2F2N4+H: 317.0; found: 317.0; LCMS (ESI)：m/z calcd for C12H9Cl2F3N4+H: 337.0; found: 337.0. [00452] Step 4. The compound [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (502 mg, 3.15 mmol, mixture with 2,7-dichloro-4-(3,3-difluoropiperidin-1-yl)-8- fluoropyrido[4,3-d]pyrimidine) was mixed with 2,7-dichloro-8-fluoro-4-(5-fluoro-3,6-dihydro- 2H-pyridin-1-yl)pyrido[4,3-d]- pyrimidine (200.0 mg, 0.63 mmol) at rt. The mixture was stirred at 85 oC for 4 h. The mixture was cooled and purified on flash chromatography column (H2O:CH3CN = 10:90 to 50:50) to afford a mixture of 7-chloro-8-fluoro-4-(5-fluoro-3,6-dihydro- 2H-pyridin-1-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidine (compound 66d) and 7-chloro-4-(3,3- difluoro-1-piperidyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidine (compound 67d) (total 420 mg,75% yield) as yellow solid. LCMS (ESI)：m/z calcd for C20H21ClF3N5O+H: 440.1; found: 440.0. LCMS (ESI)：m/z calcd for C20H22ClF4N5O+H: 460.1; found: 460.0. [00453] Step 5. To a solution of 7-chloro-8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine (360 mg, 0.41 mmol; 50% w.t. mixture with 7-chloro-4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine) in 1,4-Dioxane (15 mL) and Water (3 mL) were added K3PO4 (521.19 mg, 2.46 mmol) and [2-(2- aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane;methanesulfonate (29.8 mg, 0.04 mmol) at rt under nitrogen. The mixture was stirred at 100 oC for 4 h. The mixture was quenched with water (50 mL), extracted with EtOAc (50 mL×3), washed with brine (50 mL), dried over Na2SO4, concentrated. The crude was purified on flash chromatography column (H2O:CH3CN = 50:50) to obtain 2-[2-fluoro-8-[8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1- yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (compound 66e, 120mg, 0.1519 mmol, 37% yield) and 2-[8-[4-(3,3-difluoro-1-piperidyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (compound 67e, 150 mg, 0.1852 mmol, 45% yield) as yellow solid. LCMS (ESI)：m/z calcd for C43H51F4N5O3Si+H: 790.4; found: 790.1. LCMS (ESI)：m/z calcd for C43H52F5N5O3Si+H: 810.4; found: 810.0. [00454] Step 6. To a solution of 2-[2-fluoro-8-[8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1- yl)-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (120.0 mg, 0.15 mmol) in DCM (4 mL) was added 4M HCl in dioxane (2.0 mL, 0.39 mmol) at r.t. The reaction mixture was then stirred at 25 oC for 30 min. The mixture was concentrated to afford a crude product. LCMS (ESI)：m/z calcd for C41H47F4N5O2Si+H: 746.3; found: 746.1. [00455] Step 7. To a solution of 6-fluoro-4-[8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)- 2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7- yl]-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (110.0 mg, 0.15 mmol) in DMF (5 mL) was added CsF (88.56 mg, 1.47 mmol) at rt. The mixture was stirred at 60 oC for 4 h. The mixture was filtered and purified by prep-HPLC (H2O:CH3CN from 90:10 to 5:95, 0.1% NH4HCO3) to obtain 5-ethynyl-6-fluoro-4-[8-fluoro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (compound 66, 19.76 mg, 0.0333 mmol, 23% yield) as a brown solid. LCMS (ESI)：m/z calcd for C32H27F4N5O2+H: 590.2; found: 590.0. 1H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 7.92 – 7.83 (m, 2H), 7.40 – 7.22 (m, 3H), 5.65 – 5.55 (m, 1H), 5.42 – 5.23 (m, 1H), 4.58 – 4.52 (m, 2H), 4.40 – 4.00 (m, 4H), 3.48 – 3.38 (m, 1H), 3.30 – 3.20 (m, 2H), 3.10 – 3.00 (m, 1H), 2.56 – 1.88 (m, 9H). Example 66: Exemplary synthesis of compound 67. [00456] Step 8. To a solution of 2-[8-[4-(3,3-difluoro-1-piperidyl)-8-fluoro-2-[[(2R,8S)-2- fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (compound 66130.0 mg, 0.16 mmol) in DCM (4 mL) was added 4M HCl in dioxane (2.0 mL, 0.41 mmol) at r.t. The reaction mixture was then stirred at 25oC for 30 min. The mixture was concentrated to afford a crude product. LCMS (ESI)：m/z calcd for C41H48F5N5O2Si+H: 766.4; found: 766.1. [00457] Step 9. To a solution of 4-[4-(3,3-difluoro-1-piperidyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (130.0 mg, 0.17 mmol) in DMF (5 mL) was added CsF (101.92 mg, 1.7 mmol) at rt. The mixture was stirred at 60 oC for 4 h. The mixture was filtered and purified by prep-HPLC (H2O:CH3CN from 90:10 to 5:95, 0.1% NH4HCO3) to obtain 4-[4- (3,3-difluoro-1-piperidyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (compound 67, 28.17 mg, 0.0457 mmol, 27% yield) as a brown solid. LCMS (ESI)：m/z calcd for C32H28F5N5O2+H: 610.2; found: 610.0.1H NMR (400 MHz, MeOD) δ 9.05 (m, 1H), 7.93 – 7.84 (m, 1H), 7.43 – 7.21 (m, 3H), 5.42 – 5.22 (m, 1H), 4.41 – 3.94 (m, 6H), 3.30 – 3.18 (m, 3H), 3.10 – 2.98 (m, 1H), 2.42 – 1.84 (m, 10H). Example 67: Exemplary synthesis of compound 68.
Figure imgf000183_0001
[00458] Compound 68 was prepared using procedures analogous to those described for example 61.4-[4-(3,6-Dihydro-2H-pyridin-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen- 2-ol;2,2,2-trifluoroacetic acid (compound 68, 104.1 mg, 0.1250 mmol, 65 % yield) as yellow solid. LCMS (ESI)：m/z calcld for C36H30F9N5O6+H: 572.3, found: 572.3.1H NMR (400 MHz, MeOD) δ 9.11 (s, 1H), 7.88 (dd, J = 9.0, 5.8 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 5.86 (s, 1H), 5.56 (d, J = 50.2 Hz, 1H), 4.77 – 4.58 (m, 4H), 4.31 – 4.11 (m, 2H), 4.08 – 3.85 (m, 3H), 3.50 – 3.44 (m, 1H), 3.40 (d, J = 3.2 Hz, 1H), 2.72 – 2.33 (m, 7H), 2.20 – 2.12 (m, 1H). Example 68: Exemplary synthesis of compound 72. [00459] Synthesis of 7,7-difluoro-3-azabicyclo[4.1.0]heptane compound 72a [00460] Step 1. To a solution of benzyl 3,6-dihydro-2H-pyridine-1-carboxylate (1000.0 mg, 4.6 mmol) and NaI (689.9 mg, 4.6 mmol) in THF (40 mL) was added trimethyl(trifluoromethyl)silane (6544.69 mg, 46.03 mmol) at RT. The mixture was stirred at 60 oC for 24 h. The reaction was monitored by TLC (PE:EA = 20:1). The solution was concentrated. The residue was purified by silica gel column eluting with PE:EA = 20:1. The benzyl 7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate (430 mg, 1.61 mmol, 34.9% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.25–7.34 (m, 5H), 5.13 (s, 2H), 3.90–3.60 (m, 2H), 3.45-3.33 (m, 1H), 3.31–3.21 (m, 1H), 2.03-1.64 (m, 4H). [00461] Step 2. A mixture of benzyl 7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate (340.0 mg, 1.27 mmol) in TFA (1 mL) was stirred at 60 oC for 1 h. The solution was concentrated to afford 7,7-difluoro-3-azabicyclo[4.1.0]heptane 72a (170 mg, 1.27 mmol, crude, TFA salt) as yellow oil. LCMS (ESI): m/z calcd for C6H9F2N+H:134.1, found: 134.0. [00462] Compound 72 was prepared using procedures analogous to those described for example 3 using example 72c.4-[4-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]- 5-ethynyl-6-fluoro-naphthalen-2-ol. LCMS m/z calcd for C33H28F5N5O2+H: 622.6, found: 622.2. 1H NMR (400 MHz, MeOD): δ 9.04-9.01 (m, 1H), 7.90-7.86 (m, 1H), 7.38-7.32 (m, 2H),7.26- 7.24 (m, 1H), 5.32 (d,J=54, 1H), 4.50-4.47(m, 0.5H) , 4.44-4.23 (m, 3H), 4.17-4.05 (m, 1.5 H), 3.79-3.59 (m, 1H), 3.42-3.41(m, 0.5 H), 3.35 (s, 0.5 H), 3,27 – 3.21 (m, 3 H), 3.18 – 3.01 (m, 1H),2.39-1.87(m, 10 H). Example 69: Exemplary synthesis of compound 80. [00463] Synthesis of 4-fluoro-1,2,3,6-tetrahydropyridine compound 80c. [00464] Step 1. To a solution of Et3N.3HF (428.82 mg, 2.66 mmol) in DMA (2 mL) were successively added Et3N (0.19 mL, 1.33 mmol), XtalFluor-E (913.69 mg, 3.99 mmol) and the ketone benzyl 4-oxopiperidine-1-carboxylate (310.24 mg, 1.33mmol). After stirring at room temperature for 16 hours under inert atmosphere, the reaction mixture was quenched with an aqueous saturated solution of NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered through a pad of silica gel. Solvents were evaporated under vacuo to give crude product benzyl 4-fluoro-3,6-dihydro-2H-pyridine-1-carboxylate 2 (300 mg, 1.2752 mmol, 95% yield) as a brown oil which was used for next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.48 – 7.29 (m, 5H), 5.29 – 5.07 (m, 3H), 4.00 (bs, 1H), 3.80 (t, J = 6.2 Hz, 1H), 3.64 (dd, J = 18.1, 12.3 Hz, 2H), 2.39 (d, J = 56.9 Hz, 2H). [00465] Step 2. A solution of benzyl 4-fluoro-3,6-dihydro-2H-pyridine-1-carboxylate (260.0 mg, 1.11 mmol) in trifluoroacetic acid (5.0 mL, 18.35 mmol) was stirred at 80 oC for 5 h. The solvent was removed under vacuo to get crude 4-fluoro-1,2,3,6-tetrahydropyridine;2,2,2- trifluoroacetic acid 80a (237 mg, 1.1016 mmol, 99.67% yield) as a brown oil which was used without further purification.1H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 9.06 (s, 1H), 5.50 – 5.17 (m, 1H), 3.76 (s, 1H), 3.63 – 3.29 (m, 2H), 3.20 – 2.13 (m, 3H). [00466] Compound 80 was prepared using procedures analogous to those described for example 3 using example 80a.5-ethynyl-6-fluoro-4-[8-fluoro-4-(4-fluoro-3,6-dihydro-2H- pyridin-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol. LCMS (ESI)：m/z calcld for C32H27F4N5O2+H:590.22, found: 590.0.1H NMR (400 MHz, MeOD) δ 9.04 (s, 1H), 7.88 (dd, J = 9.0, 5.8 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 5.36 (t, J = 33.2 Hz, 2H), 4.58 (d, J = 2.3 Hz, 2H), 4.33 (ddd, J = 26.9, 10.6, 3.7 Hz, 3H), 4.18 (dd, J = 12.4, 5.6 Hz, 1H), 3.43 (d, J = 4.2 Hz, 1H), 3.31 – 3.18 (m, 3H), 3.11 – 3.00 (m, 1H), 2.68 (s, 2H), 2.32 (ddd, J = 23.7, 15.2, 7.6 Hz, 2H), 2.15 (d, J = 8.9 Hz, 1H), 2.09 – 1.98 (m, 2H), 1.93 (dd, J = 13.2, 6.4 Hz, 1H). Example 70: Exemplary synthesis of compound 87. [00467] Synthesis of 2-(5-fluoro-1,2,3,6-tetrahydropyridin-3-yl)acetonitrile 87a: [00468] Step 1: The mixture of 2-(5-fluoro-3-pyridyl)acetonitrile (200.0 mg, 1.469 mmol, 1.0 eq) and bromomethylbenzene (753.82 mg, 4.408 mmol, 3.0 eq) in Acetone (2 mL) was stirred at 60 ℃ overnight under N2. Then the mixture was cooled to room temperature and the solid was collected by filtration and washed with acetone/n-hexane (4/1) for three times, dried in vacvuo to afford 2-(1-benzyl-5-fluoro-pyridin-1-ium-3-yl)acetonitrile;bromide (440.0 mg, 1.433 mmol, 97.5% yield) as a pink solid. LCMS calculated for C14H12FN2 (M+H)+ m/z =227.1; found: 227.0. [00469] Step 2: To the solution of 2-(1-benzyl-5-fluoro-pyridin-1-ium-3- yl)acetonitrile;bromide (520.0 mg, 1.693 mmol, 1.0 eq) in Methanol (8 mL) / DCM (8 mL) was added CERIUM(III) CHLORIDE HEPTAHYDRATE (630.75 mg, 1.693 mmol, 1.0 eq) followed by NaBH4 (1286.63 mg, 33.859 mmol, 20.0 eq) at 0 ℃. A distinct bright color was observed upon addition. The reaction mixture was stirred for 20 min, and HOAc (8.0 mL, 1.693 mmol, 1.0 eq) was then added cautiously drop wise. A disappearance in color signified the completion of the reaction. [00470] Then NaOH (1 M, 150 mL) was added to the reaction mixture and it was extracted by EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by FC (silica gel, Eluant with EtOAc in PE 0 to 100%) to afford 2-(1- benzyl-5-fluoro-3,6-dihydro-2H-pyridin-3-yl)acetonitrile (150.0 mg, 0.651 mmol, 38.5% yield) as a yellow oil. LCMS calculated for C14H16FN2 (M+H)+ m/z =231.1; found: 231.1.1H NMR (400 MHz, CDCl3) δ 7.27 - 7.38 (m, 5H), 5.29 (dd, J = 14.4, 4.0 Hz, 1H), 3.61 - 3.71 (m, 2H), 3.13 (d, J = 16.0 Hz, 1H), 2.97 (d, J = 15.6 Hz, 1H), 2.58 - 2.75 (m, 2H), 2.51 - 2.56 (m, 1H), 2.47 (t, J = 5.2 Hz, 2H). [00471] Step 3: To a solution of 2-(1-benzyl-5-fluoro-3,6-dihydro-2H-pyridin-3- yl)acetonitrile (20.0 mg, 0.087 mmol) in DCE (1.5 mL) was added 1-chloroethyl carbonochloridate (37.25 mg, 0.261 mmol) and the reaction was stirred at 100 ℃ for 6 h. Then the mixture was concentrated. The residue was dissolved in Methanol (1.5 mL) and stirred at 70 ℃ for 1 h. The mixture was purified by reverse phase FC (C18, Eluant with MeOH in H2O (0.1% NH4HCO3) 10 to 50%) to afford 2-(5-fluoro-1,2,3,6-tetrahydropyridin-3-yl)acetonitrile (8.0 mg,0.057 mmol, 65.8% yield) as a white solid. LCMS calculated for C7H10FN2 (M+H)+ m/z =141.1; found: 141.2. [00472] Compound 87 was prepared using procedures analogous to those described for example 61 using 87a. 5-Ethyl-6-fluoro-4-(8-fluoro-4-(3-fluoropiperidin-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol. LCMS calculated for C34H29F4N6O2 (M+H)+ m/z =629.2; found: 629.0.1H NMR (400 MHz, MeOD) δ 9.08 (s, 1H), 7.86 (dd, J = 8.8, 5.6 Hz, 1H), 7.27 - 7.39 (m, 2H), 7.22 (dd, J = 4.4, 2.8 Hz, 1H), 5.54 - 5.67 (m, 1H), 5.31 (d, J = 54.0 Hz, 1H), 4.57 - 4.85 (m, 4H), 4.25 - 4.49 (m, 3H), 4.05 - 4.20 (m, 1H), 3.38 - 3.44 (m, 1H), 3.19 - 3.25 (m, 2H), 3.00 - 3.06 (m, 1H), 2.70 - 2.79 (m, 2H), 2.13 - 2.42 (m, 3H), 1.87 - 2.04 (m, 3H). Example 71: Exemplary synthesis of compound 96. [00473] Synthesis of ((4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol 96a: [00474] Step 1: To a solution of O1-tert-butyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (10.0 g, 40.8 mmol, 1.0 eq) in DMF (100 mL) was added NaH (1.96 g, 48.9 mmol, 1.2 eq)^at 0 °C under N2. Then the mixture was stirred at^20 oC for 30 min, and iodomethane (17.4 g, 122 mmol, 3.0 eq) was added at 0 °C. The resulting mixture was stirred at^20 oC^for 3h. The reaction mixture was quenched with saturated aqueous NH4Cl^(100 mL), and then extracted with EtOAc (80 mL × 3). The organic layer was washed with water (80 mL × 3) and brine (80 mL), dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 30% to 60% EtOAc/PE) to afford^1-(tert-butyl) 2-methyl (4R)-4- methoxypyrrolidine-1,2-dicarboxylate (10.5 g, 40.5 mmol, 99.3% yield) as a brown liquid. LCMS calculated for C12H22NO5Na (M+Na)+ m/z =282.15; found: 282.21. [00475] Step 2: To a solution of 1-(tert-butyl) 2-methyl (4R)-4-methoxypyrrolidine-1,2- dicarboxylate (10.5 g, 40.5 mmol, 1.0 eq) in THF (80 mL) was added LAH (121 mL, 121 mmol, 1M in THF, 3.0 eq)^dropwise at 0 °C under N2. Then the mixture was stirred at 80 oC for 3h.^The reaction mixture was quenched with Na2SO4-10H2O, filtered. The filtrate was concentrated^to afford^((4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol (5.40 g, 37.2 mmol, 91.8% yield) as a yellow oil. LCMS calculated for C7H16NO2 (M+H)+ m/z =146.12; found: 146.1.^ [00476] Compound 96 was prepared using procedures analogous to those described for example 2 using 96a. 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4R)-4-methoxy-1-methylpyrrolidin-2- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. LCMS calculated for C32H32F2N5O3 (M+H)+ m/z =572.25; found: 572.2.^ 1H NMR (400 MHz, MeOD) δ 9.09 (s, 1H), 7.85 (dd, J = 9.2, 5.6 Hz, 1H), 7.28 - 7.37 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 5.79 (t, J = 2.8 Hz, 2H), 4.43 - 4.59 (m, 2H), 4.19 - 4.34 (m, 4H), 3.86 - 4.02 (m, 2H), 3.38 - 3.44 (m, 1H), 3.29 (s, 3H), 3.20 (d, J = 10.8 Hz, 1H), 2.79 - 3.05 (m, 2H), 2.70 (s, 3H), 2.50 (d, J = 9.2 Hz, 3H), 2.37 - 2.42 (m, 1H), 1.73 - 2.15 (m, 2H). Example 72: Exemplary synthesis of compound 99. [00477] Synthesis of 4-fluoro-2,3,6,7-tetrahydro-1H-azepine 99a [00478] Step 1: To a solution of 4-methylbenzenesulfonamide (5000.0 mg, 29.2mmol) and 4- bromobut-1-ene (5.93 mL, 58.4 mmol) in DMF (50 mL) was added K2CO3 (2.01 g, 146.01 mmol) at r.t. The mixture was stirred at 100 oC for 18 h under argon. The mixture was diluted with EtOAc (400 mL), washed with H2O (2 × 100 mL) and brine (100 mL), dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (PE: EA=10:1 to 3:1). The product of N,N-bis(but-3-enyl)-4-methyl-benzenesulfonamide (3620 mg, 12.956 mmol, 44% yield) was obtained as yellow oil. LCMS (ESI): m/z calcd for C15H21NO2S+H: 280.1, found 280.2. [00479] Step 2: To solution of N,N-bis(but-3-enyl)-4-methyl-benzenesulfonamide (2100.0 mg, 7.52 mmol) in DCM (20 mL) was added Et3N.3HF (4.9 mL, 30.06 mmol). The mixture was cooled down to 0 oC and protected from the light. Then NBS (2006.57 mg, 11.27 mmol) was added into the mixture at 0 oC under argon atmosphere. The mixture was warmed up to r.t., and stirred at r.t. for 16 h. The mixture was concentrated to afford a crude product. The crude product was purified by silica gel chromatography (PE:EA = 15:1, UV) to afford N-(4-bromo-3- fluoro-butyl)-N-but-3-enyl-4- methyl-benzenesulfonamide (800 mg, 2.11 mmol, 28% yield ) as a colorless oil. LCMS (ESI)：m/z calcld for C15H21Br2F2NO2S+H: 378.0, found: 380.1. [00480] Step 3: To solution of N-(4-bromo-3-fluoro-butyl)-N-but-3-enyl-4-methyl- benzenesulfonamide (800.0 mg, 2.11mmol) in PhMe (10 mL) was added a solution of t-BuOK (711.94mg, 6.34mmol) in THF (4 mL). The mixture was stirred at 100 oC for 16 h. The mixture was filtered over celite and concentrated. The crude product of N-but-3-enyl-N-(3-fluorobut-3- enyl)-4-methyl- benzenesulfonamide (650 mg, crude) was obtained as a yellow oil. LCMS (ESI) ：m/z calcld for C15H20FNO2S+H: 298.13, found: 298. [00481] Step 4: To solution of N-but-3-enyl-N-(3-fluorobut-3-enyl)-4-methyl- benzenesulfonamide (200.0 mg, 0.67 mmol) in DCE (300 mL) was added Zhan-catalyst-1B (30.0 mg, 0.04 mmol). The mixture was stirred at 90 oC for 16 h under argon atmosphere. The mixture was concentrated to afford a crude product. The crude product was purified by prep- TLC (PE:EA = 5:1, UV). The product of 4-fluoro-1-(p-tolylsulfonyl)-2,3,6,7-tetrahydroazepine (60 mg, 0.2228 mmol, 33% yield) was obtained as a yellow oil. LCMS (ESI)：m/z calcld for C13H16FNO2S+H: 270.10, found: 270.0.1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 5.29 (dt, J = 12.2, 5.9 Hz, 1H), 3.44 – 3.08 (m, 4H), 2.49 (s, 2H), 2.36 (s, 3H), 2.16 (s, 2H). [00482] Step 5: The mixture of Mg (89.11 mg, 3.71 mmol) and 4-fluoro-1-(p-tolylsulfonyl)- 2,3,6,7-tetrahydroazepine (100.0 mg, 0.37mmol) in methanol (3 mL) was sonicated at r.t. for 1.5 h until the starting material was consumed totally. The mixture was concentrated to afford a crude product. The crude product was triturated in EtOAc (15 mL) and filtered. The solvent was removed to afford crude product of 4-fluoro-2,3,6,7-tetrahydro-1H-azepine (37mg,0.3213mmol, 86.544% yield) as colorless oil (compound 100a). LCMS (ESI)：m/z calcld for C6H10FN+H: 116.1, found: 116.3. [00483] Compound 99 was prepared using procedures analogous to those described for example 61 using 99a. 5-Ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(4-fluoro-2,3,6,7-tetrahydroazepin-1-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol. LCMS (ESI): m/z calcld for C33H29F4N5O2+H: 602.2, found: 602.5.1H NMR (400 MHz, MeOD) δ 9.09 (s, 1H), 7.79 (dd, J = 9.0, 5.9 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 5.45 – 5.16 (m, 2H), 4.38 – 4.27 (m, 5H), 4.23 (dd, J = 10.4, 3.9 Hz, 1H), 3.35 (d, J = 6.1 Hz, 1H), 3.23 – 3.17 (m, 2H), 3.01 (d, J = 5.2 Hz, 1H), 2.95 (d, J = 5.8 Hz, 2H), 2.62 (s, 3H), 2.37 – 2.18 (m, 2H), 2.11 (d, J = 7.5 Hz, 1H), 1.98 (dd, J = 14.0, 9.5 Hz, 2H), 1.89 (s, 1H). Example 73: Exemplary synthesis of compound 103. [00484] Synthesis of compound 103a [00485] Step1: The mixture of 2,7-dichloro-8-fluoro-4-(2,3,6,7-tetrahydroazepin-1- yl)pyrido[4,3-d]pyrimidine (200 mg, 0.640 mmol, 1.0 eq), [rac-(2R,8S)-2-[tert- butyl(diphenyl)silyl]oxy-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (666 mg, 1.68 mmol, 2.6 eq) and DIEA (0.320 mL, 1.92 mmol, 3.0 eq)^in^1,4-Dioxane (4 mL) was heated to 85 ℃ under N2 for^60 h. The mixture was diluted with water (5 mL),^extracted with EtOAc (2 × 5 mL). The organic phase was concentrated and purified by^revers phase FC ( C18 Eluant with MeOH in H2O (0.1%^HCOOH) 10 to 60%)^to give the^product tert-butyl-diphenyl-[[rac- (2R,8S)-8-[[7-chloro-8-fluoro-4-(2,3,6,7-tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]silane (332 mg, 0.494 mmol, 77.3% yield) as a^white power. LCMS calculated for C37H44ClFN5O2Si (M+H)+ m/z = 672.29; found: 672.4. [00486] Step 2: To a solution of tert-butyl-diphenyl-[[rac-(2R,8S)-8-[[7-chloro-8-fluoro-4- (2,3,6,7-tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]silane (150 mg, 0.220 mmol, 1.0 eq) in^THF (2 mL) was added^TBAF (0.670 mL, 0.670 mmol, 3.0 eq, 1M in THF). The resulting mixture was stirred at^25℃ for 3 h. The residue was purified by flash column chromatography (silica gel, eluting with 0% to 10% MeOH/DCM) to afford^rac-(2R,8S)-8-[[7-chloro-8-fluoro-4-(2,3,6,7- tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-ol (105 mg, 0.242 mmol, 108 % yield crude). LCMS calculated for C21H26ClFN5O2 (M+H)+ m/z =434.17; found: 434.3. [00487] Step 3: To a solution of^rac-(2R,8S)-8-[[7-chloro-8-fluoro-4-(2,3,6,7- tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin- 2-ol (120 mg, 0.280 mmol, 1.0 eq) in^THF (5 mL) at^0 oC, NaH (110 mg, 2.77 mmol, 10.0 eq) was added and the solution was stirred at 20 oC for 30 min. Tert-butyl 2-bromoacetate (269 mg, 1.38 mmol, 5.0 eq) was then added. The resulting mixture was stirred at 20 oC overnight. The reaction mixture was quenched with saturated aqueous NH4C1(10 mL), and then extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, concentrated and^purified by silica gel column chromatography (eluting with 0% to 10% MeOH/DCM) to afford^tert-butyl 2-[[rac-(2R,8S)-8-[[7-chloro-8-fluoro-4-(2,3,6,7- tetrahydroazepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin- 2-yl]oxy]acetate (60.0 mg, 0.110 mmol, 39.6% yield). LCMS calculated for C27H36ClFN5O4 (M+H)+^m/z =548.24; found: 548.3. [00488] Compound 103 was prepared using procedures analogous to those described for example 66 using compound 103a. 2-(((2R,7aS)-7a-(((7-(8-Ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin- 2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)acetic acid. LCMS calculated for^C35H34F2N5O5 (M+H)+ m/z =642.24; found: 642.5.1H NMR (400 MHz, MeOD) δ 9.15 (s, 1H), 7.87 (dd, J = 9.2, 5.6 Hz, 1H), 7.27 - 7.44 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 5.79 (t, J = 2.8 Hz, 2H), 4.52 - 4.69 (m, 2H), 4.41 (s, 1H), 4.22 - 4.36 (m, 4H), 3.92 (q, J = 15.2 Hz, 2H), 3.60 - 3.79 (m, 5H), 3.39 (d, J = 4.4 Hz, 1H), 2.66 - 2.75 (m, 4H), 2.37 - 2.49 (m, 3H), 2.25 - 2.37 (m, 2H), 1.99 - 2.13 (m, 1H). Example 74: Exemplary synthesis of compound 104. [00489] Step 1: To a solution of 2-bromoaniline (5.0 g, 29.1 mmol, 1.0 eq) in water (125 mL) and concentrated HCl (12.5 mL) was added dropwise an aqueous (25 mL) solution of Sodium nitrite (2306.08 mg, 33.426 mmol, 1.15 eq). The reaction mixture was stirred at 0 ℃ for 1 h and then Sodium azide (2267.53 mg, 34.880 mmol, 1.2 eq) dissolved in water (25 mL) was added dropwise. Stirring was maintained at 0 ℃ for 1 h and then the reaction mixture was allowed to warm up to room temperature. After extraction with dichloromethane, the organic layers were dried (Na2SO4), filtered, and evaporated to afford 1-azido-2-bromo-benzene (5.6 g, 28 mmol, 97.3% yield) as a brownish oil. 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 (td, J = 8.0, 1.2 Hz, 1H), 7.11 (dd, J = 8.0, 1.2 Hz, 1H), 6.97 (td, J = 8.0, 1.2 Hz, 1H). [00490] Step 2: To a mixture of 1-azido-2-bromo-benzene (5600.0 mg, 28.28 mmol, 1.0 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (15732.71 mg, 56.560 mmol, 2.0 eq) and sodium carbonate (7194.42 mg, 67.872 mmo, 2.4 eq) in 1,4-Dioxane (100 mL) / Water (10 mL) was added Pd(PPh3)4 (1633.99 mg, 1.414 mmol), and then flushed with N2 for three times. The mixture was stirred at 90 ℃ overnight under N2 atmosphere. The mixture was subsequently cooled to room temperature, concentrated, and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by FC (eluting with EtOAc in Pet.ether 0 to 40%) to give the 5-(2-azidophenyl)-1-tetrahydropyran-2-yl-pyrazole (3900.0 mg, 14.482 mmol, 51.2% yield) as an orange oil. LCMS calculated for C14H15N5O (M+H)+ m/z = 270.1; found: 186.1/158.0. [00491] Step 3: A solution of 5-(2-azidophenyl)-1-tetrahydropyran-2-yl-pyrazole (1000.0 mg, 3.713 mmol, 1.0 eq) in Phenyl ether (5 mL) was heated to 170 ℃ for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography, eluting with FC (eluting with EtOAc in Pet.ether 0 to 60%) to give the 1-tetrahydropyran-2-yl-4H-pyrazolo[4,3- b]indole (290.0 mg, 1.202 mmol, 32.4% yield) as white solid. LCMS calculated for C14H16N3O (M+H)+m/z = 242.1; found: 242.2.1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.28 - 7.36 (m, 1H), 7.14 - 7.22 (m, 1H), 5.77 (dd, J = 9.2, 2.6 Hz, 1H), 4.04 - 4.21 (m, 1H), 3.75 - 3.92 (m, 1H), 2.36 - 2.50 (m, 1H), 2.05 - 2.22 (m, 2H), 1.64 - 1.89 (m, 3H). [00492] Step 4: Under Ar atmosphere, to a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1- yl)pyrido[4,3-d]pyrimidine (50.0 mg, 0.115 mmol, 1.90 eq) in Toluene (1 mL) were added 1- tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole (33.21 mg, 0.138 mmol, 1.2 eq), Pd2(dba)3 (21.01 mg, 0.023 mmol, 0.2 eq), Cesium carbonate (111.84 mg, 0.344 mmol, 3.0 eq) and RuPhos (21.41 mg, 0.046 mmol, 0.4 eq). The reaction was stirred at 100 ℃ for 3h. Then the mixture was filtered, concentrated and purified by flash column chromatography (silica gel, eluting with MeOH in DCM 0 to 10%) to afford 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydropyrazolo[4,3-b]indole (65.0 mg, 0.101 mmol, 88.4% yield) as a brown oil. LCMS calculated for C35H39F2N8O2 (M+H)+ m/z =641.3; found:641.51H NMR (400 MHz, DMSO d6) δ 9.15 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 3.2 Hz, 1H), 7.39 - 7.47 (m, 1H), 7.34 (t, J = 7.2 Hz, 1H), 5.85 (dd, J = 9.2, 2.4 Hz, 1H), 5.68 - 5.72 (m, 2H), 5.38 (s, 0.5H), 5.25 (s, 0.5H), 4.16 - 4.21 (m, 5H), 3.98 - 4.05 (m, 1H), 3.81 - 3.89 (m, 1H), 2.81 - 2.92 (m, 1H), 2.62 (s, 4H), 2.21 - 2.36 (m, 2H), 1.95 - 2.20 (m, 7H), 1.75 - 1.93 (m, 5H), 1.63 - 1.71 (m, [00493] Step 5: To a solution of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1- (tetrahydro-2H-pyran-2-yl)-1,4-dihydropyrazolo[4,3-b]indole (45.0 mg, 0.07 mmol, 1.0 eq) in DCM (1.5 mL) was added HCl in Dioxane (0.53 mL, 2.11 mmol, 30 eq) and the reaction was stirred at room temperature for 2h. Then the mixture was concentrated and purified by Prep- HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% FA) / MeOH at flow rate : 35 mL/min to afford 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1,4- dihydropyrazolo[4,3-b]indole (25.46 mg, 0.041 mmol, 59.0 % yield, compound 104) as a white solid. LCMS calculated for C30H31F2N8O (M+H)+ m/z =557.3; found:557.5.1H NMR (400 MHz, CD3OD) δ 8.96 - 9.15 (m, 1H), 7.96 (dd, J = 29.6, 8.0 Hz, 2H), 7.63 - 7.71 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.49 (d, J =52.4 Hz, 1H), 4.44 - 4.58 (m, 2H), 4.09 - 4.27 (m, 4H), 3.56 - 3.86 (m, 3H), 2.01 - 2.73 (m, 11H). Example 75: Exemplary synthesis of compound 105. [00494] Step 1: The mixture of 4-nitrobenzoic acid (39.94 mg, 0.239mmol, 3.0 eq), Ph3P (62.68 mg, 0.239 mmol, 3.0 eq), (2R,7aS)-7a-(((4-(cyclohept-4-en-1-yl)-7-(8-ethynyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (50.0 mg, 0.080 mmol) and 4A Molecular sieve (150.0 mg) in THF (1mL) was cooled to 0 ℃. DIAD (0.04 mL, 0.239 mmol, 3.0 eq) was added dropwise under Ar and the mixture was warmed to RT. After 1.5 h, the mixture was diluted with DCM and washed with water, then concentrated, and purified by FC (silica gel, Eluant with MeOH in DCM 0 to 5%) to afford (2S,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl 4-nitrobenzoate (28.0 mg, 0.036 mmol, 45.3% yield). LCMS calculated for C42H39F2N6O7 (M+H)+ m/z = 777.28; found: 777.2. [00495] Step 2: To a solution of (2S,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl 4-nitrobenzoate (28.0 mg, 0.036 mmol, 1.0 eq) in Methanol (2mL) was added K2CO3 (2.49 mg, 0.018 mmol, 0.5 eq) at 20℃. The reaction was stirred at 20 ℃ for 3h. The mixture was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeOH at flow rate : 35 mL/min to afford (2S,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (13.0 mg, 0.021mmol, 57.5% yield) as a yellow solid. LCMS calculated for C35H36F2N5O4 (M+H)+m/z =628.27; found: 628.7. (2S,7aS)-7a-(((7- (8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol. LCMS calculated for C33H32F2N5O3 (M+H)+m/z =584.24; found: 584.2.1H NMR (400 MHz, CD3OD) δ 8.98 - 9.21 (m, 1H), 7.85 (dd, J = 8.8, 5.2 Hz, 1H), 7.25 - 7.40 (m, 2H), 7.16 - 7.24 (m, 1H), 5.68 - 5.88 (m, 2H), 4.43 - 4.56 (m, 3H), 4.19 - 4.36 (m, 4H), 3.39 (s, 1H), 3.17 - 3.21 (m, 2H), 2.95 (dd, J = 11.2, 4.4 Hz, 1H), 2.78 - 2.86 (m, 1H), 2.65 - 2.75 (m, 4H), 2.10 - 2.22 (m, 2H), 1.90 - 2.08 (m, 3H), 1.78 - 1.88 (m, 1H). Example 76: Exemplary synthesis of compound 108. [00496] Compound 108 was prepared using procedures analogous to those described for example 66 using compound 107. To a solution of (S)-7a-(((7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin- 2-yl)oxy)methyl)tetrahydro-1H-pyrrolizin-2(3H)-one (3.2 mg, 0.005 mmol, 1.0 eq) in Methanol (1 mL) and Water (0.4 mL) were added NaOAc (4.51 mg, 0.055 mmol, 10 eq) and O- methylhydroxylamine;hydrochloride (5.05 mg, 0.061 mmol, 11 eq) at 20 ℃. The reaction was stirred at 20 ℃ for 16 h. The mixture was purified by Prep-HPLC (MeCN in H2O(0.1% NH4HCO3) 10 to 60%) to afford (S,E)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro- 1H-pyrrolizin-2(3H)-one O-methyl oxime (1.06 mg, 0.002 mmol, 29.8% yield) as a yellow solid. LCMS calculated for C34H33F2N6O3 (M+H)+m/z =611.25; found: 610.8.1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 7.85 (dd, J = 9.2, 5.6 Hz, 1H), 7.33 (dd, J = 16.4, 5.6 Hz, 2H), 7.21 (d, J = 2.4 Hz, 1H), 5.79 (t, J = 2.8 Hz, 2H), 4.37 - 4.48 (m, 1H), 4.20 - 4.33 (m, 5H), 3.85 - 3.98 (m, 1H), 3.77 - 3.82 (m, 3H), 3.44 - 3.58 (m, 1H), 3.37 - 3.42 (m, 1H), 3.15 - 3.25 (m, 1H), 2.82 - 3.00 (m, 1H), 2.63 - 2.79 (m, 6H), 2.11 - 2.18 (m, 2H), 1.91 - 2.05 (m, 3H). Example 77: Exemplary synthesis of compound 109. [00497] Synthesis of 5-chloro-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole 109a [00498] Step 1: To a solution of 2-bromo-6-chloro-aniline (5.00 g, 24.2 mmol, 1.0 eq) in water (125 mL) and concentrated HCl (5 mL) was added an aqueous (25 mL) solution of Sodium nitrite (1.92 g, 27.8 mmol, 1.2 eq) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h and then Sodium azide (1.89 g, 29.1 mmol, 1.2 eq) dissolved in water (25 mL) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 h and then warmed up to room temperature. TLC showed reaction was completed. After extraction with dichloromethane, the organic layers were dried with Na2SO4, filtered, and evaporated to afford 2-azido-1-bromo-3- chloro-benzene (5.60 g, 21.7 mmol, 89.5% yield) as a brownish oil. [00499] Step 2: The mixture of 2-azido-1-bromo-3-chloro-benzene (5.04 g, 21.7 mmol, 1.0 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (7.24 g, 26.0 mmol, 1.2 eq), Pd(PPh3)4 (1.25 g, 1.08 mmol, 0.05 eq) and^sodium carbonate (5.52 g, 52.0 mmol, 2.4 eq) in 1,4-Dioxane (80 mL) / Water (20 mL) was purged with N2 for three times and then stirred at 90 ℃ overnight. It was subsequently cooled to room temperature, concentrated, and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash chromatography (eluting with EtOAc in Pet.ether 25% to 35%) to give the^product 5-(2- azido-3-chloro-phenyl)-1-tetrahydropyran-2-yl-pyrazole (2.40 g, 7.90 mmol, 36.4% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.38 (d, J = 1.6 Hz, 1H), 5.02 (dd, J = 10.4, 2.4 Hz, 1H), 3.98 - 4.08 (m, 1H), 3.45 (td, J = 11.2, 2.4 Hz, 1H), 2.45 - 2.64 (m, 1H), 2.02 - 2.16 (m, 1H), 1.85 - 1.94 (m, 1H), 1.46 - 1.80 (m, 3H). [00500] Step 3: A solution of 5-(2-azido-3-chloro-phenyl)-1-tetrahydropyran-2-yl-pyrazole (1.20 g, 3.95 mmoll, 1.0 eq) in Phenyl ether (5.00 ml) was heated to 170 oC for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography (eluting with 10-30% ethyl acetate in PE) to give the 5-chloro-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3- b]indole (130 mg, 0.472 mmol, 11.9% yield) as a light yellow oil. LCMS calculated for C14H15ClN3O (M+H)+ m/z = 276.1; found: 276.0. [00501] Compound 109 was prepared using procedures analogous to those described for example 105 using compound 111aa. 1-(7-(5-chloropyrazolo[4,3-b]indol-4(1H)-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azepane-4-carbonitrile. LCMS calculated for C31H30ClF2N9O (M+H)+ m/z = 618.2; found: 618.0. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.29 - 7.41 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 5.38 (d, J = 53.6 Hz, 1H), 4.12 - 4.52 (m, 2H), 3.65 - 4.01 (m, 4H), 3.25 - 3.64 (m, 3H), 2.80 - 3.11 (m, 2H), 2.00 - 2.57 (m, 9H), 1.65 - 2.00 (m, 3H). Example 78: Exemplary synthesis of compound 110 and 111. [00502] Step 1. A solution of (S)-7a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)tetrahydro-1H-pyrrolizin-2(3H)-one (23.0 mg, 0.037 mmol, 1.0 eq) and Titannium(IV) isopropoxide (41.79 mg, 0.147 mmol, 4.0 eq) in NH3-MeOH (7M，3 mL). After overnight at 20 ℃， NaBH4 (2.23 mg, 0.059 mmol, 1.6 eq) was added and the mixture was stirred for 4 h. Then the mixture was extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, concentrated and purified by reverse phase FC (C18, Eluant with MeOH in H2O (0.1% NH4HCO3) 10 to 60%) to afford (7aS)-7a-(((7-(8-ethynyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-amine (6.0 mg, 0.0010 mmol, 26.0% yield). LCMS calculated for C35H37F2N6O3 (M+H)+ m/z =627.28; found: 626.8. [00503] Step 2. To a solution of (7aS)-7a-(((7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-amine (6.0 mg, 0.010 mmol, 1.0 eq) in DCM (2 mL) was added pyridine (3.79 mg, 0.048 mmol, 5.0 eq) and methanesulfonyl chloride (5.48 mg, 0.48 mmol, 5.0 eq) at 20 ℃. After 1 h, the mixture was extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4 powder, concentrated and purified by prep-TLC (silica gel, Eluant with MeOH/DCM=1/10) to afford N-((2S,7aS)-7a-(((7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H- azepin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2- yl)methanesulfonamide (2.6 mg, 0.004 mmol, 38.5% yield). LCMS calculated for C36H39F2N6O5S (M+H)+m/z =705.26; found: 704.6. [00504] Compound 110. N-((2S,7aS)-7a-(((7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)methanesulfonamide (sulfonamide configuration arbitrarily assigned). LCMS calculated for C34H35F2N6O4S (M+H)+m/z = 661.23; found: 661.001H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 7.86 (dd, J = 9.2, 5.6 Hz, 1H), 7.29 - 7.37 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 5.68 - 5.83 (m, 2H), 4.24 - 4.34 (m, 6H), 3.40 (s, 1H), 3.36 - 3.39 (m, 1H), 3.13 - 3.20 (m, 2H), 2.99 - 3.04 (m, 1H), 2.98 (s, 3H), 2.74 - 2.79 (m, 1H), 2.66 - 2.74 (m, 4H), 1.79 - 2.32 (m, 9H). [00505] Compound 111. N-((2R,7aS)-7a-(((7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)methanesulfonamide (sulfonamide configuration arbitrarily assigned). LCMS calculated for C34H35F2N6O4S (M+H)+m/z = 661.23; found: 661.001H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 7.86 (dd, J = 9.2, 5.6 Hz, 1H), 7.26 - 7.40 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 5.67 - 5.83 (m, 2H), 4.22 - 4.35 (m, 6H), 3.41 - 3.46 (m, 1H), 3.39 (s, 1H), 2.98 - 3.06 (m, 2H), 2.96 (s, 3H), 2.78 - 2.87 (m, 2H), 2.68 - 2.75 (m, 4H), 1.60 - 2.08 (m, 9H). Example 79: Exemplary synthesis of compound 113. [00506] Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydropyrazolo[4,3-b]indole-3- carbonitrile 113a [00507] Step 1: To a solution of 1-tettrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole (730.0 mg, 3.025 mmol, 1.0 eq) in THF (2 mL) was added DMAP (739.2 mg, 6.051 mmol, 2.0 eq), followed by Di-tert-butyl dicarbonate (990.44 mg, 4.538 mmol, 1.5 eq) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 h. Then the mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and purified by FC (silica gel, eluting with EtOAc in Pet.Ether 0 to 30%) to afford tert-butyl 1-tetrahydropyran- 2-ylpyrazolo[4,3-b]indole-4-carboxylate (1020.0 mg, 2.988 mmol, 98.8% yield) as a colorless oil. LCMS calculated for C19H24N3O3 (M+H)+ m/z =342.2; found:342.0. [00508] Step 2: To a solution of tert-butyl 1-tetrahydropyran-2-ylpyrazolo[4,3-b]indole-4- carboxylate (900.0 mg, 2.636 mmol, 1.90 eq) in MeCN (1.5 mL) was added NBS (516 mg, 2.90 mmol, 1.1 eq) and the reaction was stirred at room temperature overnight. Then the reaction was quenched with Na2S2O3 solution and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. The residue was purified by FC (silica gel, eluting with EtOAc in Pet.Ether 0 to 30%) to afford tert-butyl 3-bromo-1-tetrahydropyran-2-yl- pyrazolo[4,3-b]indole-4-carboxylate (420.0 mg, 0.999 mmol, 37.9% yield) as a white solid. LCMS calculated for C19H23BrN3O3 (M+H)+ m/z =420.1; found:419.8, 421.8. [00509] Step 3: The mixture of tert-butyl 3-bromo-1-tetrahydropyran-2-yl-pyrazolo[4,3- b]indole-4-carboxylate (100.0 mg, 0.238 mmol, 1.0 eq), Zn(CN)2 (111.75 mg, 0.952 mmol, 4.0 eq), Pd2(dba)3 (8.72mg, 0.010 mmol, 0.04 eq), Pd(dppf)Cl2 (10.44 mg, 0.014 mmol, 0.06 eq) and Zn powder (3.89 mg, 0.060 mmol, 0.25 eq) in DMA (2 mL) was bubbled with Ar for 2 min. Then irritated with microwave to 140 ℃ for 4 h. Then the mixture was partitioned between EtOAc and H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by FC (silica gel, eluting with EtOAc in Pet.Ether 0 to 50%) to afford 1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]indole-3-carbonitrile (60.0 mg, 0.225 mmol, 94.7% yield) as a white solid. LCMS calculated for C15H15N4O (M+H)+ m/z =267.1; found:267.3. Compound 113 was prepared using procedures analogous to those described for example 74 using compound 113a. 4-(4-(4-cyanoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1,4-dihydropyrazolo[4,3-b]indole- 3-carbonitrile. LCMS calculated for C32H31F2N10O (M+H)+m/z =609.3; found:609.6.1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 8.4, 4.0 Hz, 1H), 7.44 - 7.52 (m, 1H), 7.34 - 7.40 (m, 1H), 5.33 (d, J = 54.4 Hz, 1H), 4.26 - 4.38 (m, 2H), 4.00 - 4.23 (m, 4H), 3.32 - 3.41 (m, 1H), 3.19 - 3.29 (m, 2H), 3.10 - 3.18 (m, 1H), 3.01 - 3.09 (m, 1H), 2.22 - 2.44 (m, 5H), 2.08 - 2.21 (m, 2H), 1.86 - 2.07 (m, 5H). Table 1. Compounds 1-243
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000201_0002
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Example 80: Nucleotide Exchange Assay: [00510] Ras proteins cycle between an active, GTP bound state, and an inactive GDP-bound state. This activity is tightly regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs, such as SOS1/2, activate Ras proteins by exchanging GDP for GTP, thus returning Ras to its active conformation (Simanshu, Nissley, & McCormick, 2017). Therefore, a small molecule that binds K-Ras in a manner that prevents SOS-mediated nucleotide exchange locks KRas in its inactive state. Homogenous time resolved fluorescence (HTRF) was used to detect SOS-mediated binding of a fluorescent GTP analog, GTP-DY-647P1 (Jena Biosciences NU-820-647P1) to GST-tagged KRASG12D (2-169, Reaction Biology, MSC- 11-539). [00511] GST-tagged KRASG12D (2-169) and anti-GST MAb Tb Cryptate Gold (CisBio 61GSTTLB) were diluted into assay buffer (20 mM HEPES, pH 7.3, 150 mM NaCl, 5 mM MgCl2, 0.05% BSA 0.0025% NP40, 1 mM DTT) to prepare a 2.5X donor solution.5X compound was added to the protein mixture and incubated for 1 h at RT.2.5X acceptor solution containing SOS1cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY-647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 5 nM GST-tagged KRASG12D (2-169), 20 nM SOScat, and 150 nM GTP. The reaction was monitored using at RT with the Envision multimode plate reader (Ex/Em 337/665, 620 nM) up to 90 minutes at 5 minute intervals. Data was blanked to reactions without SOS1 and % inhibition was calculated such that DMSO only = 0% and blank = 100%. Curve fitting was done using a 4 parameter fit. Example 80: Protein Constructs for Protein-Protein Interaction: Table 2: Assay, Protein construct, and protein construct sequences
Figure imgf000238_0001
Example 81. Recombinant Protein Production: [00512] Biotinylated KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020). Briefly, KRAS (1-169) proteins were expressed in E. coli at 18°C with an upstream TEV cleavage site (ENLFYQS) followed an Avi tag sequence (GLNDIFEAQKIEWHE). KRAS expression constructs contained both a His6 and maltose-binding protein (MBP) tags at the N-terminus for Ni-NTA column purification prior to overnight TEV cleavage and MBP column purification. The avi-tagged NRAS expression construct contained both a His6 tag and SUMO cleavage sige at the N-terminus for Ni-NTA column purification followed by His-ULP1 digestion overnight. All avi- tagged RAS proteins were dialyzed into buffer containing ATP, biotin, and BirA followed by purification over a second Ni-NTA column and then run over a size exclusion HiLoadTM 26/600 SuperdexTM column in 20 mM HEPES, pH 7.5, 300 mM NaCl, 5 mM MgCl2, and 1 mM TCEP. Fractions containing the protein of interest were pooled, concentrated, and confirmed by intact mass spectrometry. To prepare ‘GTP’ loaded KRAS and NRAS, biotinylated KRAS or NRAS was nucleotide exchanged from GDP-bound protein to GppNHp-bound (Jena Biosciences, NU- 401-50) protein in the presence of alkaline phosphatase and excess GppNHp as previously described and the resulting nucleotide content was confirmed by HPLC reverse phase analytical chromatography (Donohue, et al., 2019) (Tran, et al., 2021). [00513] His-tagged RAF1 (52-131) was similarly expressed in E. coli at 18°C overnight with an upstream TEV cleavage site. His-tagged RAF1 expression construct contained both a His6 and MBP tags at the N-terminus for Ni-NTA column purification followed by MBP-tagged TEV digestion overnight. RAF1 protein samples were further purified over a MBP column followed by a Ni-NTA column and a second MBP column. The fractions containing the protein of interest were pooled, concentrated, and further purified over a HiLoadTM 16/600 SuperdexTM 75 pg size exclusion column into 20mM HEPES, pH8.0, 200mM NaCl, 5mM TCEP. NEA KRAS G12D IC50 (uM) values of selected compounds are depicted in Table 4 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 82: Protein-Protein Interaction (PPI) Assay: [00514] When RAS proteins are in the active GTP-bound conformation, they bind the effector protein RAF1 at the N-terminus Ras-binding domain (RBD, residues 52-131) (Tran, et al., 2021). Homogenous time resolved fluorescence (HTRF) was used to monitor the interaction between wt or mutant KRAS and RAF1 or wt NRAS and RAF1. Compounds were assayed in the presence of KRAS G12D/V and RAF1 versus wt KRAS to assess activity against mutant and w.t. KRAS. Similarly, compounds were then assayed in the presence of w.t. NRAS and RAF1 to assess RAS isoform selectivity. In all assay formats, His-tagged RAF1 protein was incubated with the HTRF donor, anti-6His Tb Cryptate gold (Cisbio 61DB10RDF), and biotinylated RAS proteins were incubated with the HTRF acceptor, streptavidin-d2 (CisBio 610SADLA). The intensity of the fluorescence signal emitted is proportional to binding between the two proteins. The donor solution was prepared by mixing 16 nM His-tagged RAF1 in protein dilution buffer with 1:100 anti-6His Tb cryptate in PPI-Terbium detection buffer. 16 nM biotinylated RAS protein was diluted into protein dilution buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1 mM MgCl2, 1 mM TCEP, 0.005% Tween20) and mixed with 1:2000 Streptavidin-d2 diluted in PPI-Terbium detection buffer (CisBio 61DB10RDF).50X compound in DMSO was mixed with 16 nM KRAS- acceptor solution and incubated for 30 minutes at room temperature. After compound pre- incubation with KRAS, the RAF1 donor solution was added to the KRAS-acceptor solution and incubated for 1 hour at room temperature. The fluorescence signal emitted was monitored at 665 nm and 615 nm using an Envision multimode plate reader. The HTRF ratio (665/615) was calculated and normalized to 0% inhibition in the absence of compound and 100% inhibition in the presence of untagged RAF1 protein. PPI KRAS G12D/RAF1, KRAS G12V/RAF1, w.t.KRAS/RAF1 and NRAS/RAF1 IC50 (uM) values of selected compounds are depicted in Table 4 and Table 5 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. [00515] Compounds described herein are active against KRAS G12 mutant and other alleles representative by PPI-G12D, PPI-G12V and PPI-w.t.KRAS potency for broad activity against mutant KRAS and wtKRAS amplification driven malignancies. Compounds described herein are selective for the KRAS isoform representative by lack of activity in the PPI-NRAS assay. Example 83. pERK Inhibition cellular HTRF assay in PANC-1 and AGS Cell Lines (Method A) [00516] The Phospho-ERK cellular HTRF assay measures ERK protein phosphorylated at Thr202/Tyr204 as a readout of MAPK pathway activation (Cisbio 64ERKPEH). PANC-1 cells (ATCC CRL-1469), and AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37oC in a humid atmosphere of 5% CO2 in the air (PANC-1 cells: high glucose DMEM medium; AGS cells: RPMI 1640 medium). [00517] One day 1, the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (PANC-1: 20,000 cells/well; AGS: 30,000 cells/well). On day 2, the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (PANC-1: 2 hours; AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit. Then, the cell lysates are treated with the detection reagents overnight at 4oC in darkness. On day 3, the fluorescence intensities at the wavelengths 665 and 620 nm are measured by the Envision plate reader (Perkin Elmer). The data are processed and fitted to a 4-parameter logistic model for IC50 calculations (GraphPad Prism 9). [00518] PANC1 pERK IC50 (uM) values of selected compounds are depicted in Table 3 with compounds having a value between 0.1 uM to 2 uM as ++++; 2 uM to 12 uM as +++; 12 uM to 20 uM as ++; and > 20 uM as +. AGS pERK HTRF (Method A) IC50 (uM) values of selected compounds are depicted in Table 4 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.
Figure imgf000241_0001
Figure imgf000242_0001
Example 84. pERK In Cell Western (ICW) assay (Method B) [00519] pERK ICW is a high throughput screening assay to evaluate the cellular potency of mutant KRAS small molecule inhibitors. KRAS mutant cell line AGS (KRASG12D) wer purchased from ATCC and maintained in DMEM and RPMI medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin. [00520] Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 384-well plate (Greiner 781091) at density of 5,000 cells/well for AGS, and allowed to grow overnight in a 37˚C CO2 incubator. The next day, compounds were dispensed into wells with a ½ log, 10-point serial dilution and top concentration of 10 µM using Tecan D300e dispenser and incubated for 3 hours in a 37 ˚C CO2 incubator. Cells were then fixed with paraformaldehyde (Electron Microscopy Sciences, 15710, 4% final concentration) for 30 min, permeabilized with wash buffer (1X PBS + 0.1% Triton X-100) for 30 min and blocked with Odyssey blocking buffer (Li-COR 927-70001) for 1 hour, all at room temperature (RT). Phospho-ERK antibody (CST 4370L) was diluted 1:500 in Odyssey blocking + 0.2% Tween 20 and incubated with cells overnight at 4 ˚C. The next day, plates were washed 5x with wash buffer, incubated with IRDye 800 CW, Goat anti-Rabbit secondary antibody (Li-COR 926-32211, 1:500) and DRAQ5 (CST 4084L, 1:5,000) diluted in in Odyssey blocking + 0.2% Tween 20 for 1 hour, washed 5x, and imaged on an Odyssey CLx imaging system. [00521] For data analysis, signal intensities from 800 (phosphor-ERK) and 700 (DRAQ5) channels were extracted, and phospho-ERK signals were normalized to DRAQ5 signals for each well and percent of DMSO control values were computed. Data were then imported into Graphpad Prism to compute half-maximal inhibitory concentrations (IC50) using a 4-parameter variable slope model. Z-factor for each plate was computed from signals derived from wells treated with either DMSO or 5 µM of Trametinib. AGS pERK ICW (Method B) IC50 (uM) values of selected compounds are depicted in Table 4 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. [00522] Table 4 includes NEA KRAS G12D IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC50 (uM) values (<0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA), AGS pERK HTRF (Method A) IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; 0.1 uM to 1 uM as ++; 1 uM to 20 uM as + and >20 uM as NA), and AGS pERK ICW (Method B) IC50 (uM) values (0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA) of selected compounds. ND indicates not determined.
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
[00523] Table 5 includes KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI IC50 (uM) values of selected compounds; with compounds having a value <0.1 uM as ++++; 0.1 uM to 1 uM as +++; >1 uM to 10 uM as ++; >10 uM to 100 uM as +; and >100 uM as NA.
Figure imgf000248_0002
Figure imgf000249_0001
[00524] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I): Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, Cl-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L- heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C6 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl- , (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R9’ is further selected from 7- , 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; and wherein the C3-C12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)S(O)2(R20), -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen, C1-6 alkoxy, and cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
2. The compound or salt of claim 1, wherein Y is O.
3. The compound or salt of claim 2, wherein L is selected from unsubstituted C1-C4 alkylene.
4. The compound or salt of any one of claims 1 to 3, wherein R2 is selected from optionally substituted -L-heterocycle.
5. The compound or salt of claim 4, wherein Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted.
6. The compound or salt of claims 4 or 5, wherein for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =NO-C1-C3 alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.
7. The compound or salt of any one of claims 4 to 6, wherein for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, C1-C3 alkyl, -OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle.
8. The compound or salt of any one of claims 1 to 7, Y-R2 is selected from , , , , , , and .
9. The compound or salt of claim 8, wherein Y-R2 is selected from , , and .
10. The compound or salt of claim 8, wherein Y-R2 is .
11. The compound or salt of any one of claims 1 to 10, wherein R4 is selected from halogen and hydrogen.
12. The compound or salt of claim 11, wherein R4 is selected from halogen.
13. The compound or salt of claims 11 or 12, wherein R4 is fluorine.
14. The compound or salt of claim 11, wherein R4 is hydrogen.
15. The compound or salt of any one of claims 1 to 14, wherein R3 is selected from an optionally substituted 9- to 15-memebered heteroaryl optionally substituted C6-C10 aryl.
16. The compound or salt of claim 15, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2; and the 9- to 15-memebered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1- C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2.
17. The compound or salt of claim 16, wherein R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , and .
18. The compound or salt of any one of claims 1 to 16, wherein R3 is selected from C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2.
19. The compound or salt of claim 18, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
20. The compound or salt of claim 19, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, and C1-3 alkyl.
21. The compound or salt of claims 16 or 19, wherein R3 is , , , and .
22. The compound or salt of claim 20, wherein R3 is naphthalene and the naphthalene is substituted with one or more substituents independently selected from fluorine, and hydroxy.
23. The compound or salt of any one of claims 15 to 22, wherein R3 is .
24. The compound or salt of any one of claims claim 1 to 23, wherein for R9’, the 5- to 12- membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur.
25. The compound or salt of any one of claims claim 1 to 24, wherein for R9’, the 5- to 12- membered heterocycle is bound to Formula (I) via the only 1 nitrogen atom.
26. The compound or salt of any one of claims 25, wherein R9’ is selected from a 5- to 8- membered heterocycle, wherein the 5- to 8-membered heterocycle contains only 1 nitrogen atom, or R9’ is further selected from 8-, 10, 11-membered spiro heterocycle and 10-membered fused heterocycle, wherein the 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle each contain only 1 nitrogen atom; and wherein the 5- to 8-membered heterocycle, 8-, 10-, 11-membered spiro heterocycle, and 10-membered fused heterocycle, are each optionally substituted.
27. The compound or salt of claim 26, wherein the 5- to 8-membered heterocycle is a monocyclic 5- to 8-membered heterocycle.
28. The compound or salt of claim 26, wherein the 5- to 8-membered heterocycle is an unsaturated 5- to 8-membered heterocycle.
29. The compound or salt of any one of claims 24 to 28, wherein the one or more optional substituents of R9’ are each independently selected from halogen, -B(OR20)2, -OR20, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
30. The compound or salt of any one of claims 24 to 28, wherein R9’ is selected from 6- to 7- membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle, is optionally substituted; and wherein the 6- to 7-membered heterocycle of R9’ is bound to Formula (I) via the only 1 nitrogen atom.
31. The compound or salt of claim 30, wherein R9’ is selected from , , , , , , and , any of which is optionally substituted.
32. The compound or salt of claim 31, wherein R9’ is selected from , , , , and , any of which is optionally substituted. In some cases, the one or more optional substituents of R9’ are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl.
33. The compound or salt of claim 32, wherein R9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
34. The compound or salt of any one of claims 24 to 28, wherein R9’ is selected from 6- to 7- membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur, wherein the 6- to 7-membered heterocycle.
35. The compound or salt of claim 34, wherein the optionally one or more additional heteroatoms are selected from sulfur.
36. The compound or salt of claim 35, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms.
37. The compound or salt of any one of claims 34 to 36, wherein the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle.
38. The compound or salt of claim 37, wherein R9’ is selected from , , , , , and , each of which is optionally substituted.
39. The compound or salt of claim 38, wherein the one or more optional substituents of R9’ are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl.
40. The compound or salt of claim 39, wherein R9’ is selected from
Figure imgf000257_0002
, ,
Figure imgf000257_0001
41. The compound or salt of any one of claims claim 1 to 23, wherein R9’ is selected from C3-C12 carbocycle; 5- to 8-membered monocyclic heterocycle, 7- to 12-membered bridged heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur.
42. The compound or salt of any one of claims 1 to 23, wherein R9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12- membered fused heterocycle, each of which is optionally substituted.
43. The compound or salt of claim 42, wherein the 5- to 10-membered heterocycle is selected from a 5- to 10- membered monocyclic heterocycle and a 5- to 10-membered bridged heterocycle, each of which is optionally substituted.
44. The compound or salt of claims 42 or 43, wherein R9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
45. The compound or salt of any one of claims 42 to 44, wherein R9’ is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
46. The compound or salt of anyone of claims 42 to 45, wherein for R9’, R20 of -OR20, - N(R20)2, is selected from hydrogen and C1-6 alkyl.
47. The compound or salt of anyone of claims 42 to 46, wherein R9’ is selected from C6-C7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted.
48. The compound or salt of anyone of claims 42 to 47, wherein R9’ is selected from C6-C7 carbocycle, each of which is optionally substituted.
49. The compound or salt of anyone of claims 42 to 47, wherein R9’ is 5- to 9-membered heterocycle, wherein the 5- to 9- membered heterocycle contains only 1 nitrogen atom.
50. The compound or salt of claim 49, wherein R9’ is selected from optionally substituted 5- to 9-membered heterocycle, each of which is optionally substituted.
51. The compound or salt of anyone of claims 42 to 45, wherein R9’ is selected from optionally substituted 7- to 8-membered spiroheterocycle, each of which is optionally substituted.
52. The compound or salt of anyone of claims 42 to 45, wherein R9’ is selected from optionally substituted 6-, 9-, 10-, 11-, and 12--membered fused heterocycle, each of which is optionally substituted.
53. The compound or salt of anyone of claims 42 to 52, wherein R9’ is selected from , , , , , , , , , , , . , , , , , , , , , , , , and , each of which are optionally substituted.
54. The compound or salt of claims 42 or 53 wherein R9’ is selected from , , and , each of which are optionally substituted.
55. The compound or salt of claim 53, wherein R9’ is selected from , , , , and , each of which are optionally substituted.
56. The compound or salt of claim 53, wherein R9’ is selected from , , . , , , , , , , , , , , , and , each of which are optionally substituted.
57. The compound or salt of claim 53, wherein R9’ is which is optionally substituted.
58. The compound or salt of any one of claims 1 to 53, wherein R9’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
59. The compound or salt of any one of claims 1 to 48, wherein R9’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
60. The compound or salt of claim 59, wherein R9’ is selected from an optionally substituted unsaturated 6-membered heterocycle.
61. The compound or salt of claim 59, wherein R9’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
62. The compound or salt of claims 59 to 61, wherein R9’ is selected from , , , , and wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
63. The compound or salt of claim 62, wherein R9’ is selected from , , , , , , , ,
Figure imgf000262_0001
64. The compound or salt of any one of claims 59 to 61, wherein R9’ is selected from , , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
65. The compound or salt of claims 61 or 64, wherein R9’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
66. The compound or salt of claims 61 or 64, wherein R9’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
67. The compound or salt of claim 66, wherein R9’ is selected from , , , and .
68. The compound or salt of any one of claims 1 to 48, wherein R9’ is selected from an optionally substituted 6-membered unsaturated heterocycle and 6-membered saturated heterocycle.
69. The compound or salt of claim 68, wherein R9’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
70. The compound or salt of claim 69, wherein R9’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
71. The compound or salt of claim 70, wherein R9’ is selected from , , and .
72. The compound or salt of any one of claims 1 to 48, wherein R9’ is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
73. The compound or salt of claim 72, wherein R9’ is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl.
74. The compound or salt of claim 73, wherein R9’ is .
75. The compound or salt of any one of claims 1 to 74, wherein the compound does not include an electrophilic substituent.
76. A compound of Formula (II): Formula (II); or a pharmaceutically acceptable salt thereof, wherein: R13 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R19’ is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -B(OR20)2, - N(R20) S(O)2(R20), -N(R20)C(O)N(R20)2, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; Y is selected from a bond, O and NR5; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; Q is selected from a bond and O; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-Cl-C6 haloalkyl, -L-O-R5, -L-NR5C(O)-aryl, -L-COOH, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; and each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl- , (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo.
77. The compound or salt of claim 76, wherein Y is O.
78. The compound or salt of claims 76 to 77, wherein L is selected from unsubstituted C1-C4 alkylene.
79. The compound or salt of any one of claims 76 to 78, wherein R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5.
80. The compound or salt of any one of claims 76 to 79, wherein R2 is selected from optionally substituted -L-heterocycle and -L-N(R5)2.
81. The compound or salt of any one of claims 76 to 80, wherein R2 is selected from optionally substituted -L-heterocycle.
82. The compound or salt of any one of claims 76 to 81, wherein R2 is selected from and , wherein the heterocycle portion is optionally substituted.
83. The compound or salt of any one of claims 76 to 82, wherein for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo.
84. The compound or salt of any one of claims 76 to 83, wherein Y-R2 is selected from , , and .
85. The compound or salt of any one of claims 76 to 83 wherein R19’ is selected from an optionally substituted C3-C7 carbocycle and optionally substituted 5- to 11-membered heterocycle.
86. The compound or salt of claim 85, wherein R19’ is selected from an optionally substituted C3-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
87. The compound or salt of claim 86, wherein R19’ is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
88. The compound or salt of claim 87, wherein for R19’, the 5- to 11-membered saturated heterocycle contains at most 2 nitrogen atoms.
89. The compound or salt of claim 87, wherein for R19’, the 5- to 11-membered saturated heterocycle contains at only 1 nitrogen atom.
90. The compound or salt of claim 87 or 89, wherein for R19’, the 5- to 11-membered saturated heterocycle contains at least 1 oxygen atom.
91. The compound or salt of any one of claims 76 to 90, wherein R19’ is selected from, , , , , , , , . , , , , , , , , , , , , , , , , , , , , , , , , , and , each of which are optionally substituted.
92. The compound or salt of any one of claims 76 to 90, wherein R19’ is selected from C6 saturated or partially saturated carbocycle and 5- to 11-membered saturated heterocycle, each of which are optionally substituted with one or more substituents independently selected from - OR20, -N(R20)2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
93. The compound or salt of claim 92, wherein for R19’, R20 of -OR20 and -N(R20)2 is selected from hydrogen and C1-3 alkyl.
94. The compound or salt of claim 93, wherein R20 is hydrogen.
95. The compound or salt of any one of claims 76 to 94, wherein R19’ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
96. The compound or salt of any one of claims 76 to 94, wherein R19’ is selected from
Figure imgf000269_0001
, , , , , , , , , , , , , , , , and .
97. The compound or salt of claim 76, wherein R19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle and saturated 6- to 8-membered monocyclic heterocycle.
98. The compound or salt of claim 97, wherein R19’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
99. The compound or salt of claim 98, wherein R19’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
100. The compound or salt of claim 98, wherein R19’ is selected from an optionally substituted unsaturated 6-membered heterocycle.
101. The compound or salt of any one of claims 97 to 100, wherein R19’ is selected from , , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
102. The compound or salt of claim 101, wherein R19’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
103. The compound or salt of claim 102, wherein R19’ is selected from , , , and .
104. The compound or salt of claim 97, wherein R19’ is selected from an optionally substituted 6-membered heterocycle.
105. The compound or salt of claim 104 , wherein R19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
106. The compound or salt of claim 105, wherein R19’ is selected from and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
107. The compound or salt of claim 106, wherein R19’ is selected from , , and .
108. The compound or salt of claim 97, wherein R19’ is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, - OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
109. The compound or salt of claim 108, wherein R19’ is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl.
110. The compound or salt of any one of claims 76 to 109, wherein R4 is selected from halogen and hydrogen.
111. The compound or salt of claim 110, wherein R4 is selected from halogen.
112. The compound or salt of claim 111, wherein R4 is fluorine.
113. The compound or salt of any one of claims 76 to 112, wherein R13 is selected from C6- C10 aryl, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl.
114. The compound or salt of claim 113, wherein R13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, - OR20, -N(R20)2, -C(O)R20, -NO2, =O, =S, =N(R20), C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
115. The compound or salt of claims 113 or 114, wherein for R13, R20 is selected from hydrogen and C1-3 alkyl.
116. The compound or salt of any one of claims 113, wherein R13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
117. The compound or salt of claim 116, wherein R13 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, - OH, and C1-3 alkyl.
118. The compound or salt of any one of claims 116 to 117, wherein R13 is selected from , , , and .
119. The compound or salt of any one of claims 76 to 118, wherein the compound does not include an electrophilic substituent.
120. A compound of Formula (III): Formula (III); or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, Cl-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L- C(O)N(R5)2, -L- C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the the aryl portion of -L-NR5C(O)-aryl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and the heteroaryl of -L- heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents are selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen and C1-C3 alkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo;; Q is selected from a bond and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R29’ is selected from an unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - N(R20)S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and each R20 is independently selected from hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
121. The compound or salt of claim 120, wherein the unsaturated 5- to 12-membered heterocycle of R29’ contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur.
122. The compound or salt of claim 120, wherein the unsaturated 5- to 12-membered heterocycle of R29’ contains at least 1 nitrogen atom.
123. The compound or salt of claim 120, wherein the unsaturated 5- to 12-membered heterocycle of R29’ contains only 1 nitrogen atom.
124. The compound or salt of any one of claims 120 to 123, wherein the unsaturated 5- to 12- membered heterocycle of R29’ contains at least 1 double bond.
125. The compound or salt of any one of claims 120 to 123, wherein the unsaturated 5- to 12- membered heterocycle of R29’ contains at most 1 double bond.
126. The compound or salt of any one of claims 120 to 123, wherein the unsaturated 5- to 12- membered heterocycle of R29’ contains at least 1 carbon-carbon double bond.
127. The compound or salt of any one of claims 120 to 123, wherein the unsaturated 5- to 12- membered heterocycle of R29’ contains at most 1 carbon-carbon double bond.
128. The compound or salt of any one of claims 120 to 127, wherein R29’ is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
129. The compound or salt of any one of claims 120 to 128, wherein R29’ is selected from an optionally substituted unsaturated 6- to 7-membered heterocycle.
130. The compound or salt of any one of claims 120 to 129, wherein R29’ is selected from an optionally substituted unsaturated 7-membered heterocycle.
131. The compound or salt of any one of claims 120 to 129, wherein R29’ is selected from an optionally substituted unsaturated 6-membered heterocycle.
132. The compound or salt of any one of claims 120 to 131, wherein for R29’, the one or more optional substituents are independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)2, -S(O)2(R20), -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
133. The compound or salt of claim 132, wherein for R29’, the one or more optional substituents are independently selected from halogen, -OH, -NH2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
134. The compound or salt of claim 133, wherein for R29’, the one or more optional substituents are independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
135. The compound or salt of claim 134, wherein for R29’, the one or more optional substituents are independently selected from halogen and C1-6 haloalkyl.
136. The compound or salt of claim 135, wherein for R29’, the one or more optional substituents are independently selected from halogen.
137. The compound or salt of any one of claims 120 to 134, wherein R29’ is selected from , , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
138. The compound or salt of claim 137, wherein R29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
139. The compound or salt of claim 138, wherein R29’ is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen and C1-6 haloalkyl.
140. The compound or salt of claim 139, wherein R29’ is selected from , , , and .
141. The compound or salt of claim 140, wherein R29’ is selected from and .
142. The compound or salt of claim 140, wherein R29’ is selected from , and .
143. The compound or salt of claim 120, wherein R29’ is selected from and is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
144. The compound or salt of claim 143, wherein R29’ is selected from , and .
145. The compound or salt of any one of claims 120 to 143, wherein Y is O.
146. The compound or salt of claim 145, wherein L is selected from unsubstituted C1-C4 alkylene.
147. The compound or salt of claim 146, wherein R2 is selected from optionally substituted - L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5.
148. The compound or salt of any one of claims 146 to 147, wherein R2 is selected from optionally substituted -L-heterocycle and -L-N(R5)2.
149. The compound or salt of any one of claims 146 to 148, wherein R2 is selected from optionally substituted -L-heterocycle.
150. The compound or salt of any one of claims 146 to 149, wherein R2 is selected from and , wherein the heterocycle portion is optionally substituted.
151. The compound or salt of claim 150, wherein for R2, the heterocycle portion is optionally substituted with one or more R6, wherein R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo.
152. The compound or salt of any one of claims 120 to 151, wherein R2 is selected from , , and .
153. The compound or salt of any one of claims 120 to 152, wherein R4 is selected from halogen and hydrogen.
154. The compound or salt of claim 153, wherein R4 is selected from halogen.
155. The compound or salt of claim 154, wherein R4 is fluorine.
156. The compound or salt of claim 153, wherein R4 is hydrogen.
157. The compound or salt of any one of claims 120 to 156, wherein R3 is selected from C6- C10 aryl, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2.
158. The compound or salt of claim 157, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, - OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C2-C4 alkynyl, and C1-6 haloalkyl.
159. The compound or salt of claims 157 or 158, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, -OH, C2-C4 alkynyl, and C1-3 alkyl.
160. The compound or salt of any one of claims 157 to 159, wherein R3 is selected from , , , , and .
161. The compound or salt of claim 160, wherein R3 is selected from and .
162. The compound or salt of claim 120, wherein R3’ is selected from 12- to 13-membered heteroaryl, wherein the 12- to 13-membered heteroaryl is optionally substituted with one or more substituents.
163. The compound or salt of claim 162, wherein R3’ is selected from a 12- to 13-membered tricyclic heteroaryl.
164. The compound or salt of claims 162 or 163, wherein the heteroaryl includes at least one nitrogen atom.
165. The compound or salt of any one of claims 162 or 164, wherein R3 is selected from , , , , , , , , , , and .
166. The compound or salt of any one of claims 162 or 164, wherein R3 is selected from an unsubstituted heteroaryl.
167. The compound or salt of any one of claims 162 or 164, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2.
168. The compound or salt of claim 167, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2.
169. The compound or salt of claim 168, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen.
170. The compound or salt of claim 169, R3 is selected from , , and .
171. The compound or salt of claim 170, R3 is selected from ,and .
172. The compound or salt of claim 171, R3 is selected from .
173. The compound or salt of claim 172, In some cases, R3 is selected from .
174. The compound or salt any one of claims 162 to 164, wherein the one or more optional substituents of R3 are independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-Cl- C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C3-C6 cycloalkyl.
175. The compound or salt of claim 165, wherein the one or more optional substituents of R3 are independently selected from halogen, cyano, hydroxy, C2-C4 alkenyl, C2-C4 alkynyl, and C3- C6 cycloalkyl.
176. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 175 and a pharmaceutically acceptable excipient.
177. A method of treating a disease or disorder, using a compound or salt of any one of claims 1 to 175 or a pharmaceutical composition of claim 176.
178. A method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of any one of claims 1 to 175 or a pharmaceutical composition of claim 176.
179. A method of inhibiting KRas G12D and/or other G12 alleles, using a compound or salt of any one of claims 1 to 175 or a pharmaceutical composition of claim 176.
180. A method of inhibiting KRas G12D and/or other alleles, using a compound or salt of any one of claims 1 to 175 or a pharmaceutical composition of claim 176.
PCT/US2022/031846 2021-06-01 2022-06-01 Kras modulators and uses thereof WO2022256459A1 (en)

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