WO2022261210A1 - Kras modulators and uses thereof - Google Patents

Kras modulators and uses thereof Download PDF

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WO2022261210A1
WO2022261210A1 PCT/US2022/032680 US2022032680W WO2022261210A1 WO 2022261210 A1 WO2022261210 A1 WO 2022261210A1 US 2022032680 W US2022032680 W US 2022032680W WO 2022261210 A1 WO2022261210 A1 WO 2022261210A1
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compound
salt
optionally substituted
heterocycle
alkyl
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PCT/US2022/032680
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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 WO2022261210A1 publication Critical patent/WO2022261210A1/en

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    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 No. 63/208,448 filed on June 8, 2021; the entire contents 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).
  • MPK 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. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state.
  • Ras 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
  • 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.
  • 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.
  • 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.
  • the present disclosure provides a compound of Formula (I): R 12 or a pharmaceutically acce ptable salt thereof, wherein: Y is selected from a bond, O, S and NR 5 ; R 2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R 9 ; each R 5 is independently selected from hydrogen and C1-C3 alkyl; each Z is selected from C 1 -C 4 alkylene; m is selected from 0 to 3; each R 3 is independently selected from C1-C3 alkyl, oxo, haloalkyl, hydroxy
  • 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.
  • 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).
  • an alkyl comprises one to eight carbon atoms (i.e., C 1 -C 8 alkyl).
  • an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl).
  • 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., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., 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).
  • 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).
  • 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.
  • 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.
  • –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • –C1-6alkylene- 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., C 2 -C 8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., 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.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C 2 -C 12 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl).
  • an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C x-y alkenyl and C x-y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term –Cx-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 –C x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • –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.
  • "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., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., 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., C 2 -C 10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., 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., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (i.e., 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., C 2 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).
  • 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.
  • Heterocycloalkyl refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms.
  • the heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thi
  • 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).
  • 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, S and NR 5 ; R 2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R 9 ; each R 5 is independently selected from hydrogen and C1-C3 alkyl; each Z is selected from C 1 -C 4 alkylene; m is selected from 0 to 3;
  • Y is O. In some cases, Y is a bond. In some cases, Y is NR 5 .
  • R 2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R 9 .
  • the heterocycloalkyl may be a 5- to 12-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8- membered heterocycloalkyl.
  • the heterocycloalkyl may be a 5-membered heterocycloalkyl.
  • the heterocycloalkyl may be an 8-membered heterocycloalkyl.
  • the heterocycloalkyl has at least 1 nitrogen atom.
  • the heterocycloalkyl has at most 1 nitrogen atom.
  • the heterocyloalkyl has only 1 heteroatom, wherein the heteroatom is nitrogen.
  • R 2 is selected from alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 9 .
  • Z is C 1 -C 4 alkylene.
  • R 10 is independently selected from hydrogen, and C1-C3 alkyl.
  • R 5 is independently selected from hydrogen or C 1 -C 3 alkyl.
  • R 2 is selected from —Z— NR 5 R 10 .
  • Z is C1-C4 alkylene.
  • R 10 is independently selected from hydrogen, and C 1 -C 3 alkyl.
  • R 5 is independently selected from hydrogen or C 1 -C 3 alkyl.
  • R 2 is selected from —Z— NR 5 R 10 and heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 9 .
  • Z is C 1 -C 4 alkylene.
  • R 10 is independently selected from hydrogen, and C1-C3 alkyl.
  • R 5 is independently selected from hydrogen or C1-C3 alkyl.
  • R 2 is heterocycloalkyl, optionally substituted with one or more R 9 .
  • R 2 is dialkylaminylalkyl (e.g., -C1- C6alkyl-N(methyl)2).
  • R 2 is alkylaminylalkyl (e.g., -C1-C6alkyl-N(H)(methyl)).
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 9 .
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 9 . In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 9 .
  • 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. In some cases, 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.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 9 .
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 9 .
  • R 9 of R 2 is independently selected at each occurrence from oxo, hydroxyl, hydroxyalkyl, halogen, C1-C6 alkyl, haloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl.
  • R 9 of R 2 is independently selected at each occurrence from hydroxyl, hydroxyalkyl, halogen, C 1 -C 6 alkyl, haloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl. In some cases, R 9 of R 2 is independently selected at each occurrence from hydroxyl, hydroxyalkyl, halogen, C 1 -C 6 alkyl, haloalkyl, or alkoxy. In some cases, R 9 of R 2 is independently selected at each occurrence from C1-C6 alkyl and halogen. In some cases, R 9 of R 2 is C1-C6 alkyl.
  • R 9 of R 2 is halogen.
  • Y-R 2 is selected from F . In some cases, Y-R 2 is . In some cases, Y-R 2 is [0067] In som e embodiments, for a compound or salt ( ), m is 0. In some cases, m is 1. [0068] In some embodiments, for a compound or salt of Formula (I), R 3 is independently selected from C 1 -C 3 alkyl, haloalkyl, hydroxyl and halogen. In some cases, R 3 is independently selected from haloalkyl and halogen. In some cases, R 3 is halogen.
  • L is selected from a bond. In some cases, L is C 1 -C 3 alkylene.
  • R 4 is selected from hydrogen, cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 .
  • R 4 is selected from heterocycle and aryl, wherein the heterocycle and aryl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ; each R 6 is independently selected from cycloalkyl, heterocycle, heterocycloalkyl, aryl, and heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 7 ; each R 7 is independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl and Q-haloalkyl, wherein Q is selected from O and S; and each R 8 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl,
  • R 4 is selected from optionally substituted C6-C10 aryl. In some cases, R 4 is an optionally substituted bicyclic C8-C10 aryl. [0073] In some embodiments, for a compound or salt of Formula (I), R 4 is optionally substituted naphthalene. In some cases, the naphthalene is optionally substituted with one or more R 7 or R 8 . In some cases, R 4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R 7 .
  • R 4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R 8 .
  • R 8 of R 4 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -N(R 5 )2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , -N(R 5 ) 2 , or heteroaryl.
  • R 8 of R 4 is independently selected from C1-C3 alkyl, heteroalkyl, -N(R 5 )2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , -N(R 5 )2, or heteroaryl.
  • R 8 of R 4 is independently selected from C 1 -C 3 alkyl, heteroalkyl, -N(R 5 ) 2 , wherein the C 1 -C 3 alkyl may be optionally substituted with halogen, -OR 5 , -N(R 5 )2, or heteroaryl.
  • R 8 of R 4 is independently selected from C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen, - OR 5 , -N(R 5 ) 2 , or heteroaryl.
  • R 5 is hydrogen.
  • R 5 is C 1 -C 3 alkyl.
  • R 7 of R 4 is independently selected from halogen, hydroxyl, C1-C6 alkyl, alkoxy, haloalkyl, amino, and hydroxyalkyl.
  • R 7 of R 4 is independently selected from halogen, hydroxyl, C1-C6 alkyl, haloalkyl, and hydroxyalkyl. In some cases, R 7 of R 4 is independently selected from halogen, hydroxyl, and C 1 - C6 alkyl. In some cases, R 7 of R 4 is independently selected from halogen and hydroxyl. n some cases, R 7 of R 4 is independently selected from halogen. In some cases, R 7 of R 4 is independently selected from chlorine and hydroxyl.
  • R 7 of R 4 is independently selected from chlorine and fluorine
  • R 4 is selected from [0076]
  • R 12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more substituents selected from hydroxy, C l -C 6 alkyl, C l -C 6 hydroxyalkyl, C l -C 6 alkoxy, C l -C 6 aminoalkyl, C l -C 6 haloalkyl, and -N(R 20 )2; wherein when R 12 is piperazine, piperazine is optionally substituted by one or more substituents selected from halogen, hydroxy, C l -C 6 aminoalkyl, C l -C 6 haloalkyl, C 1 - C 6 alkoxy, and -N(R 20 ); and wherein when R 12 is 3,8-diazabicyclo[3.2.1
  • R 12 is selected from an optionally substituted C3-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
  • R 12 is selected from an optionally substituted C 6- C 7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
  • R 12 is selected from an optionally substituted C 6- C 7 saturated or unsaturated carbocycle and optionally substituted 5- to 7- membered saturated heterocycle.
  • R 12 is selected from an optionally substituted 5- to 11-membered saturated heterocycle.
  • the heterocycle is monocyclic.
  • the heterocycle contains only 1 heteroatom.
  • the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen.
  • the heterocycle is bound to Formula (I) via the 1 heteroatom.
  • the heterocycle is bound to Formula (I) via the only 1 nitrogen atom.
  • the optionally substituted 5- to 11- membered saturated heterocycle is selected from a 6- to 8-membered saturated heterocycle.
  • R 12 is selected from an optionally substituted 6- to 8-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R 12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R 12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R 12 is bonded to Formula (I) via the only 1 nitrogen.
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 ) 2 .
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and hydroxy.
  • R 12 is selected from each of which is optionally substituted.
  • R 12 is selected from , each of which is optionally substituted.
  • R 12 is selected from , each of which is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and -N(R 20 )2.
  • R 12 is selected from , each of which is optionally substituted with one or more substituents selecte d from hydroxy, Cl-C6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OC l -C 6 alkyl, and cyano.
  • each of which is optionally substituted with one or more substituents selected from hydroxy.
  • R 12 is selected from an optionally substituted 6-membered saturated heterocycle.
  • the heterocycle is monocyclic.
  • the heterocycle contains only 1 heteroatom.
  • the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen.
  • the heterocycle is bound to Formula (I) via the 1 heteroatom.
  • the heterocycle is bound to Formula (I) via the only 1 nitrogen atom.
  • R 12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen.
  • R 12 is selected from an optionally substituted 6- membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R 12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R 12 is bonded to Formula (I) via the only 1 nitrogen. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 )2.
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and hydroxy.
  • R 12 is selected from each of which is optionally substituted.
  • R 12 is selected from , which is optionally substituted.
  • R 12 is selected from which is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and -N(R 20 )2.
  • R 12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)C l -C 6 alkyl-OH, - NC(O)OCl-C6 alkyl, and cyano. In some cases, R 12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy. In s ome cases, R 12 is selected from and In some cases, R 12 is . In some cases, R 12 is . [0082] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from an optionally substituted 7-membered saturated heterocycle.
  • the heterocycle is monocyclic. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R 12 is selected from an optionally substituted 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R 12 is selected from an optionally substituted 7- membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen.
  • R 12 is selected from an optionally substituted 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R 12 is bonded to Formula (I) via the only 1 nitrogen.
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 ) 2 .
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and hydroxy.
  • R 12 is which is optionally substituted.
  • R 12 is , which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and -N(R 20 ) 2 .
  • R 12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy, Cl-C 6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OCl- C6 alkyl, and cyano. In some cases, R 12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy, - NC(O)C l -C 6 alkyl-OH, -NC(O)OC l -C 6 alkyl, and cyano. In some cases, R 12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy and y .
  • R 12 is selected from which is optionally substituted with one or more substituents selected from hydroxy. In some cases, R 12 is selected from and In some cases, R 12 is selected from and In some cases, R 12 is selected from In some cases, R 12 is [0 083] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from an optionally substituted 8-membered saturated heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom.
  • the heterocycle is bound to Formula (I) via the only 1 nitrogen atom.
  • R 12 is selected from an optionally substituted 8-membered saturated bridged heterocycle.
  • R 12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen.
  • R 12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen.
  • R 12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R 12 is bonded to Formula (I) via the only 1 nitrogen.
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 ) 2 .
  • the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and hydroxy.
  • R 12 is , which is optionally substituted.
  • R 12 is selected from each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, and -N(R 20 ) 2 . In some cases, R 12 is selected from each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OCl-C6 alkyl, and cyano. In some cases, R 12 is selected from which is optionally substituted with one or more substituents selected from-N(R 20 )2.
  • R 12 is selected from which is optionally substituted with one or more substituents selected from -NH2. In some cases, R 12 is selected from and [ 0084] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from an optionally substituted 6- to 8-membered saturated heterocycle, each of which contains only 1 heteroatom, wherein the heteroatom is nitrogen, and each of which is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 ) 2 ; Y-R 2 is selected from R 4 is naphthalene, wherein the naphthalene is optionally su t t t t t tuents selected from halogen, hydroxyl, and C1-C6 alkyl; L is a bond; and m is 0.
  • R 12 is bound to Formula (I) via the only 1 heteroatom.
  • R 12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle, optionally substituted 7- membered saturated monocyclic heterocycle, and an optionally substituted 8-membered saturated bridged heterocycle, each of which is optionally substituted with one or more substituents selected from hydroxy, C l -C 6 cyanoalkyl, -NC(O)R 20 , -NC(O)OR 20 , cyano, hydroxy, and -N(R 20 ) 2 ; Y-R 2 is selected from R 4 is naphthalene, wherein the naphthalene is optionally subs tituted with one or more substituents selected from halogen, hydroxyl, and C1-C6 alkyl; L is a bond; and m is 0. [0086] In some embodiments, for a compound
  • R 12 is selected from, s [0089] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from an optionally substituted C 6- C 7 saturated or unsaturated carbocycle. In some cases, R 12 is selected from an optionally substituted C6-C7 saturated carbocycle. In some cases, R 12 is selected from an optionally substituted C6-C7 unsaturated carbocycle. [0090] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle. In some cases, R 12 is selected from a substituted 5- to 7-membered saturated heterocycle.
  • R 12 is selected from an optionally substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom. In some cases, R 12 is selected from a substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom. [0092] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from a substituted 5- to 11-membered saturated heterocycle, wherein when the heterocycle contains 2 nitrogen atoms, the heterocycle is substituted with hydroxy, C l -C 6 alkyl, C l -C 6 hydroxyalkyl, C l - C6 aminoalkyl, and -N(R 20 ).
  • R 12 is selected from a substituted 5- to 11-membered saturated monocyclic heterocycle, wherein when the monocyclic heterocycle contains 2 nitrogen atoms, the heterocycle is substituted with hydroxy, C l -C 6 alkyl, C l - C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ).
  • R 20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • R 12 is selected from an optionally substituted 5- to 11-membered saturated spiro-heterocycle. In some cases, R 12 is selected from a substituted 5- to 11-membered saturated spiro-heterocycle.
  • R 12 is selected from an optionally substituted 5- to 11-membered saturated fused-heterocycle. In some cases, R 12 is selected from a substituted 5- to 11-membered saturated fused-heterocycle. [0096] In some embodiments, for a compound or salt of Formula (I), R 12 is an optionally substituted 5- to 11-membered saturated bridged-heterocycle. In some cases, R 12 is a substituted 5- to 11-membered saturated bridged-heterocycle.
  • R 13 of R 12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl- C 6 aminoalkyl, and -N(R 20 ). In some cases, R 13 of R 12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ). In some cases, R 13 of R 12 is independently selected from at each occurrence from -N(R 20 ).
  • R 20 is selected from hydrogen and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo.
  • R 13 of R 12 is independently selected from at each occurrence from C l -C 6 aminoalkyl, and -N(R 20 ).
  • R 20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • R 20 of R 13 is selected from hydrogen and C1-3 alkyl.
  • R 20 of R 13 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • R 20 of is selected from hydrogen and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo.
  • R 20 of is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from -OH, -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -O-C 1-10 alkyl, and oxo.
  • R 20 of is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • R 13 of R 12 is independently selected from at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R 20 , -NC(O)OR 20 , C l -C 6 alkoxy, C l -C 6 aminoalkyl, C l -C 6 cyanoalkyl, C l -C 6 haloalkyl, and -N(R 20 ) 2 .
  • R 13 of R 12 is independently selected from at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R 20 , -NC(O)OR 20 , Cl-C6 alkoxy, Cl- C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R 20 )2.
  • R 13 of R 12 is independently selected from at each occurrence from cyano.
  • R 13 of R 12 is independently selected from at each occurrence from hydroxy.
  • R 13 of R 12 is independently selected from at each occurrence from Cl-C6 alkyl.
  • R 13 of R 12 is independently selected from at each occurrence from C l -C 6 hydroxyalkyl. In some cases, R 13 of R 12 is independently selected from at each occurrence from -NC(O)R 20 . In some cases, R 13 of R 12 is independently selected from at each occurrence from -NC(O)OR 20 . In some cases, R 13 of R 12 is independently selected from at each occurrence from C l -C 6 alkoxy. In some cases, R 13 of R 12 is independently selected from at each occurrence from C l -C 6 aminoalkyl. In some cases, R 13 of R 12 is independently selected from at each occurrence from Cl-C6 cyanoalkyl.
  • R 13 of R 12 is independently selected from at each occurrence from Cl-C6 haloalkyl. In some cases, R 13 of R 12 is independently selected from at each occurrence from -N(R 20 ) 2 . In some cases, R 13 of R 12 is independently selected from at each occurrence from -NH2. [00102] In some embodiments, for a compound or salt of Formula (I), R 20 of R 13 is hydrogen. [00103] In some embodiments, R 12 is substituted with one or more substituents selected from hydroxy, C l -C 6 alkyl, C l -C 6 hydroxyalkyl, C l -C 6 aminoalkyl, and -N(R 20 ). [00104] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from
  • R 12 is selected from [00106] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from H N
  • R 12 is selected from
  • R is selected from H 2 N
  • R is selected from
  • R is selected from an optionally substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the optional substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ), wherein R 20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • the heterocycle of R 12 has 1 nitrogen atom.
  • R 12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the optional substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ), wherein R 20 is selected from hydrogen and C1-3 alkyl.
  • the heterocycle of R 12 has 1 nitrogen atom.
  • R 12 is selected from a substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ), wherein R 20 is selected from hydrogen and C1- 3 alkyl.
  • the heterocycle of R 12 has 1 nitrogen atom.
  • R 12 is selected from [00114] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from [00114] In some embodiments, for a compound or salt of Formula (I), R is selected from a substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has 1 nitrogen atom and has at least one hydroxy substituent, wherein the other substituents are optionally selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R 20 ), wherein R 20 is selected from hydrogen and C 1-3 alkyl. In some cases, the heterocycle of R 12 has 1 nitrogen atom.
  • R 12 is selected from [00116] In some embodiments, for a compound or salt of Formula (I), R 12 is selected from [00117] In some embodiments, for a compound or salt of Formula (I), R 12 is piperazine, and R 14 of piperazine is independently selected at each occurrence from halogen, Cl-C6 aminoalkyl, Cl- C 6 haloalkyl, and -N(R 20 ) 2 . In some cases, R 14 of piperazine is independently selected at each occurrence from Cl-C6 aminoalkyl and -N(R 20 )2. In some cases, R 20 of R 14 is selected from hydrogen and C1-3 alkyl.
  • R 20 of R 14 is hydrogen.
  • R 12 is an optionally substituted 3,8-diazabicyclo[3.2.1]octane. In some cases, when R 12 is 3,8- diazabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane is substituted by one or more R 13 . In some cases, when R 12 is is substituted by one or more R 13 . In some cases, R 12 is substituted by one or more R 13 .
  • R 13 is independently selected at eac h occurrence from hydroxy, C l -C 6 alkyl, C l -C 6 hydroxyalkyl, C l -C 6 alkoxy, C l -C 6 aminoalkyl, and -N(R 20 )2.
  • R 20 is independently selected from hydrogen; and C1-6 alkyl.
  • R12 is no .
  • R 12 is not [00119] In some embod iments, for a compound or salt of Formul a (I), when R is a bridged heterocycle, the bridge heterocycle is substituted by one or more R 13 .
  • R 12 is selected from C 3 -C 12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more R 13 ; wherein R 12 is not piperazine and not 3,8-diazabicyclo[3.2.1]octane.
  • R 12 is not piperazine.
  • the compound is not a Michael acceptor.
  • the compound does not include an electrophilic substituent.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates 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) (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,
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • 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 ⁇ . 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.
  • an aerosol forming device such as a jet, vibrating porous plate or ultrasonic nebulizer
  • 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, AeroNebTM and AeroDoseTM 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 AerosonicTM (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffestoff (Deutschland) GmbH, Heiden, Germany) and UltraAire ® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
  • AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (A
  • 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.
  • Transdermal devices inserts, patches, bandages
  • 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.
  • 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 [00170]
  • the present disclosure provides compounds that inhibit KRas G12 mutants.
  • the method may inhibit KRas G12 mutants activity in a cell.
  • inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants.
  • a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • a compound of Formula (I) or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants.
  • the ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and/or other G12 mutants activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • the KRas G12D and/or other G12 mutants -associated cancer is lung cancer.
  • 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), 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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer is also provided herein.
  • a compound of Formula (I), 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), 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.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
  • a use of a compound of Formula (I), 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 is also provided herein.
  • 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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a KRas G12D mutation and/or other G12 mutants e.g., a KRas G12D and/or other G12 mutants- associated cancer
  • a regulatory agency-approved e.g., FDA- approved, assay or kit
  • administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • 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.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the 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.
  • 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.
  • 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 N-[anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate (25.0 mg, 0.0395 mmol, 19.7% yield) as an oil.
  • Example 2 Exemplary synthesis of compound 4 [00198] Step 1. Synthesis of tert-butyl 2-chloro-4-(4-oxoazepan-1-yl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (4b): To a solution of tert-butyl 2,4-dichloro-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4a, 100 mg, 0.330 mmol, 1.0 eq) in DMSO (4 mL) were added azepan-4-one; hydrochloride (59.0 mg, 0.390 mmol, 1.2 eq) and DIEA (106 mg, 0.821 mmol, 2.5 eq).
  • reaction mixture was quenched with saturated NH4Cl aqueous solution and diluted with DCM (40 mL). The organic layer was washed with water (2 x 25 mL) and brine (20 mL), dried over Na 2 SO 4 , concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 50% EA/PE) to afford tert-butyl 2-chloro-4-(4-hydroxyazepan-1-yl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4c, 890 mg, 2.61 mmol, 88.5% yield) as a white solid.
  • Step 4 1-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4e): To a solution of tert-butyl 4-(4- hydroxyazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate (4d, 250 mg, 0.540 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 1h.
  • Step 6 1-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4): To a mixture of 1-[7-(3-benzyloxy- 1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-yl]azepan-4-ol (4f, 15.0 mg, 0.0253 mmol, 1.0 eq) in methanol (3 mL) was added Pd/C (10%, 17.4 mg, 0.0152 m
  • KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020). Briefly, KRAS (1-169) proteins were expressed in E. coli at 18°C with an upstream TEV cleavage site (ENLFYQS) followed an Avi tag sequence (GLNDIFEAQKIEWHE). KRAS expression constructs contained both a His6 and maltose-binding protein (MBP) tags at the N-terminus for Ni-NTA column purification prior to overnight TEV cleavage and MBP column purification.
  • MBP maltose-binding protein
  • All avi-tagged KRAS 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.
  • NAA Nucleotide Exchange Assay
  • GTPase activating proteins GAPs
  • GEFs guanine nucleotide exchange factors
  • HTRF Homogenous time resolved fluorescence
  • 5X compound was added to the protein mixture and incubated for 1 h at RT.2.5X acceptor solution containing 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.
  • 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 7 Protein-Protein Interaction (PPI) Assay: [00211] 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
  • 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.
  • 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, and w.t.KRAS/RAF1 IC 50 (uM) values of selected compounds are depicted in Table 3 and Table 4 with compounds having a value ⁇ 0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA.
  • AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37 o C in a humid atmosphere of 5% CO 2 in the air (AGS cells: RPMI 1640 medium).
  • AGS cells RPMI 1640 medium.
  • One day 1 the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (AGS: 30,000 cells/well).
  • the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit.
  • the cell lysates are treated with the detection reagents overnight at 4 o C in darkness.
  • 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 IC 50 calculations (GraphPad Prism 9).
  • AGS pERK HTRF IC50 (uM) values of selected compounds are depicted in Table 3 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, [00216]
  • Table 3 includes NEA KRAS G12D IC 50 (uM) values ( ⁇ 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC50 (uM) values ( ⁇ 0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to
  • Table 3 IC50 (uM) values for various assays
  • Table 4 includes KRASG12V/RAF1, and wtKRAS/RAF1 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.
  • 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.

Abstract

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

Description

KRAS MODULATORS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Applications No. 63/208,448 filed on June 8, 2021; the entire contents 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) 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 of Formula (I): R12 or a pharmaceutically acce
Figure imgf000003_0001
ptable salt thereof, wherein: Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R9; each R5 is independently selected from hydrogen and C1-C3 alkyl; each Z is selected from C1-C4 alkylene; m is selected from 0 to 3; each R3 is independently selected from C1-C3 alkyl, oxo, haloalkyl, hydroxyl and halogen; L is selected from a bond, —C(O)—, and C1-C3 alkylene; R4 is selected from hydrogen, cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from R6, R7 and R8; each R6 is independently selected from cycloalkyl, heterocycle, heterocycloalkyl, aryl, and heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R7; each R7 is independently selected from halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl and Q-haloalkyl, wherein Q is selected from O and S; each R8 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, and —N(R5)2, wherein the C1-C3 alkyl is optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, —N(R5)2, and heteroaryl; each R9 is independently selected from hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycle, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, and dialkylaminylalkyl, wherein the C1-C6 alkyl is optionally substituted with cycloalkyl; each R10 is independently selected from hydrogen, acyl, C1-C3 alkyl, heteroalkyl and hydroxyalkyl; R12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more R13; wherein when R12 is piperazine, piperazine is optionally substituted by one or more R14; and wherein when R12 is 3,8-diazabicyclo[3.2.1]octane, the 3,8- diazabicyclo[3.2.1]octane is substituted by one or more R13; R13 is independently selected at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R20, -NC(O)OR20, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R20)2, and R14 is independently selected at each occurrence from halogen, hydroxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, C1-C6 alkoxy, and -N(R20)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, 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. INCORPORATION BY REFERENCE [0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by references contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION [0011] 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. [0012] 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 [0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0014] "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. [0015] 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. [0016] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0017] "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. [0018] "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. [0019] 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. [0020] "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). [0021] "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). [0022] "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). [0023] "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. [0024] "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. [0025] "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. [0026] “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. [0027] 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. [0028] "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. [0029] "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. [0030] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rc is an alkylene chain as described above. [0031] "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. [0032] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents. [0033] 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. [0034] "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. [0035] "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. [0036] "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. [0037] "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. [0038] "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. [0039] “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. [0040] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. [0041] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group. [0042] "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. [0043] 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. [0044] 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. [0045] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb -C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb -C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. [0046] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0047] 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. [0048] 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. [0049] 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. [0050] 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. [0051] 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. [0052] 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. [0053] 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 [0054] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. [0055] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R9; each R5 is independently selected from hydrogen and C1-C3 alkyl; each Z is selected from C1-C4 alkylene; m is selected from 0 to 3; each R3 is independently selected from C1-C3 alkyl, oxo, haloalkyl, hydroxyl and halogen; L is selected from a bond, —C(O)—, and C1-C3 alkylene; R4 is selected from hydrogen, cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from R6, R7 and R8; each R6 is independently selected from cycloalkyl, heterocycle, heterocycloalkyl, aryl, and heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R7; each R7 is independently selected from halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl and Q-haloalkyl, wherein Q is selected from O and S; each R8 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, and —N(R5)2, wherein the C1-C3 alkyl is optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, —N(R5)2, and heteroaryl; each R9 is independently selected from hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycle, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, and dialkylaminylalkyl, wherein the C1-C6 alkyl is optionally substituted with cycloalkyl; each R10 is independently selected from hydrogen, acyl, C1-C3 alkyl, heteroalkyl and hydroxyalkyl; R12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more R13; wherein when R12 is piperazine, piperazine is optionally substituted by one or more R14; and wherein when R12 is 3,8-diazabicyclo[3.2.1]octane, the 3,8- diazabicyclo[3.2.1]octane is substituted by one or more R13; R13 is independently selected at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R20, -NC(O)OR20, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R20)2, and R14 is independently selected at each occurrence from halogen, hydroxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, C1-C6 alkoxy, and -N(R20)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [0056] In some embodiments, for a compound or salt of Formula (I), Y is O. In some cases, Y is a bond. In some cases, Y is NR5. [0057] In some embodiments, for a compound or salt of Formula (I), R2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R9. [0058] In some embodiments, for a compound or salt of Formula (I), for R2, the heterocycloalkyl may be a 5- to 12-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8- membered heterocycloalkyl. The heterocycloalkyl may be a 5-membered heterocycloalkyl. The heterocycloalkyl may be an 8-membered heterocycloalkyl. In some cases, the heterocycloalkyl has at least 1 nitrogen atom. In some cases, the heterocycloalkyl has at most 1 nitrogen atom. In some cases, the heterocyloalkyl has only 1 heteroatom, wherein the heteroatom is nitrogen. [0059] In some embodiments, for a compound or salt of Formula (I), R2 is selected from alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R9. In some cases, Z is C1-C4 alkylene. In some cases, R10 is independently selected from hydrogen, and C1-C3 alkyl. In some cases, R5 is independently selected from hydrogen or C1-C3 alkyl. [0060] In some embodiments, for a compound or salt of Formula (I), R2 is selected from —Z— NR5R10. In some cases, Z is C1-C4 alkylene. In some cases, R10 is independently selected from hydrogen, and C1-C3 alkyl. In some cases, R5 is independently selected from hydrogen or C1-C3 alkyl. [0061] In some embodiments, for a compound or salt of Formula (I), R2 is selected from —Z— NR5R10 and heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R9. In some cases, Z is C1-C4 alkylene. In some cases, R10 is independently selected from hydrogen, and C1-C3 alkyl. In some cases, R5 is independently selected from hydrogen or C1-C3 alkyl. [0062] In some embodiments, for a compound or salt of Formula (I), R2 is heterocycloalkyl, optionally substituted with one or more R9. In some cases, R2 is dialkylaminylalkyl (e.g., -C1- C6alkyl-N(methyl)2). In some cases, R2 is alkylaminylalkyl (e.g., -C1-C6alkyl-N(H)(methyl)). [0063] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from wherein the heterocycle portion is optionally substituted with
Figure imgf000018_0001
one or more R9. In some cases, Y-R2 is selected from wherein the heterocycle portion is optionally substituted with one or more R9
Figure imgf000018_0002
. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R9.
Figure imgf000018_0005
[0064] In some embodiments, for a compound or salt of Formula (I), 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
Figure imgf000018_0003
optionally substituted. In some cases, R2 is selected from wherein
Figure imgf000018_0004
the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R9. In
Figure imgf000019_0001
some cases, Y-R2 is selected from wherein the heterocycle portion is optionally
Figure imgf000019_0002
substituted with one or more R9. [0065] In some embodiments, for a compound or salt of Formula (I), R9 of R2 is independently selected at each occurrence from oxo, hydroxyl, hydroxyalkyl, halogen, C1-C6 alkyl, haloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl. In some cases, R9 of R2 is independently selected at each occurrence from hydroxyl, hydroxyalkyl, halogen, C1-C6 alkyl, haloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl. In some cases, R9 of R2 is independently selected at each occurrence from hydroxyl, hydroxyalkyl, halogen, C1-C6 alkyl, haloalkyl, or alkoxy. In some cases, R9 of R2 is independently selected at each occurrence from C1-C6 alkyl and halogen. In some cases, R9 of R2 is C1-C6 alkyl. In some cases, R9 of R2 is halogen. [0066] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from F . In some
Figure imgf000019_0003
cases, Y-R2 is . In some cases, Y-R2 is [0067] In som
Figure imgf000019_0005
e embodiments, for a compound or salt
Figure imgf000019_0004
( ), m is 0. In some cases, m is 1. [0068] In some embodiments, for a compound or salt of Formula (I), R3 is independently selected from C1-C3 alkyl, haloalkyl, hydroxyl and halogen. In some cases, R3 is independently selected from haloalkyl and halogen. In some cases, R3 is halogen. [0069] In some embodiments, for a compound or salt of Formula (I), L is selected from a bond. In some cases, L is C1-C3 alkylene. [0070] In some embodiments, for a compound or salt of Formula (I), R4 is selected from hydrogen, cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from R6, R7 and R8. [0071] In some embodiments, for a compound or salt of Formula (I), R4 is selected from heterocycle and aryl, wherein the heterocycle and aryl are each optionally substituted with one or more substituents selected from R6, R7 and R8; each R6 is independently selected from cycloalkyl, heterocycle, heterocycloalkyl, aryl, and heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R7; each R7 is independently selected from halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl and Q-haloalkyl, wherein Q is selected from O and S; and each R8 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, and —N(R5)2, wherein the C1-C3 alkyl is optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, —N(R5)2, and heteroaryl. [0072] In some embodiments, for a compound or salt of Formula (I), R4 is selected from optionally substituted C6-C10 aryl. In some cases, R4 is an optionally substituted bicyclic C8-C10 aryl. [0073] In some embodiments, for a compound or salt of Formula (I), R4 is optionally substituted naphthalene. In some cases, the naphthalene is optionally substituted with one or more R7 or R8. In some cases, R4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R7. In some cases, R4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R8. [0074] In some embodiments, for a compound or salt of Formula (I), R8 of R4 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -N(R5)2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, -OR5, -N(R5)2, or heteroaryl. In some cases, R8 of R4 is independently selected from C1-C3 alkyl, heteroalkyl, -N(R5)2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, -OR5, -N(R5)2, or heteroaryl. In some cases, R8 of R4 is independently selected from C1-C3 alkyl, heteroalkyl, -N(R5)2, wherein the C1-C3 alkyl may be optionally substituted with halogen, -OR5, -N(R5)2, or heteroaryl. In some cases, R8 of R4 is independently selected from C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen, - OR5, -N(R5)2, or heteroaryl. In some cases, R5 is hydrogen. In some cases, R5 is C1-C3 alkyl. [0075] In some embodiments, for a compound or salt of Formula (I), R7 of R4 is independently selected from halogen, hydroxyl, C1-C6 alkyl, alkoxy, haloalkyl, amino, and hydroxyalkyl. In some case, R7 of R4 is independently selected from halogen, hydroxyl, C1-C6 alkyl, haloalkyl, and hydroxyalkyl. In some cases, R7 of R4 is independently selected from halogen, hydroxyl, and C1- C6 alkyl. In some cases, R7 of R4 is independently selected from halogen and hydroxyl. n some cases, R7 of R4 is independently selected from halogen. In some cases, R7 of R4 is independently selected from chlorine and hydroxyl. In some cases, R7 of R4 is independently selected from chlorine and fluorine In some cases, R4 is selected from
Figure imgf000021_0001
Figure imgf000021_0002
[0076] In some embodiments, for a compound or salt of Formula (I), R12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more substituents selected from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, and -N(R20)2; wherein when R12 is piperazine, piperazine is optionally substituted by one or more substituents selected from halogen, hydroxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, C1- C6 alkoxy, and -N(R20); and wherein when R12 is 3,8-diazabicyclo[3.2.1]octane, the 3,8- diazabicyclo[3.2.1]octane is substituted by one or more substituents selected form hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, and -N(R20)2. [0077] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted C3-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle. [0078] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle. [0079] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 7- membered saturated heterocycle. [0080] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 11-membered saturated heterocycle. In some cases, the heterocycle is monocyclic. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the optionally substituted 5- to 11- membered saturated heterocycle is selected from a 6- to 8-membered saturated heterocycle. In some cases, R12 is selected from an optionally substituted 6- to 8-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R12 is bonded to Formula (I) via the only 1 nitrogen. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and hydroxy. In some cases, R12 is selected from each of which is optionally substituted. In
Figure imgf000022_0001
some cases, R12 is selected from , each of which is optionally substituted. In some
Figure imgf000022_0002
cases, R12 is selected from , each of which is optionally substituted with one or
Figure imgf000022_0004
more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. In some cases, R12 is selected from , each of which is optionally substituted with one or more substituents selecte
Figure imgf000022_0003
d from hydroxy, Cl-C6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OCl-C6 alkyl, and cyano. In some cases, each of which is optionally substituted with one or more substituents selected from hydroxy. [0081] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 6-membered saturated heterocycle. In some cases, the heterocycle is monocyclic. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 6- membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R12 is bonded to Formula (I) via the only 1 nitrogen. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and hydroxy. In some cases, R12 is selected from each of which is optionally substituted. In some cases, R12 is selected from , which is
Figure imgf000023_0001
Figure imgf000023_0002
optionally substituted. In some cases, R12 is selected from which is optionally substituted
Figure imgf000023_0003
with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. In some cases, R12 is selected from , which is optionally substituted
Figure imgf000023_0004
with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, - NC(O)OCl-C6 alkyl, and cyano. In some cases, R12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy. In s
Figure imgf000023_0005
ome cases, R12 is selected from and In some cases, R12 is . In some cases, R12 is .
Figure imgf000023_0009
Figure imgf000023_0008
Figure imgf000023_0007
Figure imgf000023_0006
[0082] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 7-membered saturated heterocycle. In some cases, the heterocycle is monocyclic. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R12 is selected from an optionally substituted 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 7- membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 7-membered saturated monocyclic heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R12 is bonded to Formula (I) via the only 1 nitrogen. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and hydroxy. In some cases, R12 is which is
Figure imgf000024_0001
optionally substituted. In some cases, R12 is , which is optionally substituted with one or
Figure imgf000024_0002
more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. In some cases, R12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy, Cl-C
Figure imgf000024_0003
6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OCl- C6 alkyl, and cyano. In some cases, R12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy, -
Figure imgf000024_0004
NC(O)Cl-C6 alkyl-OH, -NC(O)OCl-C6 alkyl, and cyano. In some cases, R12 is selected from , which is optionally substituted with one or more substituents selected from hydroxy and
Figure imgf000024_0005
y . In some cases, R12 is selected from which is optionally substituted with one or more substituents selected from hydroxy. In
Figure imgf000024_0006
some cases, R12 is selected from and
Figure imgf000025_0001
In some cases, R12 is selected from and
Figure imgf000025_0002
In some cases, R12 is selected from In some cases, R12 is
Figure imgf000025_0003
[0
Figure imgf000025_0004
083] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 8-membered saturated heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle contains only 1 heteroatom. In some cases, the heterocycle contains only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, the heterocycle is bound to Formula (I) via the 1 heteroatom. In some cases, the heterocycle is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R12 is selected from an optionally substituted 8-membered saturated bridged heterocycle. In some cases, R12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen. In some cases, R12 is selected from an optionally substituted 8-membered saturated bridged heterocycle containing only 1 heteroatom, wherein the heteroatom is nitrogen; and wherein R12 is bonded to Formula (I) via the only 1 nitrogen. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2. In some cases, the heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and hydroxy. In some cases, R12 is , which is optionally substituted. In some cases, R12 is selected from
Figure imgf000026_0002
Figure imgf000026_0001
each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. In some cases, R12 is selected from each of which is optionally substituted with one or more substituents selected from
Figure imgf000026_0003
hydroxy, Cl-C6 cyanoalkyl, -NC(O)Cl-C6 alkyl-OH, -NC(O)OCl-C6 alkyl, and cyano. In some cases, R12 is selected from which is optionally substituted with one or more substituents
Figure imgf000026_0004
selected from-N(R20)2. In some cases, R12 is selected from which is optionally substituted
Figure imgf000026_0005
with one or more substituents selected from -NH2. In some cases, R12 is selected from and
Figure imgf000026_0006
[
Figure imgf000026_0007
0084] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 6- to 8-membered saturated heterocycle, each of which contains only 1 heteroatom, wherein the heteroatom is nitrogen, and each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2; Y-R2 is selected from R4 is naphthalene, wherein the naphthalene is optionally su
Figure imgf000026_0008
t t t t t tuents selected from halogen, hydroxyl, and C1-C6 alkyl; L is a bond; and m is 0. In some cases, R12 is bound to Formula (I) via the only 1 heteroatom. [0085] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 6-membered saturated monocyclic heterocycle, optionally substituted 7- membered saturated monocyclic heterocycle, and an optionally substituted 8-membered saturated bridged heterocycle, each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2; Y-R2 is selected from R4 is naphthalene, wherein the naphthalene is optionally subs
Figure imgf000027_0003
tituted with one or more substituents selected from halogen, hydroxyl, and C1-C6 alkyl; L is a bond; and m is 0. [0086] In some embodiments, for a compound or salt of Formula (I), R12 is selected from,
Figure imgf000027_0001
[0087] In some embodiments, for a compound or salt of Formula (I), R12 is selected from,
Figure imgf000027_0002
Figure imgf000028_0001
[0088] In some embodiments, for a compound or salt of Formula (I), R12 is selected from, s
Figure imgf000028_0002
[0089] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle. In some cases, R12 is selected from an optionally substituted C6-C7 saturated carbocycle. In some cases, R12 is selected from an optionally substituted C6-C7 unsaturated carbocycle. [0090] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle. In some cases, R12 is selected from a substituted 5- to 7-membered saturated heterocycle. [0091] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom. In some cases, R12 is selected from a substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom. [0092] In some embodiments, for a compound or salt of Formula (I), R12 is selected from a substituted 5- to 11-membered saturated heterocycle, wherein when the heterocycle contains 2 nitrogen atoms, the heterocycle is substituted with hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl- C6 aminoalkyl, and -N(R20). I [0093] In some embodiments, for a compound or salt of Formula (I), R12 is selected from a substituted 5- to 11-membered saturated monocyclic heterocycle, wherein when the monocyclic heterocycle contains 2 nitrogen atoms, the heterocycle is substituted with hydroxy, Cl-C6 alkyl, Cl- C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20). In some cases, R20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. [0094] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 11-membered saturated spiro-heterocycle. In some cases, R12 is selected from a substituted 5- to 11-membered saturated spiro-heterocycle. [0095] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 11-membered saturated fused-heterocycle. In some cases, R12 is selected from a substituted 5- to 11-membered saturated fused-heterocycle. [0096] In some embodiments, for a compound or salt of Formula (I), R12 is an optionally substituted 5- to 11-membered saturated bridged-heterocycle. In some cases, R12 is a substituted 5- to 11-membered saturated bridged-heterocycle. [0097] In some embodiments, for a compound or salt of Formula (I), R13 of R12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl- C6 aminoalkyl, and -N(R20). In some cases, R13 of R12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20). In some cases, R13 of R12 is independently selected from at each occurrence from -N(R20). In some cases, R20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. [0098] In some embodiments, for a compound or salt of Formula (I), R13 of R12 is independently selected from at each occurrence from Cl-C6 aminoalkyl, and -N(R20). In some cases, R20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. [0099] In some embodiments, for a compound or salt of Formula (I), R20 of R13 is selected from hydrogen and C1-3 alkyl. [00100] In some embodiments, for a compound or salt of Formula (I), R20 of R13 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. In some cases, R20 of is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. In some cases, R20 of is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from -OH, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -O-C1-10 alkyl, and oxo. In some cases, R20 of is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. [00101] In some embodiments, for a compound or salt of Formula (I), R13 of R12 is independently selected from at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R20, -NC(O)OR20, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R20)2. In some cases, R13 of R12 is independently selected from at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R20, -NC(O)OR20, Cl-C6 alkoxy, Cl- C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R20)2. In some cases, R13 of R12 is independently selected from at each occurrence from cyano. In some cases, R13 of R12 is independently selected from at each occurrence from hydroxy. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 alkyl. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 hydroxyalkyl. In some cases, R13 of R12 is independently selected from at each occurrence from -NC(O)R20. In some cases, R13 of R12 is independently selected from at each occurrence from -NC(O)OR20. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 alkoxy. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 aminoalkyl. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 cyanoalkyl. In some cases, R13 of R12 is independently selected from at each occurrence from Cl-C6 haloalkyl. In some cases, R13 of R12 is independently selected from at each occurrence from -N(R20)2. In some cases, R13 of R12 is independently selected from at each occurrence from -NH2. [00102] In some embodiments, for a compound or salt of Formula (I), R20 of R13 is hydrogen. [00103] In some embodiments, R12 is
Figure imgf000031_0002
substituted with one or more substituents selected from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20). [00104] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000031_0001
Figure imgf000032_0001
[00105] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000032_0002
Figure imgf000033_0001
[00106] In some embodiments, for a compound or salt of Formula (I), R12 is selected from H N
Figure imgf000034_0001
Figure imgf000035_0001
[00107] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000035_0002
, , [
Figure imgf000036_0001
00108] In some embodiments, for a compound or salt of Formula (I), R is selected from H2N
Figure imgf000036_0002
Figure imgf000037_0001
[00109] In some embodiments, for a compound or salt of Formula (I), R is selected from
Figure imgf000037_0002
Figure imgf000038_0001
[00110] In some embodiments, for a compound or salt of Formula (I), R is selected from an optionally substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the optional substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. In some cases, the heterocycle of R12 has 1 nitrogen atom. [00111] In some embodiments, for a compound or salt of Formula (I), R12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the optional substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl. In some cases, the heterocycle of R12 has 1 nitrogen atom. [00112] In some embodiments, for a compound or salt of Formula (I), R12 is selected from a substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1- 3 alkyl. In some cases, the heterocycle of R12 has 1 nitrogen atom. [00113] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000039_0001
[00114] In some embodiments, for a compound or salt of Formula (I), R is selected from a substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has 1 nitrogen atom and has at least one hydroxy substituent, wherein the other substituents are optionally selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl. In some cases, the heterocycle of R12 has 1 nitrogen atom. [00115] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000040_0001
[00116] In some embodiments, for a compound or salt of Formula (I), R12 is selected from
Figure imgf000040_0002
[00117] In some embodiments, for a compound or salt of Formula (I), R12 is piperazine, and R14 of piperazine is independently selected at each occurrence from halogen, Cl-C6 aminoalkyl, Cl- C6 haloalkyl, and -N(R20)2. In some cases, R14 of piperazine is independently selected at each occurrence from Cl-C6 aminoalkyl and -N(R20)2. In some cases, R20 of R14 is selected from hydrogen and C1-3 alkyl. In some cases, R20 of R14 is hydrogen. [00118] In some embodiments, for a compound or salt of Formula (I), R12 is an optionally substituted 3,8-diazabicyclo[3.2.1]octane. In some cases, when R12 is 3,8- diazabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane is substituted by one or more R13. In some cases, when R12 is is substituted by one or more R13. In some
Figure imgf000040_0003
cases, R12 is substituted by one or more R13. In some cases, R13 is independently selected at eac
Figure imgf000040_0004
h occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl-C6 aminoalkyl, and -N(R20)2. In some cases, R20 is independently selected from hydrogen; and C1-6 alkyl. In some cases, R12 is no . In some cases, R12 is not [00119] In some embod
Figure imgf000040_0005
iments, for a compound or salt of Formul
Figure imgf000040_0006
a (I), when R is a bridged heterocycle, the bridge heterocycle is substituted by one or more R13. [00120] In some embodiments, for a compound or salt of Formula (I), R12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more R13; wherein R12 is not piperazine and not 3,8-diazabicyclo[3.2.1]octane. [00121] In some embodiments, for a compound or salt of Formula (I), R12 is not piperazine. [00122] In some embodiments, for a compound or salt of Formula (I), the compound is not a Michael acceptor. [00123] In some embodiments, for a compound or salt of Formula (I), the compound does not include an electrophilic substituent. [00124] In some embodiments, for a compound of Formula (I), the compound or salt does not include an electrophilic substituent. [00125] In some embodiments, for a compound of Formula (I), the compound or salt does not form a covalent bond with any of the KRAS G12D and/or other G12 mutants. [00126] In some embodiments, for a compound of Formula (I), the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants. [00127] In some embodiments, for a compound of Formula (I), the compound or salt is not a covalent inhibitor for KRAS G12D and/or other G12 mutants. [00128] 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. [00129] 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. [00130] 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 imgf000042_0001
[00131] 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. [00132] 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. [00133] 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. [00134] 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. [00135] 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. [00136] 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. [00137] 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. [00138] 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. [00139] 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. [00140] 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. [00141] 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. [00142] 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. [00143] 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. [00144] 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 [00145] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I) (also referred to herein as “a pharmaceutical agent”). [00146] 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). [00147] 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. [00148] 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. [00149] 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. [00150] 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. [00151] 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. [00152] 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. [00153] 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. [00154] 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. [00155] 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. [00156] 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. [00157] 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. [00158] 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. [00159] 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. [00160] 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. [00161] 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. [00162] 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 μ. 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. [00163] 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 μ. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 μ 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, AeroNebTM and AeroDoseTM 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 AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. [00164] 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. [00165] 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. [00166] 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. [00167] 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. [00168] 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. [00169] 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 [00170] In an aspect, the present disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method may inhibit KRas G12 mutants activity in a cell. In some cases, inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants. In some cases, a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and/or other G12 mutants, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants. The ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods. [00171] 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. [00172] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), 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), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In some cases, the KRas G12D and/or other G12 mutants -associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co- administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. [00173] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [00174] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. [00175] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of KRas G12D and/or other G12 mutants. [00176] Also provided herein is a compound of Formula (I), 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. [00177] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. [00178] Also provided herein is a use of a compound of Formula (I), 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. [00179] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder. [00180] 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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [00181] 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. [00182] 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. [00183] 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. [00184] 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. [00185] 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. [00186] 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. [00187] 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. [00188] 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. [00189] 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. [00190] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. Preparation of Compounds [00191] 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. [00192] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES [00193] 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. [00194] The present disclosure provides processes for preparing compounds the compounds described herein (described in greater detail below). [00195] Certain compounds of Tables 1 can be prepared employing appropriate reagents in the schemes described herein. Preparation of Compounds Example 1. Exemplary synthesis of compound 1 [001
Figure imgf000059_0001
96] Step 1. Synthesis of tert-butyl N-[anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]carbamate (1b): To a solution of 7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol (doi.org/10.1021/acs.jmedchem.9b02052) (1a, 85.0 mg, 0.200 mmol, 1.0 eq) in ACN (4 mL) were added DBU (45.7 mg, 0.300 mmol, 1.5 eq) and BOP (115 mg, 0.260 mmol, 1.3 eq). The mixture was stirred at room temperature for 15 mins. tert-Butyl N-[anti-3-azabicyclo[3.2.1]octan-8- yl]carbamate (67.9 mg, 0.300 mmol, 1.5 eq) was added into the mixture. The mixture was stirred at 40 oC 24 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 tert-butyl N-[anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate (25.0 mg, 0.0395 mmol, 19.7% yield) as an oil. LCMS calculated for C35H46ClN6O3 (M+H)+ m/z = 633.33; found: 633.3/635.3. [00197] Step 2. anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8-amine (1): To a mixture of tert-butyl N-[anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-8- yl]carbamate (1b, 25.0 mg, 0.0395 mmol, 1.0 eq) in DCM (1.5 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) / ACN at flow rate : 50 mL / min to afford anti-3-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-amine;2,2,2-trifluoroacetic acid (1, 16.7 mg, 0.0246 mmol, 62.4% yield) as a light yellow solid. LCMS calculated for C30H38ClN6O (M+H)+ m/z = 533.28; found: 533.3/535.3.1H NMR (400 MHz, CD3OD) δ 7.84 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.48 - 7.56 (m, 2 H), 7.32 - 7.41 (m, 2 H), 4.70 - 4.79 (m, 1 H), 4.51 - 4.63 (m, 2 H), 4.35 (d, J = 18.0 Hz, 1H), 3.97 - 4.13 (m, 1 H), 3.82 - 3.93 (m, 1 H), 3.66 - 3.80 (m, 2 H), 3.53 - 3.64 (m, 2 H), 3.41 - 3.52 (m, 1 H), 3.09 - 3.22 (m, 3 H), 3.05 (s, 3 H), 2.69 (d, J = 14.8 Hz, 1 H), 2.53 (s, 2 H), 2.33 - 2.45 (m, 1 H), 1.87 - 2.25 (m, 7 H), 1.74 (t, J = 9.6 Hz, 1 H). Example 2. Exemplary synthesis of compound 4 [00198] Step 1. Synthesis of tert-butyl 2-chloro-4-(4-oxoazepan-1-yl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (4b): To a solution of tert-butyl 2,4-dichloro-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4a, 100 mg, 0.330 mmol, 1.0 eq) in DMSO (4 mL) were added azepan-4-one; hydrochloride (59.0 mg, 0.390 mmol, 1.2 eq) and DIEA (106 mg, 0.821 mmol, 2.5 eq). The solution was stirred at room temperature for 3 h. The resulting mixture was diluted with water (20 mL), and extracted with dichloromethane (3 x 115 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 50% EA/PE) afford tert-butyl 2-chloro-4- (4-oxoazepan-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4b, 117 mg, 0.307 mmol, 93.2% yield) as an oil. LCMS calculated for C18H26ClN4O3 (M+H)+ m/z = 381.2; found: 381.2/383.2.1H NMR (400 MHz, DMSO-d6) δ 4.33 (s, 2 H), 3.89 (t, J = 6.0 Hz, 2 H), 3.76 (t, J = 5.6 Hz, 2 H), 3.47 (t, J = 5.2 Hz, 2 H), 2.60 - 2.68 (m, 6 H), 1.80 - 1.89 (m, 2 H), 1.43 (s, 9 H). [00199] Step 2. tert-butyl 2-chloro-4-(4-hydroxyazepan-1-yl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate (4c): To a mixture of tert-butyl 2-chloro-4-(4-oxoazepan-1-yl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4b, 1.00 g, 2.63 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (149 mg, 3.94 mmol, 1.5 eq) at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl aqueous solution and diluted with DCM (40 mL). The organic layer was washed with water (2 x 25 mL) and brine (20 mL), dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 50% EA/PE) to afford tert-butyl 2-chloro-4-(4-hydroxyazepan-1-yl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4c, 890 mg, 2.61 mmol, 88.5% yield) as a white solid. LCMS calculated for C18H28ClN4O3 (M+H)+ m/z = 383.2; found: 383.2/385.2. 1H NMR (400 MHz, DMSO-d6) δ 4.54 (d, J = 4.0 Hz, 1 H), 4.31 (s, 2 H), 3.38 - 3.73 (m, 7 H), 2.73 (t, J = 4.8 Hz, 2 H), 1.82 - 1.99 (m, 2 H), 1.57 - 1.77 (m, 3 H), 1.46 - 1.56 (m, 1 H), 1.43 (s, 9 H). [00200] Step 3. tert-butyl 4-(4-hydroxyazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4d): To a mixture of tert- butyl 2-chloro-4-(4-hydroxyazepan-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4c, 500 mg, 1.31 mmol, 1.0 eq) in toluene (6 mL) were added [(2S)-1-methylpyrrolidin-2- yl]methanol (180 mg, 1.57 mmol, 1.2 eq), RuPhos (122 mg, 0.260 mmol, 0.2 eq), Pd2(dba)3 (120 mg, 0.130 mmol, 0.1 eq) and cesium carbonate (1.27 g, 3.92 mmol, 3.0 eq). The mixture was degassed and refilled with N2 for three times. The reaction was stirred at 110 °C overnight. 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 tert-butyl 4-(4-hydroxyazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4d, 290 mg, 0.630 mmol, 48.1% yield) as an oil. LCMS calculated for C24H40N5O4 (M+H)+ m/z = 462.3; found: 462.4. [00201] Step 4: 1-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4e): To a solution of tert-butyl 4-(4- hydroxyazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate (4d, 250 mg, 0.540 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 1h. 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% NH4HCO3) / MeOH at flow rate : 35 mL / min to afford 1-[2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4e, 74.0 mg, 0.205 mmol, 37.8% yield) as a white solid. LCMS calculated for C19H32N5O2 (M+H)+ m/z = 362.3; found: 362.2. [00202] Step 5.1-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4f): To a solution of 1- [2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl]azepan-4-ol (4e, 74.0 mg, 0.200 mmol, 1.0 eq) in DMF (2 mL) were added 3-benzyloxy-1- bromo-naphthalene (76.9 mg, 0.250 mmol, 1.2 eq), RuPhos (19.1 mg, 0.0400 mmol, 0.2 eq), Pd2(dba)3 (18.8 mg, 0.0200 mmol, 0.1 eq) and cesium carbonate (200 mg, 0.610 mmol, 3.0 eq). The mixture was degassed and refilled with N2 for three times. The reaction was stirred at 90 °C overnight. The resulting mixture was filtered, and then the filtrate was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 10% MeOH/DCM) to afford 1- [7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4f, 30.0 mg, 0.0505 mmol, 24.7% yield) as a yellow solid. LCMS calculated for C36H44N5O3 (M+H)+ m/z = 594.3; found: 594.5. [00203] Step 6: 1-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4): To a mixture of 1-[7-(3-benzyloxy- 1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-yl]azepan-4-ol (4f, 15.0 mg, 0.0253 mmol, 1.0 eq) in methanol (3 mL) was added Pd/C (10%, 17.4 mg, 0.0152 mmol, 0.6 eq). The reaction was stirred at 40 °C for 3h. 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% NH4HCO3) / MeOH at flow rate : 35 mL / min to afford 1-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]azepan-4-ol (4, 5.19 mg, 0.00940 mmol, 37.1% yield) as a yellow solid. LCMS calculated for C29H38N5O3 (M+H)+ m/z = 504.3; found: 504.2.1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.36 (dt, J = 7.6 Hz, 1.2 Hz, 1 H), 7.26 (dt, J = 7.6 Hz, 1.2 Hz, 1 H), 6.86 (d, J = 2.0 Hz, 1 H), 6.78 (s, 1 H), 4.58 (s, 1 H), 4.39 - 4.46 (m, 2 H), 4.09 (s, 2 H), 3.65 - 3.92 (m, 6 H), 3.09 - 3.17 (m, 1 H), 3.01 (s, 2 H), 2.69 (s, 3 H), 2.62 - 2.67 (m, 1 H), 2.12 - 2.24 (m, 2 H), 1.99 - 2.10 (m, 1 H), 1.76 - 1.98 (m, 7 H), 1.63 - 1.75 (m, 1 H). Example 3. Compound 5 [00204] 2-(1-(2-(((2R,7aS)-2
Figure imgf000063_0001
-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-4-yl)acetonitrile. LCMS calcd. for C33H39FN6O2 (M+H)+ m/z = 571.71; found: 571.2. 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.33 - 7.38 (m, 1H), 7.23 - 7.29 (m, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.28 (d, J = 55.6 Hz, 1H), 4.03 - 4.20 (m, 2H), 3.91 - 4.02 (m, 2H), 3.20 - 3.77 (m, 4H), 2.84 - 3.07 (m, 2H), 2.46 (d, J = 6.4 Hz, 2H), 1.76 - 2.33 (m, 12H), 1.38 - 1.52 (m, 1H). [00205] Table 1. Compounds 1-13 Cmp Structure Spectroscopic Data
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Example 4. Protein Constructs for Protein-Protein Interaction: Table 2: Assay, Protein construct, and protein construct sequences
Figure imgf000068_0001
Example 5. Recombinant Protein Production: [00206] 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. All avi-tagged KRAS 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, biotinylated KRAS 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). [00207] His-tagged RAF1 (52-131) was similarly expressed in E. coli at 18°C overnight with an upstream TEV cleavage site. His-tagged RAF1 expression construct contained both a His6 and MBP tags at the N-terminus for Ni-NTA column purification followed by MBP-tagged TEV digestion overnight. RAF1 protein samples were further purified over a MBP column followed by a Ni-NTA column and a second MBP column. The fractions containing the protein of interest were pooled, concentrated, and further purified over a HiLoadTM 16/600 SuperdexTM 75 pg size exclusion column into 20mM HEPES, pH8.0, 200mM NaCl, 5mM TCEP. Example 6. Nucleotide Exchange Assay (NEA): [00208] 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). [00209] 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. [00210] 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 7. Protein-Protein Interaction (PPI) Assay: [00211] 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. Compounds were assayed in the presence of KRAS G12D/V and RAF1 versus wt KRAS to assess activity against mutant KRAS. 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. [00212] PPI KRAS G12D/RAF1, KRAS G12V/RAF1, and w.t.KRAS/RAF1 IC50 (uM) values of selected compounds are depicted in Table 3 and Table 4 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 w.t.KRAS amplification driven malignancies. Example 8. pERK Inhibition cellular HTRF assay in AGS Cell Line: [00213] The Phospho-ERK cellular HTRF assay measures ERK protein phosphorylated at Thr202/Tyr204 as a readout of MAPK pathway activation (Cisbio 64ERKPEH). AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37oC in a humid atmosphere of 5% CO2 in the air (AGS cells: RPMI 1640 medium). [00214] One day 1, the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (AGS: 30,000 cells/well). On day 2, the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit. Then, the cell lysates are treated with the detection reagents overnight at 4oC in darkness. On day 3, the fluorescence intensities at the wavelengths 665 and 620 nm are measured by the Envision plate reader (Perkin Elmer). The data are processed and fitted to a 4-parameter logistic model for IC50 calculations (GraphPad Prism 9). [00215] AGS pERK HTRF IC50 (uM) values of selected compounds are depicted in Table 3 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, [00216] Table 3 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 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) of selected compounds. ND indicates not determined. Table 3: IC50 (uM) values for various assays
Figure imgf000071_0001
[00217] Table 4 includes KRASG12V/RAF1, and wtKRAS/RAF1 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 imgf000072_0001
[00218] 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): R12
Figure imgf000073_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the Z, heterocycle, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more R9; each R5 is independently selected from hydrogen and C1-C3 alkyl; each Z is selected from C1-C4 alkylene; m is selected from 0 to 3; each R3 is independently selected from C1-C3 alkyl, oxo, haloalkyl, hydroxyl and halogen; L is selected from a bond, —C(O)—, and C1-C3 alkylene; R4 is selected from hydrogen, cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from R6, R7 and R8; each R6 is independently selected from cycloalkyl, heterocycle, heterocycloalkyl, aryl, and heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R7; each R7 is independently selected from halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl and Q-haloalkyl, wherein Q is selected from O and S; each R8 is independently selected from oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, and —N(R5)2, wherein the C1-C3 alkyl is optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, —N(R5)2, and heteroaryl; each R9 is independently selected from hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycle, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, and dialkylaminylalkyl, wherein the C1-C6 alkyl is optionally substituted with cycloalkyl; each R10 is independently selected from hydrogen, acyl, C1-C3 alkyl, heteroalkyl and hydroxyalkyl; R12 is selected from C3-C12 carbocycle and 3- to 12-membered heterocycle optionally substituted by one or more R13; wherein when R12 is piperazine, piperazine is optionally substituted by one or more R14; and wherein when R12 is 3,8-diazabicyclo[3.2.1]octane, the 3,8- diazabicyclo[3.2.1]octane is substituted by one or more R13; R13 is independently selected at each occurrence from cyano, hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, -NC(O)R20, -NC(O)OR20, Cl-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 cyanoalkyl, Cl-C6 haloalkyl, and -N(R20)2, and R14 is independently selected at each occurrence from halogen, hydroxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, C1-C6 alkoxy, and -N(R20)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, 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 claims 1 or 2, wherein R2 is selected from —Z—NR5R10 and heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R9.
4. The compound or salt of claims 3, wherein Z is selected from C1-C4 alkylene.
5. The compound or salt of claims 3 or 4, wherein R10 is independently selected from hydrogen, and C1-C3 alkyl.
6. The compound or salt of any one of claims 1 to 3, wherein R2 is heterocycloalkyl, optionally substituted with one or more R9.
7. The compound or salt of any one of claims 1 to 3, and 6, wherein Y-R2 is selected from wherein the heterocycle portion is optionally
Figure imgf000075_0001
substituted with one or more R9.
8. The compound or salt of claim 7, wherein R9 of R2 is independently selected at each occurrence from oxo, hydroxyl, hydroxyalkyl, halogen, C1-C6 alkyl, haloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl.
9. The compound or salt of claim 8, wherein R9 of R2 is independently selected at each occurrence from C1-C6 alkyl and halogen.
10. The compound or salt of claim 9, wherein Y-R2 is selected from
Figure imgf000075_0002
11.
Figure imgf000075_0003
The compound or salt of any one of claims 1 to 10, wherein m is 0.
12. The compound or salt of any one of claims 1 to 11, wherein L is selected from a bond.
13. The compound or salt of any one of claims 1 to 12, wherein R4 is selected from optionally substituted C6-C10 aryl.
14. The compound or salt of claim 13, wherein R4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R7 or R8.
15. The compound or salt of claims 13 or 14, wherein R4 is naphthalene, wherein the naphthalene is optionally substituted with one or more R7.
16. The compound or salt of any one of claims 13 to 15, wherein R7 of R4 is independently selected from halogen, hydroxyl, C1-C6 alkyl, alkoxy, haloalkyl, amino, and hydroxyalkyl.
17. The compound or salt of any one of claims 13 to 16, wherein R7 of R4 is independently selected from halogen, hydroxyl, and C1-C6 alkyl.
18. The compound or salt of any one of claims 13 to 17, wherein R4 is selected from
Figure imgf000075_0004
19. The compound or salt of any one of claims 1 to 18, wherein R12 is selected from an optionally substituted C3-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
20. The compound or salt of claim 19, wherein R12 is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 11-membered saturated heterocycle.
21. The compound or salt of claim 20, wherein R12 is selected from an optionally substituted C6-C7 saturated or unsaturated carbocycle and optionally substituted 5- to 7-membered saturated heterocycle.
22. The compound or salt of any one of claims 19 to 21, wherein R12 is selected from,
Figure imgf000076_0001
and each of which are optionally substituted.
Figure imgf000076_0002
23. The compound or salt of any one of claims 19 to 22, wherein R12 is selected from,
Figure imgf000077_0001
and , each of which are optionally substituted.
24. The
Figure imgf000077_0002
compound or salt of any one of claims 19 to 23, wherein R12 is selected from,
Figure imgf000077_0003
p y
25. The compound or salt of any one of claims 1 to 21, wherein R12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle.
26. The compound or salt of claim 25, wherein R12 is selected from a substituted 5- to 7- membered saturated heterocycle.
27. The compound or salt of any one of claims 1 to 20, wherein R12 is selected from an optionally substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom.
28. The compound or salt of any one of claims 1 to 20, wherein R12 is selected from a substituted 5- to 11-membered saturated heterocycle that contains at most 1 nitrogen atom.
29. The compound or salt of any one of claims 1 to 21, wherein R12 is selected from an optionally substituted 5- to 11-membered saturated spiro-heterocycle.
30. The compound or salt of any one of claims 1 to 21, wherein R12 is selected from a substituted 5- to 11-membered saturated spiro-heterocycle.
31. The compound or salt of any one of claims 1 to 21, wherein R12 is selected from an optionally substituted 5- to 11-membered saturated fused-heterocycle.
32. The compound or salt of any one of claims 1 to 21, wherein R12 is selected from a substituted 5- to 11-membered saturated fused-heterocycle.
33. The compound or salt of any one of claims 1 to 21, wherein R12 is an optionally substituted 5- to 11-membered saturated bridged-heterocycle.
34. The compound or salt of any one of claims 1 to 21, wherein R12 is a substituted 5- to 11- membered saturated bridged-heterocycle.
35. The compound or salt of any one of claims 1 to 34, wherein R13 of R12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 alkoxy, Cl-C6 aminoalkyl, and -N(R20).
36. The compound or salt of claim 35, wherein R13 of R12 is independently selected from at each occurrence from hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and - N(R20).
37. The compound or salt of claim 36, wherein R13 of R12 is independently selected from at each occurrence from Cl-C6 aminoalkyl, and -N(R20).
38. The compound or salt of any one of claims 35 to 37, wherein R20 of R13 is selected from hydrogen and C1-3 alkyl.
39. The compound or salt of claim 38, wherein R20 of R13 is hydrogen.
40. The compound or salt of any one of claims 1 to 39, wherein R12 is selected from
Figure imgf000079_0001
Figure imgf000080_0001
41. The compound or salt of any one of claims 1 to 39, wherein R12 is selected from
Figure imgf000080_0002
Figure imgf000081_0001
42. The compound or salt of any one of claims 1 to 39, wherein R12 is selected from
Figure imgf000082_0001
43
Figure imgf000083_0001
. The compound or salt of any one of claims 1 to 39, wherein R12 is selected from
Figure imgf000083_0002
44
Figure imgf000084_0001
p y ,
Figure imgf000084_0002
Figure imgf000085_0001
45. The compound or salt of any one of claims 1 to 39, wherein R12 is selected from H2N
Figure imgf000085_0002
Figure imgf000086_0001
46. The compound or salt of any one of claims 19 to 21, wherein R12 is selected from an optionally substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the optional substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl.
47. The compound or salt of claim 46, wherein R12 is selected from a substituted 5- to 7- membered saturated heterocycle, wherein the heterocycle has at most 1 nitrogen and the substituents are independently selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl.
48. The compound or salt of claims 46 or 47, wherein the heterocycle of R12 has only 1 nitrogen atom.
49. The compound or salt of any one of claims 1 to 48, wherein R12 is selected from
50.
Figure imgf000087_0001
The compound or salt of claim 19 to 21, wherein R12 is selected from a substituted 5- to 7-membered saturated heterocycle, wherein the heterocycle has only 1 nitrogen and has at least one hydroxy substituent, wherein the other substituents are optionally selected from one or more hydroxy, Cl-C6 alkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, and -N(R20), wherein R20 is selected from hydrogen and C1-3 alkyl.
51. The compound or salt of claim 50, wherein R12 is selected from
Figure imgf000088_0001
52. The compound or salt of claim 19 to 21, wherein R12 is selected from
Figure imgf000088_0002
53. The compound or salt of any one of claim 1, wherein R12 is piperazine, and R14 of piperazine is independently selected at each occurrence from halogen, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, and -N(R20)2.
54. The compound or salt of claim 53, wherein R14 of piperazine is independently selected at each occurrence from Cl-C6 aminoalkyl and -N(R20)2.
55. The compound or salt of claim 54, wherein R20 of R14 is selected from hydrogen and C1-3 alkyl.
56. The compound or salt of claim 55, wherein R20 of R14 is hydrogen.
57. The compound or salt of any one of claims 1 to 52, wherein R12 is not piperazine.
58. The compound or salt of claim 1, R12 is selected from optionally substituted 3- to 12- membered heterocycle, wherein the 3- to 12-membered heterocycle contains only 1 heteroatom, wherein the only 1 heteroatom is nitrogen.
59. The compound or salt of claim 58, R12 is selected from optionally substituted 3- to 12- membered heterocycle, wherein the 3- to 12-membered heterocycle contains only 1 heteroatom, wherein the only 1 heteroatom is nitrogen, and R12 is bound to Formula (I) via the only 1 heteroatom.
60. The compound or salt of claims 58 to 59, wherein Y is a bond and R2 is selected from heterocycle and heterocycloalkyl, and wherein the heterocycle and heterocycloalkyl are each optionally substituted with one or more R9.
61. The compound or salt of any one of claims 58 to 60, wherein Y is a bond, m is 0, L is a bond, and R2 is selected from heterocycloalkyl, and wherein the heterocycloalkyl are each optionally substituted with one or more R9.
62. The compound or salt of claims 60 to 61, wherein Y-R2 is selected from
Figure imgf000089_0002
and wherein the heterocycle portion is optionally substituted with one or mor
Figure imgf000089_0001
e R9.
63. The compound or salt of any one of claims 60 to 62, wherein Y-R2 is selected from wherein the heterocycle portion is optionally substituted with one or more
Figure imgf000089_0007
R9.
64. The compound or salt of any one of claims 60 to 63, R9 of R2 is independently selected at each occurrence from C1-C6 alkyl and halogen.
65. The compound or salt of claim 64, wherein Y-R2 is selected from
Figure imgf000089_0003
Figure imgf000089_0005
66. The compound or salt of claim 65, wherein Y-R2 is selected from and
Figure imgf000089_0004
67.
Figure imgf000089_0006
r salt of any one of claims 58 to 66, wherein R4 is selected from heterocycle and aryl, each of which is optionally substituted with one or more substituents selected from R6, R7 and R8;
68. The compound or salt of claim 67, wherein R4 is selected from C6-C10 aryl, each of which is optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, and hydroxyalkyl.
69. The compound or salt of claim 68, wherein R4 is selected from C10 aryl, which is optionally substituted with one or more substituents selected from halogen, and hydroxy.
70. The compound or salt of claim 69, wherein R4 is selected from
Figure imgf000090_0001
71. T
Figure imgf000090_0002
he compound or salt of any one of claims 58 to 70, wherein R12 is selected from optionally substituted 6- to 8-membered saturated heterocycle. 72. The compound or salt of claim 71, wherein R12 is selected from optionally substituted 6- to 8-membered saturated heterocycle, wherein the 6- to 8-membered saturated heterocycle is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, hydroxy, and -N(R20)2. 73. The compound or salt of claim 72, wherein R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle, and an optionally substituted 8- membered saturated bridged heterocycle. 74. The compound or salt of claim 73, wherein R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle, and an optionally substituted 8- membered saturated bridged heterocycle, each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. 75. The compound or salt of claim 74, wherein R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle, each of which is optionally substituted with one or more substituents selected from hydroxy, Cl-C6 cyanoalkyl, - NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. 76. The compound or salt of claim 74, wherein R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle, and an optionally substituted 8- membered saturated bridged heterocycle, each of which is optionally substituted with one or more substituents selected from -NC(O)R20, -NC(O)OR20, hydroxy, and -N(R20)2. 77. The compound or salt of claim 76, wherein R12 is selected from an optionally substituted 6- to 7-membered saturated monocyclic heterocycle, and an optionally substituted 8- membered saturated bridged heterocycle, each of which is optionally substituted with one or more substituents selected from hydroxy. 78. The compound or salt of any one of claims 71 to 77, wherein R12 is selected from
Figure imgf000091_0007
each of which is optionally substituted.
Figure imgf000091_0005
79. The compound or salt of claim 78, wherein R12 is selected from , and
Figure imgf000091_0006
, each of which is optionally substituted with one or more substituents selected
Figure imgf000091_0004
from hydroxy, Cl-C6 cyanoalkyl, -NC(O)R20, -NC(O)OR20, cyano, and -N(R20)2. 80. The compound or salt of claim 79, wherein R12 is selected from and
Figure imgf000091_0002
, each of which is optionally substituted with one or more substituents selected f
Figure imgf000091_0003
rom hydroxy. 81. The compound or salt of claim 1, wherein the compound is selected from
Figure imgf000091_0001
Figure imgf000092_0001
pharmaceutically acceptable salt of any one thereof. 82. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 81 and a pharmaceutically acceptable excipient. 83. A method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of any one of claims 1 to 81 or a pharmaceutical composition of claim 82. 84. A method of inhibiting KRas G12D and/or other G12 alleles, using a compound or salt of any one of claims 1 to 81 or a pharmaceutical composition of claim 82. 85. A method of inhibiting KRas G12D and/or other alleles, using a compound or salt of any one of claims 1 to 81 or a pharmaceutical composition of claim 82.
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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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