WO2022115439A1 - Inhibiteurs de kras g12c et leurs utilisations - Google Patents

Inhibiteurs de kras g12c et leurs utilisations Download PDF

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WO2022115439A1
WO2022115439A1 PCT/US2021/060541 US2021060541W WO2022115439A1 WO 2022115439 A1 WO2022115439 A1 WO 2022115439A1 US 2021060541 W US2021060541 W US 2021060541W WO 2022115439 A1 WO2022115439 A1 WO 2022115439A1
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mmol
alkyl
compound
independently
mixture
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PCT/US2021/060541
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English (en)
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Justin A. HILF
Tristin E. ROSE
Michael D. Bartberger
Brendan M. O'boyle
Corey M. REEVES
Oliver C. LOSON
Brian M. Stoltz
Martina MCDERMOTT
Neil A. O'BRIEN
Dennis Slamon
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California Institute Of Technology
1200 Pharma Llc
The Regents Of The University Of California
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Publication of WO2022115439A1 publication Critical patent/WO2022115439A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • KRAS G12C INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63/118498, filed November 25, 2020, which is incorporated by reference herein in its entirety.
  • BACKGROUND Mutations in KRAS are known to be oncogenic and are common in pancreatic, lung, colorectal, gall, thyroid and bile duct cancers.
  • Mutation of Glycine 12 to Cysteine in KRAS is a relatively common genotype in non-small cell lung cancers and colorectal cancers. This mutation offers a selective, covalent inhibition strategy against mutant KRAS and spares wildtype KRAS, thus offering specificity against cancer cells.
  • KRAS G12C inhibitors for treating KRAS G12C-mediated cancers (i.e., cancers that are mediated, entirely or partly, by KRAS G12C mutation).
  • the compounds and compositions of the present invention provide means for selectively inhibiting KRAS G12C and for treating cancers, particularly those that are mediated by the KRAS G12C mutation.
  • the invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein.
  • DETAILED DESCRIPTION Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls” the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • alkenyl groups substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 6 carbon atoms, preferably from 1 to about 3 unless otherwise defined.
  • straight chained and branched alkyl groups include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.
  • a C 1 –C 6 straight chained or branched alkyl group is also referred to as a “lower alkyl” group.
  • alkyl (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, a halogen (e.g., fluoro), a hydroxyl, an oxo, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a halogen
  • the substituents on substituted alkyls are selected from C 1 –C 6 alkyl, C 3 –C 6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkyls are described below.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF 3 , -CN, and the like.
  • the term “C x –C y ,” when used in conjunction with a chemical moiety, such as, alkyl or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • the term “Cx–Cy alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups.
  • haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.
  • C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive.
  • substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group wherein each R A independently represent a hydrogen, hydrocarbyl group, aryl, heteroaryl, acyl, or alkoxy, or two R A are taken together with the N atom to which they are attached complete a heterocycle having from 3 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R A independently represents a hydrogen or a hydrocarbyl group, or two R A are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 6- to 10- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, aniline, and the like.
  • the term “carbocycle” refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • the term carbocycle includes both aromatic carbocycles and non- aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkyl and cycloalkenyl rings.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7- tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene.
  • Carbocycles may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3- to about 10-carbon atoms, from 3- to 8-carbon atoms, or more typically from 3- to 6-carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings (e.g., fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds).
  • a “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • bridged bicyclic compound refers to a bicyclic molecule in which the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • norbornane also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings each sharing three of their five carbon atoms.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and halogen as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, for example, wherein no two heteroatoms are adjacent.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, and combinations thereof.
  • fused bicyclic compound refers to a bicyclic molecule in which two rings share two adjacent atoms.
  • the rings share one covalent bond, i.e., the so-called bridgehead atoms are directly connected (e.g., ⁇ -thujene and decalin).
  • bridgehead atoms are directly connected (e.g., ⁇ -thujene and decalin).
  • each of the rings shares two adjacent atoms with the other ring, and the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, quinoline, quinoxaline, naphthyridine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, preferably 3- to 7-membered rings, more preferably 5- to 6-membered rings, in some instances, most preferably a 5-membered ring, in other instances, most preferably a 6-membered ring, which ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, oxazolines, imidazolines and the like.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • spirocyclic compound refers to a bicyclic molecule in which the two rings have only one single atom, the spiro atom, in common.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone, or substituents replacing a hydrogen on one or more nitrogens of the backbone. 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, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • Substitutions can be one or more and the same or different for appropriate organic compounds.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • TMS trialkylsilyl ethers
  • glycol ethers such as ethylene
  • the term includes compositions, excipients, adjuvants, polymers and other materials 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 salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt that is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt as used herein means any non-toxic organic or inorganic salt of any base compounds disclosed herein.
  • Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono- , di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of compounds disclosed herein are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of the invention for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds of the invention, or any of their intermediates.
  • Illustrative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11–30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (enthafen) isomers. In each instance, the disclosure includes both mixtures and separate individual isomers. Some of the compounds may also exist in tautomeric forms.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of the invention).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • At least one instance of R 4 is OCF 3 , SCF 3 , OCFH 2 , SCFH 2 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl.
  • n is 0. In certain embodiments, p is 1. In certain embodiments, B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, n is 0, p is 1, and B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, n is 0, p is 1, and B is a 6- membered saturated or partially saturated cycloalkyl or heterocyclyl.
  • A is a 6-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring substituted with one R 8b and one R 8c .
  • A is a 6-membered heterocyclyl.
  • A is piperazinyl.
  • At least one of R 4 , R 5 , R 6 , and R 7 is OCF 3 , SCF 3 , CFH 2 , SCFH 2 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl.
  • n is 0.
  • B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, n is 0, and B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, n is 0, and B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, the compounds of Formula Ia have the structure of Formula Ib: (Formula Ib) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula Ia have the structure of Formula Ic: (Formula Ic) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula Ia have the structure of Formula Id: (Formula Id) or a pharmaceutically acceptable salt thereof.
  • R 8d is H or halogen (such as F). In other embodiments, R 8d is H or F.
  • the compounds of Formula II have the structure of Formula IIa: (Formula IIa) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula II have the structure of Formula IIb: (Formula IIb) or a pharmaceutically acceptable salt thereof.
  • R 8d is H or halogen (such as F).
  • the compounds of Formula III have the structure of Formula IIIa: (Formula IIIa) or a pharmaceutically acceptable salt thereof.
  • B is a 6- membered saturated or partially saturated cycloalkyl or heterocyclyl.
  • the compounds of Formula III have the structure of Formula IIIb: (Formula IIIb) or a pharmaceutically acceptable salt thereof.
  • B is a 6- membered saturated or partially saturated cycloalkyl or heterocyclyl.
  • the compounds of Formula III have the structure of Formula IIIc: (Formula IIIc) or a pharmaceutically acceptable salt thereof.
  • B is a 6- membered saturated or partially saturated cycloalkyl or heterocyclyl.
  • R 8d is H or halogen (such as F).
  • the compounds of Formula IV have the structure of Formula IVa: (Formula IVa) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula IV have the structure of Formula IVa-1 or IVa-2: (Formula IVa-1), (Formula IVa-2), or a pharmaceutically acceptable salt thereof, wherein: y 1c is CH 2 , C(H)(CH 3 ), N(H), N(CH 3 ), O or S; and R 5 and R 7 are each independently H, CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, Cl,
  • R 5 is H, CH 3 , F, Cl or OH
  • R 7 is CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 OH, C(CH), propargyl, CN, cyclopropyl or cyclobutyl.
  • the compounds of Formula IV have the structure of Formula IVb: (Formula IVb) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula IV have the structure of Formula IVc: (Formula IVc) or a pharmaceutically acceptable salt thereof.
  • R 8d is H or halogen (such as F).
  • the compounds of Formula IV' have the structure of Formula IVa': (Formula IVa') or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula IV' have the structure of Formula IVa'-1 or IVa'-2: (Formula IVa'-1), (Formula IVa'-2), or a pharmaceutically acceptable salt thereof, wherein: y 1c is CH 2 , C(H)(CH 3 ), N(H), N(CH 3 ), O or S; and R 5 and R 7 are each independently H, CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CHF 2 , CH 2 CHF 2
  • R 5 is H, CH 3 , F, Cl or OH
  • R 7 is CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 OH, C(CH), propargyl, CN, cyclopropyl or cyclobutyl.
  • the compounds of Formula IV' have the structure of Formula IVb': (Formula IVb') or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula IV' have the structure of Formula IVc': (Formula IVc') or a pharmaceutically acceptable salt thereof.
  • R 8d is H or halogen (such as F).
  • the compounds of Formula V have the structure of Formula Va: (Formula Va) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula V have the structure of Formula Va-1 or Va-2: (Formula Va-1), (Formula Va-2), or a pharmaceutically acceptable salt thereof, wherein: y 1c is CH 2 , C(H)(CH 3 ), N(H), N(CH 3 ), O or S; and R 5 and R 7 are each independently H, CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, Cl, CH 2 OH,
  • R 5 is H, CH 3 , F, Cl or OH
  • R 7 is CH 3 , CH 2 CH 3 , N(H)(CH 3 ), N(H)(CH 2 CH 3 ), OCH 3 , OCH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH 2 F, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 OH, C(CH), propargyl, CN, cyclopropyl or cyclobutyl.
  • the compounds of Formula V have the structure of Formula Vb: (Formula Vb) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula V have the structure of Formula Vc: (Formula Vc) or a pharmaceutically acceptable salt thereof.
  • the invention relates to any compound described herein, or a pharmaceutically acceptable salt thereof, wherein: R 8a is C 1 -C 3 alkyl substituted with one R 9 ; R 9 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 10 ; and R 10 in each occurrence is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl.
  • the invention relates to compounds of Formula Id, IIa, IIIa, IIIb, or IIIc, or pharmaceutically acceptable salts thereof, wherein: R 8a is C 1 -C 3 alkyl substituted with one R 9 ; R 9 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 10 ; and R 10 in each occurrence is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl. In some aspects, C 1 -C 3 alkyl is methylene.
  • R 8d , R 8e , R 9 or R 11 is C 1 -C 3 alkyl, each independently may be methylene.
  • R 8 is C 1 -C 3 alkyl, and C 1 -C 3 alkyl is methylene.
  • R 9 is heterocyclyl substituted with one R 10 , and R 10 is methyl.
  • heterocyclyl is pyrrolidine and the N atom of pyrrolidine is methyl substituted.
  • y 2a is C(R 11 ) 2 , and R 11 is H in one occurrence and is H, CH 3 or OCH 3 in the other. In other aspects, y 2a is O. In further aspects, y 2a is N(R 3 ) and R 3 is H. In yet further aspects, y 2a is S.
  • y 1a is C(R 11 ) 2 , and R 11 is H in one occurrence and is H, CH 3 or OCH 3 in the other. In some aspects, y 1a is O. In some aspects, y 1a is N(R 3 ). In some aspects, y 1a is S. In other aspects, y 2b is C(R 11 ) 2 , and y 2c is O, N(R 3 ) or S. In some aspects, y 2b is C(R 11 ) 2 , and R 11 is H in one occurrence and is H, CH 3 or OCH 3 in the other. In further aspects, y 2c is O. In further aspects, y 2c is N(R 3 ). In further aspects, y 2c is S.
  • y 2b is O, N(R 3 ) or S
  • y 2c is C(R 11 ) 2
  • y 2c is C(R 11 ) 2
  • R 11 is H in one occurrence and is H, CH 3 or OCH 3 in the other.
  • y 2b is O.
  • y 2b is N(R 3 ).
  • y 2b is S.
  • the invention relates to a compound of Formula IIIa, IIIb or IIIc, such as IIIa, or a pharmaceutically acceptable salt thereof, wherein: B is a 6-membered saturated cycloalkyl or heterocyclyl; x 1 is C(R 1 )(R 2 ); is a single bond; y 1a is (C(R 11 ) 2 )m; y 2b is (C(R 11 ) 2 )m; y 2c is (C(R 11 ) 2 ) m or N(R 3 ); z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each independently H; R 3 in each occurrence is independently C 1 -C 4 alkyl; R 4 , R 5 , R 6 , and R 7 are each independently H, OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCF
  • the compound has a has a KRASG12C kobs/[i] of about 1000 M- 1 s -1 or greater. In yet further aspects, the compound has an average IC 50 of greater than 1000 nM for the drug-resistant cell lines of Table 5. In yet further aspects, the compound has an average IC 50 of about 1000 nM or lower for the drug-sensitive cell lines of Table 5.
  • the invention relates to a compound of Formula IVa, IVb or IVc, or a pharmaceutically acceptable salt thereof, wherein: x 1 is C(R 1 )(R 2 ); y 1b and y 1c are each (C(R 11 ) 2 ) m ; z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each H; R 11 in each occurrence is H; and m in each occurrence is 1.
  • the invention relates to a compound of Formula IVa', IVb' or IVc', or a pharmaceutically acceptable salt thereof, wherein: x 1 is C(R 1 )(R 2 ); y 1b and y 1c are each (C(R 11 ) 2 )m; z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each H; R 11 in each occurrence is H; and m in each occurrence is 1.
  • the invention relates to a compound of Formula IVa, IVb or IVc, or a pharmaceutically acceptable salt thereof, wherein: x 1 is C(R 1 )(R 2 ); y 1b and y 1c are each (C(R 11 ) 2 ) m ; z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each H; R 4 , R 5 , R 6 , and R 7 are each independently H, OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W)
  • the invention relates to a compound of Formula IVa', IVb' or IVc', or a pharmaceutically acceptable salt thereof, wherein: x 1 is C(R 1 )(R 2 ); y 1b and y 1c are each (C(R 11 ) 2 )m; z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each H; R 4 , R 5 , R 6 , and R 7 are each independently H, OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W)
  • the compound has a has a KRASG12C k obs /[i] of about 1000 M- 1 s -1 or greater. In yet further aspects, the compound has an average IC 50 of greater than 1000 nM for the drug-resistant cell lines of Table 5. In yet further aspects, the compound has an average IC 50 of about 1000 nM or lower for the drug-sensitive cell lines of Table 5.
  • the invention relates to a compound of Formula Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, wherein: x 1 is C(R 1 )(R 2 ); y 1a , y 1b and y 1c are each (C(R 11 ) 2 )m; z 1 , z 2 , z 3 and z 4 are each C; R 1 and R 2 are each H; R 4 , R 5 , R 6 , and R 7 are each independently H, OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C
  • the compound has a has a KRASG12C k obs /[i] of about 1000 M- 1 s -1 or greater. In yet further aspects, the compound has an average IC 50 of greater than 1000 nM for the drug-resistant cell lines of Table 5. In yet further aspects, the compound has an average IC 50 of about 1000 nM or lower for the drug-sensitive cell lines of Table 5.
  • the invention relates to compounds of Formula I, Ia, Ib, Ic, III, IIIa, IIIb or IIIc, or pharmaceutically acceptable salts thereof, wherein B is a 5- or 6- membered cycloalkyl. In some embodiments, the invention relates to compounds of Formula I, Ia, Ib, Ic, III, IIIa, IIIb or IIIc, or pharmaceutically acceptable salts thereof, wherein B is a 5- or 6- membered heterocyclyl.
  • the 5- or 6-membered heterocyclyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, sulfolanyl, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, thiomorpholinyl, thiomorpholinyl dioxide, morpholinyl, 1,4- dithianyl, thianyl, lactamyl and lactonyl.
  • x 2 is O.
  • R 3 when R 3 is C 1 -C 4 alkyl, C 1 -C 4 alkyl is methyl or ethyl.
  • the invention relates to a compound of Formula I, Ia, Ib, Ic, II, III, IV, IV', or V, or a pharmaceutically acceptable salt thereof, wherein R 8d is F.
  • the invention relates to a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein R 8b is C 1 -C 3 alkyl-CN.
  • the invention relates to a compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, wherein R8c is H and R8e is H.
  • the invention relates to a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, IV', IVa', IVb', IVc', V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, wherein R 11 is C 1 -C 3 alkyl. In further aspects, C 1 -C 3 alkyl is methyl or ethyl. In some embodiments, the invention relates to a compound of Formula I, Ia, Ib, Ic, Id, III, IIIa, IIIb or IIIc, or a pharmaceutically acceptable salt thereof, wherein m, in each occurrence, is 1.
  • the invention relates to a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, wherein R 8d is H, F, methyl, ethyl, OCH 3 , CH 2 OH or CH 2 OCH 3 , and R 8e is H, methyl, ethyl, F, CF 3 , CF 2 H or CH 2 F.
  • the invention relates to a compound of formula Ib, Ic, II, III, IV, IV', or V, or a pharmaceutically acceptable salt thereof, wherein R 8d is H, F, methyl, ethyl, OCH 3 , CH 2 OH or CH 2 OCH 3 .
  • the compound is not a compound in Table 1, Table 2, or Table 3A.
  • the invention relates to a compound selected from Table 6.
  • the compound is not included in Table 1, Table 2, or Table 3A.
  • the invention relates to a compound selected from Table 3B.
  • the compound is selected from C-49 and C-52.
  • the compound is selected from the group consisting of C-71, C-72, C-73 and C-74.
  • the compound is not included in Table 1, Table 2, or Table 3A.
  • the invention relates to a compound selected from Table 6, wherein the compound has a KRASG12C kobs/[i] of about 1000 M -1 s -1 or greater. In some embodiments, the compound is not included in Table 1, Table 2, or Table 3A. In some embodiments, the invention relates to a compound selected from Table 3B, wherein the compound has a KRASG12C k obs /[i] of about 1000 M -1 s -1 or greater. In some embodiments, the compound is not included in Table 1, Table 2, or Table 3A. In some aspects, the invention relates to a compound of Formula IVa' having a structure selected from: or a pharmaceutically salt thereof.
  • the invention relates to a compound of Formula IVb' having a structure selected from: , or a pharmaceutically salt thereof.
  • the invention relates to a compound of Formula Va having a structure selected from: , , , or a pharmaceutically salt thereof.
  • the invention relates to a compound of Formula Vb having a structure selected from: , , or a pharmaceutically salt thereof.
  • the invention relates to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient.
  • the compound may be a compound of Formula IV or Formual IV' (such as a compound of Formula IVa, IVb, IVc, IVa', IVb', or IVc'), or a pharmaceutically acceptable salt thereof.
  • methods of synthesizing a pharmaceutical agent and/or composition comprising preparing a compound described herein (or a pharmaceutically acceptable salt thereof), according to a method as described herein, and synthesizing the pharmaceutical agent and/or composition from the compound (or pharmaceutically acceptable salt thereof), e.g., by carrying out one or more chemical reactions on the compound and/or combining the pharmaceutical agent with one or more pharmaceutically acceptable carriers and/or excipients.
  • the compound is a compound of Formula IV or Formula IV' (such as a compound of Formula IVa, IVb, IVc, IVa', IVb', or IVc'), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical agent and/or composition prepared from the compound described herein (or a pharmaceutically acceptable salt thereof) 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 compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • 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 (including sprinkle capsule and gelatin 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 a lotion, cream, or ointment.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Example Methods of Treatment/Use The compounds described herein are inhibitors of KRAS G12C and therefore may be useful for treating diseases wherein the underlying pathology is (at least in part) mediated by KRAS G12C.
  • diseases include cancer and other diseases in which there is a disorder of transcription, cell proliferation, apoptosis, or differentiation.
  • the method of treating cancer in a subject in need thereof comprises administering to the subject an effective amount of any of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • the compound may be a compound of Formula IV or IV' (such as a compound of Formula IVa, IVb, IVc, IVa', IVb', or IVc'), or a pharmaceutically acceptable salt thereof.
  • the cancer may be selected from carcinoma (e.g., a carcinoma of the endometrium, bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma)), sarcoma (e.g., a sarcoma such as Kaposi's, osteosarcoma, tumor of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma), kidney, epidermis, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix,
  • carcinoma
  • lymphoid lineage e.g. leukemia, acute lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukaemia, B-cell lymphoma (such
  • cancers include a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; seminoma; teratocarcinoma; xeroderma pigmentosum; retinoblastoma; keratoctanthoma; and thyroid follicular cancer.
  • the treated cancer is selected from pancreatic cancer, gall bladder, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, and bile duct cancer.
  • the treated cancer is selected from pancreatic cancer, colorectal cancer, and lung cancer (including non-small cell lung cancer).
  • the subject is a mammal, for example, a human.
  • methods of inhibiting KRAS G12C in a cell comprising contacting said cell with any of the compounds described herein, or a pharmaceutically acceptable salt thereof, such that KRAS G12C enzyme is inhibited in said cell.
  • the cell is a cancer cell.
  • proliferation of the cell is inhibited or cell death is induced.
  • a method of treating a disease treatable by inhibition of KRAS G12C in a subject comprising administering to the subject in recognized need of such treatment, an effective amount of any of the compounds described herein and/or a pharmaceutically acceptable salt thereof.
  • Diseases treatable by inhibition of KRAS G12C include, for example, cancers.
  • Further exemplary diseases include pancreatic cancer, gall bladder, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, and bile duct cancer.
  • the methods of treatment comprise administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Individual embodiments include methods of treating any one of the above-mentioned disorders or diseases by administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Certain embodiments include a method of modulating KRAS G12C activity in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • Additional embodiments provide a method for the treatment of a disorder or a disease mediated by KRAS G12C in a subject in need thereof, comprising administering to the subject an effective amount of the compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, IV', IVa', IVb', IVc', V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof.
  • inventions provide a method of treating a disorder or a disease mediated by KRAS G12C, in a subject in need of treatment thereof comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the disorder or the disease is selected from carcinomas with genetic aberrations that activate KRAS activity. These include, but are not limited to, cancers.
  • the present method also provides the use of a compound of invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by KRAS G12C.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof is used for the treatment of a disorder or a disease mediated by KRAS G12C.
  • Yet other embodiments of the present method provide a compound according to Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, IV', IVa', IVb', IVc', V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Still other embodiments of the present method encompass the use of a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, IV', IVa', IVb', IVc', V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by KRAS G12C.
  • Example of Predicted Affinity for KRAS G12C of Example Compounds The covalent KRAS G12C inhibitor MRTX1257: is known in the art to be potent and selective, and has been shown to have desirable pharmacokinetic properties.
  • MRTX1257 has also been shown to have desirable efficacy in xenograft models of cancer.
  • MOE version 2019.0101 Molecular Operating Environment, Chemical Computing Group, Montreal, CA
  • compounds were covalently docked into a modified version of KRAS G12C protein (PDB accession code 6N2K).
  • the receptor geometry was generated by minimization of the binding site residues of 6N2K in the presence of MRTX1257.
  • Estimated binding affinities (in arbitrary units) were computed for each compound covalently docked into this modified receptor, where more negative values correspond to higher estimated predicted affinities. See Table 1.
  • the predicted binding affinity of MRTX1257 in this receptor was -10.7148.
  • Additional specific embodiments of the invention include those compounds listed in Table 2.
  • the identifying number (“Cmpd”), the chemical structure (“Structure”), and the predicted binding affinity for KRAS G12C (in arbitrary units, A.U.) (“Score”) from two distinct methods (“MMGBSA” and “CovDock”) are disclosed for each compound.
  • Specific embodiments of the invention include those compounds listed in Table 3B.
  • the identifying number (“Cmpd”), the chemical structure (“Structure”), and the example method used to synthesize the compound (“Method”) are disclosed for each compound. INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
  • Example 1 Synthesis of Tetrahydronaphthalene, Tetrahydroquinoline and Chromane Functionalized Compounds Preparation of Intermediate 1-1
  • Intermediate 1-1 The starting material, 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.288 g, 6.34 mmol), was dissolved in tetrahydrofuran (25 mL) and transferred into a cold (-78°C) solution of lithium diisopropylamide (7.3 mmoles, 0.5 M solution in tetrahydrofuran/hexane, freshly prepared from diisopropylamine/n-BuLi).
  • Compounds obtained with this synthetic route include, but are not limited to, those where X is H, Cl, F, OH, CH 3 or OCH 3 , R, in each occurrence and if present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or 2.
  • X is H, Cl, F, CH 3 or OCH 3 , R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or
  • Compounds obtained with this synthetic route include, but are not limited to, those where X is H, Cl, F, CH 3 or OCH 3 , R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or 2.
  • the catalyst for the Tsuji step can be chosen in an R or S configuration to yield an enantioenriched product at the quaternary stereo center.
  • Compounds obtained with this synthetic route include, but are not limited to, those where X is H, Cl, F, CH 3 or OCH 3 , R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or 2.
  • R in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or 2.
  • R substituents for R would be readily apparent to one of skill in the art, particularly those substituents that are found in commercially available molecules used in the first step of this synthesis.
  • the amine in the morpholine can be substituted with optionally substituted alkyl using procedures that would be readily apparent to a person of ordinary skill in the art.
  • the ketone in compounds obtained with this synthetic route can be transformed to C(H)OH, CH 2 , OCH 3 , C(H)F or CF 2 using procedures that would be known to a person of ordinary skill in the art.
  • Example 2 Synthesis of Indane Functionalized Compounds This synthesis produces racemic mixtures, and separation of the enantiomers using chiral HPLC or SFC chromatography with optimized conditions would be readily achieved by one of ordinary skill in the art.
  • Compounds obtained with this synthetic route include, but are not limited to, those where X is H, Cl, F, CH 3 or OCH 3 , R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cycl
  • Compounds obtained with this synthetic route include, but are not limited to, those where X is H, Cl, F, CH 3 or OCH 3 , R, in each occurrence and when present, is independently H, OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclopropyl or cyclobutyl, and n is 0, 1 or 2.
  • Example 4 Synthesis of Compounds C-1 through C-8, C-15 and C-16 Synthesis of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline A solution of 5,6,7,8-tetrahydroquinazoline-2,4-diol (750 g, 4.51 mol) in POCl 3 (3.30 kg, 21.5 mol) was stirred at 110 °C for 4 hours.
  • the headspace was purged with argon and the vial was capped.
  • the mixture was stirred at room temperature for 30 minutes before being warmed to 40°C and stirring overnight.
  • the mixture was cooled, diluted with DCM (5 mL), and filtered through a plug of celite, which was washed with more DCM (20 mL).
  • the headspace was purged with argon, MeCN (4 mL) was added, and the vial was capped. The mixture was warmed to 80°C and stirred overnight. Upon completion, the mixture was cooled, diluted with DCM (5 mL), and filtered through a plug of celite, which was washed with more DCM (20 mL).
  • reaction mixture was diluted with DCM (2 mL) and filtered through a plug of celite, washing with more DCM (10 mL). The solvent was removed in vacuo and the crude tert-butyl (2S)-2-(cyanomethyl)-4-((2R)-4-methyl-2'-(((S)- 1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene- 2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.
  • the mixture was stirred at room temperature for 30 minutes before being warmed to 40°C and stirred overnight. Upon completion, the mixture was cooled, diluted with DCM (15 mL), and filtered through a plug of celite, which was washed with more DCM (30 mL).
  • the vial was sealed and placed under a hydrogen atmosphere using a balloon. The reaction was vigorously stirred overnight. Upon completion, the reaction mixture was diluted with DCM (5 mL) and filtered through a plug of celite, washing with more DCM (20 mL).
  • Tetralin-1-one (3.64 mL, 27 mmol) was added and the mixture was warmed to room temperature and treated with diallyl carbonate (5.89 mL, 41 mmol). The mixture was stirred for 12 hours then carefully quenched by the addition of sat NH4Cl then extracted with EtOAc (3 times). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered through a thin pad of silica gel, and concentrated.
  • allyl 2-(4-ethoxy-4-oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate (3.27 g, 9.5 mmol) was dissolved in toluene (40 mL) and sparged for 20 minutes, then added to the catalyst mixture and stirring continued for 15 hours.
  • the reaction was opened to air and amended with a small amount of silica gel and stirred for 5 minutes, then filtered through a thin pad of silica gel rinsing with 8:2 hexanes:EtOAc.
  • the vessel was evacuated and backfilled with H 2 then heated to 90°C for 2 hours.
  • the mixture was cooled, filtered through Celite, concentrated, and co-evaporated from toluene once, then further dried in vacuo to give the crude 4-(2-fluorophenyl)butanoic acid (6.40 g, 35.1 mmol, 98% yield).
  • Rf 0.39 (7:3 hexanes:EtOAc + 2% AcOH), which was carried on to the next step without further purification.
  • intermediate 6-1 allyl 2-(4-ethoxy-4-oxobutyl)-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (2.3 g, 6.4 mmol), was dissolved in MTBE (40mL) and sparged for 20 minutes then added to the catalyst mixture. After 16 hours, the reaction was opened to air and amended with 0.3 vol hexanes and a small amount of silica gel.
  • Boc 2 O 49 ⁇ L, 0.21 mmol was added and stirring continued for 2 hours.
  • the mixture was then diluted with EtOAc and washed with sat NH 4 Cl, brine, dried over Na 2 SO 4 , concentrated, and purified by flash column chromatography on silica gel (0 ⁇ 30% EtOAc in hexanes) to give tert-butyl (R)-4-((R)-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'- quinazolin]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (84.3 mg, >100% yield) as a white foam.
  • the headspace was purged with argon and the flask was fitted with a condenser.
  • the mixture was stirred at room temperature for 30 minutes before being warmed to 50°C and stirring overnight. Upon completion, the mixture was cooled, diluted with DCM (50 mL), and filtered through a plug of celite, which was washed with more DCM (100 mL).
  • di-tert-butyl dicarbonate (240 mg, 1.1 mmol) was added and the reaction was heated to 40°C and stirred for 2 hours.
  • the reaction mixture was cooled to room temperature and poured into saturated NaHCO 3 (15 mL, aq.) and extracted with DCM (10 mL * 3). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Boc 2 O (85.3 ⁇ L, 0.37 mmol) was added and the mixture was stirred for 15 hours then diluted with EtOAc and washed with sat NH 4 Cl, brine, dried over Na 2 SO 4 , filtered through a thin pad of silica gel, and concentrated.
  • Boc 2 O (85 ⁇ L, 0.37 mmol) was then added and stirring continued for 16 hours.
  • the mixture was diluted with EtOAc and washed with half-saturated NaHCO 3 (2 times), brine, dried over Na 2 SO 4 , filtered through a thin pad of silica gel, and concentrated, and purified by flash column chromatography on silica gel (0 ⁇ 30% EtOAc in hexanes) to give tert-butyl (R)-4-((S)-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene- 2,7'-quinazolin]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (148.1 mg, >100% yield) as a white foam.
  • allyl 2-(4-ethoxy-4- oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (2.68 g, 7.8 mmol) was dissolved in toluene (30 mL) and sparged with N 2 for 20 minutes then added to the catalyst mixture. After 13 hours, the reaction was warmed to 40°C. After an additional 24 hours, the mixture was cooled, opened to air, and amended with a small amount of silica gel and stirred for 10 minutes, then filtered through a thin pad of silica gel.
  • allyl 2-(3-ethoxy-3-oxopropyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate 255.1 mg, 0.77 mmol was dissolved in MTBE (5 mL) and sparged for 20 minutes, then added to the catalyst mixture and the reaction was stirred at 25°C. After 14 hours, the reaction was opened to air and amended with a small amount of silica gel and stirred for 10 minutes then filtered through a thin pad of silica gel rinsing with 1:1 hexanes:EtOAc.
  • the vessel was charged with H 2 and stirred for 15 hours then filtered through Celite and concentrated. The residue was dissolved in Methanol (5 mL), cooled to 0°C, and treated with SOCl 2 (340 ⁇ L, 4.6 mmol) then warmed to room temperature. After 70 minutes, the mixture was poured into H 2 O and extracted with EtOAc (2 times).
  • Boc 2 O (77.2 mg, 0.35 mmol) was added and the mixture was stirred overnight.
  • the mixture was poured into saturated NaHCO 3 and extracted with EtOAc (3 times). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (5 ⁇ 40% EtOAc in hexanes).
  • Individual stereoisomers of the spirocyclic center may be prepared by catalytic and/or stereoselective variants of the above reaction sequence, or may be resolved from the racemic form by chiral chromatography or other conventional techniques.
  • Compounds obtained by this synthetic route include, but are not limited to, those where X is H, F, CH 3 , or OCH 3 ; R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclo
  • Individual stereoisomers of the spirocyclic center may be prepared by catalytic and/or stereoselective variants of the above reaction sequence, or may be resolved from the racemic form by chiral chromatography or other conventional techniques.
  • Compounds obtained by this synthetic route include, but are not limited to, those where X is H, F, CH 3 , or OCH 3 ; R, in each occurrence and when present, is independently OH, F, Cl, Br, N(R 3 ) 2 , CF 3 , OCF 3 , SCF 3 , CH 3 , CFH 2 , OCFH 2 , SCFH 2 , OCH 3 , SCH 3 , (W) q CF 2 H, (W) q C 2 -C 4 alkyl, (W) q C 2 -C 4 haloalkyl, (W) q C 2 -C 4 alkenyl, (W) q C 2 -C 4 alkynyl, CN, cyclo
  • KRASG12C (1 ⁇ M) was incubated at 22oC with test compounds at a final concentration of 10 ⁇ M in a buffer containing 20 mM HEPES, 150 mM NaCl, 1 mM MgCl 2 , 1 mM DTT, pH 7.5 and a final DMSO concentration of 2 % vol. Aliquots were removed at 0, 1, 3, 5, and 30 minutes, quenched by dilution into 0.1 volume of 6.2% formic acid, and analyzed by HPLC-MS using a Water Acquity equipped with a Waters LCT Premier XE. Mass spectra were deconvoluted using MaxEnt and the extent of inhibitor incorporation was measured ratiometrically.
  • the pseudo-first kobs/[I] (M -1 •s -1 ) order rate constant was calculated from the rate determined by non-linear least squares fitting to the first order rate equation:
  • Cell Line Growth Retardation Assay Cells were seeded at densities of 1,000-5,000 cells per well in 48-well tissue culture plates. After a 24 h rest period, cells were treated with compound at 10 ⁇ M, 1 ⁇ M, 0.4 ⁇ M, 0.08 ⁇ M, 0.016 ⁇ M, and 0.0032 ⁇ M. A group of cells were treated with the vehicle in which the compound was prepared and served as a control. Prior to treatment, cells were counted and this count was used as a baseline for the calculation of growth inhibition.
  • the cells were grown in the presence of compounds for 6 days and were counted on day 6. All cell counting was performed using a Synentec Cellavista plate imager. Growth inhibition was calculated as a ratio of cell population doublings in the presence of compound versus the absence of compound. If treatment resulted in a net loss of cells from baseline, percent lethality was defined as the decrease in cell numbers in treated wells compared with counts on day 1 of non-treated wells post-seeding. IC 50 values for each compound were calculated by fitting curves to data points from each dose–response assay using the Proc NLIN function in SAS for Windows version 9.2 (SAS Institute, Inc.).
  • IC 50 s were calculated for each cell line using the same technique described above. Average IC 50 s for the sensitive and resistant cohorts were calculated as arithmetic means of the group. See Table 4. “A” represents an IC 50 of 1 ⁇ M or less, “B” represents an IC 50 of greater than 1 ⁇ M and less than 5 ⁇ M, and “C” represents an IC 50 of greater than 5 ⁇ M.
  • Caco-2 Assay (P app A to B) The degree of bi-directional human intestinal permeability for compounds was estimated using a Caco-2 cell permeability assay. Caco-2 cells were seeded onto polyethylene membranes in 96-well plates.
  • the growth medium was refreshed every 4 to 5 days until cells formed a confluent cell monolayer.
  • HBSS with 10 mM HEPES at pH 7.4 was used as the transport buffer.
  • Compounds were tested at 2 ⁇ M bi-directionally in duplicate.
  • Digoxin, nadolol and metoprolol were included as standards.
  • Digoxin was tested at 10 ⁇ M bi-directionally in duplicate, while nadolol and metoprolol were tested at 2 ⁇ M in the A to B direction in duplicate.
  • the final DMSO concentration was adjusted to less than 1% for all experiments.
  • the plate was incubated for 2 hours in a CO 2 incubator at 37°C, with 5% CO 2 at saturated humidity.
  • Efflux Ratio P app (BA) / P app (AB)
  • Vd is the volume in the donor chambers, which are 0.075 mL on the apical side and 0.25 mL on the basolateral side
  • C d and C r are the final concentrations of transport compound in donor and receiver chambers, respectively.
  • Measurement of Compound Metabolic Stability The metabolic stability of compounds was determined in hepatocytes from human, mice and rats.
  • % Remaining Compound Peak Area Ratios of Tested Compound vs. Internal Standard at End Point Peak Area Ratios of Tested Compound vs.
  • IC 50 values were used to select compounds having structural and functional features defined in the subgenera of Formula (IIIa).
  • a desirable property of compounds examined in sensitive and resistant cell lines, as described above, is having an average IC 50 for the drug-sensitive cell lines of Table 5 of about 1 ⁇ M or lower and having an average IC 50 for the drug-resistant cell lines of Table 5 of greater than 1 ⁇ M.
  • Table 3A Table 3B. Table 4. Table 5.

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Abstract

L'invention concerne des composés de formule I, et des sels pharmaceutiquement acceptables de ceux-ci, et des procédés de fabrication et d'utilisation de ceux-ci. Les composés de l'invention sont efficaces pour inhiber la protéine KRAS avec une mutation G12C et sont appropriés pour être utilisés dans des procédés de traitement de cancers à médiation, en totalité ou en partie, par mutation de KRAS G12C.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023086383A1 (fr) * 2021-11-09 2023-05-19 1200 Pharma Llc Inhibiteurs de kras g12c sélectionnés et leurs utilisations
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035031A1 (fr) * 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035031A1 (fr) * 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023086383A1 (fr) * 2021-11-09 2023-05-19 1200 Pharma Llc Inhibiteurs de kras g12c sélectionnés et leurs utilisations
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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