COMPOUND, PHARMACEUTICAL COMPOSITION, USES OF A COMPOUND AND CONJUGATE

Description

"Compound, Pharmaceutical Composition, Uses of a Compound and Conjugate" Divided from BR 11 2024 006769-6 Background of the Invention

[0001] The vast majority of small molecule drugs act by binding to a functionally important pocket in a target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMGCoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many of these drug / target interaction pairs are known may have led some to believe that a small molecule modulator could be discovered for most, if not all, proteins given a reasonable amount of time, effort, and resources. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered refractory or intractable to the discovery of the aforementioned small molecule drugs.These targets are commonly referred to as "drug-resistant" targets. These drug-resistant targets include a vast and largely unexplored reservoir of clinically important human proteins. Thus, there is great interest in discovering new molecular modalities capable of modulating the function of such drug-resistant targets.

[0002] It has been well established in the literature that Ras proteins (KRas, H-Ras, and N-Ras) play an essential role in several human cancers and are therefore appropriate targets for anticancer therapy. In fact, mutations in Ras proteins are responsible for approximately 30% of all human cancers in the United States, many of which are fatal. The dysregulation of Ras proteins by activation mutations, overexpression, or Petition 870260055674, dated 09 / 06 / 2026, page 15 / 412 2 / 328 Upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by inhibiting the intrinsic and GTP-dependent GTPase activator protein (GAP) hydrolysis rates of GTP, significantly shifting the population of mutant Ras proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts against Ras over the past decades, only one drug targeting the K-Ras G12C mutant has been approved (sotorasib). Further efforts are needed to discover additional drugs for cancers driven by other Ras mutations. Brief Description of the Invention

[0004] Ras inhibitors are provided here. The approach described here involves the formation of a high-affinity, three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras) and a widely expressed cytosolic chaperone (presenting protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described here induce a novel binding pocket in Ras, leading to the formation of a high-affinity triple complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA). Without being limited by theory, the inventors believe that one way in which the effect Petition 870260055674, dated 09 / 06 / 2026, page 16 / 412 3 / 328 The inhibitory effect on Ras is effected by the compounds of the invention and the complexes, or conjugates, they form by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF and PI3K, which are necessary to propagate the oncogenic signal.

[0005] As such, in some embodiments, the invention provides a compound, or pharmaceutically acceptable salt thereof, of structural formula I: where A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each selected independently from CH2, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, Petition 870260055674, dated 09 / 06 / 2026, page 17 / 412 4 / 328 isotopically enriched for deuterium.

[0006] In some embodiments, the invention provides a compound, or pharmaceutically acceptable salt thereof, of structural formula II: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0007] In some embodiments, the invention provides a compound, or pharmaceutically acceptable salt thereof, of structural formula V: Petition 870260055674, dated 09 / 06 / 2026, page 18 / 412 5 / 328 wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0008] In some embodiments, the invention provides a compound, or pharmaceutically acceptable salt thereof, of structural formula VI: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is C1-C6 optionally substituted alkyl, 3 to 6 cycloalkyl Petition 870260055674, dated 09 / 06 / 2026, page 19 / 412 6 / 328 members optionally substituted or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0009] In some embodiments, the invention provides a compound, or pharmaceutically acceptable salt thereof, of structural formula VII: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0010] In some embodiments, the invention also provides a compound, or pharmaceutically acceptable salt thereof, selected from Petition 870260055674, dated 09 / 06 / 2026, page 20 / 412 7 / 328 Table 1 or Table 2.

[0011] Pharmaceutical compositions are also provided comprising a compound of Formula I, Formula II, Formula V, Formula VI or Formula VII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Pharmaceutical compositions are also provided comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] Also provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, a method is provided for treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0014] A method is further provided for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0015] It is specifically contemplated that any limitation discussed in relation to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention. Petition 870260055674, dated 09 / 06 / 2026, p. 21 / 412 8 / 328 Chemical Definitions and Terms

[0016] In this application, unless otherwise indicated in the context, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or”, unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the invention supports a definition that refers only to alternatives and “and / or”; (iii) the terms “comprising” and “including” are understood as encompassing discriminated components or steps, presented separately or in conjunction with one or more additional components or steps; and (iv) where ranges are provided, outcomes are included.

[0017] As used in this document, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method to be employed in determining the value. In certain embodiments, the term “about” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater or less than) of a stated value, unless stated otherwise or otherwise evident from the context (for example, when such a number exceeds 100% of a possible value).

[0018] As used in this document, the term “adjacent” in the context of describing adjacent atoms refers to divalent atoms that are directly connected by a covalent bond.

[0019] A “compound of the present invention” and similar terms as used herein, whether explicitly stated or not, refer to Ras inhibitors described herein, including compounds of any of Formula I to Formula VII, or subformulas thereof, and compounds of Table 1 or Table 2, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers thereof. Petition 870260055674, dated 09 / 06 / 2026, p. 22 / 412 9 / 328

[0020] The expression “wild type” refers to an entity having a structure or activity as found in nature in a “normal” state or context (as opposed to mutant, diseased, altered, etc.). Those versed in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0021] Those skilled in the art will appreciate that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., wherein one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium). Unless otherwise indicated or clear from the context, a represented structure may be understood as representing any isomeric or isotopic form, individually or in combination.

[0022] The compounds described herein may be asymmetric (e.g., with one or more stereocenters). All stereoisomers, such as diastereomers and enantiomers, are targeted unless otherwise indicated. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[0023] In some forms, one or more compounds here Petition 870260055674, dated 09 / 06 / 2026, p. 23 / 412 10 / 328 described may exist in different tautomeric forms. As will become clear from the context, unless explicitly excluded, references to such compounds encompass all these tautomeric forms. In some embodiments, tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state with the same empirical formula and total charge as a reference form. Examples of fractions with prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.In some embodiments, the tautomeric forms may be in equilibrium or sterically blocked in one form by appropriate substitution. In certain embodiments, the tautomeric forms result from acetal interconversion.

[0024] Unless otherwise indicated, the structures described in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds (e.g., those labeled with 3H and 14C) may be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes may be useful for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain... Petition 870260055674, dated 09 / 06 / 2026, page 24 / 412 11 / 328 Therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by carbon enriched by 13C- or 14C. Positron-emitting isotopes, such as 15O, 13N, 11C, and 18F, are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labeled compounds are known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared following procedures analogous to those disclosed for the compounds of the present invention described herein, replacing an isotopically labeled reagent with a non-isotopically labeled reagent.

[0025] As used interchangeably herein, “deuterium substituted”, “deuterated” or “deuterium enriched” refers to a compound of the invention, or a fraction thereof, having a deuterium (D or 2H) level that has been enriched to be greater than 0.015%, the natural abundance of deuterium. In certain embodiments, a composition of the invention has a minimum isotopic enrichment factor of at least 5 (0.075% deuterium incorporation), for example, at least 10 (0.15% deuterium incorporation). In other embodiments, a composition has an isotopic enrichment factor of at least 50 (deuterium incorporation at 0.75%), at least 500 (deuterium incorporation at 7.5%), at least 2,000 (deuterium incorporation at 30%), at least 3,000 (deuterium incorporation at 45%), at least 4,000 (deuterium incorporation at 60%), at least 4,500 (deuterium incorporation at 67.5%), at least 5,000 (deuterium incorporation at 75%), at least 5.500 (82.5% deuterium incorporation), at least 6,000 (90% deuterium incorporation), or at least 6,600 (99% deuterium incorporation).

[0026] Non-limiting examples of fractions that may contain a Petition 870260055674, dated 09 / 06 / 2026, page 25 / 412 12 / 328 or more deuterium substitutions in compounds of the present invention, wherein any “R” position can be deuterium (D), include: Additional examples include fractions, such as: R and deuteration of fractions similar to R1, where the definition of R1 is found in this document (for example, in compounds of any of Formulas I-VII). Deuteration of fractions within a crosslinking group (for example, an optionally substituted aziridine fraction) in compounds of the present invention is also contemplated, where the crosslinking group is defined in this document (see, for example, Generic Formulas IVII and their subformulas, as well as specific examples of W described in this document, such as: Petition 870260055674, dated 09 / 06 / 2026, p. 26 / 412 13 / 328 ). Furthermore, the deuteration of available positions in any fraction A of compounds of The formulas described here are also included, such as: Furthermore, deuterium substitution can also occur in compounds of the present invention in the ligand position of compounds of the formulas described herein, such as:

[0027] In Another option, silylation substitution, is also considered, as is the position of the ligand, as follows: , or . Additional examples of silylation include fractions such as: Petition 870260055674, dated 09 / 06 / 2026, p. 27 / 412 14 / 328 and silylation substitution of like fractions of type R1, where the definition of R1 is found in this document (e.g., in compounds of any of Formulas I-VII).

[0028] As is known in the art, many chemical entities can adopt a variety of different solid forms, such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any of these forms, including in any solid form. In some embodiments, the compounds described or represented in this document can be supplied or used in hydrate or solvate form.

[0029] In several places in this descriptive report, the substituents of the compounds of the present invention are disclosed in groups or in bands. It is specifically intended that the present invention includes any and all individual subcombinations of the members of these groups and bands. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions in which the substituents are disclosed in groups or in bands, unless otherwise indicated, the present invention is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing any and all individual subcombinations of members at each position.

[0030] The term “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, where X is Petition 870260055674, dated 09 / 06 / 2026, p. 28 / 412 15 / 328 optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described in this document, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are substituted by a suitable substituent, for example, any of the substituents or groups described herein.For example, in the term “optionally substituted C1-C6 alkyl-C2C9 heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. The combinations of substituents provided for by the present invention are preferably those that result in the formation of stable or chemically viable compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed in this document.

[0031] Suitable monovalent substituents on a replaceable carbon atom of an “optionally substituted” group may independently be deuterium; halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o4R°. [OO32]-O-(CH2)o-4C(O)OR°; -(CH2)o-4CH(OR°)2; -(CH2)o-4SR°; (CH2)o-4Ph, which can be replaced by R°; -(CH2)o-4O(CH2)o-1Ph which can be replaced by R; -CH=CHPh, which can be replaced by R°; -(CH2)oPetition 870260055674, dated 09 / 06 / 2026, page 29 / 412 16 / 328 4O(CH2)o-pyridyl that can be substituted by R; Saturated or unsaturated heterocycloalkyl of 4 to 8 members (e.g., pyridyl); Saturated or unsaturated cycloalkyl of 3 to 8 members (e.g., cyclopropyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)o4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)o-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(O)R°; -C(S)R°; -(CH2)o4C(O)OR°; -(CH2)o-4-C(0)-N(R°)2; -(CH2)o-4-C(O)-N(R°)-S(O)2-R°; -C(NCN)NRo2; -(CH2)o-4C(O)SR°; -(CH2)o-4C(O)OSiR°3; -(CH2)o-4OC(O)R°; -OC(O)(CH2)o-4SR°; -SC(S)SR°; -(CH2)o-4SC(O)R°; -(CH2)o-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; (CH2)o-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°;C(NOR°)R°; -(CH2)o-4SSR°; -(CH2)o-4S(0)2R°; -(CH2)o-4S(0)20R°; -(CH2)o4OS(O)2R°; -S(O)2NR°2; -(CH2)o-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°;N(OR°)R°; -C(N0Ro)NRO2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(0)(0Ro)2;OP(O)R°2; -OP(O)(OR°)2;-0P(0)(0Ro)Ro, -SiR°3; -(C1-C4 straight or branched alkylene)ON(R°)2; or -(C1-C4 straight or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-C6 aliphatic, -CH2Ph, -O(CH2)o-1Ph, -CH2(5- to 6-membered heteroaryl ring), or a saturated, partially unsaturated 3- to 6-membered aryl ring having o-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, taken together with their intervening atom(s), form a saturated, partially unsaturated or aryl mono- or bicyclic ring of 3- to 12 members having o-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0033] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) may independently be halogen, -(CH2)o-2R*, Petition 870260055674, dated 09 / 06 / 2026, page 30 / 412 17 / 328 -(haloR·), -(CH2)o-2OH, -(CH2)o-2OR·, -(CH2)q-2CH(OR')2; -O(haloR·), -CN, -N3, -(CH2)o-2C(O)R·, -(CH2)q-2C(O)OH, -(CH2)q-2C(O)OR· -(CH2)q-2SR· -(CH2)q2SH, -(CH2)q-2NH2, -(CH2)q-2NHR·, -(CH2)q-2NR^2, -NO2, -SiR^3, -OSiR\ C(O)SR· -(C1-4 linear or branched alkylene)C(O)OR·, or -SSR· wherein each R· is unsubstituted or where preceded by “halo” is substituted only by one or more halogens and is independently selected from aliphatic C1-C4, CH2Ph, -O(CH2)o-iPh, or a partially saturated 5- to 6-membered ring unsaturated or aryl with q-4 heteroatoms selected independently from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include = O and = S.

[0034] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =nr*, =nor*, O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from C1-6 aliphatic hydrogen that may be substituted as defined below, or a saturated, partially unsaturated 5- to 6-membered unsubstituted aryl ring with q-4 heteroatoms selected independently from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are attached to vicinal replaceable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from C1-C6 aliphatic hydrogen may be substituted as defined below, or a 5- to 6-membered unsubstituted saturated, partially unsaturated or aryl ring with q-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0035] Suitable substituents in the aliphatic group of R* include halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR·), -CN, -C(O)OH, -C(O)OR·, NH2, -NHR·, -NRV or -NO2, wherein each R· is unsubstituted or where preceded by “halo” is substituted only by one or more halogens and is Petition 870260055674, dated 09 / 06 / 2026, page 31 / 412 18 / 328 independently C1-C4 aliphatic, -CH2Ph, -O(CH2)o-iPh, or a saturated, partially unsaturated, or aryl ring of 5 to 6 members with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on a replaceable nitrogen of an “optionally substituted” group include -Rf, -NRf2, -C(O)Rf, -C(O)ORf, C(O)C(O)Rf, -C(O)CH2C(O)Rf, -S(O)2Rf, -S(O)2NRf2, -C(S)NRf2, -C(NH)NRf2, or -N(Rf)S(O)2Rf; wherein each Rf independently hydrogen, C1-C6 aliphatic which may be substituted as defined below, -OPh unsubstituted, or a saturated, partially unsaturated or aryl ring of 3 to 6 members unsubstituted with 0-4 heteroatoms independently selected of nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Rf, taken together with their intervening atoms, form a saturated, partially unsaturated or aryl mono- or bicyclic ring of 3 to 12 members unsubstituted with 0-4 heteroatoms independently selected of nitrogen, oxygen or sulfur.

[0037] Suitable substituents on an aliphatic group of Rf are independently halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR·), -CN, C(O)OH, -C(O)OR·, -NH2, -NHR·, -NR% or -NO2, wherein each R· is unsubstituted or wherein preceded by “halo” is substituted only by one or more halogens and is independently C1-C4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a saturated, partially unsaturated or aryl ring of 5 to 6 members with 0-4 heteroatoms selected independently from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of Rf include = O and = S.

[0038] The term “acetyl”, as used in this document, refers to the group -C(O)CH3.

[0039] The term “alkoxy”, as used in this document, refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the remainder of the Petition 870260055674, dated 09 / 06 / 2026, page 32 / 412 19 / 328 compound made up of an oxygen atom.

[0040] The term “alkyl”, as used in this document, refers to a saturated, linear or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., it is linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0041] The term “alkylene”, as used in this document, represents a divalent saturated hydrocarbon group derived from a linear or branched chain saturated hydrocarbon by the removal of two hydrogen atoms and is exemplified by methylene, ethylene, isopropylene and the like. The term “Cx-Cy alkylene” represents alkylene groups having x and y carbons between them. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (for example, C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene). In some embodiments, the alkylene may be further substituted by 1, 2, 3, or 4 substituent groups, as defined in this document.

[0042] The term “alkenyl”, as used in this document, represents monovalent linear or branched chain groups of, unless otherwise specified, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyls include cis and trans isomers. The term “alkenylene”, as used in this document, represents divalent linear or branched chain groups of, unless otherwise specified, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds. Petition 870260055674, dated 09 / 06 / 2026, p. 33 / 412 20 / 328

[0043] The term “alkynyl”, as used in this document, represents monovalent linear or branched chain groups of 2 to 20 carbon atoms (for example, 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0044] The term “amino”, as used in this document, represents -N(R^)2, for example, -NH2 and -N(CH3)2.

[0045] The term “aminoalkyl”, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with one or more amino moieties.

[0046] The term “amino acid,” as used in this document, refers to a molecule with a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). As used in this document, the term “amino acid,” in its broadest sense, refers to any compound or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid."Standard amino acid" refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. Petition 870260055674, dated 09 / 06 / 2026, page 34 / 412 21 / 328

[0047] The term “aryl”, as used in this document, represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, in which the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring may be attached to its pendant group on any heteroatom or carbon ring atom that results in a stable structure, and any of the ring atoms may optionally be substituted unless otherwise specified.

[0048] The term “Co”, as used in this document, represents a connection. For example, part of the term -N(C(O)-(Co-C5 alkylene-H)- includes N(C(O)-(C0 alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0049] The terms “carbocyclic” and “carbocyclyl”, as used herein, refer to an optionally substituted 3- to 12-membered monocyclic, bicyclic, or tricyclic ring structure that may be bridging, fused, or spirocyclic, in which all rings are formed from carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can optionally be substituted unless otherwise specified.

[0050] The term “carbonyl”, as used in this document, represents a C(O) group, which can also be represented as C=O.

[0051] The term “carboxyl”, as used in this document, means -CO2H, (C=O)(OH), COOH or C(O)OH or the non-protonated counterparts.

[0052] The term “cyan”, as used in this document, Petition 870260055674, dated 09 / 06 / 2026, p. 35 / 412 22 / 328 represents a group -CN.

[0053] The term “cycloalkyl”, as used in this document, represents a monovalent saturated cyclic hydrocarbon group, which may be bridging, fused or spirocyclic having from three to eight carbons in the ring, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0054] The term “cycloalkenyl”, as used in this document, represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which may be bridging, fused or spirocyclic, having three to eight carbons in the ring, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0055] The term “diastereomer”, as used in this document, means stereoisomers that are not mirror images of each other and are not superimposed on each other.

[0056] The term “enantiomer”, as used in this document, means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0057] The term “haloacetyl”, as used in this document, refers to an acetyl group in which at least one of the hydrogens has been replaced by a halogen.

[0058] The term “haloalkyl”, as used in this document, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same different halogen moieties.

[0059] The term “halogen”, as used in this document, represents a halogen selected from bromine, chlorine, iodine or fluorine. Petition 870260055674, dated 09 / 06 / 2026, p. 36 / 412 23 / 328

[0060] The term “heteroalkyl”, as used in this document, refers to an “alkyl” group, as defined herein, in which at least one carbon atom has been replaced by a heteroatom (for example, an O, N, or S atom). The heteroatom may appear in the middle or at the end of the radical.

[0061] The term “heteroaryl”, as used in this document, represents a monovalent, monocyclic or polycyclic ring structure containing at least one fully aromatic ring: that is, they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O or S in that aromatic ring. Exemplary unsubstituted heteroaryl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9) carbons. The term “heteroaryl” includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more aryl or carbocyclic rings, for example, a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl.A heteroaryl ring can be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. In some embodiments, the heteroaryl is substituted with the 1, 2, 3, or 4 substituent groups, as defined for a heterocyclyl group.

[0062] The term “heterocycloalkyl”, as used in this document, represents a monovalent, monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic, in which at least one ring is non-aromatic and in which the non-aromatic ring contains one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has from zero to two double bonds, and the 6- and 7-membered rings have from zero to three double bonds. Petition 870260055674, dated 09 / 06 / 2026, p. 37 / 412 24 / 328 double bonds. Exemplary unsubstituted heterocycloalkyl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heterocycloalkyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons or heteroatoms bridge to two non-adjacent members of a monocyclic ring, for example, a quinuclidinyl group. The term “heterocycloalkyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, for example, an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphtiridine.A heterocycloalkyl ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can optionally be substituted unless otherwise specified.

[0063] The term “hydroxy”, as used in this document, represents an -OH group.

[0064] The term “hydroxyalkyl”, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with one or more -OH moieties.

[0065] The term “isomer,” as used in this document, means any tautomer, stereoisomer, atropiomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention may have one or more chiral centers or double bonds and therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the Petition 870260055674, dated 09 / 06 / 2026, page 38 / 412 25 / 328 invention, the chemical structures represented in this document and, therefore, the compounds of the invention, encompass all corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, for example, racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0066] As used in this document, a “monovalent organic fraction” is less than 500 kDa. In some embodiments, a “monovalent organic fraction” is less than 400 kDa. In some embodiments, a “monovalent organic fraction” is less than 300 kDa. In some embodiments, a “monovalent organic fraction” is less than 200 kDa. In some embodiments, a “monovalent organic fraction” is less than 100 kDa. In some embodiments, a “monovalent organic fraction” is less than 50 kDa. In some embodiments, a “monovalent organic fraction” is less than 25 kDa. In some embodiments, a “monovalent organic fraction” is less than 20 kDa. In some embodiments, a “monovalent organic fraction” is less than 15 kDa. In some embodiments, a “monovalent organic fraction” is less than 10 kDa. In some embodiments, a "monovalent organic fraction" is less than 1 kDa. In some embodiments, a "monovalent organic fraction" is less than 500 g / mol.In some forms, a "monovalent organic fraction" ranges from 500 g / mol to 500 kDa. Petition 870260055674, dated 09 / 06 / 2026, p. 39 / 412 26 / 328

[0067] The term “stereoisomer”, as used in this document, refers to all possible different isomeric and conformational forms that a compound may possess (for example, a compound of any formula described herein), in particular all stereochemically and conformationally possible isomeric forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0068] The term “sulfonyl”, as used in this document, represents an -S(O)2- group.

[0069] The term “thiocarbonyl”, as used in this document, refers to a -C(S)- group.

[0070] Those skilled in the art, upon reading the present invention, will understand that certain compounds described herein may be supplied or used in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a specific form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form.In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound than a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing one conformational isomer ((Z) or (E)) of a double bond may be considered a different form from one containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is an isotope. Petition 870260055674, dated 09 / 06 / 2026, page 40 / 412 27 / 328 different from what is present in a reference preparation may be considered a different form. Brief Description of the Drawings

[0071] FIG. 1 shows that the covalent KRAS G12D inhibitors, Compound A and Compound B, representative of the compounds of the present invention, demonstrated strong and durable RAS pathway modulation in a KRASG12D / wt mouse HPAC xenograft model of human pancreatic adenocarcinoma. Modulation of the RAS / ERK signaling pathway was assessed by measuring the level of human DUSP6 mRNA in a qPCR assay. Both Compound A and Compound B led to inhibition of DUSP6 mRNA levels in HPAC xenografted tumors 4h after dosing, indicating strong RAS pathway modulation.

[0072] FIG. 2 shows that Compound A and Compound B exhibited strong tumor crosslinking at 4 hours and up to 24 hours, consistent with significant inhibition of DUSP6. Tumor samples collected from the assay in FIG. 1 were homogenized for protein extraction. Protein lysates were subjected to western blotting with Rabbit Ras mAb (Abcam ab108602) and β-actin mAb (CST-4967). The appearance of higher molecular weight (MW) bands (crosslinked KRAS G12D bands) is detected from tumor samples where the compounds covalently bind to KRAS G12D proteins.

[0073] FIG. 3A shows that both Compound A and Compound B, administered as single agents at 100 mg / kg po daily, led to regression of all tumors (regression defined as >10% tumor regression from baseline) at the end of treatment (Day 28 after treatment initiation) in a KRAS G12D heterozygous HPAC CDX mouse xenograft model.

[0074] FIG. 3B shows that there was no loss of body weight. Petition 870260055674, dated 09 / 06 / 2026, page 41 / 412 28 / 328 observed from Compound A (100 mg / kg po qd) or Compound B (100 mg / kg po qd), indicating that both compounds at 100 mg / kg are well tolerated in a KRASG12D / wtde HPAC mouse xenograft model of human pancreatic adenocarcinoma.

[0075] FIG. 3C shows that 8 of 10 tumors and 9 of 10 tumors achieved complete regression (complete regression defined as >85% tumor regression from baseline) on Day 28 in the Compound A (100 mg / kg po qd) and Compound B (100 mg / kg po qd) groups, respectively, in a KRASG12D / wt HPAC mouse xenograft model of human pancreatic adenocarcinoma. Detailed Description of the Invention Compounds

[0076] Ras inhibitors are provided here. The approach described here involves the formation of a high-affinity, three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras) and a widely expressed cytosolic chaperone (presenting protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described here induce a novel binding pocket in Ras, leading to the formation of a high-affinity triple complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA).Without being limited by theory, the inventors believe that one way in which the inhibitory effect on Ras is effected by the compounds of the invention and the complexes, or conjugates, they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF, which are necessary to propagate the oncogenic signal.

[0077] Without being limited by theory, the inventors postulate that Petition 870260055674, dated 09 / 06 / 2026, page 42 / 412 29 / 328 Both covalent and non-covalent interactions of a compound of the present invention with Ras and the chaperone protein (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. In some embodiments, a compound of the present invention forms a covalent adduct with a side chain of a Ras protein (e.g., the -CH2-COOH or -CH2-COO- side chain of aspartic acid at position 12 or 13 of a mutant Ras protein). Covalent adducts can also be formed with other Ras side chains. In addition, or alternatively, non-covalent interactions may be involved: for example, van der Waals, hydrophobic, hydrophilic, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors.Consequently, a variety of Ras proteins can be inhibited by compounds of the present invention (for example, K-Ras, N-Ras, H-Ras and mutants thereof at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D and Q61L and others described herein).

[0078] Methods for determining covalent adduct formation are known in the art. One method for determining covalent adduct formation is to perform a “crosslinking” test, as described below: Note - the following protocol describes a procedure for monitoring the crosslinking of K-Ras G12D (GMP-PNP) to a compound of the invention. This protocol can also be performed by substituting other Ras proteins or nucleotides.

[0079] The aim of this biochemical assay is to measure the ability of test compounds to covalently label nucleotide-loaded K-Ras isoforms. In assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 5 μM Cyclophilin A and 2 μM test compound, a 5 μM stock of GMP-PNP-loaded K-Ras (1-169) G12D is diluted 10 times to produce a final concentration of 0.5 μM; with the final sample volume being 100 μE. Petition 870260055674, dated 09 / 06 / 2026, p. 43 / 412 30 / 328

[0080] The sample is incubated at 25°C for a period(s) of up to 24 hours before quenching by the addition of 10 μL of 5% formic acid. Quenched samples are centrifuged at 15000 rpm for 15 minutes in a benchtop centrifuge before injecting a 10 μL aliquot onto a C4 reversed-phase column and eluting to the mass spectrometer with an increasing gradient of acetonitrile in the mobile phase. Raw data analysis can be performed using Waters MassLynx MS software, with % binding calculated from the deconvolved protein peaks for labeled and unlabeled K-Ras.

[0081] Therefore, a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula 0 is provided in this document: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each selected independently from CH2, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is C1-C6 optionally substituted alkyl, 3 to 6 cycloalkyl Petition 870260055674, dated 09 / 06 / 2026, page 44 / 412 31 / 328 members optionally substituted or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0082] In some embodiments, a compound of the present invention has the structure of Formula I, or a pharmaceutically acceptable salt thereof: Formula I wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each selected independently from CH2, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0083] In some embodiments, a compound of the present invention has the structure of Formula Ia, Formula Ib, Formula Ic or a pharmaceutically acceptable salt thereof: Petition 870260055674, dated 09 / 06 / 2026, p. 45 / 412 32 / 328 where each D indicates a hydrogen atom with an isotopic enrichment factor for deuterium of at least 5.

[0084] In certain embodiments, the invention relates to compounds having the structure of Formula II, or a pharmaceutically acceptable salt thereof: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. Petition 870260055674, dated 09 / 06 / 2026, page 46 / 412 33 / 328 optionally replaced; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0085] In some embodiments, a compound of the present invention has the structure of Formula V, or a pharmaceutically acceptable salt thereof: substituted, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0086] In some embodiments, a compound of the present Petition 870260055674, dated 09 / 06 / 2026, page 47 / 412 34 / 328 invention has the structure of Formula VI, or a pharmaceutically acceptable salt thereof: Formula VI wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0087] In certain embodiments, the invention relates to compounds having the structure of Formula VII, or a pharmaceutically acceptable salt thereof: Formula VII wherein A is optionally a 3- to 6-membered heterocycloalkylene Petition 870260055674, dated 09 / 06 / 2026, pp. 48 / 412 35 / 328 substituted, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0088] In some embodiments, a compound of the present invention has the structure of Formula Va, Formula Vb, Formula Vc or a pharmaceutically acceptable salt thereof: Petition 870260055674, dated 09 / 06 / 2026, pp. 49 / 412 36 / 328 where each D indicates a hydrogen atom with an isotopic enrichment factor for deuterium of at least 5.

[0089] In some embodiments, a compound of the present invention has the structure of Formula Vd, Formula Ve, Formula Vf or a pharmaceutically acceptable salt thereof: Formula Vd, D Formula Vee, Petition 870260055674, dated 09 / 06 / 2026, p. 50 / 412 37 / 328 where each D indicates a hydrogen atom with an isotopic enrichment factor for deuterium of at least 5.

[0090] In some embodiments, A is optionally substituted thiazol-di-yl, optionally substituted oxazol-di-yl, optionally substituted morpholine-di-yl, optionally substituted pyrrolidine-di-yl, optionally substituted piperidine-di-yl, or optionally substituted phenylene. In some embodiments, A is optionally substituted thiazol-di-yl or optionally substituted morpholine-di-yl. In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is: or In some modalities, A is

[0091] In some embodiments of a compound of the present invention, A is optionally substituted phenylene. In some embodiments, A is: In some modalities, A is Petition 870260055674, dated 09 / 06 / 2026, p. 51 / 412 38 / 328

[0092] In some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is an optionally substituted 6-membered heterocycloalkylene. In some embodiments, A is selected from a stereoisomer of the same: following, or In some embodiments, A is selected from the following, or a stereoisomer thereof:

[0093] In some embodiments of a compound of the present invention, R1 is optionally substituted hydrogen or a 3- to 10-membered heterocycloalkyl compound. In some embodiments of a compound of the present invention, R1 is a 3- to 10-membered heterocycloalkyl compound, optionally substituted. In some embodiments of a compound of the present invention, R1 is:

[0094] In some embodiments of a compound of the present , where each D indicates a hydrogen with an isotopic enrichment factor for deuterium of Petition 870260055674, dated 09 / 06 / 2026, p. 52 / 412 39 / 328 at least 5.

[0095] In some embodiments of a compound of the present invention, R2 is:Dou^CF3. [0096Emlãlgum^ embodiments of u^compound of the present invention, R2é:D, , D , orCF3, and where each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0097] In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments of a compound of the present and: or modalities, R3é: iTquil optionally replaced. In some models, R3éFqd3. ..... . r .jIn some modalities, R3e: N . In some Xc'CD, :^- , where each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0098] In some embodiments of a compound of the present invention, R3 is optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3 is: or . In some modalities, R3é:

[0099] In some embodiments of a compound of the present or invention, R3 is; R2 is or

[0100] In some modes, R2 is or A-CF3; R3 is or or NS Petition 870260055674, dated 09 / 06 / 2026, p. 53 / 412 40 / 328

[0101] In some embodiments of a compound of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X1 is CH2. In some embodiments, X2 is CH2. In some embodiments, X3 is CH2. In some embodiments, m is 1, n is 1 and each of X1, X2, and X3 is CH2.

[0102] In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Certain compounds of the present invention Petition 870260055674, dated 09 / 06 / 2026, page 54 / 412 41 / 328 Ex# Structure A3 A4 A5 Petition 870260055674, dated 09 / 06 / 2026, page 55 / 412 42 / 328 Ex# Structure A6 Petition 870260055674, dated 09 / 06 / 2026, page 56 / 412 43 / 328 Ex# Structure A9 A10 A11 Petition 870260055674, dated 09 / 06 / 2026, p. 57 / 412 44 / 328 Petition 870260055674, dated 09 / 06 / 2026, p. 58 / 412 45 / 328 Ex# Structure A15 A17 Petition 870260055674, dated 09 / 06 / 2026, p. 59 / 412 46 / 328 Ex# Structure A18 A19 Petition 870260055674, dated 09 / 06 / 2026, p. 60 / 412 47 / 328 Ex# Structure A21 A22 A23 Petition 870260055674, dated 09 / 06 / 2026, p. 61 / 412 48 / 328 Ex# Structure A24 A25 A26 Petition 870260055674, dated 09 / 06 / 2026, p. 62 / 412 49 / 328 Ex# Structure A27 A28 A29 Petition 870260055674, dated 09 / 06 / 2026, p. 63 / 412 50 / 328 Example: Structure / 1 ' ll DD A30 <z Hl J )= / / \ \--F F F MeO L· Â H 1 II VD j-rV A Ô 0 ft A31 < HI / J )= / 0 X ' r,x· Í Μβ%Λ A a s xdd A32 < Ml J )= / F F <i Petition 870260055674, dated 09 / 06 / 2026, p. 64 / 412 51 / 328 Ex# Structure A33 A34 A35 Petition 870260055674, dated 09 / 06 / 2026, p. 65 / 412 52 / 328 Ex# Structure A36 A37 A38 Petition 870260055674, dated 09 / 06 / 2026, p. 66 / 412 53 / 328 Petition 870260055674, dated 09 / 06 / 2026, p. 67 / 412 54 / 328 Petition 870260055674, dated 09 / 06 / 2026, p. 68 / 412 55 / 328 Ex# Structure B8 O. B9 Moo CF3 Petition 870260055674, dated 09 / 06 / 2026, page 69 / 412 56 / 328 Ex# Structure B28 °V QT° ο rA / > 7 / -N B29 Υν / αΧ Me0\ (Ά)H Γ x <z HJJ )= / O CF· <( B30 ^Z^ LXa / T / \ Q ’'M ω \__ / zz o \ )=o g o^z / o

[0103] Note that some compounds are shown with planar or wedge-shaped bonds. In some cases, the relative stereochemistry of the stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. In some cases, a single Example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the previous table are contemplated by the present invention. In particular embodiments, an atropisomer of a compound from the previous table is contemplated.

[0104] In some embodiments, a supplied compound is a Petition 870260055674, dated 09 / 06 / 2026, p. 70 / 412 57 / 328 compound shown in Table 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention is selected from Table 2 or a pharmaceutically acceptable salt or atropisomer thereof. Petition 870260055674, dated 09 / 06 / 2026, p. 71 / 412 58 / 328 Ex# Structure B4 B! B6 Petition 870260055674, dated 09 / 06 / 2026, p. 72 / 412 59 / 328 Petition 870260055674, dated 09 / 06 / 2026, p. 73 / 412 60 / 328 Example: Structure B13 A D0D N ' DD <f B14 / w MeO L- H Λ / / x hb O A ° < HI J >= / nAA Kl DU C > 'A0 N / DD<f B15 -F Aí A · / I ' i s O0À0 > =a DI C) D ad DD B16 0 Λ < / Petition 870260055674, dated 09 / 06 / 2026, p. 74 / 412 61 / 328 Ex# Structure B17 z / =0 / —Z / ~=i O=\ O ZI m \ o O '—Y )—( ! YQ ° ÍXV, B18 oo T | -zb—\ )=\ Ά-\ ° QH < M m / —N ok <í B20 O^,- C^N_O „ ​​​​V? % !X v00· J. Me0\_ A Ã o X < Ml J Π iD WDD <( Petition 870260055674, dated 09 / 06 / 2026, p. 75 / 412 62 / 328 Ex# Structure B21 B23 MeO ?!íxyí MeO CF3 Petition 870260055674, dated 09 / 06 / 2026, p. 76 / 412 63 / 328 The example corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the previous table are contemplated by the present invention. In particular embodiments, an atropisomer of a Petition 870260055674, dated 09 / 06 / 2026, p. 77 / 412 64 / 328, as shown in the previous table, is included.

[0106] In some embodiments, a compound of the present invention is a compound selected from Table 3, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is a compound selected from Table 3, or a pharmaceutically acceptable salt or atropisomer thereof.

[0107] In some embodiments, a compound of the present invention is not a compound selected from Table 3. In some embodiments, a compound of the present invention is not a compound selected from Table 3, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is not a compound selected from Table 3, or a pharmaceutically acceptable salt or atropisomer thereof. Petition 870260055674, dated 09 / 06 / 2026, page 78 / 412 65 / 328 Ex# Structure C3 C4 C C6 Petition 870260055674, dated 09 / 06 / 2026, page 79 / 412 66 / 328 The invention includes a cross-linking group (e.g., an optionally substituted aziridine moiety) linked to an organic moiety that is a Ras-binding moiety, wherein upon contact of the compound with a protein Petition 870260055674, dated 09 / 06 / 2026, page 80 / 412 67 / 328 In Ras, compounds bind to the Ras protein to form a conjugate. For example, the crosslinking group (e.g., an optionally substituted aziridine moiety) of the compound may link, for example, by crosslinking, with an amino acid of the Ras protein to form the conjugate. In some embodiments, the Ras-binding moiety is a K-Ras-binding moiety. In some embodiments, the K-Ras-binding moiety binds to a residue of a K-Ras Switch-II binding pocket of the K-Ras protein. In some embodiments, the Ras-binding moiety is an H-Ras-binding moiety that binds to a residue of an H-Ras Switch-II binding pocket of an H-Ras protein. In some embodiments, the Ras-binding moiety is an NRas-binding moiety that binds to a residue of an N-Ras Switch-II binding pocket of an N-Ras protein. The Ras-binding fraction typically has a molecular weight less than 1,200 Da. See, for example, Johnson et al., 292:12981-12993 (2017) for a description of Ras protein domains, incorporated here by reference.

[0109] In some embodiments, a compound of the present invention is or acts as a prodrug, such as with respect to administration to a cell or to a subject in need.

[0110] Pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are also provided.

[0111] A conjugate or salt thereof is also provided, comprising the structure of Formula III: M-P1; Formula III; where P1 is a monovalent organic fraction; and M has the structure of Formula IV: Petition 870260055674, dated 09 / 06 / 2026, page 81 / 412 68 / 328 Formula IV, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each selected independently from CH2, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen of Formula IV is independently, optionally, isotopically enriched for deuterium.

[0112] In some embodiments of the conjugates of the present invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12D or K-Ras G13D. In some embodiments of the conjugates of the present invention, M is linked to an amino acid residue of Petition 870260055674, dated 09 / 06 / 2026, p. 82 / 412 69 / 328 monovalent organic fraction.

[0113] In some embodiments, a compound of the present invention improved oral bioavailability (%F) compared to what is known in the art. Methods for measuring oral bioavailability are known in the art, and one such method is provided below: Oral bioavailability can be determined in BALB / c mice. Following intravenous (IV) bolus administration and oral gavage (PO) of a test compound, approximately 30 pL of whole blood samples are collected at designated time points in tubes containing K2EDTA. For some compounds, blood samples are centrifuged at 4,600 rpm at 4°C for approximately 5 minutes, and plasma samples are stored at -80°C before bioanalysis. Blood or plasma samples are extracted by protein precipitation and analyzed by tandem mass spectrometry (UPLC MS / MS) on, for example, an AB Sciex Triple Quad 6500+ mass spectrometer coupled to an Acquity UPLC system using positive ionization by electrospray.

[0114] All PK parameters can be derived from blood (or plasma) concentration over time with non-compartmental analysis data using WinNonlin. Bioavailability (F%, also %F) is estimated using the following equation (I): jllTCi ii F pij ÜÜSfljir F% =-- (I) AUCinf.po is the area under the blood (or plasma) concentration over time from time zero to infinity after PO administration; AUCinfjv is the area under the blood (or plasma) concentration over time from time zero to infinity after IV administration; Doseiv is the total dose administered IV; Petition 870260055674, dated 09 / 06 / 2026, page 83 / 412 70 / 328 Dosepo is the total dose administered orally.

[0115] In general, F% (or %F) values ​​greater than 10% are preferred.

[0116] Of the 19 compounds in Table 1 described herein that were tested for oral bioavailability, all but three had a %F greater than 10%. In addition, all but three crosslinked the G12D residue of K-Ras greater than 60% over a 6-hour period in the biochemical crosslinking assay described in this document. Thirteen of the compounds tested had both a %F greater than 10% and crosslinked the G12D residue of K-Ras more than 60%. Without being limited by theory, the inventors claim that the N-methylaziridine moiety of the compounds described herein is primarily responsible for this unexpected activity.

[0117] In some embodiments, a compound of the present invention is selective for one or more particular Ras mutants relative to other Ras or wild-type mutants compared to what is known in the art. Methods for measuring such selectivity are known in the art, such as the Ras-Raf binding assay, a protocol for which is provided herein: The aim of this biochemical assay is to measure the ability of the test compounds to facilitate the formation of the ternary complex between a nucleotide-laden Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFRBD construct, inhibiting Ras signaling via an RAF effector.

[0118] In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, unlabeled Cyclophilin A, His6-K-Ras-GMPPNP (or another Ras variant), and GST-BRAFrbd are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compound Petition 870260055674, dated 09 / 06 / 2026, p. 84 / 412 71 / 328 is present in plate wells as a 10-point, 3-fold dilution series, starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, a mixture of Anti-His Eu-W1024 and anti-GST allophycocyanin is then added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction is incubated for a further 1.5 hours. The TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate the disruption of a Ras:RAF complex are identified as those that cause a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0119] Consequently, in some embodiments, the compounds of the present invention are selective for KRASG12Dm with respect to other Ras mutants or with respect to the wild type. The compounds of the present invention may also exhibit greater selectivity with respect to other RAS mutants disclosed in this document, or combinations thereof.

[0120] In some embodiments, a compound of the present invention is more potent against one or more specific Ras mutants relative to other Ras or wild-type mutants compared to what is known in the art. Methods for measuring such potency are known in the art, such as the pERK assay, the protocol of which is provided in the Examples below. Consequently, in some embodiments, the compounds of the present invention exhibit greater potency against KRASG12Ddo than what is known in the art. The compounds of the present invention may also exhibit greater potency against other Ras mutants disclosed herein, or combinations thereof.

[0121] In some embodiments, a compound of the present invention exhibits a greater detrimental effect on cell viability in relation to one or more particular Ras mutants compared to other Ras or wild-type mutants compared to what is known in the art. The methods of Petition 870260055674, dated 09 / 06 / 2026, page 85 / 412 72 / 328 cell viability measurement methods are known in the art, such as the CellTiter-Glo® cell viability assay described herein: Note - The following protocol describes a procedure for monitoring the cell viability of K-Ras mutant cancer cell lines in response to a compound of the invention. Other RAS isoforms may be employed, although the number of cells to be seeded will vary based on the cell line used.

[0122] The aim of this cell assay is to determine the effects of test compounds on the proliferation of human Ras cancer cell lines (e.g., NCI-H358 (K-Ras G12C), AsPC-1 (K-Ras G12D), and Capan-1 (K-Ras G12V)) over a 5-day treatment period by quantifying the amount of ATP present at the endpoint using CellTiter-Glo® 2.0 Reagent (Promega).

[0123] Cells are seeded at 250 cells / well in 40 pL of growth medium in 384-well assay plates and incubated overnight in a humidified atmosphere of 5% CO2 at 37°C. On the day of the assay, 10 mM stock solutions of the test compounds are first diluted in 3 mM solutions with 100% DMSO. The well-mixed compound solutions (15 pL) are transferred to the next wells containing 30 pL of 100% DMSO and repeated until a 3-fold serial dilution of concentration 9 (initial assay concentration of 10 pM) is made. The test compounds (132.5 nL) are dispensed directly into the assay plates containing cells. The plates are shaken for 15 seconds at 300 rpm, centrifuged, and incubated in a humidified atmosphere of 5% CO2 at 37°C for 5 days. On day 5, the assay plates and their contents are equilibrated at room temperature for approximately 30 minutes. The reagent used is CellTiter-Glo® 2.0 (25 pL) is added and the contents of the plate are mixed for 2 minutes in an orbital shaker before incubation at room temperature for 10 minutes. A. Petition 870260055674, dated 09 / 06 / 2026, page 86 / 412 73 / 328 luminescence is measured using the PerkinElmer Enspire. The data are normalized by the following: (Sample signal / DMSO mean)*100. The data are fitted using a four-parameter logistic fit.

[0124] Consequently, in some embodiments, the compounds of the present invention exhibit a greater decrease in cell viability compared to KRASG12D compared to what is known in the art. The compounds of the present invention may also exhibit a greater decrease in cell viability compared to other RAS mutants disclosed herein, or combinations thereof.

[0125] In some embodiments, a compound of the present invention may exhibit greater metabolic stability, permeability, or solubility, or a combination thereof, versus what is known in the art. The compounds of the present invention may exhibit improved acid stability, such as in a simulated gastric fluid stability assay. Methods for measuring such properties are known in the art. A compound of the present invention may exhibit better Ras crosslinking than a compound known in the art. A method for measuring Ras crosslinking is provided herein. In some embodiments, a compound of the present invention may exhibit improvements with respect to any of the following properties, or a combination thereof, compared to what is known in the art: selectivity, potency, cell viability, metabolic stability, acid stability, crosslinking, permeability, or solubility.

[0126] Also provided is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may, for example, be pancreatic cancer, colorectal cancer, or lung cancer. Petition 870260055674, dated 09 / 06 / 2026, page 87 / 412 74 / 328 non-small cell carcinomas, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung carcinoma. In some forms, the cancer comprises a Ras mutation, such as K-Ras G12D or K-Ras G13D. Other Ras mutations are described in this document.

[0127] A method of treating a Ras protein-related disorder in a subject in need thereof is further provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0128] A method is further provided for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12D or K-Ras G13D. Other Ras proteins are described herein. The cell may be a cancerous cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid gland adenocarcinoma cell, a myelodysplastic syndrome cell, or a squamous cell lung carcinoma cell. Other types of cancer are described in this document. The cell may be in vivo or in vitro.

[0129] With respect to the compounds of the present invention, one stereoisomer may exhibit better inhibition than another stereoisomer. For example, one atropisomer may exhibit inhibition, while the other atropisomer may exhibit little or no inhibition.

[0130] In some embodiments, a method or use described in this document also includes administering additional anticancer therapy. In Petition 870260055674, dated 09 / 06 / 2026, page 88 / 412 75 / 328 In some modalities, the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some modalities, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described in this document. Synthesis Methods

[0131] The compounds described in this document can be prepared from commercially available starting materials or synthesized using known organic, inorganic or enzymatic processes.

[0132] The compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described in the Schemes below together with synthetic methods known in the art of organic chemistry or variations thereof as understood by one skilled in the art. These methods include, but are not limited to, the methods described in the Schemes below.

[0133] The compounds in Table 1 in this document were prepared using methods disclosed in this document or were prepared using methods disclosed in this document combined with the knowledge of a person skilled in the art. The compounds in Table 2 can be prepared using methods disclosed in this document or can be prepared using methods disclosed in this document combined with the knowledge of a person skilled in the art. Petition 870260055674, dated 09 / 06 / 2026, page 89 / 412 76 / 328 Scheme 1. General synthesis of aziridine-containing macrocycles

[0134] As shown in Scheme 1, compounds of this type can be prepared by reacting an appropriate amine (1) with a protected amine-containing carboxylic acid (2) in the presence of standard amide coupling reagents to give 3, followed by deprotection of the amine to produce 4. Coupling of an aziridine carboxylate (5) in the presence of standard amide coupling reagents provides the final compound (6). Pharmaceutical Compositions and Methods of Use. Pharmaceutical compositions and methods of administration.

[0135] The compounds with which the invention relates are Ras inhibitors and are useful in the treatment of cancer. Therefore, one embodiment of the present invention provides pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions.

[0136] As used in this document, the term “pharmaceutical composition” refers to a compound, such as a compound of the present invention, or a pharmaceutically acceptable salt, formulated together with a pharmaceutically acceptable excipient.

[0137] In some embodiments, a compound is present in Petition 870260055674, dated 09 / 06 / 2026, p. 90 / 412 77 / 328 a pharmaceutical composition in a unit dose quantity appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, potions (aqueous or non-aqueous solutions or suspensions), tablets, for example, those intended for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment or a controlled-release patch or spray applied to the skin, lungs or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucous surfaces.

[0138] A “pharmaceutically acceptable excipient,” as used in this document, refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving the active compound) with the properties of being non-toxic and non-inflammatory in a subject. Typical excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, colorants (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated hydroxytoluene (BHT) optionally Petition 870260055674, dated 09 / 06 / 2026, page 91 / 412 78 / 328 substituted, calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol. Those skilled in the art are familiar with a variety of useful agents and materials as excipients. See, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients.

[0139] The compounds described herein, whether expressly stated or not, may be supplied or used in salt form, for example, a pharmaceutically acceptable salt form, unless expressly stated otherwise. The term “pharmaceutically acceptable salt,” as used in this document, refers to salts of the compounds described herein that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are Petition 870260055674, dated 09 / 06 / 2026, page 92 / 412 79 / 328 described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reaction of the free base group with a suitable organic acid.

[0140] The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or the salts may, in the case of acidic forms of the compounds of the invention, be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric or tartaric acids to form acid addition salts and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines and the like to form basic salts. The methods for preparing the appropriate salts are well established in the art.

[0141] Representative acid addition salts include acetate, adipate salts, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanate, hexanoate, hydrobromide, hydrochloride, iodide, optionally substituted 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, Petition 870260055674, dated 09 / 06 / 2026, page 93 / 412 80 / 328 pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline-earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

[0142] As used in this document, the term “subject” refers to any member of the animal kingdom. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, a genetically modified animal, or a clone.

[0143] As used in this document, the term “dosage form” refers to a physically distinct unit of a compound (for example, a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such amount is a unit dosage amount (or a whole fraction thereof) appropriate for administration according to a dosage regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosage regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to Petition 870260055674, dated 09 / 06 / 2026, page 94 / 412 81 / 328 a particular subject is determined by one or more attending physicians, and may involve administering multiple dosage forms.

[0144] As used in this document, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses, all of which are separated from each other by a period of time of the same duration; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same single dose quantity. In some embodiments, different doses within a dosing regimen are of different quantities.In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose of the same dose amount as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered through a relevant population (i.e., it is a therapeutic dosing regimen).

[0145] A “therapeutic regimen” refers to a dosage regimen whose administration through a relevant population is correlated with a desired or beneficial therapeutic outcome. Petition 870260055674, dated 09 / 06 / 2026, page 95 / 412 82 / 328

[0146] The term “treatment” (also “treating” or “treating”), in its broadest sense, refers to any administration of a substance (for example, a compound of the present invention) that partially or completely relieves, improves, alleviates, inhibits, delays the onset, reduces the severity, or reduces the incidence of one or more symptoms, features, or causes of a specific disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder, or condition, or to a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, the treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or condition. In some embodiments, the treatment may be to a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition.In some modalities, treatment may involve a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder, or condition.

[0147] The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition according to a therapeutic dosage regimen, to treat the disease, disorder, or condition. In some modalities, a therapeutically effective amount is one that reduces the incidence or severity or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will realize that the expression “therapeutically effective amount” does not, in fact, require that successful treatment be achieved in a particular individual. Instead, a therapeutically effective amount may be the amount that provides a particular desired pharmacological response in a significant number of Petition 870260055674, dated 09 / 06 / 2026, page 96 / 412 83 / 328 subjects when administered to patients in need of such treatment. It is specifically understood that certain subjects may, in fact, be “refractory” to a “therapeutically effective amount.” In some modalities, the reference to a therapeutically effective amount may be a reference to an amount measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will realize that, in some modalities, a therapeutically effective amount may be formulated or administered in a single dose. In some modalities, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.

[0148] For use as treatment of subjects, the compounds of the invention, or a pharmaceutically acceptable salt thereof, may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration and the type of treatment desired, for example, prevention, prophylaxis or therapy, the compounds, or a pharmaceutically acceptable salt thereof, are formulated in ways consistent with these parameters. A summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0149] The compositions can be prepared according to conventional methods of mixing, granulation or coating, respectively, and the present pharmaceutical compositions may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume. In Petition 870260055674, dated 09 / 06 / 2026, p. 97 / 412 84 / 328 In some embodiments, the compounds, or a pharmaceutically acceptable salt thereof, described herein may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.

[0150] The composition may be supplied in a dosage form that is suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, ​​intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Thus, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels, including hydrogels, pastes, ointments, creams, plasters, salves, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated in accordance with conventional pharmaceutical practice.

[0151] As used in this document, the term “administration” refers to the administration of a composition (e.g., a compound, or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous.

[0152] The formulations can be prepared in a way Petition 870260055674, dated 09 / 06 / 2026, p. 98 / 412 85 / 328 suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent, as well as, in some cases, adjuvants, buffers, preservatives, and the like. The compounds, or a pharmaceutically acceptable salt thereof, may also be administered in liposomal compositions or as microemulsions.

[0153] For injection, formulations may be prepared in conventional forms such as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline solution, dextrose, glycerol and the like. Such compositions may also contain quantities of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate and so forth.

[0154] Several sustained-release drug delivery systems have also been devised. See, for example, US Patent 5,624,677.

[0155] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal distribution, and intranasal administration. Oral administration is also suitable for compounds of the invention, or a pharmaceutically acceptable salt thereof. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0156] Each compound, or a pharmaceutically acceptable salt thereof, as described herein, may be formulated in a variety of ways known in the art. For example, the first and second agents of Petition 870260055674, dated 09 / 06 / 2026, page 99 / 412 86 / 328 combination therapy can be formulated together or separately. Other combination therapy modalities are described herein.

[0157] Individually or separately formulated agents may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and a powder, one suppository and a liquid in one vial, two topical creams, etc. The kit may include optional components that assist in administering the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. In addition, the unit dose kit may contain instructions for the preparation and administration of the compositions.The kit may be manufactured as a single-use unit dose for one subject, multiple uses for a specific subject (at a constant dose or where the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”). The kit components may be assembled into boxes, blister packs, bottles, tubes, and the like.

[0158] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharmaceutically acceptable non-toxic excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, alginate Petition 870260055674, dated 09 / 06 / 2026, page 100 / 412 87 / 328 sodium, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum and magnesium silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adhesive agents (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffering agents and the like.

[0159] Two or more compounds may be mixed in a tablet, capsule or other vehicle, or they may be partitioned. In one example, the first compound is contained inside the tablet and the second compound is outside, so that a substantial portion of the second compound is released before the release of the first compound.

[0160] Formulations for oral use may also be supplied as chewable tablets or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Powders, granules and pellets may be prepared using the above-mentioned ingredients in tablets and capsules in a conventional manner using, for example, a mixer, a fluid bed apparatus or a spray drying apparatus.

[0161] Controlled dissolution or release by diffusion can be achieved by appropriately coating a tablet, capsule, pellet or granule formulation of compounds, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix. A controlled-release coating may include one or more of the following substances: Petition 870260055674, dated 09 / 06 / 2026, page 101 / 412 88 / 328 of coating mentioned above or, for example, shellac, beeswax, glycol wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, optionally substituted 2-hydroxymethacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate or polyethylene glycols. In a controlled-release matrix formulation, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, poly(vinyl chloride), polyethylene, or halogenated fluorocarbon.

[0162] Liquid forms in which the compounds or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0163] Generally, when administered to a human, the oral dosage of any of the compounds of the invention, or a pharmaceutically acceptable salt thereof, will depend on the nature of the compound and can be readily determined by one skilled in the art. A dosage may be, for example, about 0.001 mg to about 2,000 mg per day, about 1 mg to about 1,000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1,500 mg per day, about 500 mg to about 1,500 mg per day, about 500 mg to about 2,000 mg per day, or any range derivable therefrom. In some embodiments, the daily dose range for Petition 870260055674, dated 09 / 06 / 2026, p. 102 / 412 89 / 328 oral administration, for example, may be within the range of about 0.001 mg to about 2,000 mg per kg of human body weight, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

[0164] In some embodiments, the pharmaceutical composition may further comprise an additional compound with antiproliferative activity. Depending on the mode of administration, the compounds, or a pharmaceutically acceptable salt thereof, will be formulated in compositions suitable to permit easy distribution. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents.

[0165] It will be understood that the pharmaceutical compounds and compositions of the present invention can be formulated and used in combination therapies, that is, the pharmaceutical compounds and compositions can be formulated or administered simultaneously with, before or after one or more other desired therapies or medical procedures. The particular combination of therapies (therapeutics or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapies or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed can achieve a desired effect for the same disorder, or can achieve different effects (for example, control of any adverse effects).

[0166] The administration of each drug in a therapy of Petition 870260055674, dated 09 / 06 / 2026, page 103 / 412 The 90 / 328 combination, as described in this document, can independently be administered one to four times daily for one day to one year, and may even be for the subject's lifetime. Long-term chronic administration may be indicated. Methods of Use

[0167] In some embodiments, the invention discloses a method of treating a disease or disorder that is characterized by aberrant Ras activity due to a Ras mutant. In some embodiments, the disease or disorder is a cancer.

[0168] Consequently, a method of treating cancer in a subject in need thereof is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal, endometrial, or melanoma.Also provided is a method for treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or salt.

[0169] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, compositions Petition 870260055674, dated 09 / 06 / 2026, page 104 / 412 91 / 328 pharmaceutical compositions comprising such compounds or salts and methods provided in this document can 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, the cancers that can be treated by the compounds or salts thereof, the pharmaceutical compositions comprising such compounds or salts and the methods of the invention include, but are not limited to, types of tumors such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, pulmonary, oral, ovarian, prostate and thyroid carcinomas and sarcomas. Other cancers include, for example: Cardiac, for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung, for example: bronchogenic carcinoma (squamous cell carcinoma, small undifferentiated cell carcinoma, large undifferentiated cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatic hamartoma, mesothelioma; Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract, for example: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate Petition 870260055674, dated 09 / 06 / 2026, page 105 / 412 92 / 328 (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver, for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract, for example: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, exotic chondrosarcoma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, neurofibromatosis type 1, meningioma, glioma, sarcoma); Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, endometrial carcinoma of the uterine body), cervix (cervical carcinoma, pre-tumoral 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, Petition 870260055674, dated 09 / 06 / 2026, page 106 / 412 93 / 328 melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia); myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms); multiple myeloma; myelodysplastic syndromes, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, soft dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0170] In some embodiments, the Ras protein is of the wild type (RasWT). Consequently, in some embodiments, a compound of the present invention is employed in a method of treating a patient with a cancer comprising a RasWT (e.g., K-RasWT, H-RasWT, or N-RasWT). In some embodiments, the Ras protein is an amplification of Ras (e.g., K-Rasamp). Consequently, in some embodiments, a compound of the present invention is employed in a method of treating a patient with a cancer comprising a Rasamp (K-Rasamp, H-Rasamp, or N-Rasamp). In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described in this document. In some embodiments, a mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Petition 870260055674, dated 09 / 06 / 2026, page 107 / 412 94 / 328 Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; or a combination of any of the above. In some embodiments, a compound may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, a compound may inhibit both K-Ras G12D and K-Ras G13D. In some embodiments, a compound may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, a compound of the present invention inhibits RasWT in addition to one or more additional Ras mutations (e.g., K-, H-, or N-RasWT and K-Ras G12D). In some embodiments, a compound of the present invention inhibits RasAMP in addition to one or more additional Ras mutations (e.g., K-, H-, or N-RasAMP and K-Ras G12D).

[0171] Methods for detecting Ras mutations are known in the art. Such means include, but are not limited to, direct sequencing and the use of a high-sensitivity diagnostic assay (labeled CE-IVD), for example, as described in Domagala, et al., Pol J Pathol 3: 145164 (2012), herein incorporated by reference in its lifetime, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0172] In some modalities, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12D. In some modalities, the cancer is colorectal cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12D. In Petition 870260055674, dated 09 / 06 / 2026, page 108 / 412 95 / 328 In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12D. In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises an N-Ras mutation, such as N-Ras G12D. In either of the above, if not already specified, a compound may inhibit Ras^ (e.g., K-, M- or N-Ras^) or RasamP (e.g., K-, H- or N-RasamP) equally.

[0173] Also provided is a method for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. A compound, or a pharmaceutically acceptable salt thereof, may inhibit more than one type of Ras protein in a cell. A method for inhibiting RAF-Ras binding, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is also provided. The cell may be a cancerous cell. The cancerous cell may be of any type of cancer described in this document. The cell may be in vivo or in vitro. Combination Therapy

[0174] The methods of the invention may include a compound of the invention used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from combinations and permutations of drugs or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0175] A compound of the present invention can be administered Petition 870260055674, dated 09 / 06 / 2026, p. 109 / 412 96 / 328 before, after, or simultaneously with one or more of these additional therapies. When combined, dosages of a compound of the invention and dosages of one or more additional therapies (e.g., non-drug treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). A compound of the present invention and an additional therapy, such as an anticancer agent, may be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be near or far in time.

[0176] In some embodiments, additional therapy is the administration of side-effect limiting agents (e.g., agents intended to decrease the occurrence or severity of side effects of treatment). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent that treats nausea. Examples of agents that may be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0177] In some modalities, one or more additional therapies include non-drug treatment (e.g., surgery or radiotherapy). In some modalities, one or more additional therapies include a therapeutic agent (e.g., a compound or biologic that is an antiangiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some modalities, one or more additional therapies include non-drug treatment (e.g., surgery or radiotherapy) and a therapeutic agent (e.g., a compound or biologic that is an antiangiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). Petition 870260055674, dated 09 / 06 / 2026, page 110 / 412 97 / 328 autophagy inhibitor). In other modalities, one or more additional therapies include two therapeutic agents. In still other modalities, one or more additional therapies include three therapeutic agents. In some modalities, one or more additional therapies include four or more therapeutic agents.

[0178] In this Combination Therapy section, all references are incorporated by reference to the agents described, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof, whether explicitly stated as such or not. Drug-free therapies

[0179] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and adoptive T-cell transfer therapy (ACT).

[0180] In some embodiments, the compounds of the invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the invention can be used as neoadjuvant therapy before surgery.

[0181] Radiation therapy can be used to inhibit abnormal cell growth or to treat a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiation therapy are known in the art. Radiotherapy can be administered by one of several methods, or a combination of methods, including, without limitation, external beam therapy, internal radiotherapy, implant radiation, stereotactic radiosurgery, systemic radiotherapy, and permanent or temporary interstitial radiotherapy and brachytherapy. The term “brachytherapy,” as used in this document, refers to radiotherapy delivered by a spatially radioactive material. Petition 870260055674, dated 09 / 06 / 2026, p. 111 / 412 98 / 328 confined inserted into the body in or near a tumor or other site of proliferative tissue disease. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide, such as 1-125, 1-131, Yb-169, lr192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays.Radioactive material can also be a fluid made from any solution of radionuclide(s), for example, a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a suitable fluid substance containing small particles of solid radionuclides, such as Au-198 or Y-90. Furthermore, the radionuclide(s) can be incorporated in the form of a gel or radioactive microspheres.

[0182] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiation treatment for the purpose of killing or inhibiting the growth of such cells. Thus, this invention further relates to a method for sensitizing abnormal cells in a mammal to radiation treatment comprising administering to the mammal an amount of a compound of the present invention, an amount which is effective in sensitizing abnormal cells to radiation treatment. The amount of the compound in this method can be determined according to the means for determining effective amounts of such compounds described herein. In some embodiments, the compounds of the present invention can be used as an adjuvant therapy after radiation therapy or as a neoadjuvant therapy before radiation therapy. Petition 870260055674, dated 09 / 06 / 2026, page 112 / 412 99 / 328

[0183] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer therapy (ACT). In some embodiments, the T cell is an activated T cell. The T cell can be modified to express a chimeric antigen receptor (CAR). CAR-modified T cells (CAR-T cells) can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR into a T cell. Prior to the expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from various sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used.In some embodiments, the T cell is an autologous T cell. Whether before or after genetic modification of T cells to express a desirable protein (e.g., a CAR), T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041. Therapeutic agents

[0184] A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated with it. A compound of the present invention may be combined with a second, third, or fourth therapeutic agent, or more. A compound of the present invention may be combined with one or more therapeutic agents along with one or more non-drug therapies.

[0185] For example, a therapeutic agent could be a steroid. Petition 870260055674, dated 09 / 06 / 2026, p. 113 / 412 100 / 328 Steroids are known in the art. Therefore, in some modalities, one or more additional therapies include a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chlorprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, butyl-fluocortin, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide and salts or derivatives thereof.

[0186] Other examples of therapeutic agents that can be used in combination therapy with a compound of the present invention include compounds described in the following patents: US Patents 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764 and 8,623,885, and International Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0187] A therapeutic agent may be a biological product (e.g., a cytokine (e.g., interferon or an interleukin, such as IL-2)) used in the treatment of cancer or symptoms associated with it. Biological products are Petition 870260055674, dated 09 / 06 / 2026, page 114 / 412 101 / 328 known in the art. In some embodiments, the biologic is an immunoglobulin-based biologic, for example, a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anticancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0188] A therapeutic agent may be a T-cell checkpoint inhibitor. Such checkpoint inhibitors are known in the art. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, for example, an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor... Petition 870260055674, dated 09 / 06 / 2026, page 115 / 412 102 / 328 is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of ligands from the B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B7 families, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene and Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, I-7F9 and KW-6002.

[0189] A therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab). Other anti-TIGIT antibodies are known in the art.

[0190] A therapeutic agent may be an agent that treats cancer or symptoms associated with it (for example, a cytotoxic agent, small non-peptidic molecules, or other compound useful in treating cancer or symptoms associated with it, collectively, an “anticancer agent”). Anticancer agents may be, for example, chemotherapeutic or targeted therapy agents. Such agents are known in the art.

[0191] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopilotoxins, antibiotics, L-asparaginase, inhibitors of Petition 870260055674, dated 09 / 06 / 2026, page 116 / 412 103 / 328 topoisomerase, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical suppressants, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some modalities, one or more additional therapies include two or more anticancer agents. The two or more anticancer agents may be used in a cocktail to be administered in combination or administered separately. Appropriate dosage regimens of combination anticancer agents are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0192] Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamylamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenemethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; calistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues KW2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictiin A; spongistatin;Nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembin, fenesterin, prednimustine, trofosfamide, mustard; Petition 870260055674, dated 09 / 06 / 2026, page 117 / 412 104 / 328 uracilo; nitrosureias tais como carmustina, clorozotocina, fotemustina, lomustina, nimustina e ranimustina; antibióticos, como os antibióticos enediinos (por exemplo, caliqueamicina, como caliqueamicina gamall e caliqueamicina omegall (ver, por exemplo, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dinemicina tal como dinemicina A; bisfosfonatos tais como clodronato; uma esperançaicina;neocarzinostatin chromophore and related chromoprotein antibiotic chromophores enediyne, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxidoxorubicin, epirubicin, esorrubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorrubicin, streptonigrin, streptozocin, tubercidine, ubenimex, zinostatin, zorrubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamipine, thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglathone; aldofosfamide glycoside; aminolevulinic acid; enyluracil; amsacrine; bestrabucil; bisantherene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; an epothilone such as epothilone B; etoglucoside; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; Petition 870260055674, dated 09 / 06 / 2026, page 118 / 412 105 / 328 fenamete; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxine; sizophyran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes such as T-2 toxin, verracurine A, roridine A and anguidin; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; Taxoids, for example, Taxol® (paclitaxel), Abraxane® (engineered nanoparticle formulation with albumin, free of cremophore) and Taxotere® (doxetaxel); chlorambucil; tamoxifen (Nolvadex™); raloxifene; 4(5)-imidazole aromatase inhibitors; 4-hydroxytamoxifen; trioxifene; ceoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine;Platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novanthrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperaricins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the foregoing.

[0193] Additional, non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17desmethoxygeldanamycin, alfaradine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., non-cell cycle-specific antineoplastic agents, and other antineoplastics described herein), herbs Petition 870260055674, dated 09 / 06 / 2026, page 119 / 412 106 / 328 antitumor drugs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, briostatin, butionine sulfoximine, CBV (chemotherapy), caliculin, dichloroacetic acid, discodermolide, elsamitrucine, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, inhibitors of proteasome, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar,thesistaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0194] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells that lack the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogues, melphalan, and chlorambucil), ethyleneimines, and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., a CDK4 / 6 inhibitor such as abemaciclib, ribociclib, palbociclib;seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638 and; SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), trazenos Petition 870260055674, dated 09 / 06 / 2026, page 120 / 412 107 / 328 dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites, such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlordeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidal, suberoyl anilide hydroamic acid, vorinostat, belinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Matrix 520), DNA-binding agents (e.g., Zalypsis®), PI3K inhibitors, such as PI3K delta inhibitor (e.g.,GS-1101 and TGR1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; Multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormonal agonists, such as leukemia-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., elotuzumab). for example, GSK2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062),Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY, Petition 870260055674, dated 09 / 06 / 2026, page 121 / 412 108 / 328 382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0195] In some embodiments, an anticancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogous or derivative variant of the foregoing.

[0196] In some embodiments, the anticancer agent is a HER2 inhibitor. HER2 inhibitors are known in the art. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543 and JNJ-26483327.

[0197] In some embodiments, an anticancer agent is an ALK inhibitor. ALK inhibitors are known in the art. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005 and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of WO05016894.

[0198] In some embodiments, an anticancer agent is an inhibitor of a downstream member of a Tyrosine Kinase Receptor (RTK) / Growth Factor Receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892 or BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof), an SOS1 inhibitor (e.g., BI Petition 870260055674, dated 09 / 06 / 2026, page 122 / 412 109 / 328 1701963, BI-3406, SDR5, BAY-293 or RMC-5845, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312.

[0199] In some embodiments, an anticancer agent is an SOS1 inhibitor. SOS1 inhibitors are known in the art. In some embodiments, the SOS1 inhibitor is selected from those disclosed in WO 2022146698, WO 2022081912, WO 2022058344, WO 2022026465, WO 2022017519, WO 2021173524, WO 2021130731, WO 2021127429, WO 2021092115, WO 2021105960, WO 2021074227, WO 2020180768, WO 2020180770, WO 2020173935, WO 2020146470, WO 2019201848, WO 2019122129, WO 2018172250 and WO 2018115380, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof. In some embodiments, a compound of the present invention is used in combination with an SOS1 inhibitor to treat K-Ras G13D cancer.

[0200] In some embodiments, an anticancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. Such agents are known in the art. In some embodiments, an anticancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active state or bound to GTP. In some embodiments, the Ras inhibitor targets Ras in its inactive state or bound to GDP. In some embodiments, the Ras inhibitor is, such as a K-Ras G12C inhibitor, such as AMG 510 (sotorasib), MRTX1257, MRTX849 (adagrasib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, Petition 870260055674, dated 09 / 06 / 2026, page 123 / 412 110 / 328 LY3537982, JDQ443, AZ4625, JAB-21822, JAB-21000, IBI351, ERAS-3490, RMC-6291 or GDC-6036, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12D inhibitor, such as MRTX1133 or JAB-22000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.In some embodiments, the Ras inhibitor is selected from a Ras(ON) inhibitor disclosed below, incorporated herein by reference in its entirety, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof: WO 2021091982, WO 2021091967, WO 2021091956, and WO 2020132597. Other examples of RAS inhibitors are known in the art, such as the following, incorporated herein by reference in their entirety: WO 20220133038, WO 2022133345, WO 2022132200, WO. 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO Petição 870260055674, de 09 / 06 / 2026, pág. 124 / 412 111 / 328 2019241157, YOU 2019232419, YOU 2019217691, YOU 2019217307, YOU 2019215203, YOU 2019213526, YOU 2019213516, YOU 2019155399, YOU 2019150305, YOU 2019110751, YOU 2019099524, YOU 2019051291, YOU 2018218070, YOU 2018217651, YOU 2018218071, YOU 2018218069, YOU 2018206539, YOU 2018143315, YOU 2018140600, YOU 2018140599, YOU 2018140598, YOU 2018140514, YOU 2018140513, YOU 2018140512, YOU 2018119183, YOU 2018112420, YOU 2018068017, YOU 2018064510, YOU 2017201161, YOU 2017172979, YOU 2017100546, YOU 2017087528, YOU 2017058807, YOU 2017058805, YOU 2017058728, YOU 2017058902, YOU 2017058792, YOU 2017058768, YOU 2017058915, YOU 2017015562, YOU 2016168540, 2016164675, 2016049568, 2016049524, 2016164675, 2016049568, 2015054572, WO 2014152588, WO 2014143659, and WO 2013155223, or a salt, solvate, isomer (e.g., stereoisomer), pro-drug or pharmaceutically acceptable tautomer thereof.

[0201] In some embodiments, a therapeutic agent that can be combined with a compound of the present invention is a MAP kinase (MAPK) pathway inhibitor (or “MAPK inhibitor”). Such agents are known in the art. MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA) 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. November 25, 2014;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. March 1, 2011;17(5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC5573, or LY3009120. Petition 870260055674, dated 09 / 06 / 2026, page 125 / 412 112 / 328

[0202] In some embodiments, an anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways. Such agents are known in the art. The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI587; GSK2126458.

[0203] In some embodiments, an anticancer agent is a PD-1 or PD-L1 antagonist. Such agents are known in the art.

[0204] In some modalities, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies. In some modalities, additional therapeutic agents include FGFR inhibitors, PARP inhibitors, BET inhibitors, PRMT5i inhibitors, MAT2A inhibitors, VEGF inhibitors, and HDAC inhibitors. In some modalities, a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0205] IGF-1R inhibitors are known in the art and include linsitinib, or a pharmaceutically acceptable salt thereof.

[0206] EGFR inhibitors are known in the art and include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA inhibitors. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or partially block EGFR. Petition 870260055674, dated 09 / 06 / 2026, page 126 / 412 113 / 328 completely activates EGFR by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor may be the monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment with the same binding specificity.

[0207] Small molecule EGFR antagonists include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some modalities, the EGFR inhibitor is osimertinib (Tagrisso®). Other, non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; US Pat. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; Pat. US 5,789,427; Pat. US 5,650,415; Pat. US 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Additional, non-limiting examples of inhibitors. Petition 870260055674, dated 09 / 06 / 2026, page 127 / 412 114 / 328 of small molecule EGFR include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, an EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0208] MEK inhibitors are known in the art and include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from ΔE51^58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0209] PI3K inhibitors are known in the art and include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06 / 044453; 4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4morpholinylpyrido-[3',2':4.5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem);PIK 75 acid (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin3-yl)methylene]-1-methyl-hydrazide-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-Petition 870260055674, dated 09 / 06 / 2026, page 128 / 412; 115 / 328 hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (available from Axon Medchem); BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, CUDC-907, and AEZS-136.

[0210] AKT inhibitors are known in the art and include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibits Aktl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-carbinol and derivatives thereof (e.g., Pat. US 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Suppl): 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15): 5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and tricyribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0211] mTOR inhibitors are known in the art and include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, for example, PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, for example, as disclosed in WO98 / 02441 and WO01 / 14387, for example, AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40 Petition 870260055674, dated 09 / 06 / 2026, page 129 / 412 116 / 328 epi-(tetrazolite)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentiniloxy-32(S)-dihydrorapanicin; derivatives disclosed in W005 / 005434; derivatives disclosed in US Patents Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552, having the following structure:

[0212] BRAF inhibitors that can be used in combination with compounds of the invention are known in the art and include, for example, vemurafenib, dabrafenib, and encorafenib. A BRAF may comprise a BRAF Class 3 mutation. In some embodiments, the BRAF Class 3 mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596ReA762E.

[0213] MCL-1 inhibitors are known in the art and include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia protein-1 (MCL-1) is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 has been closely associated with the progression of Petition 870260055674, dated 09 / 06 / 2026, p. 130 / 412 117 / 328 tumor, as well as resistance, not only to traditional chemotherapies, but also to targeted therapies, including BCL-2 inhibitors such as ABT263.

[0214] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 inhibitors are known in the art. SHP2 is a non-receptor tyrosine phosphatase protein encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src 2 homology domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive and self-inhibited conformation stabilized by a linkage network involving residues of the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0215] SHP2 is involved in signaling through the RAS-mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphoinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases, such as Noonan Syndrome and Leopard Syndrome, as well as in human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer. Some of these mutations destabilize the self-inhibited conformation of SHP2 and promote autoactivation or activation of the SHP2 growth factor-enhanced gene. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases, including cancer. An SHP2 inhibitor (e.g., RMC-4550 or SHP099) in combination with a RAS pathway inhibitor (e.g., a MEK inhibitor) has been shown to inhibit the proliferation of Petition 870260055674, dated 09 / 06 / 2026, page 131 / 412 118 / 328 multiple cancer cell lines in vitro (e.g., pancreatic, lung, ovarian, and breast cancer). Thus, combination therapy involving an SHP2 inhibitor with a RAS pathway inhibitor may be a general strategy to prevent tumor resistance in a wide range of malignancies.

[0216] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al. Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO 2022135568, WO 2021176072, WO 2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928,WO 2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO 2016203406, WO 2016203405, WO, Petition 870260055674, dated 09 / 06 / 2026, page 132 / 412 119 / 328 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, US 20210085677, US 10858359, US 10934302, US 10954243, US 10988466, US 11001561, US 11033547, US 11034705, or US 11044675, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, each of which is incorporated herein by reference.

[0217] In some embodiments, an SHP2 inhibitor binds to the active site. In some embodiments, an SHP2 inhibitor is an irreversible mixed-type inhibitor. In some embodiments, an SHP2 inhibitor binds to an allosteric site, for example, a non-covalent allosteric inhibitor. In some embodiments, an SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets the cysteine ​​residue (C333) that lies outside the active site of the phosphatase. In some embodiments, an SHP2 inhibitor is a reversible inhibitor. In some embodiments, an SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155, having the structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC4550, having the following structure: or a salt, solvate, isomer (e.g., stereoisomer), propional Petition 870260055674, dated 09 / 06 / 2026, page 133 / 412 120 / 328 pharmaceutically acceptable drug or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4630, having the following structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0218] In some forms, the SHP2 inhibitor is JAB-3068, having the following structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RLY-1971, having the following structure: or a salt, solvate, isomer (e.g., stereoisomer), pro Petition 870260055674, dated 09 / 06 / 2026, page 134 / 412 121 / 328 pharmaceutically acceptable drug or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is SH3809. In some embodiments, the SHP2 inhibitor is PF-07284892, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0219] In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a HER2 inhibitor, an SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, an SHP2 inhibitor, and a PD-L1 inhibitor. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, a Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, a Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SOS1 inhibitor. In some embodiments, a Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SHP2 inhibitor.In some embodiments, a Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, a Ras inhibitor of the present invention is used in combination with an SHP2 inhibitor and a Ras inhibitor that inhibits multiple isoforms and / or mutants of Ras (e.g., RMC-6236). In some embodiments, the cancer is colorectal cancer and the treatment comprises the administration of an inhibitor. Petition 870260055674, dated 09 / 06 / 2026, page 135 / 412 122 / 328 of Ras of the present invention in combination with a second or third therapeutic agent, such as an SHP2 inhibitor and a Ras inhibitor that inhibits multiple isoforms and / or mutants of Ras. In some embodiments, the cancer is cholangiocarcinoma and the treatment comprises the administration of a Ras inhibitor of the present invention, sorafenib, and a chemotherapeutic agent. In some embodiments, the cancer is gastric cancer and the treatment comprises the administration of a Ras inhibitor of the present invention and an FGFR inhibitor (e.g., FGFR2i or FGFR4i). In some embodiments, a Ras inhibitor of the present invention is used in combination with immunotherapy, optionally in combination with a chemotherapeutic agent.

[0220] Proteasome inhibitors are known in the art and include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®) and oprozomib.

[0221] Immunological therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents. Other immune therapies are known in the art.

[0222] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0223] Exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6): 1757-1761; and WO06 / 121168 A1), as well as described elsewhere in this document.

[0224] FGFR inhibitors are known in the art, such as pemigatinib and erdafitinib, including FGFR2 inhibitors and inhibitors of Petition 870260055674, dated 09 / 06 / 2026, page 136 / 412 123 / 328 FGFR4. See, for example, Cancers (Basel), June 2021; 13(12) 2968.

[0225] BET inhibitors are known in the art, such as romidepsin, panobinostat and belinostat. See, for example, British J. Cancer 124:1478 (2021).

[0226] PRMT5i inhibitors are known in the art, such as PF-0693999, PJ-68 and MRTX1719. See, for example, Biomed. Pharmacotherapy 144:112252 (2021).

[0227] MAT2A inhibitors are known in the art, such as AG-270 and IDE397. See, for example, Exp Opin Ther Patents (2022) DOI: 10.1080 / 13543776.2022.2119127.

[0228] GITR agonists are known in the art and include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as a GITR fusion protein described in U.S. Pat. 6,111,090, U.S. Pat. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or an anti-GITR antibody described, for example, in U.S. Pat. 7,025,962, EP 1947183, U.S. Pat. 7,812,135, U.S. Pat. 8,388,967, U.S. Pat. 8,591,886, Pat. US 7,618,632, EP 1866339 and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0229] Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an antiangiogenic agent. Antiangiogenic agents are known in the art and include, but are not limited to, synthetically prepared chemical compositions in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. An antiangiogenic agent may be an agonist, antagonist, allosteric modulator, toxin, or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition) and thus promote cell death or stop growth. Petition 870260055674, dated 09 / 06 / 2026, page 137 / 412 124 / 328 cellular. In some modalities, one or more additional therapies include an antiangiogenic agent.

[0230] Antiangiogenic agents may be MMP2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of antiangiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085 and US Patents 5,863,949 and 5,861,510. The preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity.Most preferred are those that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.

[0231] Other exemplary antiangiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that bind specifically to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that bind specifically to VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand-binding region thereof), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that bind specifically to them), VEGF inhibitors, inhibitory agents of Petition 870260055674, dated 09 / 06 / 2026, p. 138 / 412 125 / 328 EGFR (e.g., antibodies or antigen-binding regions that bind specifically to them), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that bind specifically to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that bind specifically to them). Other antiangiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., antibodies specifically binding to or binding to antigen-specific regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM distintegrin domain to antagonize integrin binding to its ligands (US 2002 / 0042368), anti-eph receptor or anti-ephrin antibodies specifically binding to or binding to antigen-specific regions (US Patents 5,981).245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of the patent family thereof) and anti-PDGF-BB antagonists (e.g., specific binding antibodies or antigen-binding regions), as well as antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them).Additional antiangiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550. Petition 870260055674, dated 09 / 06 / 2026, page 139 / 412 126 / 328 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen fragment-E (BioActa, UK); angiogenic inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenic inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA);CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and antiangiogenic BPI derivative (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (PINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors (EntreMed, USA); pegaptanib (PINN) (Gilead Sciences, USA); xanthorrhizole (Yonsei University, South Korea);Vaccine, based on genes, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California, San Diego, USA); PX 478,; Petition 870260055674, dated 09 / 06 / 2026, page 140 / 412 127 / 328 (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); angiogenic vaccine, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-1alpha inhibitors (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK);KRN 633 (Kirin Brewery, Japan); intraocular drug delivery system, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands and University of Minnesota, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitors; SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY res 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA);GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladina, (Nippon Shinyaku,; Petition 870260055674, dated 09 / 06 / 2026, page 141 / 412 128 / 328 Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (Genaera, USA); RPI 4610 (Sirna, USA); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonists (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); Truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin inhibitor 1 (Allegheny Health, Education and Research Foundation, USA).

[0232] Other examples of therapeutic agents that can be used in combination with compounds of the invention include agents (e.g., antibodies, antigen-binding regions or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also known as Dispersing Factor) antagonists, and antibodies or antigen-binding regions that specifically bind to their receptor, c-Met. Such agents are known in the art.

[0233] Another example of a therapeutic agent that can be used in combination with compounds of the invention is an autophagy inhibitor. Autophagy inhibitors are known in the art and include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA that inhibits protein expression. Petition 870260055674, dated 09 / 06 / 2026, page 142 / 412 129 / 328, including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some modalities, one or more additional therapies include an autophagy inhibitor.

[0234] Another example of a therapeutic agent that can be used in combination with compounds of the invention is an antineoplastic agent, which are known in the art. In some embodiments, one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleucin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestortim, arglabine, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmolleucin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileucin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxyfluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac HIT, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab,eflornithine, issite, epirubicin, epoetin beta, etoposide phosphate, exemenenene, exeminide, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibadronic acid, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-N3, interferon alpha-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, interferon gamma-1a natural, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentin sulfate, letrozole, leukocyte interferon alpha, leuprorelin, levamisole + fluorouracil, Petition 870260055674, dated 09 / 06 / 2026, page 143 / 412 130 / 328 liarozole, loboplatin, lonidamine, lovastatin, masoprocol, melaraprol, metoclopramide, mifepristone, miltefosine, mirmostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartagrasm utamide, noscapine, new erythropoiesis-stimulating protein, NSC 631570 octreotide, oprel vekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, sodium porfimer, raloxifene, raltitrexed, Rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) Lexidronam, Sargograma, sizofiran, sobuzoxaxane, Sonermin, stonciochloride-89, suramin, tasonermin, tazarotene, tegafur, temoporphine, temozolomide, teniposide, tetrachloridecaoxide, thalidomide, timalfasine,thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinnostatin or zoledronic acid estimalamer; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifen, LDI 200 (Milkhaus), leridistim, lintuzumab, MAb CA 125 (Biomira), MAb against cancer (Japan) Pharmaceutical DevelopmentMAb HER-2 and Fc (Medarex), idiotypic MAb 105AD7 (CRC Technology), idiotypic MAb CEA (Trilex), LYM-1 -iodine 131 MAb (Clone Techni), yttrium polymorphic epithelial mucin 90 MAb (Antisoma), Petition 870260055674, dated 09 / 06 / 2026, page 144 / 412 131 / 328 marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P 30, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopoietin, ethyl ethiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), oncolyzed melanoma vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital) or valspodar.

[0235] Additional examples of therapeutic agents that may be used in combination with compounds of the invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); adotrastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); Certolizumab pegal (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®);gemtuzumab ozogamycin (Mylotarg®); golima (Symphony®); ibritumomabe thioxetane (Zevalin®); inflicts (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumuma (Arzerra®); omalizumab (Xolair®); Petition 870260055674, dated 09 / 06 / 2026, p. 145 / 412 132 / 328 palivizumab (Synagis®); pertuzuma (Pearl®); pertuzuma (Pearl®); ranibizumab (Lucentis®); raxibacumabe (Abthrax®); tocilizumab (Actemra®); toxoplasmosis; tumorigenesis-131; tocitumabe and tocitumomabe-i-131 (Bexxar®); ustequinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0236] The compounds described in this document may be used in combination with the agents disclosed in this document or other suitable agents, depending on the condition to be treated. Therefore, in some embodiments, one or more compounds of the invention will be co-administered with other therapies, as described in this document. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This combination administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described herein may be formulated together in the same dosage form and administered simultaneously.Alternatively, a compound of the invention and any of the therapies described in this document may be administered simultaneously, where both agents are present in separate formulations. In another alternative, a compound of the present invention may be administered and followed by any of the therapies described in this document, or vice versa. In some embodiments of the separate administration protocol, a compound of the invention and any of the therapies described in this document are administered with an interval of a few minutes, or a few hours, or a few days apart.

[0237] In some modalities of any of the methods described in this document, the first therapy (e.g., a compound of Petition 870260055674, dated 09 / 06 / 2026, p. 146 / 412 133 / 328 invention) and one or more additional therapies are administered simultaneously or sequentially, in any order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21 or 1-30 days before or after one or more additional therapies.

[0238] The invention also provides kits including (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions for performing any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described in this document, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions for performing any of the methods described in this document.

[0239] As one aspect of the present invention contemplates the treatment of the disease or associated symptoms with a combination of pharmaceutically active compounds that can be administered separately, the invention further relates to the combination of separate pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The kit may comprise a container for holding the separate compositions, such as a divided bottle or a divided foil pack. Additional examples of containers include syringes, boxes, and pouches. In some embodiments, the kit may comprise instructions for the use of the separate components. The kit form is Petition 870260055674, dated 09 / 06 / 2026, p. 147 / 412 134 / 328 is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the healthcare professional's prescription. Numbered Modes

[0240] 1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is C1-C6 optionally substituted alkyl, C1-C6 optionally substituted heteroalkyl, optionally 3- to 6-membered cycloalkyl Petition 870260055674, dated 09 / 06 / 2026, page 148 / 412 135 / 328 substituted or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

[0241] 2. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I: wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each selected independently from CH2, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium. Petition 870260055674, dated 09 / 06 / 2026, p. 149 / 412 136 / 328

[0242] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of any one of Formula Ia, Formula Ib or Formula Ic: Formula Ib, Formula Ic, where each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0243] 4. The compound of any of the embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or Petition 870260055674, dated 09 / 06 / 2026, p. 150 / 412 137 / 328 optionally substituted 3- to 10-membered heterocycloalkyl.

[0244] 5. The compound of any of the embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted 3 to 10 membered heterocycloalkyl.

[0245] 6. The compound of embodiment 5, or pharmaceutically acceptable thereof, where R1 is: a salt the, or

[0246] 7. The pharmaceutically acceptable compound of embodiment 5, or a salt thereof, , where each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0247] 8. The compound of any of the embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, where m is 1.

[0248] 9. The compound of any of the embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, where n is 1.

[0249] 10. The compound of any of the embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, and X3 is CH2. Petition 870260055674, dated 09 / 06 / 2026, p. 151 / 412 138 / 328

[0250] 11. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula II: Formula II

[0251] 12. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula V:

[0252] 13. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, having the structure of any one of Formula Va, Formula Vb or Formula Vc: Formula Va, Petition 870260055674, dated 09 / 06 / 2026, p. 152 / 412 139 / 328 where each D indicates a hydrogen atom with an isotopic enrichment factor for deuterium of at least 5.

[0253] 14. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, having the structure of any of the Formula Vd, Formula Ve or Formula Vf: Formula Vd, Petition 870260055674, dated 09 / 06 / 2026, p. 153 / 412 140 / 328 Formula Vf, where each D indicates a hydrogen atom with an isotopic enrichment factor for deuterium of at least 5.

[0254] 15. The compound of embodiment 1, or a salt Petition 870260055674, dated 09 / 06 / 2026, p. 154 / 412 141 / 328

[0255] 16. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula VII: oxide Formula VII

[0256] 17. The compound of any of the embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazol-di-yl, optionally substituted oxazol-di-yl, optionally substituted morpholine-di-yl, optionally substituted pyrrolidine-di-yl, optionally substituted piperidine-di-yl or optionally substituted phenylene.

[0257] 18. The compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazol-di-yl or optionally substituted morpholine-di-yl.

[0258] 19. The compound of any of the embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5- to 10-membered heteroarylene.

[0259] 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, where A is: or NA JL z Petition 870260055674, dated 09 / 06 / 2026, p. 155 / 412 142 / 328

[0260] 21. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, where A is:

[0261] 22. The compound of any of the embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted phenylene.

[0262] 23. The compound of modality 22, or a salt pharmaceutically acceptable of the same, where A is: or a pharmaceutically acceptable salt thereof, where A is:

[0264] 25. The compound of any of the embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene.

[0265] 26. The compound of embodiment 25, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered heterocycloalkylene.

[0266] 27. The compound of embodiment 25, or a pharmaceutically acceptable salt thereof, wherein A is selected from the following, or a stereoisomer thereof: or Petition 870260055674, dated 09 / 06 / 2026, p. 156 / 412 143 / 328

[0267] 28. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein A is selected from the following, or a stereoisomer thereof:

[0268] 29. The compound of any of the embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, where R2 is: or

[0269] 30. The compound of any of embodiments 1 to 28, DD or a pharmaceutically acceptable salt thereof, wherein R2 is: D , dD D Dá- , D , or - , and wherein each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0270] 31. The compound of any of the embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl.

[0271] 32. The compound of any of the embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted C1-C6 alkyl.

[0272] 33. The compound of type 32, or a salt pharmaceutically acceptable of the same, where R3 is: orF

[0273] 34. The compound of type 33, or a salt Petition 870260055674, dated 09 / 06 / 2026, p. 157 / 412 144 / 328 pharmaceutically acceptable of the same, where R3 is: N.

[0274] 35. The compound of embodiment 32, or a pharmaceutically acceptable JJD3 salt thereof, wherein R3 is: IC°3, and wherein each D indicates a hydrogen with an isotopic enrichment factor for deuterium of at least 5.

[0275] 36. The compound of any of the embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R3 is or optionally substituted 3 to 6 membered cycloalkyl.

[0276] 37. The compound of type 36, or a salt pharmaceutically acceptable of the same, where R3 is: I or .

[0277] 38. The compound of embodiment 36 or a pharmaceutically acceptable salt thereof, wherein R3 is or optionally substituted 5-membered cycloalkyl.

[0278] 39. The compound of type 38, or a salt pharmaceutically acceptable of the same, where R3 is: .

[0279] 40. The compound of any of the embodiments 11 to 16, or a pharmaceutically acceptable salt thereof, where:

[0280] 41. The compound of any of the modalities 11 to 16, where: Petition 870260055674, dated 09 / 06 / 2026, p. 158 / 412 145 / 328

[0281] 42. The compound of any of the embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound of Table 3.

[0282] 43. Compound, or a pharmaceutically acceptable salt thereof, characterized in that it has the structure of a compound from Table 1 or Table 2.

[0283] 44. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments 1 to 43 and a pharmaceutically acceptable excipient.

[0284] 45. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of embodiments 1 to 43 or a pharmaceutical composition of embodiment 44.

[0285] 46. The modality 45 method, in which the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer, or endometrial cancer.

[0286] 47. The method, according to modality 45 or 46, in which the cancer comprises a Ras mutation.

[0287] 48. The method of modality 47, in which the Ras mutation is K-Ras G12D or K-Ras G13D.

[0288] 49. Treatment method for a disorder related to Petition 870260055674, dated 09 / 06 / 2026, page 159 / 412 146 / 328 Ras protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of embodiments 1 to 43 or a pharmaceutical composition of embodiment 44.

[0289] 50. Method for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of embodiments 1 to 43 or a pharmaceutical composition of embodiment 44.

[0290] 51. The method of modality 49 or 50, in which the Ras protein is K-Ras G12D or K-Ras G13D.

[0291] 52. The 50 or 51 modality method, in which the cell is a cancerous cell.

[0292] 53. The method of modality 52, in which the cancer cell is a pancreatic cancer cell, a non-small cell lung cancer cell, a colorectal cancer cell or an endometrial cell.

[0293] 54. The method or use of any of the modalities 45 to 53, wherein the method further comprises the administration of additional anticancer therapy.

[0294] 55. The method of modality 54, in which the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor or a combination thereof.

[0295] 56. The method of modality 54 or 55, in which the therapy Petition 870260055674, dated 09 / 06 / 2026, page 160 / 412 147 / 328 additional anticancer agent is a SHP2 inhibitor.

[0296] 57. A conjugate, or a salt thereof, comprising the structure of Formula III: M-P1 Formula III where P1 is a monovalent organic fraction; and M has the structure of Formula IV: Formula IV, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is optionally substituted C1-C6 hydrogen heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is C1-C6 optionally substituted alkyl, optionally substituted 3- to 6-membered cycloalkyl, C1-C6 optionally substituted heteroalkyl or optionally substituted heterocycloalkyl, Petition 870260055674, dated 09 / 06 / 2026, page 161 / 412 148 / 328 and wherein each Formula IV hydrogen is independently, optionally, isotopically enriched for deuterium.

[0297] 58. Conjugate, according to embodiment 57, or a salt thereof, wherein A is optionally substituted thiazol-di-yl, optionally substituted oxazol-di-yl, optionally substituted morpholine-di-yl, optionally substituted pyrrolidin di-yl, optionally substituted piperidine-di-yl or optionally substituted phenylene.

[0298] 59. Conjugated, according to modality 57 or 58, or one 59, 60, salt of the same, where R1 is:

[0299] 60. The conjugate of any of the modalities 57 a or a salt thereof, where m is 1, n is 1 and each of X1, X2, and X3 is CH2.

[0300] 61. The conjugate of any of the embodiments 57a or a salt thereof, wherein the monovalent organic fraction is a protein.

[0301] 62. Conjugated, according to embodiment 61, or a salt thereof, wherein the protein is a Ras protein.

[0302] 63. Conjugated, according to embodiment 62, or a salt thereof, wherein the Ras protein is K-Ras G12D or K-Ras G13D.

[0303] 64. Conjugated, according to any of the embodiments from 57 to 63, wherein M is linked to an amino acid residue of the monovalent organic fraction. Examples

[0304] The invention is further illustrated by the following examples and summary schemes, which should not be interpreted as limiting this invention in scope or spirit to the specific procedures described in this document. It should be understood that the examples are provided to illustrate particular embodiments and that no limitation of the scope of the invention is intended in this way. It should also be understood that resources may be available in Petition 870260055674, dated 09 / 06 / 2026, p. 162 / 412 149 / 328 various other embodiments, modifications and equivalents thereof, which may suggest the same to those skilled in the art, without departing from the spirit of the present invention and / or the scope of the appended claims. Chemical Syntheses

[0305] The definitions used in the following examples and in another The components in this document are: CH2Cl2, DCM Methylene chloride, Dichloromethane CH3CN, MeCN Acetonitrile CuI Copper(I) iodide DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide EtOAc Ethyl acetate H2O Water HCl Hydrochloric acid K3PO4 Potassium phosphate (tribasic) MeOH Methanol N32SO4 Sodium sulfate NMP N-methylpyrrolidone Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Synthesis of Intermediates Intermediate 1: Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl1pyridin3-yl|indol-3-yl)-2,2-dimethylpropan-1-ol TBDPS l2, AugOTf THF MeO Pd(dppf)CI2(Bpin)2, KOAc toluene MeO Petition 870260055674, dated 09 / 06 / 2026, page 163 / 412 150 / 328 dioxane, H2O —O Pd(dppf)CI2, K2CO3 Step 1: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy) 2,2-dimethylpropan-1-one

[0306] To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (65 g, 137 mmol, crude) in DCM (120 mL) at 0°C under a N2 atmosphere, 1M SnCl4 in DCM (137 mL, 137 mmol) was added slowly. The mixture was stirred at 0°C for 30 min, then a solution of 5-bromo-1H-indol (26.8 g, 137 mmol) in DCM (40 mL) was added dropwise. The mixture was stirred at 0°C for 45 min, then diluted with EtOAc (300 mL), washed with brine (4 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to the product (55 g, 75% yield). LCMS (ESI) m / z [M + Na] calculated for C29H32BrNO2SiNa 556.1; Found: 556.3. Step 2: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)2,2-dimethylpropan-1-one

[0307] To a mixture of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (50 g, 93.6 mmol) in THF (100 mL) at 0°C under a N2 atmosphere, LiBH4 (6.1 g, 281 mmol) was added. The mixture was heated to 60°C and stirred for 20 h, then MeOH (10 mL) and EtOAc (100 mL) were added and the mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was diluted with DCM (50 mL), cooled to 10°C, and diludine (9.5 g, 37.4 mmol) and TsOH^H2O (890 mg, 4.7 mmol) were added. The mixture was stirred at 10°C for 2 h, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by chromatography. Petition 870260055674, dated 09 / 06 / 2026, page 164 / 412 151 / 328 silica gel column to give the product (41 g, 84% yield). LCMS (ESI) m / z [M + H] calculated for C29H34BrNOSi: 519.2; found: 520.1. Step 3: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2dimethylpropyl)-2-iodo-1H-indole

[0308] To a mixture of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (1.5 g, 2.9 mmol) and I2 (731 mg, 2.9 mmol) in THF (15 mL) at room temperature, AgOTf (888 mg, 3.5 mmol) was added. The mixture was stirred at room temperature for 2 h, then diluted with EtOAc (200 mL) and washed with aqueous sat. Na2S2O3 (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (900 mg, 72% yield) as a solid. Step 4: Synthesis of (1S)-1-(3-bromopyridin-2-yl)ethanol

[0309] To a stirred mixture of HCO2H (66.3 g, 1.44 mol) in Et3N (728 g, 7.2 mol) at 0°C under an Ar atmosphere, (4S,5S)-2-chloro-2-methyl-1-(4-methylbenzenesulfonyl)-4,5-diphenyl-1,3-diaza-2-rutencyclopentanecymene (3.9 g, 6.0 mmol) was added in portions. The mixture was heated to 40°C and stirred for 15 min, then cooled to room temperature and 1-(3-bromopyridin-2-yl)ethanone (120 g, 600 mmol) was added in portions. The mixture was heated to 40°C and stirred for a further 2 h, then the solvent was concentrated under reduced pressure. Brine (2 L) was added to the residue, the mixture was extracted with EtOAc (4 x 700 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (100 g, 74% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C7H8BrNO: 201.98; found: 201.9. Step 5: Synthesis of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine

[0310] To a stirred mixture of (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 495 mmol) in DMF (1 L) at 0°C was added NaH, a 60% dispersion in Petition 870260055674, dated 09 / 06 / 2026, page 165 / 412 152 / 328 oil (14.25 g, 594 mmol) in portions. The mixture was stirred at 0°C for 1 h. Honey (140.5 g, 990 mmol) was added dropwise at 0°C and the mixture was heated to room temperature and stirred for 2 h. The mixture was cooled to 0°C and aqueous NH4Cl sat. (5 L) was added. The mixture was extracted with EtOAc (3 x 1.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (90 g, 75% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C8HwBrNO: 215.99; found: 215.9. Step 6: Synthesis of 2-[(1S)-1-methoxyethyl1-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine

[0311] To a stirred mixture of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 417 mmol) in toluene (900 mL) at room temperature under an Ar atmosphere, bis(pinacolate)diboron (127 g, 500 mmol) and KOAc (81.8 g, 833 mmol) and Pd(dppf)Cl2 (30.5 g, 41.7 mmol) were added. The mixture was heated to 100°C and stirred for 3 h. The filtrate was concentrated under reduced pressure and the residue was purified by Al2O3 column chromatography to give the product (100 g, 63% yield) as a semisolid. LCMS (ESI) m / z [M + H] calculated for C14H22BNO3: 264.17; found: 264.1. Step 7: Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2dimethylpropyl1-2-[2-[(1S)-1-methoxyethyl1pyridin-3-yl1-1H-indole

[0312] To a stirred mixture of 5-bromo-3-[3-[(tertbutyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-iodo-1H-indole (140 g, 217 mmol) and 2-[(1 S )1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 380 mmol) in dioxane (1.4 L) at room temperature under an Ar atmosphere was added K2CO3 (74.8 g, 541 mmol), Pd(dppf)Cl2 (15.9 g, 21.7 mmol) and H2O (280 mL) in portions. The mixture was heated to 85°C and stirred for 4 h, then cold H2O (5 L) was added and the mixture was extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 1 L) and dried. Petition 870260055674, dated 09 / 06 / 2026, page 166 / 412 153 / 328 on anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to generate the product (71 g, 45% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C37H43BrN2O2Si: 655.23; found: 655.1. Step 8: Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy1-2,2dimethylpropyl1-1-ethyl-2-[2-[(1S)-1-methoxyethyl1pyridin-3-yl1indole

[0313] To a stirred mixture of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indol (71 g, 108 mmol) in DMF (0.8 L) at 0°C under a N2 atmosphere, Cs2CO3 (70.6 g, 217 mmol) and EtI (33.8 g, 217 mmol) were added in portions. The mixture was heated to room temperature and stirred for 16 h, then H2O (4 L) was added and the mixture was extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 x 1 L), dried over Anhydrous Na2SO4 was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (66 g, 80% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C39H47BrN2O2Si: 683.26; found: 683.3. Step 9: Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3yl|indol-3-yl)-2,2-dimethylpropan-1-ol

[0314] To a stirred mixture of TBAF (172.6 g, 660 mmol) in THF (660 mL) at room temperature under a N2 atmosphere, 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indole (66 g, 97 mmol) was added in portions. The mixture was heated to 50°C and stirred for 16 h, cooled, diluted with H2O (5 L), and extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to generate the product (30 g, 62% of Petition 870260055674, dated 09 / 06 / 2026, page 167 / 412 154 / 328 yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C23H29BrN2Ü2: 445.14; found: 445.1. Intermediate 2. Alternative Synthesis via the Fisher Indole Pathway. nh2hci HCl then, TFA EtOH DMF (Ultrafine Granule) Step 1: Synthesis of 5-[2-[(1S)-1-methoxyethyl]pyridin-3-yl1-2,2-dimethyl-5oxopentanoic acid

[0315] To a mixture of i-PrMgCl (2M in THF, 0.5 L) at -10°C under a N2 atmosphere, n-BuLi, 2.5 M in hexane (333 mL, 833 mmol) was added dropwise over 15 min. The mixture was stirred for 30 min at 10°C and then 3-bromo-2-[(1 S )-1-methoxyethyl]pyridine (180 g, 833 mmol) in THF (0.5 L) was added dropwise over 30 min at -10°C. The resulting mixture was heated to -5°C and stirred for 1 h, then 3,3-dimethyloxane-2,6-dione (118 g, 833 mmol) in THF (1.2 L) was added dropwise over 30 min at 5°C. The mixture was heated to 0°C and stirred for 1.5 h, then quenched with the addition of 4M HCl pre-cooled in dioxane (0.6 L) at 0°C to adjust the pH to ~5. The mixture was diluted with H2O (3 L) at 0°C and extracted with EtOAc (3 x 2.5 L).The combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product (87 g, 34% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C15H21NO4: 280.15; found: 280.1. Petition 870260055674, dated 09 / 06 / 2026, page 168 / 412 155 / 328 Step 2: Synthesis of 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl1pyridin-3-yl|-1Hindol-3-yl)-2,2-dimethylpropanoic and ethyl acid (S)-3-(5-bromo-2-(2-(1methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate

[0316] To a mixture of 5-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]2,2-dimethyl-5-oxopentanoic acid (78 g, 279 mmol) in EtOH (0.78 L) at room temperature under a N2 atmosphere, (4-bromophenyl)hydrazine HCl salt (68.7 g, 307 mmol) was added in portions. The mixture was heated to 85°C and stirred for 2 h, cooled to room temperature, then 4M HCl in dioxane (69.8 mL, 279 mmol) was added dropwise. The mixture was heated to 85°C and stirred for a further 3 h, then concentrated under reduced pressure and the residue was dissolved in TFA (0.78 L). The mixture was heated to 60°C and stirred for 1.5 h, concentrated under reduced pressure, and the residue adjusted to pH ~5 with aqueous saturated NaHCO3, then extracted with EtOAc (3 x 1.5 L). The combined organic layers were dried over anhydrous Na2SO4, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to the product (78 g, crude).LCMS (ESI) m / z [M + H] calculated for C21H23BrN2O3: 430.1 and C23H27BrN2O3: 459.12; found: 431.1 (carboxylic acid) and 459.1. Step 3: Synthesis of ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3yl|indol-3-yl)-2,2-dimethylpropanoate

[0317] To a mixture of 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indol-3-yl)-2,2-dimethylpropanoic acid and ethyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (198 g, 459 mmol) in DMF (1.8 L) at 0°C under a N2 atmosphere, Cs2CO3 (449 g, 1.38 mol) was added in portions. EtI (215 g, 1.38 mmol) in DMF (200 mL) was then added dropwise at 0°C. The mixture was heated to room temperature and stirred for 4 h, then diluted with brine (5 L) and extracted with EtOAc (3 x 2.5 L). The combined organic layers were washed with Petition 870260055674, dated 09 / 06 / 2026, p. 169 / 412 156 / 328 brine (2 x 1.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (160 g, 57% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C25H31BrN2O3: 487.17; found: 487.2. Step 4: Synthesis of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1Hindol-3-yl)-2,2-dimethylpropan-1-ol

[0318] To a mixture of ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropanoate (160 g, 328 mmol) in THF (1.6 L) at 0°C under a N2 atmosphere, LiBH4 (28.6 g, 1.3 mol) was added. The mixture was heated to 60°C for 16 h, cooled, and quenched with pre-cooled aqueous saturated solution (0°C) NH4Cl (5 L). The mixture was extracted with EtOAc (3 x 2 L), and the combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give two atropisomers of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1-hindol-3-yl)-2,2-dimethylpropan-1-ol (as simple atropisomers) (60 g, 38% yield) and (40 g, 26% yield), both as solids. LCMS (ESI) m / z [M + H] calculated for C23H29BrN2O2: 445.14; found: 445.2. Intermediate 3: Synthesis of (63S,4S)-4-amino-11 -ethyl-12-(2-((S)-1 methoxyethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexa-hydro-11H-8oxa-1(5,3)-indola-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-5,7 1 H0Y° ovo CX^N'Boc Ji Boc Pd(dppf)CI2 1 Γ h Mel, NaHCO3 KOAc, (BPin)2 J .A) DMFBr 1 >y° °Y° N Pd(DtBPF)CI2 ] \ \ H K2co3n Ί- V---3 dioxa in H, H Petition 870260055674, of 09 / 06 / 2026, p. 170 / 412 157 / 328 Step 1: Synthesis of methyl (S)-3-(3-bromophenyl)-2-((tercBUTOXICARBONYL)AMINO)PROPANOATE

[0319] To a solution of (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (100 g, 290 mmol) in DMF (1 L) at room temperature was added NaHCO3 (48.8 g, 581.1 mmol) and MeI (61.9 g, 435.8 mmol). The reaction mixture was stirred for 16 h and then quenched with H2O (1 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (3 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (13% EtOAc / petroleum ether) to give the final product (109 g, crude). LCMS (ESI) m / z [M+Na] calculated for Ci5H2oBrNO4 380.05; found: 380.0. Step 2: Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0320] To a stirred solution of methyl (2S)-3-(3-bromophenyl)-2[(tert-butoxycarbonyl)amino]propanoate (108 g, 301.5 mmol) and bis(pinacolate)diboron (99.53 g, 391.93 mmol) in dioxane (3.2 L) was added Petition 870260055674, dated 09 / 06 / 2026, p. 171 / 412 158 / 328 KOAc (73.97 g, 753.70 mmol) and Pd(dppf)Cl2 (22.06 g, 30.15 mmol). The reaction mixture was heated to 90°C for 3 h, then cooled to room temperature and extracted with EtOAc (2 x 3 L). The combined organic layers were washed with brine (3 x 800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% EtOAc / petroleum ether) to yield the product (96 g, 78.6% yield). LCMS (ESI) m / z [M+Na] calculated for C21H32BNO6 428.22; found: 428.1. Step 3: Synthesis of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0321] To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (94 g, 231.9 mmol) and 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (75.19 g, 231.93 mmol) in dioxane (1.5 L) and H2O (300 mL) were added K2CO3 (64.11 g, 463.85 mmol) and Pd(DtBPF)Cl2 (15.12 g, 23.19 mmol). The reaction mixture was heated to 70°C and stirred for 4 h. The reaction mixture was extracted with EtOAc (2 x 2 L) and the combined organic layers were washed with brine (3 x 600 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc / petroleum ether) to yield the product (130 g, crude). LCMS (ESI) m / z [M + H] calculated for C30H38N2O6 523.28; found: 523.1. Step 4: Synthesis of Methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1Hindol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0322] To a solution of methyl (2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-1H-indol-5-yl]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (95.0 g, 181.8 mmol) and iodine (36.91 g, 145.41 mmol) in THF (1 L) at -10°C were added AgOTf (70.0 g, 272.7 mmol) and NaHCO3 (22.9 g, 272.65 mmol). The reaction mixture was stirred for 30 min and then quenched by the addition of Petition 870260055674, dated 09 / 06 / 2026, p. 172 / 412 159 / 328 Aqueous saturated Na2S2O3 (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 1 L) and the combined organic layers were washed with brine (3 x 500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / PET ether) to provide the desired product (49.3 g, 41.8% yield). LCMS (ESI) m / z [M + H] calculated for C30H37IN2O6: 649.18; found: 649.1. Step 5: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoic acid

[0323] A solution of methyl (2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-2-iodo-1H-indol-5-yl]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (60 g, 92.5 mmol) in THF (600 mL) was added to a solution of LiOH*H2O (19.41 g, 462.5 mmol) in H2O (460 mL). The resulting solution was stirred overnight and then the pH was adjusted to 6 with HCl (1 M). The resulting solution was extracted with EtOAc (2 x 500 mL) and the combined organic layers were washed with saturated brine (2 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide the desired product (45 g, 82.1% yield). LCMS (ESI) m / z [M + Na] calculated for C27H33IN2O6 615.13; found: 615.1. Step 6: Synthesis of Methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate

[0324] To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl]phenyl]propanoic acid (30 g, 50.6 mmol) and methyl (3S)-1,2-diazinane-3-carboxylate (10.9 g, 75.9 mmol) in DCM (400 mL) were added NMM (40.97 g, 405.08 mmol), HOBt (2.05 g, 15.19 mmol) and EDCI (19.41 g, 101.27 mmol). The reaction mixture was stirred overnight and then washed with aqueous sat. NH4Cl. (2 x 200 mL) and saturated brine (2 x 200 mL), and the mixture was dried over Na2SO4, filtered and concentrated under reduced pressure to Petition 870260055674, dated 09 / 06 / 2026, p. 173 / 412 160 / 328 generate the desired product (14 g, 38.5% yield). LCMS (ESI) m / z [M + H] calculated for C33H43IN4O6 718.23; found: 719.4. Step 7: Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid

[0325] To a solution of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (92 g, 128.0 mmol) in THF (920 mL) at 0°C was added a solution of LiOH*H2O (26.86 g, 640.10 mmol) in H2O (640 mL). The reaction mixture was stirred for 2 h and then concentrated under reduced pressure to yield the product (90 g, crude). LCMS (ESI) m / z [M + H] calculated for C32H41IN4O6 705.22; Found: 705.1. Step 8: Synthesis of tert-butyl ((63S,4S)-12-iodo-10,10-dimethyl-5,7-dioxo61 ,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine2(1,3)-benzenecycloundecaphane-4-yl)carbamate

[0326] To a solution of (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl]phenyl]propanoyl]-1,2-diazinane-3-carboxylic acid (90 g, 127.73 mmol) in DCM (10 L) at 0°C were added HOBt (34.52 g, 255.46 mmol), DIPEA (330.17 g, 2554.62 mmol) and EDCI (367.29 g, 1915.96 mmol). The reaction mixture was stirred for 16 h and then concentrated under reduced pressure. The mixture was extracted with DCM (2 x 2 L) and the combined organic layers were washed with brine (3 x 1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to yield the product (70 g, 79.8% yield). LCMS (ESI) m / z [M + H] calculated for C32H39IN4O5 687.21; found: 687.1. Petition 870260055674, dated 09 / 06 / 2026, p. 174 / 412 161 / 328 Step 9: Synthesis of tert-butyl ((63S,4S)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5tetramethyl-1 ,3,2-dioxaborolan-2-yl)-61 ,62,63,64,65,66-hexa-hydro-11H-8-oxa1(5,3)-indola-6(1,3)-pyridazine-2(1,3)-benzenecycloundecafano-4-yl)carbamate

[0327] A 1 L round-bottom flask was loaded with tert-butyl ((63S,4S)-12-iodo-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecafano-4-yl)carbamate (22.0 g, 32.042 mmol), toluene (300.0 mL), Pd2(dba)3 (3.52 g, 3.845 mmol), S-Phos (3.95 g, 9.613 mmol) and KOAc (9.43 g, 96.127 mmol) at room temperature. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan (26.66 g, 208.275 mmol) was added dropwise to the mixture with stirring at room temperature. The resulting solution was stirred for 3 hours at 60°C. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography to give the product (22 g, 90% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C38H51BN4O7 687.3; found: 687.4. Step 10: Synthesis of tert-butyl ((63S,4S)-12-(2-((S)-1-methoxyethyl)pyridin-3yl)-1 0,10-dimethyl-5,7-dioxo-61 ,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-4-yl)carbamate

[0328] A mixture of tert-butyl ((63S,4S)-10,10-dimethyl-5,7-dioxo12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8oxa-1 and K3PO4 (1.2 g, 6.0 mmol) in dioxane (50 mL) and A 10 mL solution of H2O under a N2 atmosphere was heated to 70°C and stirred for 2 h. The mixture was diluted with 50 mL of H2O and extracted with 3 x 50 mL of EtOAc. The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by gel electrophoresis column chromatography. Petition 870260055674, dated 09 / 06 / 2026, p. 175 / 412 162 / 328 of silica to generate the product (1.5 g, 74% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C40H49N5O6 695.4; found: 696.5. Step 11: Synthesis of tert-butyl ((63S,4S)-11 -ethyl-12-(2-((S)-1 methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-4YL)CARBAMATE

[0329] A solution of tert-butyl ((63S,4S)-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecafano-4-yl) carbamate (20 g, 28.7 mmol) and Cs2CO3 (18.7 g, 57.5 mmol) in DMF (150 mL) at 0°C was added to a solution of EtI (13.45 g, 86.22 mmol) in DMF (50 mL). The resulting mixture was stirred overnight at 35°C and then diluted with H2O (500 mL). The mixture was extracted with EtOAc (2 x 300 mL) and the combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the product (4.23 g, 18.8% yield) and the atropisomer (5.78 g, 25.7% yield) as solids. LCMS (ESI) m / z [M + H] calculated for C42H53N5O6 724.4; found: 724.6. Step 12: Synthesis of (63S,4S)-4-amino-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin3-yl)-1 0,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1 (5,3)-indole6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-5,7-dione

[0330] A mixture of tert-butyl ((63S,4S)-11-ethyl-12-(2((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)carbamate (1.3 g, 1.7 mmol) in TFA (10 mL) and DCM (20 mL) was stirred at 0°C for 2 h. The mixture was concentrated under reduced pressure to provide the product (1.30 g, crude) as a Petition 870260055674, dated 09 / 06 / 2026, page 176 / 412 163 / 328 solid. LCMS (ESI) m / z [M + H] calculated for C37H45N5O4 623.3; Found: 624.4. Intermediate 4: Synthesis of tert-butyl ((63S,4S,Z)-11 -ethyl-12-(2-((S)-1 methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro11H-8-oxa-2(4,2)-thiazole-1(5,3)-indole-6(1,3)-pyridazinecycloundecaphane-4yl)carbamate PdCI2dppf B2PIN2, toluene toluene KOAc Pd(dppf)CI2toluene / dloxane / H2O Toluene / dioxane Step 1: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-((tertbutoxycarbonyl)amino)propanoic acid

[0331] To a solution of (2 S )-3-(4-bromo-1,3-thiazol-2-yl) 2-[(tert-butoxycarbonyl)amino]propanoate (110 g, 301.2 mmol) in THF (500 mL) and H2O (200 mL) at room temperature was added LiOH (21.64 g, 903.6 mmol). The resulting mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting residue was adjusted to pH 6 with 1 M HCl and then extracted with DCM (3 x 500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the desired product (108 g, crude). LCMS (ESI) m / z [M + H] calculated for CnH15BrN2O4S: 351.00; found: 351.0. Petition 870260055674, dated 09 / 06 / 2026, page 177 / 412 164 / 328 Step 2: Synthesis of methyl (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tertbutoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate

[0332] To a solution of (S)-3-(4-bromothiazol-2-yl)2-((tert-butoxycarbonyl)amino)propanoic acid (70 g, 199.3 mmol) in DCM (500 mL) at 0°C was added methyl salt ((3S)-1,2-diazinane-3-carboxylate bis(trifluoroacetic acid) (111.28 g, 298.96 mmol), NMM (219.12 mL, 1993.0 mmol), EDCI (76.41 g, 398.6 mmol) and HOBt (5.39 g, 39.89 mmol). The resulting solution was heated to room temperature and stirred for 1 h. Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.50%). EtOAc / pet ether) to provide the desired product (88.1 g, 93% yield). Step 3: Synthesis of (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol

[0333] To a solution of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (60 g, 134.7 mmol) in toluene (500 mL) at room temperature was added bis(pinacolato)diboron (51.31 g, 202.1 mmol), Pd(dppf)Cl2 (9.86 g, 13.48 mmol) and KOAc (26.44 g, 269.4 mmol). The reaction mixture was then heated to 90°C and stirred for 2 h. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. Purification by silica gel column chromatography (0.50% EtOAc / petroleum ether) yielded the desired product (60.6 g, 94% yield). LCMS (ESI) m / z [M + H] calculated for C29H41BN2O4: 493.32; found: 493.3. Petition 870260055674, dated 09 / 06 / 2026, page 178 / 412 165 / 328 Step 4: Methyl Synthesis (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1Hindol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate

[0334] To a solution of (S )-3-(1-ethyl-2-(2-(1methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol3-yl)-2,2-dimethylpropan-1-ol (30 g, 60.9 mmol) in toluene (600 mL), To dioxane (200 mL) and H2O (200 mL) at room temperature, methyl (S)1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (43.62 g, 91.4 mmol), K3PO4 (32.23 g, 152.3 mmol), and Pd(dppf)Cl2 (8.91 g, 12.18 mmol) were added. The resulting solution was heated to 70°C and stirred overnight. The reaction mixture was then cooled to room temperature and quenched with H2O (200 mL).The resulting mixture was extracted with EtOAc (3 x 1000 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-90% EtOAc / PET ether) to provide the desired product (39.7 g, 85% yield). LCMS (ESI) m / z [M + H] calculated for C40H54N6O7S: 763.39; found: 763.3. Step 5: Acid Synthesis (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic

[0335] To a solution of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (39.7 g, 52.0 mmol) in THF (400 mL) and H2O (100 mL) at room temperature was added LiOH^H2O (3.74 g, 156.2 mmol). The resulting mixture was stirred for 1.5 h and then concentrated under reduced pressure. The residue was acidified to pH 6 with 1 M HCl and Petition 870260055674, dated 09 / 06 / 2026, page 179 / 412 166 / 328 extracted with DCM (3 x 1000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the desired product (37.9 g, crude). LCMS (ESI) m / z [M + H] calculated for C39H52N6O7S: 749.37; found: 749.4. Step 6: Synthesis of tert-butyl ((63S,4S,Z)-11-ethyl-12-(2-((S)-1methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66hexa-hydro-11H-8-oxa-2(4,2)-thiazole-1(5,3)-indole-6(1,3)pyridazinecycloundecafano-4-yl)carbamate

[0336] To a solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (37.9 g, 50.6 mmol), HOBt (34.19 g, 253.0 mmol) and DIPEA (264.4 mL, 1518 mmol) in DCM (4 L) at 0°C was added EDCI (271.63 g, 1416.9 mmol). The resulting mixture was heated to room temperature and stirred overnight. The reaction mixture was then quenched with H2O and washed with 1 M HCl (4 x 1 L). The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.70% EtOAc / PET ether) to provide the desired product (30 g, 81% yield). LCMS (ESI) m / z [M + H] calculated for C39H50N6O6S: 731.36; found: 731.3. Intermediate 5: Synthesis of (63S)-4-amino-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin 3-yl)-1 0.1 0-dimethyl-21 ,22,23,26,61 ,62,63,64,65,66-decahydro-1 1 H-8-oxa-1 (5,3)indole-6(1,3)-pyridazine-2(5,1)-pyridinecycloundecaphane-5,7-dione DIPEA THE MeCN THE NHBoc (Boc)2O, DMAP MeCN dioxane Pd(dppf)CI2DCM, K2CO3dioxane / hUO dioxane Petition 870260055674, dated 09 / 06 / 2026, p. 180 / 412 167 / 328 Step 1: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)acrylate

[0337] To a solution of methyl (tert-butoxycarbonyl)-L-serinate (10 g, 45 mmol) in anhydrous MeCN (150 mL), DIPEA (17 g, 137 mmol) was added. The reaction mixture was stirred at 45°C for 2 h to give the product in solution. LCMS (ESI) m / z [M + Na] calculated for C9H15NO4 201.1; found: 224.1. Step 2: Synthesis of methyl 2-(bis(tert-butoxycarbonyl)amino)acrylate

[0338] To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (12 g, 60 mmol) in anhydrous MeCN (150 mL) at 0°C, DMAP (13 g, 90 mmol) and (Boc)2O (26 g, 120 mmol) were added. The reaction was stirred for 6 h, then quenched with H2O (100 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (12.5 g, 65% yield) as a solid. LCMS (ESI) m / z [M + Na] calculated for C14H23NO6 301.2; Found: 324.1. Step 3: Synthesis of methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(5-bromo-3,6-dihydropyridine-1(2H)-yl)propanoate

[0339] To a mixture of 5-bromo-1,2,3,6-tetrahydropyridine (8.0 g, 49 mmol) in MeOH (120 mL) under an Ar atmosphere, methyl 2 Petition 870260055674, dated 09 / 06 / 2026, p. 181 / 412 168 / 328 {bis[(tert-butoxy)carbonyl]amino}prop-2-enoate (22 g, 74 mmol). The mixture was stirred for 16 h, then concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product (12 g, 47% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C19H31BrN2O6 462.1; found: 463.1. Step 4: Synthesis of 3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)-2-((tertBUTOXYCARBONYL)AMINO)PROPANOIC ACID

[0340] To a mixture of methyl 2-(bis(tert-butoxycarbonyl)amino)-3(5-bromo-3,6-dihydropyridine-1(2H)-yl)propanoate (14 g, 30 mmol) in dioxane (30 mL) and H2O (12 mL) was added LiOH (3.6 g, 151 mmol). The mixture was heated to 35°C and stirred for 12 h, then 1M HCl was added and the pH was adjusted to ~3-4. The mixture was extracted with DCM (2 x 300 mL) and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the product (10 g, 85% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for CnH21BrN2O4 348.1; Found: 349.0. Step 5: Synthesis of methyl (3S)-1-(3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)-2((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate

[0341] To a mixture of 3-(5-bromo-3,6-dihydropyridine-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (10 g, 30 mmol), DIPEA (12 g, 93 mmol) and methyl(3S)-1,2-diazinane-3-carboxylate (5.4 g, 37 mmol) in DMF (100 mL) at 0°C under an Ar atmosphere, HATU (13 g, 34 mmol) was added. The mixture was stirred at 0°C for 2 h, then H2O was added and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography to give the product (9.0 g, 55% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for CwH31BrN4Oõ 474.1; found: 475.1. Petition 870260055674, dated 09 / 06 / 2026, page 182 / 412 169 / 328 Step 6: Methyl Synthesis (3S)-1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyeth il)pyridin-3-yl)-1H-indol-5-yl)-3,6dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylate

[0342] A mixture of methyl (3S)-1-(3-(5-bromo-3,6-dihydropyridin1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3carboxylate (9.0 g, 18 mmol), K2CO3 (4.5 g, 32 mmol), Pd(dppf)Cl2.DCM (1.4 g, 2 mmol), 3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl)-2,2-dimethylpropan-1-ol (9.8 g, 20 mmol) in dioxane (90 mL) and H2O (10 mL) under an Ar atmosphere was heated to 75°C and stirred for 2 h. H2O was added and the mixture was extracted with EtOAc (3 x 200 mL).The combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product (4.0 g, 25% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C42H60N6O7 760.5; found: 761.4. Step 7: Synthesis of (3S)-1 acid -(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylic

[0343] A mixture of methyl (3 S )-1-(2-(( tert butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(( S )-1methoxyethyl)pyridin-3-yl)-1 H (-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylate (4.1 g, 5.0 mmol) in THF (35 mL) at 0°C was added LiOH (0.60 g, 27 mmol). The mixture was stirred at 0°C for 1.5 h, then 1M HCl was added to adjust the pH to ~6-7 and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the product (3.6 g, 80% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C41H58N6O7 746.4; found: 747.4. Petition 870260055674, dated 09 / 06 / 2026, page 183 / 412 170 / 328 Step 8: Synthesis of tert-butyl((63S)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)1 0,10-dimethyl-5,7-dioxo-21,22,23,26,61,62,63,64,65,66-decahydro-1 1 H-8-oxa1(5,3)-indole-6(1,3)-pyridazine-2(5,1)-pyridinecycloundephane-4-yl)carbamate

[0344] To a mixture of (3S)-1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)yl)propanoyl)hexahydropyridazine-3-carboxylic acid (3.6 g, 5.0 mmol) and DIPEA (24 g, 190 mmol) in DCM (700 mL) under an Ar atmosphere, EDCI^HCl (28 g, 140 mmol) and HOBt (6.5 g, 50 mmol) were added. The mixture was heated to 30°C and stirred for 16 hours at 30°C, then concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and washed with H2O (2 x 200 mL), brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield the product (1.45 g, 40% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C41H56N6O6 728.4; found: 729.4. Step 9: Synthesis of (63S)-4-amino-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)1 0,10-dimethyl-21,22,23,26,61,62,63,64,65,66-decahydro-1 1 H-8-oxa-1 (5,3)-indole6(1,3)-pyridazine-2(5,1)-pyridinecycloundecaphane-5,7-dione

[0345] To a mixture of tert-butyl ((63S)-11-ethyl-12-(2-((S)1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-21,22,23,26,61,62,63,64,65,66decahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,1)pyridinecycloundecaphano-4-yl)carbamate (130 mg, 0.20 mmol) in DCM (1.0 mL) at 0°C was added TFA (0.3 mL). The mixture was heated to room temperature and stirred for 2 h, then concentrated under reduced pressure to give the product, which was used directly in the next step without further purification. LCMS (ESI) m / z [M + H] calculated for C36H48N6O4 628.4; found: 629.4. Petition 870260055674, dated 09 / 06 / 2026, p. 184 / 412 171 / 328 Intermediate 6: Synthesis of (22S,63S,4S)-4-amino-11 -ethyl-12-(2-((S)-1 methoxyethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexa-hydro-11H-8-oxa2(4,2)-morpholine-1(5,3)-indole-6(1,3)-pyridazinacicloundecafanone-5,7-5 SS-Et-Duphos-Rh Ha MeOH TBSCI DCM Step 1: Synthesis of tert-butyl (2R)-2-formylmorpholine-4-yl formate

[0346] To a solution of tert-butyl(2R)-2-(hydroxymethyl)morpholin-4-yl formate (50 g, 230 mmol) in EtOAc (1 L) was added TEMPO (715 mg, 4.6 mmol) and NaHCOa (58 g, 690 mmol) at room temperature. The mixture was cooled to -50°C, then TCCA (56 g, 241 mmol) in EtOAc (100 mL) was added dropwise over 30 min. The reaction mixture was heated to 5°C for 2 h, then quenched with 10% Na2S2O3 (200 mL) and stirred for 20 min. The resulting mixture was filtered and the organic phase was separated. The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield the product (50 g, crude) as an oil. Petition 870260055674, dated 09 / 06 / 2026, page 185 / 412 172 / 328 Step 2: Synthesis to provide tert-butyl (S,Z)-2-(2(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4CARBOXYLATE

[0347] To a solution of tert-butyl(2R)-2-formylmorpholin-4-yl formate (49 g, 153 mmol) and methyl 2-{[(benzyloxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (60 g, 183 mmol) in MeCN (300 mL) tetramethylguanidine (35 g, 306 mmol) was added at 0-10°C. The reaction mixture was stirred at 10°C for 30 min and then heated to room temperature for 2 h. The reaction mixture was diluted with DCM (200 mL) and washed with 10% citric acid (200 mL) and 10% aqueous NaHCO3 (200 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give the product (36 g, 90% yield) as a solid. LCMS (ESI) m / z [M + Na] calculated for C21H28N2O4 420.2; found: 443.1. Step 3: Synthesis of tert-butyl (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy3-oxopropyl)morpholine-4-carboxylate

[0348] To a solution of tert-butyl(S,Z)-2-(2(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (49 g, 0.12 mol) in MeOH (500 mL) was added (S,S)-EtDUPHOS-Rh (500 mg, 0.7 mmol). The mixture was stirred at room temperature under an H2 atmosphere (60 psi) for 48 h. The reaction was concentrated and purified by silica gel column chromatography to give the product (44 g, 90% yield) as a solid. LCMS (ESI) m / z [M + Na] calculated for C21H30N2O7 422.2; found: 445.2. Step 4: Synthesis of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-morpholin-2YL)PROPANOATE

[0349] To a stirred solution of tert-butyl (S )-2-(( S )-2(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)morpholine-4-carboxylate (2.2 g, 5.2 mmol) in EtOAc (2 mL) was added HCl / EtOAc (25 mL) at 15°C. Petition 870260055674, dated 09 / 06 / 2026, page 186 / 412 173 / 328 The reaction was stirred at 15°C for 2 h, then concentrated under reduced pressure to give the product (1.51 g, 90% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C16H22N2O5 322.1; found: 323.2. Step 5: Synthesis of (S)-5-bromo-3-(3-((tert-butyldimethylsilyl)oxy)-2,2dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole

[0350] To a solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropan-1-ol (100 g, 0.22 mol) and imidazole (30.6 g, 0.45 mol) in DCM (800 mL) was added TBSCl (50.7 g, 0.34 mol) in DCM (200 mL) at 0°C. The reaction was stirred at room temperature for 2 h. The resulting solution was washed with H2O (3 x 300 mL) and brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (138 g, 90% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C29H43BrN2O2Si 558.2; found: 559.2. Step 6: Methyl Synthesis (2S]-2-{[(BENZiLOXi)CARBONiL]AMiNO}-3-[(2S]-4-(3-f3[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1methoxyethyl]pyridin-3-yl}indol-5-yl)morpholin-2-yl]propanoate methyl (2S)-2{[(benzyloxy)carbonyl]amino}-3-[(2S)-morpholin-2-yl]propanoate (31.7 g, 98.2 mmol), RuPhos (16.7 g, 35.7 mmol), di-p-chlorobis(2-amino-1,1-biphenyl-2-ylC, N )dipalladium(II) (2.8 g, 4.4 mmol) and cesium carbonate (96 g, 295 mmol) followed by RuPhos-Pd-G2 (3.5 g, 4.4 mmol) was heated to 105°C under a nitrogen atmosphere. The reaction mixture was stirred for 6 hours at 105°C under a nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. Petition 870260055674, dated 09 / 06 / 2026, p. 187 / 412 174 / 328 residue was purified by TLC chromatography prep to provide the product (55 g, 73% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C45H64N4O7Si 800.5; found: 801.5. Stage 7: Acid Synthesis (2S)-2-f[(BENZYLOXi)CARBONiL|AMiNO}-3-[(2S)-4-(3-f3[(TERC-BUTYLDIMETYLSILYL)OXn-2,2-DIME TILPROPYL}-1-ETYL-2-f2-[(1S)-1methoxyethyl|pyridine-3-yl}indole-5-yl)morpholin-2-yl|propanoic

[0352] To a solution of methyl (2S)-2-{[(benzyloxy)carbonyl]amino}3-[(2S)-4-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)morpholin-2-yl]propanoate (10 g, 12 mmol) in THF (270 mL) LiOH (1.3 g, 31 mmol) was added in H2O (45 mL) at room temperature. The reaction was stirred at room temperature for 2 h, then treated with 1 N HCl to adjust the pH to 4-5 at 0-5°C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The organic phase was then concentrated under reduced pressure to give the product (9.5 g, 97% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C44H62N4O7Si 786.4; found: 787.4. Step 8: Synthesis of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(3-(3((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-et yl-2-(2-((S)-1methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate

[0353] To a stirred solution of (2S)-2{[(benzyloxy)carbonyl]amino}-3-[(2S)-4-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)morpholin-2-yl]propanoic acid (10 g, 12.7 mmol) in DMF (150 mL), methyl (S)-hexahydropyridazine-3-carboxylate (2 g, 14 mmol) was added, then cooled to 0°C, DIPEA (32.8 g, 254 mmol) was added followed by HATU (9.7 g, 25.4 mmol) at 0-5°C. The reaction mixture was stirred at 0-5°C for 1 h. The resulting mixture was diluted with EtOAc (500 mL) and H2O (200 mL) Petition 870260055674, dated 09 / 06 / 2026, p. 188 / 412 (175 / 328 mL). The organic layer was separated and washed with H2O (2 x 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to provide the product. LCMS (ESI) m / z [M + H] calculated for C50H72N6O8Si 912.5; found: 913.4. Step 9: Methyl Synthesis (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(1ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S) -1-methoxyethyl)pyridin-3-yl)-1H-indol-5yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate

[0354] A solution of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)3-((S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (8.5 g, 9 mmol) in THF (8 mL) a mixture of tetrabutylammonium fluoride (1M in THF, 180 mL, 180 mmol) and AcOH (11 g, 200 mmol) was added at room temperature. The reaction mixture was stirred at 75°C for 3 h. The resulting mixture was diluted with EtOAc (150 mL) and washed with H2O (6 x 20 mL). The organic phase was concentrated under reduced pressure to give the product (7.4 g, 100% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C44H58N6O8 799.4; found: 798.4. Step 10: Synthesis of (S)-1-((S)-2-(((benzyloxy)carbonyl)amino acid)-3-((S)-4-(1ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S) -1-methoxyethyl)pyridin-3-yl)-1H-indol-5yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid

[0355] To a solution of methyl (S)-1-((S)-2(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (8 g, 10 mmol) in THF (200 mL) was added LiOH (600 mg, 25 mmol) in H2O (30 mL). The reaction mixture was stirred at room temperature for 1 h, then treated with 1 N HCl to adjust the pH to 4-5 at 0-5°C and extracted with EtOAc (2 x 500 mL). The organic phase was washed with brine and concentrated under pressure. Petition 870260055674, dated 09 / 06 / 2026, p. 189 / 412 176 / 328 reduced to give the product (8 g, gross) as a solid. LCMS (ESI) m / z [M + H] calculated for C43H56N6O8 784.4; found: 785.4. Stage 11: Synthesis to provide benzyl ((22S,63S,4S)-11-ethyl-12-(2-((S)-1 methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexa-hydro11H-8-oxa-2(4,2)-morpholine-1(5,3)-indole-6(1,3)-pyridazinecycloundecafano-4YL)CARBAMATE

[0356] To a stirred solution of (S)-1-((S)-2(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3carboxylic acid (8 g, 10.2 mmol) and DIPEA (59 g, 459 mmol) in DCM (800 mL) EDCI (88 g, 458 mmol) and HOBt (27.6 g, 204 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to generate the product. (5 g, 66% yield) as a solid; LCMS (ESI) m / z [M + H] calculated for C43H54N6O7 766.4; found: 767.4. Step 12: Synthesis of (22S,63S,4S)-4-amino-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin3-yl)-10,10-dimethyl-61,62,63,64,65, 66-hexahydro-11H-8-oxa-2(4,2)-morpholine1(5,3)-indole-6(1,3)-pyridazinecycloundephane-5,7-dione

[0357] To a solution of benzyl ((22S,63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa2(4,2)-morpholine-1(5,3)-indole-6(1,3)-pyridazinecycloundecaphano-4-yl)carbamate (400 mg, 0.5 mmol) in MeOH (20 mL) was added Pd / C (200 mg) and ammonium acetate (834 mg, 16 mmol) at room temperature under an H2 atmosphere and the mixture was stirred for 2 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was redissolved in DCM (20 mL) and washed with H2O (5 mL x 2), then concentrated under reduced pressure to provide the product (320 mg, 97% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C35H48N6O5 632.4; found: 633.3. Petition 870260055674, dated 09 / 06 / 2026, page 190 / 412 177 / 328 Intermediate 7: Synthesis of tert-butyl ((63S,4S,Z)-11-ethyl-12-(2-((S)-1methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61 ,62,63,64,65,66-hexa-hydro-1 1 H-8-oxa-2(4,2)-thiazole-1 (5,3)-indole-6(1 ,3)pyridazinacycloundecaphano-4-yl)carbamate THF (Bpln)2ldtbpy [lr(1,S-cod)CI]2 MeO Pd(OAc)2, BINAP, Cs2COs, MeO toluene,100°C toluene MeO Br B2pln2, Pd(dppf)CI2 heated / H2O 70°C Cbz toluene, 90 °C Γ toluene * Dioxane / HhO 70°C Step 1: Synthesis of (S)-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0358] A stirred solution of (S)-3-bromo-2-(1 methoxyethyl)pyridine (80.0 g, 370.24 mmol) and bis(pinacolate)diboron (141.03 g, 555.3 mmol) in THF (320 mL) was added dtbpy (14.91 g, 55.5 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (7.46 g, 11.1 mmol) under an argon atmosphere. The resulting mixture was stirred for 16 h at 75°C. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (200 mL) and adjusted to pH 10 with a solution of Na2CO3 (40 g) and NaOH (10 g) in H2O (600 mL). The aqueous layer was extracted with EtOAc (800 mL) and then the aqueous phase was acidified to pH 6 with HCl (6 N) to precipitate the desired product (50 g, 52% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for CeHuBBrNOe: 260.01; found: 260.0. Petition 870260055674, dated 09 / 06 / 2026, pp. 191 / 412 178 / 328 Step 2: Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine

[0359] To a stirred solution of (S)-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (23.0 g, 88.5 mmol) in MeCN (230 mL) at room temperature, NIS (49.78 g, 221.2 mmol) was added. The resulting mixture was stirred overnight at 80°C under an argon atmosphere. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (2.1 L) and washed with Na2S2O3 (3 x 500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired product (20 g, 66% yield). LCMS (ESI) m / z [M + H] calculated for C8H9BrINO: 341.90; found: 341.7. Step 3: Synthesis of benzyl (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3yl)piperazine-1-carboxylate

[0360] In a 3 L round-bottom, 3-necked flask purged and maintained with an inert argon atmosphere, 3-bromo-5-iodo-2[(1 S )-1-methoxyethyl]pyridine (147 g, 429.8 mmol), benzylpiperazine-1-carboxylate (94.69 g, 429.8 mmol), Pd(OAc)2 (4.83 g, 21.4 mmol), BINAP (5.35 g, 8.6 mmol), Cs2CO3 (350.14 g, 1074.6 mmol), and toluene (1 L) were placed. The resulting solution was stirred overnight at 100°C in an oil bath. The reaction mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / hexanes) to provide the product (135 g, 65% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C20H24BrN3O3 433.1; found: 434.1. Step 4: Synthesis of benzyl (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylate

[0361] In a 3 L round-bottom, 3-necked flask purged and maintained with an inert argon atmosphere, benzyl 4[5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-yl]piperazine-1-carboxylate (135 g, 310.8 Petition 870260055674, dated 09 / 06 / 2026, p. 192 / 412 179 / 328 mmol), bis(pinacolate)diboron (86.82 g, 341.9 mmol), Pd(dppf)Cl2 (22.74 g, 31.0 mmol), KOAc (76.26 g, 777.5 mmol), toluene (1 L). The resulting solution was stirred for 2 days at 90°C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (30% EtOAc / hexane) to give the product (167 g, crude) as a solid. LCMS (ESI) m / z [M + H] calculated for C26H36BN3O5 481.3; found: 482.1. Etapa 5: Síntese de benzil (S)-4-(5-(5-bromo-3-(3-((tercbutildifenilsilyl)oxi)-2,2-dimetilpropil)-1H-indol-2-il)-6-(1metoxietil)piridin-3-il)piperazine-1-carboxylate

[0362] In a 3 L round-bottom, three-necked flask, purged and maintained with an inert argon atmosphere, was placed (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3yl)piperazine-1-carboxylate (167 g, 346.9 mmol), 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-iodo-1H-indole (224.27 g, 346.9 mmol), Pd(dppf)Cl2 (25.38 g, 34.6 mmol), dioxane (600 mL), H2O (200 mL), K3PO4 (184.09 g, 867.2 mmol), toluene (200 mL). The resulting solution was stirred overnight at 70°C in an oil bath. The reaction mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / hexane) to give the product (146 g, 48% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C49H57BrN4O4Si 872.3; found: 873.3. Step 6: Synthesis of benzyl (S)-4-(5-(5-bromo-3-(3-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate

[0363] For a stirred mixture of benzyl (S)-4-(5-(5bromo-3-(3-(( tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1 H-indol-2-yl)-6-(1 Petition 870260055674, dated 09 / 06 / 2026, page 193 / 412 180 / 328 methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (146 g, 167.0 mmol) and CS2CO3 (163.28 g, 501.1 mmol) in DMF (1200 mL) was added to ethyl iodide (52.11 g, 334.0 mmol) in portions at 0°C under a N2 atmosphere. The final reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with EtOAc (1 L) and washed with brine (3 x 1.5 L). The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (143 g, crude) as a solid that was used directly for the next step without further purification. LCMS (ESI) m / z [M + H] calculated for C51H61BrN4O4Si 900.4; found: 901.4. Step 7: Synthesis of Benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1 CARBOXYLATE

[0364] To a stirred mixture of benzyl (S)-4-(5-(5-bromo-3-(3((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3yl)piperazine-1-carboxylate (143 g, 158.5 mmol) in DMF (1250 mL) CsF (72.24 g, 475.5 mmol) was added. Then, the reaction mixture was stirred at 60°C for 2 days under a N2 atmosphere. The resulting mixture was diluted with EtOAc (1 L) and washed with brine (3 x 1 L). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% EtOAc / petroleum ether) to provide two atropisomers A (38 g, 36% yield) and B (34 g, 34% yield), both as solids. LCMS (ESI) m / z [M + H] calculated for C35H43BrN4O4 663.2; found: 662.2. Step 8: Synthesis of benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate

[0365] In a 500 mL round-bottom flask with three necks, purged and maintained with an inert nitrogen atmosphere, Petition 870260055674, dated 09 / 06 / 2026, page 194 / 412 181 / 328 was made up of benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (14 g, 21.1 mmol), bis(pinacolate)diboron (5.89 g, 23.21 mmol), Pd(dppf)Cl2 (1.54 g, 2.1 mmol), KOAc (5.18 g, 52.7 mmol), toluene (150 mL). The resulting solution was stirred for 5 hours at 90°C in an oil bath. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% EtOAc / petroleum ether) to give the product (12 g, 76% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C41H55BN4O6 710.4; found: 711.3. Step 9: Synthesis of methyl (S)-1-((S)-3-(4-(2-(5-(4((BENZYLOXY)CARBONYL)PIPERAZIN-1-YL)-2-((S)-1-METHOXYETHYL)PYRIDIN-3-YL)-1 ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexa-hydropyridazine-3-carboxylate

[0366] In a 250 mL round-bottom flask that had been purged and maintained with an inert argon atmosphere, benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (10.8 g, 15.2 mmol), methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazol-2-yl)-2-[(tert-butoxycarbonyl)amino]propanoyl]-1,2-diazinane-3-carboxylate (7.98 g, 16.7 mmol) Pd(dtbpf)Cl2 (0.99 g, 1.52 mmol), K3PO4 (8.06 g, 37.9 mmol), toluene (60 mL), dioxane (20 mL), H2O (20 mL). The resulting solution was stirred for 3 hours at 70°C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was extracted with EtOAc (2 x 50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc / hexane). The solvent was removed under reduced pressure to give the product (8 g, 51% yield) as a solid.LCMS (ESI) m / z [M + H] calculated for C52H68N8O9S 980.5; set: 980.9. Petition 870260055674, 06 / 09 / 2026, pág. 195 / 412 182 / 328 Etapa 10: Síntese de ácido (S)-1 -((S)-3-(4-(2-(5-(4((BENZYLOXI)CARBONIL)PIPERAZIN-1 -IL)-2-((S)-1 -METHOXYETIL)PIRIDIN-3-IL)-1 ethyl-3-(3-hidroxi-2,2-dimetilpropil)-1H-indol-5-il)thiazol-2-il)-2-((tercbutoxicarbonyl)amino)propanoil)hexa-hidropiridazina-3-carboxílico

[0367] To a stirred mixture of methyl (S)-1-((S)-3-(4-(2(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (12 g, 12.23 mmol) in THF (100 mL) / H2O (100 mL) LiOH (2.45 g, 61.1 mmol) was added under an N2 atmosphere and the resulting mixture was stirred for 2 h at room temperature. The THF was removed under reduced pressure. The pH of the aqueous phase was acidified to 5 with 1N HCl at 0°C. The aqueous layer was extracted with DCM (3 x 100 mL). The organic phase was concentrated under reduced pressure to give the product (10 g, 85% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C51H66N8O9S 966.5; found: 967.0. Step 11: Synthesis of benzyl 4-(5-((63S,4S,Z)-4-((tertbutoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-1 1 H-8-oxa-2(4,2)-thiazole-1 (5,3)-indole6(1,3)-pyridazinecycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3yl)piperazine-1-carboxylate

[0368] In a 3 L round bottom flask purged and maintained with an inert nitrogen atmosphere, acid was placed ( S)-1((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1 H-indol-5yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3carboxylic acid (18 g, 18.61 mmol), MeCN (1.8 L), DIPEA (96.21 g, 744.4 mmol), EDCI (107.03 g, 558.3 ​​mmol) and HOBt (25.15 g, 186.1 mmol). The solution Petition 870260055674, dated 09 / 06 / 2026, p. 196 / 412 The resulting 183 / 328 was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting solution was diluted with DCM (1 L) and washed with 1M HCl (3 x 1 L) and H2O (3 x 1 L). The organic layer was then concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc / hexane) to provide the product (10.4 g, 55% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C51H64N8O8S 948.5; found: 949.3. Step 12: Synthesis of tert-butyl ((63S,4S,Z)-11 -ethyl-12-(2-((S)-1 -methoxyethyl)5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indole-6(1,3)pyridazinecycloundecaphane-4-yl)carbamate

[0369] In a 250 mL round-bottom flask that had been purged and maintained with an inert nitrogen atmosphere, benzyl 4-(5((63S,4S,Z)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazolo-1(5,3)-indole-6(1,3)pyridazinecycloundecafano-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (10.40 g, 10.9 mmol), Pd(OH)2 / C (5 g, 46.9 mmol) and MeOH (100 mL) were placed. The resulting solution was stirred for 3 h at room temperature under a 202,650 Pa (2 atm) H2 atmosphere. The solids were filtered and the filter cake was washed with MeOH (3 x 100 mL). The combined organic phases were concentrated under reduced pressure to give the product (8.5 g, 90% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C43H58N8O6S 814.4; found: 815.3. Step 13: Synthesis of tert-butyl((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61 ,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazole-1(5,3)-indole-6(1,3)pyridazinecycloundecaphane-4-yl)carbamate

[0370] In a 1000 mL round-bottom flask, purged and maintained with an inert nitrogen atmosphere, tert-butyl Petition 870260055674, dated 09 / 06 / 2026, p. 197 / 412 184 / 328 ((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(piperazin-1 -yl)pyridin-3-yl)10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)thiazole-1(5,3)-indole-6(1,3)-pyridazinecycloundecaphane-4-yl)carbamate (8.5 g, 10.4 mmol), MeOH (100 mL), AcOH (1.88 g, 31.2 mmol). The solution was stirred for 15 min, and then HCHO (1.88 g, 23.15 mmol, 37% aqueous solution) and NaBH3CN (788 mg, 12.5 mmol) were added at room temperature. The resulting solution was stirred for 3 h. The mixture was then quenched with H2O (100 mL) and concentrated under reduced pressure to remove MeOH. The resulting solution was diluted with DCM (300 mL) and washed with H2O (3 x 100 mL). The solution was concentrated under reduced pressure to provide the product (8.2 g, 90% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C44H60N8O6S 828.4; found: 829.3. Intermediate 8: Synthesis of (63S,4S,Z)-4-amino-11-ethyl-12-(5-((S)-hexahydropyrazino[2,1 -c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1 -methoxyethyl)pyridine-3-0-1-methyl-16 ,62,63,64,65,66-hexa-hydro-11H-8-oxa-2(4,2)-thiazole-1(5,3)indole-6(1,3)-pyridazinacycloundecaphano-5,7-dione ACgO. EtjN DMAP DCM Trihydrated chloramine-T NaI Pd(OAc)?, Blnap Cs2CO3 KOAC, B2Pln2, Pd(dppf)CI2toluene toluene DIPEA, HOBT, EDO THF, HjO Toluene / dioxane / H?O K3PO4, Pd(dtbpf)Cl2 Step 1: Synthesis of (S)-3-(5-bromo-1 -ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1Hindol-3-yl)-2,2-dimethylpropyl acetate

[0371] To a stirred solution of (S )-3-(5-bromo-1-ethyl2-(2-(1-methoxyethyl)pyridin-3-yl) -1H-indol-3-yl)-2,2-dimethylpropan-1-ol (100 g, Petition 870260055674, of 09 / 06 / 2026, p. 198 / 412 185 / 328 224.517 mmol) and Et3N (45.44 g, 449.034 mmol) in DCM (1 L) were added to DMAP (2.74 g, 22.452 mmol) and AC2O (27.50 g, 269.420 mmol) in portions at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure and then diluted with EtOAc (1000 mL). The resulting mixture was washed with 1M HCl (500 mL) and then washed with saturated NaHCO3 (500 mL) and brine (500 mL) dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with petroleum ether (500 mL) to give the product (93.3 g, 85% yield) as a white solid. LCMS (ESI) m / z [M + H] calculated for C25H31BrN2O3: 487.16; found: 489.2. Step 2: Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0372] To a stirred solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (93.3 g, 191.409 mmol) and B2PIN2 (72.91 g, 287.113 mmol) in THF (370 mL) dtbpy (7.71 g, 28.711 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (6.43 g, 9.570 mmol) were added in portions at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 75°C. The resulting mixture was concentrated under reduced pressure to give the product (190 g, crude) as an oil. LCMS(ESI) m / z [M + H]; calculated for C25H32BBrN2O5: 531.17; found: 533.3. Step 3: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0373] To a stirred solution of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (110 g, 207.059 mmol) and chloramine-T trihydrate (349.96 g, 1242.354 mmol) in THF (550 Petition 870260055674, dated 09 / 06 / 2026, p. 199 / 412 A solution of NaI (186.22 g, 1242.354 mmol) in H2O (225 mL) was added in portions at 0°C under an air atmosphere. The resulting mixture was stirred overnight at 50°C under an argon atmosphere. The resulting mixture was concentrated under reduced pressure and then washed with CHCl3 (500 mL). The resulting mixture was filtered, the filter cake was washed with CHCl3 (3 x 250 mL). The filtrate was extracted with CHCl3 (3 x 500 mL). The combined organic layers were washed with Na2S2O3 (500 mL), washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18% EtOAc / petroleum ether) to provide the product (24 g, 18% yield) as a solid. LCMS(ESI) m / z [M + H]; calculated for C25H30BrIN2O3: 613.06; found: 614.7. Step 4: Synthesis of 3-(5-bromo-1-ethyl-2-(5-((S)-hexahydropyrazino[2.1cm,41oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2dimethylpropyl acetate

[0374] To a stirred solution of 3-(5-bromo-1-ethyl-2-{5iodo-2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (9 g, 14.674 mmol), (S)-octahydropyrazino[2,1-c][1,4]oxazine (2.469 g, 17.609 mmol), Cs2CO3 (11.953 g, 36.685 mmol) and BINAP (456.9 mg, 0.734 mmol) in toluene (63 mL) was added Pd(OAc)2 (329.44 mg, 1.467 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred for 6 hours at 100°C. After filtration, the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (6.9 g, 75% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C32H43BrN4O4: 627.25; found: 627.4. Stage 5: Synthesis of 3-(1-ethyl-2-(5-((S)-hexa-hydropyrazino[2,1-c1[1,41oxazin8(1H)-yl)-2-((S)-1-methoxyethyl)pyr idin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0375] A stirred acetate solution of 3-(5-bromo-1 -ethyl-2- (5((S) -hexa-hydropyrazine[2,1- c ][1,4] oxazine-8 (1H )-yl)-2-(( S )-1-methoxydino-3Pethicethyl) 870260055674, of 09 / 06 / 2026, p. 187 / 328 il)-1 H-indol-3-yl)-2,2-dimethylpropyl (3.2 g, 5.115 mmol), KOAc (1.51 g, 15.345 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.60 g, 10.230 mmol) in toluene (48 mL) was added to Pd(dppf)Cl2 (0.37 g, 0.512 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred for 1.5 h at 90°C. The resulting mixture was filtered, the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (3.0 g, 88% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C38H55BN4O6: 675.43; found: 675.1. Step 6: Synthesis of methyl (S)-1-((S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1 -ethyl-2(5-((S)-hexa-hydropyrazino[2,1-c1[1 ,41oxazin-8(1 H)-yl)-2-((S)-1 -methoxyethyl)pyridin3-yl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate

[0376] To a stirred mixture of 3-(1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (5 g, 7.433 mmol) and K3PO4 (4.26 g, 20.067 mmol) in toluene (54 mL) were added dioxane (17.82 mL, 210.307 mmol) and H2O (17.82 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred for 2 h at 70°C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (4.6 g, 66% yield) as a solid.LCMS (ESI) m / z [M + H] calculated for C49H68N8O9S: 945.49; found: 945.7. Petition 870260055674, dated 09 / 06 / 2026, p. 201 / 412 188 / 328 Step 7: Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl2-(5-((S)-hexahydropyrazino[2,1-cIU,4]oxazin-8(1H)-yl)-2-((S)-1 acid methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2yl)propanoyl)hexahydropyridazine-3-carboxylic acid

[0377] To a stirred solution of methyl (S)-1-((S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (6 g, 6.361 mmol) in THF (43 mL) was added LiOH^H2O (573.92 mg, 13.677 mmol) at 0°C. The resulting mixture was stirred for 16 h at room temperature. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to yield the product (4 g, crude) as a solid. LCMS (ESI) m / z [M + H] calculated for C45H60N8O9S: 889.43; found: 889.7. Etapa 8: Síntese de terc-butil ((63S,4S,Z)-11 -etil-12-(5-((S)-hexahidropirazino[2,1 -cIU ,4]oxazin-8(1H)-il)-2-((S)-1 -metoxietil)piridin-3-il)-1 0,10dimetil-5,7-dioxo-61 ,62,63,64,65,66-hexa-hidro-1 1 H-8-oxa-2(4,2)-tiazola-1 (5,3)indola-6(1,3)-piridazinacycloundecafano-4-il)carbamato

[0378] To a stirred solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (4 g, 4.51 mmol), HOBt (6.09 g, 45.09 mmol) and DIPEA (23.31 g, 180.36 mmol) in DCM (200 mL) was added EDCI (25.93 g, 135.27 mmol) in DCM (200 mL) dropwise at 0°C under an argon atmosphere. The resulting solution was stirred for 16 hours (h) at room temperature and then concentrated under reduced pressure. The reaction was quenched with H2O at 0°C and extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was Petition 870260055674, dated 09 / 06 / 2026, page 202 / 412 189 / 328 concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (2.0 g, 52% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C46H62N8O7S: 870.4; found: 871.8. Step 9: Synthesis of (63S,4S,Z)-4-amino-11-ethyl-12-(5-((S)-hexahydropyrazino[2,1c1[1,41oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl61 ,62,63,64,65,66-hexahydro-1 1 H-8-oxa-2(4,2)-thiazole-1(5,3)-indole-6(1,3)pyridazinecycloundecaphane-5,7-dione

[0379] To a stirred solution of tert-butyl ((63S,4S,Z)-11-ethyl-12-(5((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazolo-1(5,3)indole-6(1,3)-pyridazinecycloundecafano-4-yl)carbamate (316 mg, 0.345 mmol) in DCM (3 mL) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 h. The mixture was basified to pH 8 with aqueous saturated NaHCO3. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification. LCMS (ESI) m / z [M + H] calculated for C41H54N8O5S: 771.4; found: 771.6. Intermediate 9: Synthesis of (63S,4S,Z)-4-amino-11 -ethyl-12-(2-((S)-1 -methoxyethyl)-5((R)-octa-hydro-2H-pyrido[1,2-a]pyrazine-2-yl)pyridin-3-yl)-10,10,61 ,62,63,64,65,66-hexa-hydro-1 1 H-8-oxa-2(4,2)-thiazole-1 (5,3)-indole-6(1,3)pyridazinecycloundecaphano-5,7-dione OAc OAc MeO L- MeO H ~ fjL.Br C) I KO*c, BrPinr, Pd(dppf)CI, * ( 7 rk Γ N\ i ~ toluene toluene < H Ahb. °*« nA. A -Λ K Ac0 ANHBoc lí I MeO L- 1 Ρ ΡdΟb(2dΟ) N gk Toluene / dioxane / H2O H Petition 870260055674, of 09 / 06 / 2026, p. 203 / 412 190 / 328 Step 1: Synthesis of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octa-hydro2H-pyrido[1 ,2-a]pyrazine-2-yl)pyridin-3-yl)-1H-indol-3-yl)-dimethyl-2,2-promethyl acetate

[0380] To a stirred solution of 3-(5-bromo-1-ethyl-2-{5-iodo-2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (9 g, 14.674 mmol), (R)-octahydro-2H-pyrido[1,2-a]pyrazine (2.469 g, 17.609 mmol), CS2CO3 (11.9523 g, 36.685 mmol) and BINAP (456.85 mg, 0.734 mmol) in toluene (63 mL) was added Pd(OAc)2 (329.44 mg, 1.467 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred for 6 hours at 100°C, then the mixture was filtered, the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to give the product (6 g, 65% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C33H45BrN4Oa: 625.28; found: 627.4. Step 2: Synthesis of 3-(1-ethyl-2-(2-((S)-1 -methoxyethyl)-5-((R)-octahydro-2HpyridoH,2-a']pyrazin-2-yl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0381] To a stirred solution of 3-(5-bromo-1-ethyl-2-(2((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.2 g, 5.115 mmol), KOAc (1.51 g, 15.345 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)1,3,2-dioxaborolane (2.60 g, 10.230 mmol) in toluene (48 mL) Pd(dppf)Cl2 (0.37 g, 0.512 mmol) in portions at room temperature under an atmosphere of argon. The resulting mixture was stirred for 1.5 hours at 90°C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and purified by Petition 870260055674, dated 09 / 06 / 2026, page 204 / 412 191 / 328 Preparative TLC (8% MeOH / DCM) to provide the product (3.1 g, 81% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C39H57BN4O5: 673.45; found: 673.4. Step 3: Synthesis for methyl (S)-1 -((S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1 -ethyl2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a1pyrazin-2-yl)pyridin-3-yl)1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate

[0382] To a stirred mixture of 3-(1-ethyl-2-(2-((S)-1methoxyethyl)-5-(( R )-octahydro-2 H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indol-3-yl)-2,2-dimethylpropyl acetate (5 g, 7.433 mmol), methyl (S )-1-(( S )-3-(4-bromothiazol-2-yl)-2-(( tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (3.89 g, 8.176 mmol) and K3PO4 (4.26 g, 20.067 mmol) in toluene (54 mL), dioxane (18 mL) and H2O (18 mL) were added to Pd(dtbpf)Cl2 (969 mg, 1.486 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred for 2 hours at 70°C. The mixture was filtered, the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and the resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (6.8 g, 83% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C50H70N8O8S: 943.51; found: 943.4. Step 4: Acid Synthesis (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-oc ta-hydro-2HPIRIDOn,2-A]PYRAZIN-2-YL)PYRIDIN-3-YL)-1H-INDOL-5-YL)THIAZOL-2-YL)PROPANOYL]HEXAhydropyridazine-3-carboxylic acid

[0383] To a stirred solution of methyl (S)-1-((S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2 Petition 870260055674, dated 09 / 06 / 2026, page 205 / 412 192 / 328 a)pyrazim-2-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (6 g, 6.361 mmol) in THF (43 mL) was added dropwise to LiOH·H2O (573.92 mg, 13.677 mmol) at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide the product (4 g, crude) as a solid. LCMS (ESI) m / z [M + H] calculated C47H66N8O7S: 887.49; found: 887.6. Step 5: Synthesis of tert-butyl ((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((R)octahydro-2H-pyrido[1,2-a1pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61 ,62,63,64,65,66-hexahydro-1 1 H-8-oxa-2(4,2)-thiazole-1(5,3)-indole-6(1,3)pyridazinecycloundecaphane-4-yl)carbamate

[0384] To a stirred solution of (S)-1-((S)-2((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (4 g, 4,509 mmol), HOBt (6.09 g, 45.090 mmol) and DIPEA (23.31 g, 180.360 mmol) in DCM (200 mL) was added dropwise to EDCI (25.93 g, 135.270 mmol) in DCM (200 mL) at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure and quenched with H2O at 0°C and extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to provide the product (2.0 g, 49% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C47H64N8O6S: 869.47; found: 869.8. Petition 870260055674, dated 09 / 06 / 2026, page 206 / 412 193 / 328 Etapa 6: Síntese de (63S,4S,Z)-4-amino-11 -etil-12-(2-((S)-1 -metoxietil)-5-((R)octa-hidro-2H-pirido[1,2-a1pirazin-2-il)piridin-3-il)-10,10-dimetil61 ,62,63,64,65,66-hexa-hidro-1 1 H-8-oxa-2(4,2)-tiazola-1 (5,3)-indola-6(1 ,3)piridazinacycloundecafano-5,7-diona

[0385] To a stirred solution of tert-butyl ((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8oxa-2(4,2)-thiazolo-1(5,3)-indole-6(1,3)-pyridazinecycloundecafano-4-yl)carbamate (900 mg, 1.035 mmol) in DCM (9 mL), TFA (3 mL) was added dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The mixture was basified to pH=8 with saturated aqueous NaHCO3 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to yield the product (800 mg), which was used directly in the next step without further purification. LCMS (ESI) m / z [M + H] calculated for C42H56N8O4S: 769.42; found: 769.5. Intermediate 10: Synthesis of (63S,4S)-4-amino-12-(5-((S)-hexaHiDROPiRAZiNOf2,1-c1f1 ,4]oxazin-8(1 H)-il)-2-((S)-1 -methoxyethyl)pyridin-3-yl)10,10-dimethyl-11-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexa-hidro1 1H-8-oxa-1(5,3)-indola-6(1,3)-pyridazine-2(1,3)benzenacycloundecacaphane-5,7-diona Tol / dioxane / H2O toUdloxane / HjO Chloro(1,5-cyclooctadieno) iridio(I) dimero dtbpy, B2PIN2 chloramine T trihydrated tolueno M(0Ac)j, BINAP CjCO, Petition 870260055674, 06 / 09 / 2026, pág. 207 / 412 194 / 328 Step 1: Synthesis of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0386] To a stirred solution of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (60 g, 0.12 mol) and Et3N (24.33 g, 0.24 mol) in DCM (600 mL) were added DMAP (1.46 g, 0.012 mol) and acetic anhydride (14.7 g, 144 mmol) dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and washed with HCl (500 mL). The resulting mixture was washed with saturated aqueous NaHCO3 (500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide the product (59.6 g, 92% yield) as an oil. LCMS (ESI) m / z [M + H] calculated C25H28BrFaN2O3: 541.13; found: 543.2. Step 2: Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1(2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0387] To a stirred mixture of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (55.1 g, 101.771 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)1,3,2-dioxaborolan dimer (38.77 g, 152.656 mmol) in THF (40 mL) were added dtbpy (4.10 g, 15.266 mmol) and Chloro(1,5-cyclooctadiene)iridium(I) dimer (3.42 g, 5.089 mmol) in portions at room temperature under an atmosphere of argon. The resulting mixture was stirred for 5 hours at 75°C. The resulting mixture was concentrated under reduced pressure to give the product (102.4 g, crude) as an oil. LCMS (ESI) m / z [M + H] calculated C25H29BBrF3N2Os: 585.14; found: 585.2. Step 3: Synthesis of (S)-3-(5-bromo-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0388] To a stirred solution of acid (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3 Petition 870260055674, dated 09 / 06 / 2026, page 208 / 412 195 / 328 il)boronic (51.2 g, 87.487 mmol) and sodium chloro[(4-methylbenzene)sulfonyl]azanide (197 g, 699.896 mmol) in THF (258 mL) was added to NaI (104.91 g, 699.896 mmol) in H2O (129 mL) dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred for 16 h at 55°C. The resulting mixture was concentrated under reduced pressure and extracted with CH3Cl (2 x 200 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc / petroleum ether) to provide the product (15.3 g, 26% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C32H40BrF3N4O4: 666.0; found: 667.3. Step 4: Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-(5-((S)hexa-hydropyrazino[2,1-c1[1,41oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1(2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexa-hydropyridazine-3-carboxylate

[0389] To a stirred mixture of (S)-3-(5-bromo-2-(5iodo-2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (2.70 g, 4.046 mmol) and (S)-octahydropyrazino[2,1c][1,4]oxazine dihydrochloride (1.044 g, 4.855 mmol) in toluene (18.9 mL) was added Cs2CO3 (5932.38 mg, 18.207 mmol) and BINAP (125.97 mg, 0.202 mmol) in portions at room temperature under an argon atmosphere. Pd(OAc)2 (90.84 mg, 0.405 mmol) was added to the above mixture in portions. The resulting mixture was stirred for a further 16 hours at 90°C. The mixture was cooled to room temperature and then filtered, the filter cake was washed with EtOAc (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH / DCM) to provide the product (2.3 g, 83% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C32H40BrFaN4O4: 681.23; found: 681.4. Petition 870260055674, dated 09 / 06 / 2026, p. 209 / 412 196 / 328 Step 5: Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)2-(5-((S)-hexahydropyrazino[2,1-c1[1,41oxazin-8(1H)-yl)-2-((S)-1methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-CARBOXYLATE

[0390] In a 250 mL round-bottom 3-necked flask, methyl (S )-1-(( S )-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-(5-(( S )hexahydropyrazino[2,1 - c ][1,4]oxazin-8(1 H )-yl)-2-(( S )-1 -methoxyethyl)pyridin-3-yl)-1 (2,2,2-trifluoroethyl)-1 H -indol-5-yl)phenyl)-2-(( tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (2.33 g, 4.512 mmol) and K3PO4 (1.59 g, 7.490 mmol) were added at room temperature under an air atmosphere. To a stirred mixture of H2O (8.20 mL) and dioxane (8.20 mL) in toluene, Pd(dtbpf)Cl2 (0.29 g, 0.451 mmol) was added in portions at room temperature. The resulting mixture was stirred for 3 hours at 65°C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 x 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 150 mL) and dried over anhydrous Na2SO4.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3^-4% MeOH / DCM) to provide the product (2.7 g, 90% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C52H68F3N7O9: 991.5; found: 992.7. Step 6: Acid Synthesis (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3(2-(5-((S)-HEXA-HYDROPYRAZINOf2,1-Cyri,41OXAZIN-8(1H)-IL)-2-((S)-1methoxyethyl)pyri din-3-yl)-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2trifluoroethyl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3CARBOXYLIC

[0391] In a 3-necked round-bottom balloon of 100 mL were added methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2 Petition 870260055674, dated 09 / 06 / 2026, pp. 210 / 412 197 / 328 dimethylpropyl)-2-(5-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (3 g, 3.024 mmol) and THF (30 mL) at room temperature. Followed by LiOH (0.30 g, 12.701 mmol) in H2O (12.7 mL) in portions at 0°C. The resulting mixture was stirred for 16 h at room temperature. The mixture was acidified to pH 5 with 1N HCl. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (2.7 g, crude) as a solid. LCMS (ESI) m / z [M + H] calculated for C49H64F3N7O8: 936.48; found: 936.7. Step 7: Synthesis of tert-butyl ((63S,4S)-12-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1 H)-yl)-2-((S)-1 -methoxyethyl)pyridin-3-yl)10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1 (5,3)-indola-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphane-4-yl)carbamate

[0392] In a 2 L round-bottom 3-necked flask, (S )-1-((S )-2-(( tert- butoxycarbonyl)amino)-3-(3-(2-(5-(( S )-hexahydropyrazino[2,1 - c ][1,4]oxazin-8(1 H )-yl)-2-(( S )-1 -methoxyethyl)pyridin-3-yl)-3-(3hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1 H -indol-5-yl)phenyl)propanoyl)hexa-hydropyridazine-3-carboxylic acid (3.12 g, 3.333 mmol) and DCM (624 mL) were added at room temperature. To the above mixture, DIPEA (17.23 g, 133.320 mmol) and HOBt (4.50 g, 33.330 mmol) were added in portions at 0°C. The resulting mixture was stirred for a further 30 min. To the above mixture, EDCI (19.17 g, 99.990 mmol) was added in portions over 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with H2O at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed. Petition 870260055674, dated 09 / 06 / 2026, p. 211 / 412 198 / 328 with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3^-4% MeOH / DCM) to provide the product (3 g, 98% yield) as a solid. LCMS (ESI) m / z [M + H] calculated C49H62F3N7O7: 918.47; found: 918.8. Step 8: Synthesis of (63S,4S)-4-amino-12-(5-((S)-hexahydropyrazino[2,1c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-11 (2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-5,7-dione

[0393] To a stirred solution of tert-butyl ((63S,4S)-12-(5-((S)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-11H-8oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphano-4yl)carbamate (930 mg, 1.013 mmol) in DCM (15 mL) was added TFA (5 mL, 67.315 mmol) dissolved in DCM (5 The mixture was added dropwise (mL) at 0°C under an argon atmosphere. The resulting mixture was stirred for 2 hours at 0°C. The residue was basified to pH 8 with aqueous saturated NaHCO3. The resulting mixture was extracted with DCM, the combined organic layers were washed with brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide the product (880 mg, crude) as a solid. LCMS (ESI) m / z [M + H] calculated for C44H54F3N7O5: 818.42; found: 818.6. Intermediate 11: Synthesis of (63S,4S)-4-amino-12-(2-((S)-1-methoxyethyl)-5((R)-octa-hydro-2H-pyrido[1,2-a]pyrazine-2-yl)pyridin-3-yl)-10,10-dimethyl-11(2,2,2 -trifluoroethyl)-61,62,63,64,65,66-hexa-hydro-11H-8-oxa-1(5,3)indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphano-5,7-dione OAc OAc Γ D Dimer chloro(1,5-cyclo- Jç- mbO Ma0 octadiene)iridium(I) / - C _ Chloramine T tri- . \- NΓ hydrated N— C —<1 T rue A-' N- * {—FW THF HOB ( ™W> ,λ' < OH CF31 CFj ° ^ΝΗΒοο C7 Λ OAc N—< OAc Χ / θ'Β·^5^ L-V-\·__ / J L-Ó-Ó Γ / Br Pd(O*'coINAP ΓΝ,Βγ Pd(dtbpf)CI21 KjPO, C12CO3 / 1 \\ , N'-N^ toluene Tol / dioxane / H2O » CFS ( CF3 Petition 870260055674, of 09 / 06 / 2026, p. 212 / 412 199 / 328 Step 1: Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3yl)boronic acid

[0394] In a 100 mL round-bottom flask with 3 necks, 3-(5-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-(2,2,2-trifluoroethyl)indol-3-yl)-2,2-dimethylpropyl acetate (10 g, 18.470 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (8.44 g, 33.25 mmol) and dtbpy (0.89 g, 3.325 mmol) were added at room temperature. Chloro(1,5-cyclooctadiene)iridium(I) dimer (0.74 g, 1.108 mmol) and THF (40 mL) were added to the above mixture. The resulting mixture was stirred for a further 16 hours at 80°C. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M + H] calculated for C25H29BBrF3N2O5: 585.14; found: 585.0. Step 2: Synthesis of (S)-3-(5-bromo-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0395] To a stirred solution of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3yl)boronic acid (17.9 g, 30.586 mmol) in THF (89.5 mL), sodium chloro[(4-methylbenzene)sulfonyl]azanide (68.93 g, 244.688 mmol) and NaI (36.68 g, 244.688 mmol) in H2O (44.75 mL) were added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for a further 20 min at room temperature and then heated to 50°C for 16 h. The resulting mixture was concentrated under reduced pressure and washed with CHCl3 (300 mL). After filtration, the filter cake was washed with CHCl3 (3 x 100 mL). The filtrate was extracted with CHCl3 (3 x 200 mL). The combined organic layers were... Petition 870260055674, dated 09 / 06 / 2026, page 213 / 412 200 / 328 were washed with Na2S2O3 (300 mL) and brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc / petroleum ether) to provide the product (6.6 g, 32% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C25H27BrF3IN2O3: 667.03; found: 668.7. Step 3: Synthesis of 3-(5-bromo-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro2H-pyrido[1,2-a1pyrazin-2-yl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1H-indol3-yl)-2,2-dimethylpropyl acetate

[0396] To a stirred mixture of (S)-3-(5-bromo-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (1.4 g, 2.098 mmol) and (R)-octahydro-2H-pyrido[1,2-a]pyrazine (353.04 mg, 2.518 mmol) in toluene (10 mL) was added Cs2CO3 (3076.05 mg, 9.441 mmol), BINAP (65.32 mg, 0.105 mmol) and Pd(OAc)2 (47.10 mg, 0.210 mmol). The resulting mixture was stirred overnight at 90°C under an argon atmosphere. The reaction was quenched with H2O (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with H2O (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH / DCM) to provide the product (1 g, 49% yield) as an oil. LCMS (ESI) m / z [M + H] calculated for C33H42BrF3N4O3: 679.25; found: 679.5.Etapa 4: Síntese de metil (S)-1-((S)-3-(3-(3-(3-(3-acetoxi-2,2-dimetilpropil)2-(2-((S)-1-metoxietil)-5-((R)-octa-hidro-2H-pirido[1,2-a1pirazin-2il)piridin-3-il)-1-(2,2,2-trifluoroetil)-1H-indol-5-il)fenil)-2-((tercbutoxicarbonyl)amino)propanoil)hexa-hidropiridazina-3-carboxylato.

[0397] A stirred mixture of 3-(5-bromo-2-(2-(( S )-1-methoxyethyl)-5((R )-octa-hidro-2 H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol-3yl)-2,2-dimethylpropyl acetate (1 g, 1.471 mmol) and methyl (S)-1-((S)-2-((terc Petition 870260055674, 06 / 09 / 2026, pág. 214 / 412 201 / 328 butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (913.62 mg, 1.765 mmol) in toluene (9 mL) were added dioxane (6 mL), H2O (3 mL), K3PO4 (780.82 mg, 3.678 mmol) and Pd(dtbpf)Cl2 (95.90 mg, 0.147 mmol), the resulting mixture was stirred for 2 h at 70°C under a nitrogen atmosphere. The mixture was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with H2O (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc / petroleum ether) to provide the product (1.2 g, 74% yield) as a solid. LCMS (ESI) m / z [M + H] calculated for C53H70F3N7O8: 990.53; found: 990.8. Step 5: Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octa-hydro-2H-pyrido[1,2a]pyrazin-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)propanoyl)hexa-hydropyridazine-3-carboxylic acid

[0398] To a stirred mixture of methyl (S)-1-((S)-3-(3-(3-(3-ace...

Claims

Claims 1. COMPOUND, or a pharmaceutically acceptable salt thereof, characterized by having the structure of Formula I: wherein A is a 3- to 6-membered heterocycloalkylene comprising one or two heteroatoms independently selected from N and O, a 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 10-membered heteroarylene comprising one or two heteroatoms independently selected from N, O and S, wherein the arylene, when substituted, is substituted by -OH, F, CH2F, CHF2 or CF3; X1, X2, and X3 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1;R1 is hydrogen, optionally substituted C1-C6 heteroalkyl comprising one or two heteroatoms independently selected from N, O and S, or optionally substituted 3- to 10-membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O and S, wherein the heteroalkyl or heterocycloalkyl, when substituted, are substituted by one or two independently selected C1-C6 alkyl or cycloalkyl groups of 3- to 6 members; R2 is C1-C6 alkyl or C1-C6 alkyl substituted by one, two, or three halogens;and R3 is C1-C6 alkyl, C1-C6 alkyl substituted with one, two, or three halogens, C1-C6 heteroalkyl comprising one or two heteroatoms independently selected from N, O, and S, 3- to 4- or 6-membered cycloalkyl, or heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

2. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 is optionally substituted hydrogen or 3- to 10-membered heterocycloalkyl.

3. COMPOUND, according to the pharmaceutically acceptable claim thereof, characterized by an optionally substituted 3 to 10 membered heterocycloalkyl.

4. COMPOUND, according to the pharmaceutically acceptable claim thereof, characterized by R1 1, or by R1 3, or being: salt being salt 5. COMPOUND, according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that m is 1.

6. COMPOUND, according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that it is not 1. Petition 870260055674, dated 09 / 06 / 2026, p. 344 / 412 3 / 30 7. COMPOUND, according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that each of X1, X2, and X3 is CH2.

8. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having the structure of Formula II: Formula II 9. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having the structure of Formula V:

10. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having the structure of Formula VI: Petition 870260055674, dated 09 / 06 / 2026, p. 345 / 412 4 / 30 11. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having the structure of Formula VII: Formula VII 12. COMPOUND, according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that A is thiazol-di-yl, oxazol-di-yl, morpholine-di-yl, pyrrolidine-di-yl, piperidine-di-yl or phenylene.

13. COMPOUND, according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that A is a 5 to 10 membered heteroarylene.

14. COMPOUND, according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in that: A being: N or 15. COMPOUND, according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that A is optionally substituted with phenylene.

16. COMPOUND, according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that A being: or 17. COMPOUND, according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that A is a 3- to 6-membered heterocycloalkylene.

18. COMPOUND, according to claim 17, or a pharmaceutically acceptable salt thereof, characterized in that A is selected from the following, or a stereoisomer thereof:

19. COMPOUND, according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, characterized by R2 being:

20. COMPOUND, according to any of the claims in Petition 870260055674, dated 09 / 06 / 2026, pp. 347 / 412 6 / 30 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that R3 is C1-C6 alkyl, C1-C6 alkyl substituted with one, two or three halogens, or 3 to 4 or 6 membered cycloalkyl.

21. COMPOUND, according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, characterized in that R3 is C1-C6 alkyl or C1-C6 alkyl substituted with one, two or three halogens.

22. COMPOUND, according to claim 21, or a pharmaceutically acceptable salt thereof, characterized by R3 being: or .

23. COMPOUND, according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, characterized in that R3 is 3-, 4-, or 6-membered cycloalkyl.

24. COMPOUND, according to claim 23, or a pharmaceutically acceptable salt thereof, characterized by R3 being: .

25. COMPOUND, according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, characterized in that the compound is not a compound from the list of compounds below: Petition 870260055674, dated 09 / 06 / 2026, p. 348 / 412 7 / 30 C2 C3 CF3 C4 CF3 Petition 870260055674, dated 09 / 06 / 2026, p. 349 / 412 8 / 30 C6 C7 C8 CF3 Petition 870260055674, dated 09 / 06 / 2026, p. 350 / 412 9 / 30 26. COMPOUND, or a pharmaceutically acceptable salt thereof, characterized by having the structure of one of the compounds below: A1 A2 A3 A4 Petition 870260055674, dated 09 / 06 / 2026, p. 351 / 412 10 / 30 A5 .....A6 cf3 A8 Petition 870260055674, dated 09 / 06 / 2026, p. 352 / 412 11 / 30 A9 A10 A11 Petition 870260055674, dated 09 / 06 / 2026, p. 353 / 412 12 / 30 A13 A14 A15 A16 Petition 870260055674, dated 09 / 06 / 2026, p. 354 / 412 13 / 30 A17 A18 A19 A20 Petition 870260055674, dated 09 / 06 / 2026, p. 355 / 412 14 / 30 <( > '^y-xV. A22 cf3 A23 ... 2 N ( A24 cf3 Petition 870260055674, dated 09 / 06 / 2026, page 356 / 412 15 / 30 A25 A26 A27 A28 Petition 870260055674, dated 09 / 06 / 2026, page 357 / 412 16 / 30 A29 A30 A31 A32 Petition 870260055674, dated 09 / 06 / 2026, page <i petição 870260055674, de 09 06 2026, pág. 359 412 18 30 a37 a38 a39 a40 360 19 a41 a42 a43 361 20 b8 b9 362 21 b29 b30 b2 363 22 b3 b4 b5 b6 364 23 b10 b11 b12 b13 <f 365 24 b14 b15 b16 b17 366 25 b18 b19 b20 b21 367 26 b23 b24 368 27 b26 b2727. PHARMACEUTICAL COMPOSITION, characterized by comprising a compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 26, and a pharmaceutically acceptable excipient.

28. USE OF A COMPOUND or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 26, or a pharmaceutical composition, as defined in claim 27, characterized in that it is used in the manufacture of a drug, combination or kit for treating cancer in a subject in need thereof.

29. USE, according to claim 28, characterized by the cancer being pancreatic cancer, non-small cell lung cancer, colorectal cancer or endometrial cancer.

30. USE, according to any of claims 28 to 29, characterized by the cancer comprising a Ras mutation.

31. USE, according to claim 30, characterized by Petition 870260055674, dated 09 / 06 / 2026, page 369 / 412 28 / 30 Ras mutation being K-Ras G12D or K-Ras G13D.

32. USE OF A COMPOUND or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 26, or a pharmaceutical composition, as defined in claim 27, characterized in that it is used in the manufacture of a drug, combination or kit for treating a disorder related to the Ras protein in a subject in need thereof.

33. USE OF A COMPOUND or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 26, or a pharmaceutical composition, as defined in claim 27, characterized in that it is used in the manufacture of a drug, combination or kit for inhibiting a Ras protein in a cell.

34. USE, according to any one of claims 32 to 33, characterized in that the Ras protein is K-Ras G12D or K-Ras G13D.

35. USE, according to any one of claims 28 to 34, characterized by further comprising an additional anticancer therapy.

36. USE, according to claim 35, characterized in that the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor or a combination thereof.

37. CONJUGATE, or a salt thereof, characterized by comprising the structure of Formula III: M-P1 (Formula III) wherein P1 is a monovalent organic fraction; and M has the structure of Formula IV: Petition 870260055674, dated 09 / 06 / 2026, page.370 / 412 29 / 30 Formula IV, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X1, X2, and X3 are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted heterocycloalkyl, and wherein each hydrogen of Formula IV is independently, optionally, isotopically enriched for deuterium.

38. USE OF A COMPOUND or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 26, or a pharmaceutical composition, as defined in claim 27, and of an additional anticancer therapy, characterized in that it is in the manufacture of a combination or kit for treating cancer in a subject in need thereof, Petition 870260055674, dated 09 / 06 / 2026, p. 371 / 412 30 / 30 or to treat a Ras protein-related disorder in a subject in need thereof, or to inhibit a Ras protein in a cell, wherein the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

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