Compounds, pharmaceutical composition and methods for treating cancer in a subject, for treating a disorder related to the ras protein and for inhibiting a ras protein in a cell

Description

"Compounds, pharmaceutical composition and methods for treating cancer in a subject, for treating a disorder related to the ras protein and for inhibiting a ras protein in a cell" Fundamentals

[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 HMG-CoA 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 provided there was 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 can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019).The other 90% are currently considered refractory or intractable with respect to the discovery of small molecule drugs mentioned above. These targets are commonly referred to as drug-resistant. 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 is well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in several human cancers and are therefore suitable targets for anticancer therapy. In fact, mutations in Ras proteins are responsible for approximately 30% of Petition 870250110544, dated 02 / 12 / 2025, page 7 / 563 2 / 539 of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression, or 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., G13C) and 61 (e.g., Q61H or Q61K) of Ras are also responsible for oncogenic activity in some cancers.

[0003] Despite extensive efforts to discover drugs against Ras over the past decades, only two agents targeting the K-Ras G12C mutant have been approved in the US (sotorasib and adagrasib). Further efforts are needed to discover additional drugs for cancers driven by the various Ras mutations. Summary

[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 tricomplex, or conjugate, between the Ras protein and the chaperone. Petition 870250110544, dated 02 / 12 / 2025, page 8 / 563 3 / 539 widely expressed cytosolic cyclophilin A (CYPA). Without being limited by theory, the inventors believe that one way in which the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, that they form is 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 one aspect, the disclosure presents a compound having the structure of Formula Ia or Formula Ib: Formula Ia Formula Ib or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer 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; L is a ligand; R1 is a heteroaryl group of 5 to 10 members, optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally 3- to 6-membered cycloalkyl Petition 870250110544, dated 02 / 12 / 2025, page 9 / 563 4 / 539 replaced; R4 is hydrogen or optionally substituted C1-C6 alkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0006] In some forms, the disclosure presents a compound of Formula Ia-2: Formula Ia-2 or pharmaceutically acceptable salt, an enantiomer, a Petition 870250110544, dated 02 / 12 / 2025, p. 10 / 563 5 / 539 stereoisomer or a tautomer 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; L is a ligand; R1 is a heteroaryl group of 5 to 10 members, optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; and R4 is hydrogen or optionally substituted C1-C6 alkyl.

[0007] Pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are also provided. Pharmaceutical compositions comprising a compound selected from Tables 1 and 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are also provided.

[0008] A method is also provided 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.

[0009] 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.

[0010] A method for inhibiting a Ras protein is also provided. Petition 870250110544, dated 02 / 12 / 2025, page 11 / 563 6 / 539 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.

[0011] It is specifically contemplated that any limitation discussed in relation to one embodiment of the invention may apply 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. Chemical Definitions and Terms

[0012] In this solicitation, unless otherwise indicated by the context, (i) the term the / a means one or more; (ii) the term or is used to mean and / or, unless explicitly indicated to refer only to alternatives or to alternatives that are mutually exclusive, although the disclosure supports a definition that refers only to and / or alternatives; (iii) the terms comprising and including are understood as encompassing discriminated components or steps, presented by themselves or in conjunction with one or more additional components or steps; and (iv) where ranges are provided, outcomes are included.

[0013] 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 being employed to determine the value. In certain embodiments, the term about refers to a range of values ​​that falls 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 otherwise indicated or evident from the context (for example, when such a number exceeds 100% of a possible value). Petition 870250110544, dated 02 / 12 / 2025, p. 12 / 563 7 / 539

[0014] 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.

[0015] A compound of the present invention and similar terms as used in this document, whether explicitly mentioned or not, refer to Ras inhibitors described in this document, including compounds of Formula I and subformulas thereof, and compounds of Table 1 and Table 2, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers thereof.

[0016] The term wild type refers to an entity with a structure or activity as found in nature in a normal state or context (as opposed to mutant, diseased, altered, etc.). Those of common skill in the technique will appreciate that wild-type genes and polypeptides generally exist in multiple different forms (e.g., alleles).

[0017] Those skilled in the art will appreciate that certain compounds described in this document may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., where one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium) forms. 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.

[0018] The compounds described in this document may be asymmetric (e.g., with one or more stereocenters). All stereoisomers, such as diastereomers and enantiomers, are targeted unless otherwise indicated. The compounds in this disclosure that contain Petition 870250110544, dated 02 / 12 / 2025, page 13 / 563 8 / 539 asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive 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 this disclosure. Cis and trans geometric isomers of the compounds in this disclosure are described and can be isolated as a mixture of isomers or as separate isomeric forms.

[0019] In some embodiments, one or more compounds represented in this document may exist in different tautomeric forms. As will become clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and ring 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 linked to a form by appropriate substitution. In certain embodiments, the tautomeric forms result from acetal interconversion.

[0020] Unless otherwise indicated, structures depicted 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 Petition 870250110544, dated 02 / 12 / 2025, p. 14 / 563 9 / 539 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) can be useful in assays of tissue distribution of compounds or substrates. Tritiated isotopes (i.e., 3H) and carbon-14 (i.e., 14C) can be useful for their ease of preparation and detectability. Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain 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 with 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.

[0021] Non-limiting examples of fractions that may contain one or more deuterium substitutions in compounds of the present invention, wherein any R position may be deuterium (D), include rR Xf RRr3co R-Á and Rcr3

[0022] Additional examples include fractions such as R3CR Petition 870250110544, dated 02 / 12 / 2025, page 15 / 563 10 / 539 and deuteration of similar fractions of type R1, where the definition of R1 is found here (for example, in compounds of Formula Ia, Ib, Ia-1, Ia-2, IIa, IIb, IIa-1, IIa-2, IIIa, IIIb, IIIa-1, IIIa-2, Va, Vb, Va-1, Va-2, VIIa, VIIb, VIIa-1 or VIIa-2 and their subformulas). Furthermore, the deuteration of available positions in any portion A of compounds of the formulas described here is also contemplated, such as: R. In addition, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as: Furthermore, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as Petition 870250110544, dated 02 / 12 / 2025, p. 16 / 563 11 / 539

[0023] In addition, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as 0="< Js O ^R *JCr e .

[0024] In an additional embodiment, substitution by silylation is also contemplated, as in the linker as follows: the |

[0025] As is known in the art, many chemical entities (in particular many organic molecules and / or many small molecules) can adopt a variety of different solid forms, such as, for example, amorphous forms and / or crystalline forms (e.g., polymorphs, hydrates, solvates, etc.). 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, compounds described or represented herein may be supplied or used in hydrate or solvate form.

[0026] In several places in this descriptive report, the substituents of compounds in this disclosure are disclosed in groups or ranges. It is specifically intended that this disclosure include any and all individual subcombinations of the members of these groups and ranges. 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 substituents are disclosed in groups or ranges, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every subcombination. Petition 870250110544, dated 02 / 12 / 2025, page 17 / 563 12 / 539 individual members in each position.

[0027] The term optionally substituted X (e.g., optionally substituted alkyl) is intended to be equivalent to X, wherein X is 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 substituted term, whether preceded by the term optionally or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, for example, any of the substituents or groups described in this document.Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substituteable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may also be the same or different at each position. For example, in the optionally substituted C16-C2-C9 alkyl-C9 heteroaryl term, the alkyl moiety, the heteroaryl moiety, or both, may be optionally substituted. Combinations of substituents provided for in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. The term stable, as used in this document, 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.

[0028] Suitable monovalent substituents on a replaceable carbon atom of an optionally substituted group may independently be deuterium; halogen; -(CH2)oa 4R°; -(CH2)oa 4OR°; -O(CH2)oa 4Ro; -O-(CH2)0 a 4C(O)OR°; -(CH2)0 a 4CH(OR°)2; -(CH2)oa 4SR°; -(CH2)oa 4Ph, which Petition 870250110544, dated 02 / 12 / 2025, p. 18 / 563 13 / 539 can be replaced by R°; -(CH2)oa 4O(CH2)o-iPh which can be replaced by R°; -CH=CHPh, which can be replaced by R°; -(CH2)oa 4O(CH2)0-1-pyridyl which can be replaced by R°; saturated or unsaturated 4- to 8-membered heterocycloalkyl (e.g., pyridyl) which can be replaced by R°; saturated or unsaturated 3- to 8-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)oa 4N(R°)2; (CH2)oa 4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)oa 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)oa 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)oa 4C(O)R°; -C(O)R°, -C(S)R°; -(CH2)oa 4C(O)OR°; (CH2)oa 4-C(O)-N(Ro)2; -(CH2)oa 4-C(O)-N(Ro)-S(O)2-Ro; -C(NCN)NR°2; -(CH2)oa 4C(O)SR°; -(CH2)oa 4C(O)OSiR°3; -(CH2)oa 4OC(O)R°; -OC(O)(CH2)oa 4SR°; SC(S)SR°; -(CH2)oa 4SC(O)R°; -(CH2)oa 4C(O)NR°2; -C(S)NR°2; -C(S)SR°; (CH2)oa 4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; C(NOR°)R°;-(CH2)o a 4SSR°; -(CH2)o a 4S(O)2R°; -(CH2)o a 4S(O)2OR°; -(CH2)o a 4OS(O)2R°; -S(O)2NR°2; -(CH2)o a 4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°, -SiR°3; -(C1-4 alquileno linear ou ramificado)O-N(R°)2;or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)o-1Ph, -CH2-(5-6 membered heteroaryl ring), saturated or unsaturated 3-8 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), or a saturated, partially unsaturated, or aryl 3-6 membered ring having the 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 3-12 membered ring having the 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may; Petition 870250110544, dated 02 / 12 / 2025, page 19 / 563 14 / 539 to be replaced as defined below.

[0029] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) may independently be halogens, -(CH2)o-2R·, -(haloR·), -(CH2)o-20H, -(CH2)o-20R·, -(CH2)o-2CH(OR^)2; -O(haloR·), -CN, -N3, -(CH2)o-2C(O)R·, -(CH2)o-2C(O)OH, -(CH2)o-2C(O)OR· -(CH2)o-2SR· -(CH2)o2SH, -(CH2)o-2NH2, -(CH2)o-2NHR·, -(CH2)o-2NR% -NO2, -SíR% -OSíR% C(O)SR· -(C1-4 linear or branched alkylene)C(O)OR· or -SSR· wherein each R· is unsubstituted or wherein preceded by halo is substituted only by one or more halogens, and is independently selected from aliphatic C1-4, CH2Ph, -O(CH2)O-1Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. °Suitable divalent substituents on a saturated carbon atom of R include =O and =S.

[0030] 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 hydrogen, aliphatic C1-6 which may be substituted as defined below, or a saturated, partially unsaturated or aryl 5-6 membered ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents 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 hydrogen; aliphatic C1-6 may be substituted as defined below; or a 5-6 membered unsubstituted saturated, partially unsaturated, or aryl ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Petition 870250110544, dated 02 / 12 / 2025, page 20 / 563 15 / 539

[0031] 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·, -NR^2 or -NO2, wherein each R· is unsubstituted or where preceded by halo is substituted by only one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a saturated, partially unsaturated or aryl ring of 5-6 members with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on a replaceable nitrogen of an optionally substituted group include -Rt, -NRU, -C(O)Rt -C(O)ORt C(O)C(O)Rt, -C(O)CH2C(O)Rt -S(O)2Rt -S(O)2NRU, -C(S)NRt2, -C(NH)NRU, or -N(Rt)S(O)2Rt; wherein each Rt independently hydrogen, C1-6 aliphatic which may be substituted as defined below, -OPh unsubstituted, or a partially unsaturated, saturated, 3 to 6 membered unsubstituted aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Rt taken together with their intervening atom(s) form a partially unsaturated, saturated, 3 to 12 membered bicyclic or monocyclic aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] Suitable substituents on an aliphatic Rt group 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 when preceded by “halo” is substituted only by one or more halogens and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom Petition 870250110544, dated 02 / 12 / 2025, page 21 / 563 16 / 539 of Rt include =O and =S.

[0034] The term acetyl, as used in this document, refers to the group -C(O)CH3.

[0035] The term alkoxy, as used in this document, refers to an -OC1-C20 alkyl group, wherein the alkoxy group is bonded to the rest of the compound via an oxygen atom.

[0036] 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.

[0037] The term alkylene, as used in this document, represents a saturated divalent hydrocarbon group derived from a saturated linear or branched chain 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 replaced by 1, 2, 3 or 4 substituent groups, as defined in this document.

[0038] The term alkenyl, as used in this document, represents monovalent linear or branched chain groups of, unless otherwise indicated, 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 both cis and trans isomers. The term alkenylene, Petition 870250110544, dated 02 / 12 / 2025, p. 22 / 563 17 / 539 as used in this document represents bivalent linear or branched chain groups of, unless otherwise indicated, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0039] The term alkynyl, as used in this document, represents monovalent linear or branched chain groups of 2 to 20 carbon atoms (e.g., 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.

[0040] The term alkynyl sulfone, as used in this o.,o §_p document, represents a group comprising the structure « , wherein R is any chemically viable substituent described in this document.

[0041] The term amino, as used in this document, represents -N(Rf)2, for example, -NH2 and -N(CH3)2.

[0042] 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.

[0043] 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, a Petition 870250110544, dated 02 / 12 / 2025, p. 23 / 563 18 / 539 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. Exemplary 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.

[0044] 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 be optionally substituted unless otherwise indicated.

[0045] The term C0, as used in this document, represents a connection. For example, part of the term -N(C(O)-(C0-C5 alkylene-H)- includes N(C(O)-(Co alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0046] The terms carbocyclic and carbocyclyl, as used in this document, refer to an optionally substituted, monovalent C3-C12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, 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 may be attached to its pendant group on any ring atom. Petition 870250110544, dated 02 / 12 / 2025, p. 24 / 563 19 / 539 which results in a stable structure and any of the ring atoms can be optionally substituted, unless otherwise indicated.

[0047] The term carbonyl, as used in this document, represents a C(O) group, which can also be represented as C=O.

[0048] The term carboxyl, as used in this document, means -CO2H, (C=O)(OH), COOH or C(O)OH or the non-protonated counterparts.

[0049] The term cyan, as used here, represents a CN group.

[0050] The term cycloalkyl, as used herein, represents a monovalent saturated cyclic hydrocarbon group that may be bridged, fused, or spirocyclic having three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0051] The term cycloalkenyl, as used herein, represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group that may be bridged, fused, or spirocyclic having three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0052] 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.

[0053] The term enantiomer, as used in this document, means each individual optically active form of a compound of the invention, with 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%. Petition 870250110544, dated 02 / 12 / 2025, p. 25 / 563 20 / 539

[0054] The term guanidinyl refers to a group with the structure: r'nÁnAn-r RR, where each R is, independently, any chemically viable substituent described in this document.

[0055] The term “guanidinoalkyl alkyl”, as used herein, represents an alkyl moiety substituted at one or more carbon atoms by one or more guanidinyl moieties.

[0056] 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.

[0057] 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.

[0058] The term halogen, as used in this document, represents a halogen selected from bromine, chlorine, iodine or fluorine.

[0059] The term heteroalkyl, as used in this document, refers to an alkyl group, as defined in this document, 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.

[0060] 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 heteroaryl groups are unsubstituted groups of 1 to 12 carbons (e.g., 1 to 11, 1 to 10, 1-9, 2-12, 2-11, 2-10, or 2-9). The term heteroaryl includes bicyclic, tricyclic, and tetracyclic groups in which any one Petition 870250110544, dated 02 / 12 / 2025, page 26 / 563 21 / 539 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 may be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise indicated. In some embodiments, the heteroaryl is substituted by 1, 2, 3, or 4 substituent groups.

[0061] 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. Exemplary unsubstituted heterocycloalkyl groups are from 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 with 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, deca. Petition 870250110544, dated 02 / 12 / 2025, p. 27 / 563 22 / 539 hydroquinolinyl, dihydropyrrolopyridine and decahydronaphthyridinyl. A heterocycloalkyl ring may be attached to its pendant group on any ring atom resulting in a stable structure and any of the ring atoms may be optionally substituted unless otherwise specified.

[0062] The term “hydroxy”, as used in this document, represents an -OH group.

[0063] The term hydroxyalkyl, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms by one or more -OH moieties.

[0064] The term isomer, as used in this document, means any tautomer, stereoisomer, atropisomer, 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 invention, the chemical structures represented in this document and therefore the compounds of the invention encompass all corresponding stereoisomers, i.e., both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.Enantiomeric and stereoisomeric mixtures of the compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. The enantiomers and stereoisomers can also be obtained from stereoisomerically or externally distributed intermediates. Petition 870250110544, dated 02 / 12 / 2025, page 28 / 563 23 / 539 enantiomerically pure reagents and catalysts by well-known asymmetric synthetic methods.

[0065] As used in this document, the term linker refers to a divalent organic moiety that connects a first moiety (e.g., a portion of a macrocycle) to a second moiety (e.g., a second portion of the same macrocycle). In some embodiments, the linker results in a compound capable of achieving an IC50 of 2 μM or less in the Ras-RAF breakthrough assay protocol provided in the Examples below and provided here: The aim of this biochemical assay is to measure the ability of the test compounds to facilitate the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFrbd construct, inhibiting Ras signaling through a RAF effector.

[0066] 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 is present in the wells of the plate as a 10-point dilution series in 3-fold increments starting with 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. Petition 870250110544, dated 02 / 12 / 2025, p. 29 / 563 24 / 539

[0067] This assay can also be used to evaluate selectivity. In some embodiments, a compound of the present invention is selective for one or more specific Ras mutants (e.g., K-Ras Q61H) relative to other Ras mutants or wild type, compared to what is known in the art.

[0068] In some embodiments, the ligand comprises 20 or fewer linear atoms. In some embodiments, the ligand comprises 15 or fewer linear atoms. In some embodiments, the ligand comprises 10 or fewer linear atoms. In some embodiments, the ligand has a molecular weight less than 500 g / mol. In some embodiments, the ligand has a molecular weight less than 400 g / mol. In some embodiments, the ligand has a molecular weight less than 300 g / mol. In some embodiments, the ligand has a molecular weight less than 200 g / mol. In some embodiments, the ligand has a molecular weight less than 100 g / mol. In some embodiments, the ligand has a molecular weight less than 50 g / mol.

[0069] 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 1 kDa. Petition 870250110544, dated 02 / 12 / 2025, page 30 / 563 25 / 539 is less than 500 kDa. In some embodiments, a monovalent organic fraction varies between 500 g / mol and 500 kDa.

[0070] The term stereoisomer, as used herein, refers to all possible different isomeric forms, as well as 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 and / or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0071] The term sulfonyl, as used in this document, represents an -S(O)2- group.

[0072] The term thiocarbonyl, as used in this document, refers to a -C(S)- group.

[0073] The term vinyl ketone, as used in this document, refers to a group comprising a carbonyl group directly connected to a carbon-carbon double bond.

[0074] The term vinyl sulfone, as used in this document, refers to a group comprising a sulfonyl group directly connected to a carbon-carbon double bond.

[0075] The term inone, as used in this document, refers to a group comprising the structure < , where R is any chemically viable substituent described in this document.

[0076] Those skilled in the art, upon reading this disclosure, will appreciate 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, forms Petition 870250110544, dated 02 / 12 / 2025, p. 31 / 563 26 / 539 isomeric (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 from 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 a conformational isomer ((Z) or (E)) of a double bond may be considered a different form from that containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope from that present in a reference preparation may be considered a different form. Detailed Description of Compounds

[0077] 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 tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CIP).Without being limited by theory, the inventors believe that one way in which the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, that they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF, which are. Petition 870250110544, dated 02 / 12 / 2025, page 32 / 563 27 / 539 needed to propagate the oncogenic signal.

[0078] Without being limited by theory, the inventors postulate that 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. 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.

[0079] Consequently, a variety of Ras proteins can be inhibited by a compound of the present invention (for example, K-Ras, N-Ras, H-Ras and their mutants at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, Q61H, Q61K, Q61R and Q61L and others described herein, or a combination thereof). In some embodiments, a compound of the present invention inhibits at least one K-Ras Q61H mutant. In some embodiments, a compound of the present invention selectively inhibits at least one K-Ras Q61H mutant compared to wild-type K-Ras. In some embodiments, a compound of the present invention selectively inhibits one K-Ras Q61H mutant compared to wild-type K-Ras and one or more other K-Ras mutants.

[0080] In some embodiments, the present description presents a compound with the structure of Formula Ia or Formula Ib: Petition 870250110544, dated 02 / 12 / 2025, p. 33 / 563 28 / 539 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer 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; L is a ligand; R1 is a heteroaryl group of 5 to 10 members, optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; R4 is hydrogen or optionally substituted C1-C6 alkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0081] In some forms, the present description presents Petition 870250110544, dated 02 / 12 / 2025, p. 34 / 563 29 / 539 a compound with structural formula Ia-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer 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; L is a ligand; R1 is a heteroaryl group of 5 to 10 members, optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; R4 is hydrogen or optionally substituted C1-C6 alkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0082] In one aspect, the invention provides a compound with the structure of Formula Ia-2: Petition 870250110544, dated 02 / 12 / 2025, p. 35 / 563 30 / 539 Formula Ia-2 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer 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; L is a ligand; R1 is a heteroaryl group of 5 to 10 members, optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; and R4 is hydrogen or optionally substituted C1-C6 alkyl.

[0083] In some embodiments, the compound has the structure of Formula IIa-2: Formula IIa-2 Petition 870250110544, dated 02 / 12 / 2025, p. 36 / 563 31 / 539 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl.

[0084] In some embodiments R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl.

[0085] In some embodiments, the present description presents a compound with structural formula IIa or formula IIb: Formula IIa Formula IIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl.

[0086] In some forms, the present description presents Petition 870250110544, dated 02 / 12 / 2025, p. 37 / 563 32 / 539 a compound with structural formula IIa-1 Formula IIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0087] In some embodiments, the present description presents a compound with structural formula IIa-2 Formula IIa-2 Petition 870250110544, dated 02 / 12 / 2025, p. 38 / 563 33 / 539 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl.

[0088] In some embodiments, the present description presents a compound with structural formula IIIa-1: OK / r5r4 (R33)t , Formula IIIa-1 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0089] In some embodiments, the present description presents a compound with structural formula IIIa-2: ox / / Formula IIIa-2 Petition 870250110544, dated 02 / 12 / 2025, p. 39 / 563 34 / 539 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0090] In some forms, the compound has the structure of Formula II1a-1: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0091] In some modalities, L has the structure of Formula III: Aχι^ζλ Formula III where X1 is O or CH2 and is attached to ring A; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

[0092] In some embodiments, the compound has the structure of Va-2 Formula: Petition 870250110544, dated 02 / 12 / 2025, p. 40 / 563 35 / 539 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X1 is O or CH2; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

[0093] In some modalities, X1 is O.

[0094] In some embodiments, Z is optionally replaced by a 3- to 6-membered heterocycloalkylene. In some embodiments, Z is optionally replaced by a 5-membered heterocycloalkylene. In some embodiments, Z is optionally replaced by pyrrolidine-diyl. In some embodiments, Z is optionally replaced by pyrrolidinyl. In some embodiments, Z is optionally replaced by pyrrolidine-diyl.

[0095] In some forms, L has the structure of Formula IV: Λχΐ^ζλ Formula IV X1 is O or CH2 and is attached to ring A; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

[0096] In some categories, L has the structure of Formula VI: To the R6 Formula VI wherein B is an optionally substituted 3- to 6-membered alkylneocycloalphabetic; R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, 3- to 6-membered heterocyclyl Petition 870250110544, dated 02 / 12 / 2025, page 41 / 563 36 / 539 optionally replaced, 3- to 6-membered cycloalkyl optionally replaced, 5- to 10-membered heteroaryl optionally replaced, C6-C10 aryl optionally replaced, R7, d11 h o , I , or O ; R7 and R8 are each independently either H or C1-C6 alkyl optionally substituted; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0097] In some modalities, L has the structure of Formula VIa: N / R6 Formula VIa Petition 870250110544, dated 02 / 12 / 2025, p. 42 / 563 37 / 539

[0098] In some embodiments, the compound has the structure of Formula VIIa-2: , O , I , or o ; one, independently, H or optionally substituted C1-C6 alkyl, C2-C6 alkenyl or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, C6-C10 aryl > 9 O p11 H;r8H-*9lA0H optionally replaced, R R7 and R8 are each optionally replaced; R9 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, C1-C6 Petition 870250110544, dated 02 / 12 / 2025, page 43 / 563 38 / 539 optionally substituted heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3C10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C3-C10 cycloalkenyl, heterocycloalkenyl of 3 to 10 members optionally substituted; C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0099] In some embodiments, the compound has the structure of Formula VIIa or Formula VIIb: Formula VIIa Formula VIIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, C6-C10 aryl O i11QO r11 H optionally replaced, R, O, I, or θ; R7 and R8 are each independently either H or C1-C6 alkyl optionally substituted; R9 is C1-C6 optionally substituted alkyl, C2-C6 alkenyl Petition 870250110544, dated 02 / 12 / 2025, page 44 / 563 39 / 539 optionally substituted, 3- to 6-membered cycloalkyl optionally substituted, or 3- to 6-membered heterocyclyl optionally substituted; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0100] In some forms, the compound has the structure of Formula VIIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl Petition 870250110544, dated 02 / 12 / 2025, p. 45 / 563 40 / 539 replaced, heteroaryl of 5 to 10 members optionally replaced, C6-C10 aryl Hθ « θ d10 R11r Hb· MK optionally replaced, r7, ο , I , or 0 ; R7 and R8 are each independently, H or C1-C6 alkyl optionally substituted; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0101] In some embodiments, the compound has the structure of Formula VIIa-2: Petition 870250110544, dated 02 / 12 / 2025, p. 46 / 563 41 / 539 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, C6-C10 aryl O I II ο Ο ο11 H;rΗΗ9r-»KRoptionally substituted, R, Ο, I, or θ; R7 and R8 are each independently, H or C1-C6 alkyl optionally substituted; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R6 is O. In some embodiments, R11 is C1-C6 alkyl Petition 870250110544, dated 02 / 12 / 2025, p. 47 / 563 42 / 539 optionally substituted. In some embodiments, R11 is optionally substituted C2-C6 alkenyl. In some embodiments, R11 is optionally substituted C2-C6 alkynyl. In some embodiments, R11 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R11 is optionally substituted C2-C6 heteroalkenyl. In some embodiments, R11 is optionally substituted C2-C6 heteroalkynyl. In some embodiments, R11 is optionally substituted C3-C10 cycloalkenyl. In certain embodiments, R11 is hydrogen. In some embodiments, R11 is optionally substituted C3-C10 cycloalkyl. In some embodiments, R11 is optionally substituted 3- to 10-membered heterocyclyl. p10

[0102] In some embodiments, R6 is 1. In some embodiments, R10 is a 5 to 10 membered heteroaryl optionally substituted. In some embodiments, R10 is a 3 to 10 membered heterocyclic optionally substituted.

[0103] In some embodiments, R6 is a 3- to 6-membered heterocycle that is optionally substituted.

[0104] In some embodiments, A is optionally replaced by a 3- to 6-membered heterocycloalkylene, a 6-membered arylene, or a 5- to 10-membered heteroarylene. In some embodiments, A is optionally substituted 6-membered arylene. In some embodiments, or A is: where represents the portion of the molecule bound to the ligand. Petition 870250110544, dated 02 / 12 / 2025, p. 48 / 563 43 / 539

[0105] In some modalities, A is

[0106] In some embodiments, R2 is C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, R2 is or \^CF3 . In certain embodiments, R2 is ''ζ^^.

[0107] In some embodiments, R4 is optionally substituted C1-C6 alkyl. In some embodiments, R4 is methyl.

[0108] In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3 is ' or

[0109] In some embodiments, R5 is hydrogen. In some embodiments, R5 is an optionally substituted 3- to 10-membered heterocycloalkyl group.

[0110] In some modalities, R5 is HN or Petition 870250110544, dated 02 / 12 / 2025, p. 49 / 563 44 / 539

[0111] In some modalities, R5 is -OR5a. In some modalities, R5 is

[0112] In any embodiment described herein, a compound of the present invention may be modified with a substituent as found in any one or more of the following applications, incorporated herein by reference in their entirety: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO 2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO 2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684.

[0113] In some embodiments, a compound of the present invention is selected from Tables 1 and 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention is selected from Tables 1 and 2, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Certain Compounds of the Present Invention Petition 870250110544, dated 02 / 12 / 2025, p. 50 / 563 45 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 51 / 563 46 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 52 / 563 47 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 53 / 563 48 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 54 / 563 49 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 55 / 563 50 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 56 / 563 51 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 57 / 563 52 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 58 / 563 53 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 59 / 563 54 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 60 / 563 55 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 61 / 563 56 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 62 / 563 57 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 63 / 563 58 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 64 / 563 59 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 65 / 563 60 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 66 / 563 61 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 67 / 563 62 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 68 / 563 63 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 69 / 563 64 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 70 / 563 65 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 71 / 563 66 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 72 / 563 67 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 73 / 563 68 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 74 / 563 69 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 75 / 563 70 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 76 / 563 71 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 77 / 563 72 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 78 / 563 73 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 79 / 563 74 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 80 / 563 75 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 81 / 563 76 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 82 / 563 77 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 83 / 563 78 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 84 / 563 79 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 85 / 563 80 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 86 / 563 81 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 87 / 563 82 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 88 / 563 83 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 89 / 563 84 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 90 / 563 85 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 91 / 563 86 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 92 / 563 87 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 93 / 563 88 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 94 / 563 89 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 95 / 563 90 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 96 / 563 91 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 97 / 563 92 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 98 / 563 93 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 99 / 563 94 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 100 / 563 95 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 101 / 563 96 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 102 / 563 97 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 103 / 563 98 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 104 / 563 99 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 105 / 563 100 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 106 / 563 101 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 107 / 563 102 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 108 / 563 103 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 109 / 563 104 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 110 / 563 105 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 111 / 563 106 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 112 / 563 107 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 113 / 563 108 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 114 / 563 109 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 115 / 563 110 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 116 / 563 111 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 117 / 563 112 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 118 / 563 113 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 119 / 563 114 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 120 / 563 115 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 121 / 563 116 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 122 / 563 117 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 123 / 563 118 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 124 / 563 119 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 125 / 563 120 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 126 / 563 121 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 127 / 563 122 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 128 / 563 123 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 129 / 563 124 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 130 / 563 125 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 131 / 563 126 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 132 / 563 127 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 133 / 563 128 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 134 / 563 129 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 135 / 563 130 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 136 / 563 131 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 137 / 563 132 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 138 / 563 133 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 139 / 563 134 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 140 / 563 135 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 141 / 563 136 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 142 / 563 137 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 143 / 563 138 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 144 / 563 139 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 145 / 563 140 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 146 / 563 141 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 147 / 563 142 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 148 / 563 143 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 149 / 563 144 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 150 / 563 145 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 151 / 563 146 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 152 / 563 147 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 153 / 563 148 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 154 / 563 149 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 155 / 563 150 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 156 / 563 151 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 157 / 563 152 / 539

[0114] 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. Other isomers are contemplated among the compounds of the present invention. In particular embodiments, an atropisomer of a compound from the previous table is contemplated. The square brackets should be ignored. Table 2: Certain Compounds of the Present Invention Petition 870250110544, dated 02 / 12 / 2025, pp. 158 / 563 153 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 159 / 563 154 / 539 Petition 870250110544, dated 02 / 12 / 2025, p. 160 / 563 155 / 539 B13 °γ·ζχ° o J ΗΧχΧ -0 L í HJ 0 o ' <f B14 r π λ o ς < / B15 •rXo X X H L· X X B16 _ Y X <ΧΧΧχ 'Xvt, O o —y XX T'Xk^ B17 yO / b . J XI x X XH ^ΧΧΐ^γΧ^Ο'Χ-'Ν·' rf ( ΛΟ' <fN B18 ° X XH -X° ^ΧΧ^γΧ^ο'-Χ'Ν·' 0 Ç 4 B19 °γΌχ° ο , Τ τ 1 χ -0 χ 1 Η χ β ΛΧΧγ-'γΧΧ-'χΧχ / “Λ-Μ οΧ-ν- ο ς χ Petition 870250110544, dated 02 / 12 / 2025, pp. 161 / 563 156 / 539 B20 Qs.0 .Q . 2 -? 0 / / 0000^° ,N ' A -.-w oa N—' B21 'vQ / , . z° H 0-^0 -o / Γ A 0 ς B22 -° 0 0 h Y0000O-0r· <0 AC- <í B23 o Ο^_..< ,-N.xO V Ν' 0 IJ ηΛαΛ -o L 1 Hxly0ολϊ_ 0 ς N-^ Petition 870250110544, dated 02 / 12 / 2025, p. 162 / 563 157 / 539 Petition 870250110544, dated 02 / 12 / 2025, pp. 163 / 563 158 / 539 ​

[0115] A pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is also provided.

[0116] The compounds of the present invention are also adaptable for use in antibody-drug conjugates, as well as degradation applications.

[0117] A method of treating cancer 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. The cancer may, for example, be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung carcinoma. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, or multiple myeloma. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras Q61H, HRas Q61H, or N-Ras Q61H. Other Ras mutations are described in this document.

[0118] A method for treating a Ras protein-related disorder in a subject in need of it is also provided, the method Petition 870250110544, dated 02 / 12 / 2025, page 164 / 563 159 / 539 comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0119] 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 Q61H, H-Ras Q61H or N-Ras Q61H. Other Ras proteins are described herein. The cell may be a cancer 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. In some embodiments, the cell is a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell or a multiple myeloma cell.Other types of cancer are described in this document. The cell may be in vivo or in vitro.

[0120] With respect to compounds of the present invention, one stereoisomer may exhibit better inhibition than another stereoisomer. For example, one atropisomer may exhibit inhibition, whereas the other atropisomer may exhibit little or no inhibition.

[0121] In some embodiments, a method or use described herein further comprises administering additional anticancer therapy. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, 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, an inhibitor of Petition 870250110544, dated 02 / 12 / 2025, page 165 / 563 160 / 539 CDK4 / 6, or a combination thereof. In some modalities, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described herein. Synthesis Methods

[0122] The compounds described in this document can be made from commercially available raw materials or synthesized using known organic, inorganic and / or enzymatic processes.

[0123] 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 synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. These methods include, but are not limited to, those methods described in the Schemes below.

[0124] Compounds in Tables 1 and 2 in this document were prepared using methods disclosed herein or were prepared using methods disclosed herein combined with the knowledge of someone skilled in the art. Scheme 1. General synthesis of functionalized bis-macrocycles Petition 870250110544, dated 02 / 12 / 2025, p. 166 / 563 161 / 539

[0125] A general synthesis of functionalized bis-macrocycles is described in Scheme 1. An appropriately substituted biaryl intermediate (1) can be prepared in one step from an appropriately substituted 3-(5-bromo-2iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol intermediate and an appropriately substituted aryl boronic ester containing methyl piperasic ester by a palladium-mediated coupling followed by ester hydrolysis. Macrolactonization followed by amine and phenol deprotection can yield macrocyclic ester (2).

[0126] A suitably substituted 2-(tosyloxymethyl)-3-(amido) cyclic amine (3) can be prepared by coupling an O-protected N-methyl-L-valine (4) with a suitably substituted 2-(hydroxymethyl)-3-carboxylate cyclic amine using a peptide coupling reagent, followed by tosylation of the alcohol and deprotection of the carboxylic acid.

[0127] The final functionalized bis-macrocycles can then be made by peptide coupling of the macrocyclic ester (1) with the intermediate (3) followed by the formation of the macrocyclic ether in the presence of base. Deprotection and coupling of the amine with a suitably substituted carboxylic acid (or other coupling partner) results in a bis-macrocyclic product. (5). Scheme 2. Alternative general synthesis of macrocyclic ester intermediates (2) Petition 870250110544, dated 02 / 12 / 2025, page 167 / 563 162 / 539

[0128] Alternatively, the macrocyclic ester intermediate (2) can be prepared as described in Scheme 2. An appropriately substituted aryl boronic ester (5) can be coupled with an appropriately protected 3-(5-bromo-indol-3yl)-2,2-dimethylpropan-1-ol (6) in the presence of a palladium catalyst. This can be followed by indole iodination, alcohol deprotection, and ester hydrolysis. Subsequent coupling with methyl (S)piperasic ester, ester hydrolysis, and macrolactonization can result in an iodinated macrocyclic intermediate (7). Coupling in the presence of a palladium catalyst with an appropriately substituted aryl boronic ester (8) and N-alkylation of the indole, followed by subsequent deprotection of the amine and phenol, results in intermediate (2). Scheme 3. General synthesis of functionalized amine bis-macrocycles

[0129] A general synthesis of functionalized bis-macrocycles is described in Scheme 3. An appropriately protected hydroxyalkyl amino acid can be coupled with O-protected N-methyl-L-valine (3) by a peptide coupling reagent. Subsequent deprotection of alcohol and carboxylic acid can produce appropriately substituted intermediates (7).

[0130] A bis-macrocyclic protected amine intermediate Petition 870250110544, dated 02 / 12 / 2025, page 168 / 563 163 / 539 can be made by peptide coupling of macrocyclic ester intermediate (2) with carboxylic acid (7) followed by the formation of bis-macrocyclic ether in the presence of triphenylphosphine and an azodicarboxylate. Deprotection and coupling of the amine with a suitably substituted carboxylic acid (or other coupling partner) results in the final bismacrocyclic product. (8). Scheme 4. General synthesis of functionalized amine bis-macrocycles

[0131] A general synthesis of functionalized bis-macrocycles is described in Scheme 4. An appropriately substituted terminal alkyne (9) can be coupled with an appropriately substituted iodinated bromoarene (10) in the presence of a palladium catalyst. Subsequent reduction of the aryl alkyne intermediate (11) followed by deprotection of the amino acid N, deprotection of the carboxylic acid, macrocyclization in the presence of a peptide coupling reagent, ester hydrolysis and peptide coupling with methyl (S)-piperasic ester can yield macrocyclic intermediate (12). The functionalized bis-macrocycle (13) can then be obtained by means of a palladium-mediated coupling with an appropriately substituted 3-(5boronato-indol-3-yl)-2,2-dimethylpropan-1-ol, macrolactonization, amine deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Petition 870250110544, dated 02 / 12 / 2025, page 169 / 563 164 / 539 Scheme 5. General synthesis of functionalized amine bis-macrocycles

[0132] A general synthesis of functionalized bis-macrocycles is described in Scheme 5. A suitably substituted 5-membered 2-bromo-4-bromomethyl5-ethenyl heteroarene (14) can react with 2-((diphenylethylene)amino) ethyl acetate in the presence of a base and a chiral auxiliary. Subsequent amide coupling with a suitably substituted 2-(ethenyl)-3-(amido) cyclic amine (15), followed by an olefin metathesis reaction, ester hydrolysis and an amide coupling reaction with a methyl (S)-piperasic ester can produce a macrocycle (16).

[0133] The functionalized amine bis-macrocycle (17) can then be obtained through palladium-mediated coupling with an appropriately substituted 3-(5-boronato-indol-3-yl)2,2-dimethylpropan-1-ol, hydrolysis of the methyl ester, macrolactonization, deprotection of the amine and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Scheme 6. General synthesis of functionalized amine bis-macrocycles Petition 870250110544, dated 02 / 12 / 2025, p. 170 / 563 165 / 539

[0134] A general synthesis of functionalized bis-macrocycles is described in Scheme 6. An appropriately substituted iodinated bromoarene (10) can be coupled with a vinylboronate ester in the presence of a palladium catalyst. Hydrolysis of the vinyl ether in the presence of acid can yield aldehyde (18).

[0135] An appropriately N-functionalized O-protected amino acid (19) can be coupled to an aldehyde (18) in the presence of an acid and a reducing agent. This can be followed by deprotection of the carboxylic acid and coupling of an O-protected N-methyl-L-valine (3) in the presence of an amide coupling reagent. Subsequent deprotections of carboxylate and amine followed by cyclization in the presence of hydrolysis of a peptide coupling reagent can produce a macrocyclic intermediate (20).

[0136] An appropriately substituted biaryl intermediate (21) can then be prepared in two steps by coupling the intermediate (20) with an appropriately substituted 3-(5-boronato-indol-3-yl)-2,2-dimethylpropan-1-ol by a palladium-mediated coupling followed by ester hydrolysis. Subsequent coupling with methyl (S)piperazic ester by a peptide coupling reagent, ester hydrolysis and macrolactonization can yield functionalized amine bis-macrocycle (22).

[0137] In any embodiment described herein, a compound of the present invention may be modified with a substituent found in one or more of the following applications, using methodologies described in those applications in combination with methods provided herein and known to those skilled in the art: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO 2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO 2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684, Petition 870250110544, dated 02 / 12 / 2025, p. 171 / 563 166 / 539 each incorporated herein by reference in its entirety. Pharmaceutical Compositions and Methods of Use

[0138] The compounds involved in the invention are Ras inhibitors and are useful in the treatment of cancer. Consequently, 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.

[0139] 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 thereof, formulated together with a pharmaceutically acceptable excipient.

[0140] In some embodiments, a compound is present in a pharmaceutical composition in a unit dose amount 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, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for: oral administration, for example, solutions (aqueous or non-aqueous solutions or suspensions), tablets, for example, those intended for buccal, sublingual and / or systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, subcutaneous, intramuscular, intravenous or epidural injection, such as, for example, a sterile solution or suspension or sustained-release formulation; topical application, for example, in the form of a cream, ointment or controlled-release patch or a spray applied to the skin; intravaginal or intrarectal, for example, as a pessary, cream or foam; sublingual; ocular; transdermal. Petition 870250110544, dated 02 / 12 / 2025, page 172 / 563 167 / 539 or on nasal, pulmonary and / or other mucous surfaces.

[0141] 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 include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, colorants (colors), emollients, emulsifiers, bulking agents (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, absorbents, suspending or dispersing agents, sweeteners, or waters for hydration.Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, 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, starch glycolate, sorbitol, starch (corn), 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, et al., 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. Petition 870250110544, dated 02 / 12 / 2025, page 173 / 563 168 / 539 In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients.

[0142] The compounds described in this document, 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 in this document 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 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.Salts can be prepared in situ during the final isolation and purification of the compounds described in this document, or separately by reacting a free base group with a suitable organic acid.

[0143] 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 Petition 870250110544, dated 02 / 12 / 2025, page 174 / 563 169 / 539 Addition salts of acid 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.

[0144] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, iodide, optionally substituted 2-hydroxylethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and similar substances.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.

[0145] As used herein, the term animal 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 Petition 870250110544, dated 02 / 12 / 2025, page 175 / 563 170 / 539 a clone.

[0146] As used in this document, the term dosage form refers to a physically distinct unit of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, this amount is a unit dose amount (or a whole fraction thereof) appropriate for administration in accordance with 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 recognize that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0147] As used herein, the term dosage regimen refers to a set of unit doses (usually more than one) that are administered individually to a subject, normally separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosage regimen, which may involve one or more doses. In some embodiments, a dosage regimen comprises a plurality of doses, each of which is separated from the other by a period of time of the same length; in some embodiments, a dosage regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosage regimen are of the same unit dose quantity. In some embodiments, different doses within a dosage regimen are of different quantities.In some forms, a dosage regimen includes... Petition 870250110544, dated 02 / 12 / 2025, page 176 / 563 171 / 539 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 amount equal to the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered in a relevant population (i.e., it is a therapeutic dosing regimen).

[0148] A therapeutic regimen refers to a dosage regimen whose administration in a relevant population is correlated with a desired or beneficial therapeutic outcome.

[0149] The term treatment (also treat 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 of a subject who exhibits one or more established signs of the disease, disorder, and / or condition in question. In some embodiments, the treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / 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 disease, disorder, and / or condition. Petition 870250110544, dated 02 / 12 / 2025, page 177 / 563 172 / 539 relevant.

[0150] 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 subjects when administered to patients in need of such treatment.It is specifically understood that particular subjects may, in fact, be refractory to a therapeutically effective amount. In some modalities, 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.

[0151] 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 method of administration and the type of treatment desired, Petition 870250110544, dated 02 / 12 / 2025, p. 178 / 563 173 / 539 for example, prevention, prophylaxis or therapy, the compounds, or a pharmaceutically acceptable salt thereof, are formulated in a manner 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. Boilan, 1988-1999, Marcel Dekker, New York, each of which is hereby incorporated by reference.

[0152] The compositions may 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 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.

[0153] The composition may be supplied in a dosage form 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, drains, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic administration or aerosols. Compositions may be formulated in accordance with pharmaceutical practice. Petition 870250110544, dated 02 / 12 / 2025, page 179 / 563 174 / 539 conventional.

[0154] 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 in this document) 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.

[0155] Formulations may be prepared in a manner 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.

[0156] Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, salt, dextrose, glycerol, or ethanol. These 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 and sorbitan monolaurate, and so forth. Petition 870250110544, dated 02 / 12 / 2025, page 180 / 563 175 / 539

[0157] Several sustained-release drug delivery systems have also been devised. See, for example, US Patent No. 5,624,677.

[0158] 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 pharmaceutically acceptable salts thereof. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0159] Each compound, or a pharmaceutically acceptable salt thereof, as described in this document, 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. Other combination therapy modalities are described in this document.

[0160] 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 a 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 components of the kit may be... Petition 870250110544, dated 02 / 12 / 2025, page 181 / 563 176 / 539 assembled in boxes, blister packs, bottles, tubes and similar.

[0161] Oral formulations include tablets containing the active ingredients in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may be, for example, inert diluents or bulking agents (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, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum and magnesium silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricating, slip 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.

[0162] 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 within 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.

[0163] Oral formulations 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 Petition 870250110544, dated 02 / 12 / 2025, page 182 / 563 177 / 539 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 can be prepared using the ingredients mentioned above in tablets and capsules in a conventional manner using, for example, a mixer, a fluid bed apparatus or a spray drying apparatus.

[0164] Controlled dissolution or release by diffusion may be achieved by appropriately coating a tablet, capsule, pellet or granulated 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 coating substances mentioned above or, for example, shellac, beeswax, glycoceryl 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 methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

[0165] The liquid forms in which the compounds, salts and pharmaceutical compositions of the present application may be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, oil of Petition 870250110544, dated 02 / 12 / 2025, page 183 / 563 178 / 539 sesame, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0166] Generally, when administered to a human being, 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 easily determined by a person 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 derivable range.

[0167] 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.

[0168] It will be appreciated 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 subsequent to, one or more other desired therapies or medical procedures. The particular combination of therapies (therapeutics or Petition 870250110544, dated 02 / 12 / 2025, page 184 / 563 179 / 539 procedures) to be employed 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 assessed whether the therapies employed can achieve a desired effect for the same disorder, or can achieve different effects (e.g., control of any adverse effects).

[0169] The administration of each drug in a combination therapy, as described in this document, may independently be from one to four times a day for one day to one year, and may even be for the subject's life. Long-term chronic administration may be indicated. Methods of Use

[0170] 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.

[0171] Consequently, a method is also provided 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, 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, appendix 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 appendix cancer, endometrial cancer, or melanoma. It is also Petition 870250110544, dated 02 / 12 / 2025, page 185 / 563 180 / 539 provides 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.

[0172] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods provided herein may be used for the treatment of a wide variety of cancers, including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that can be treated by the compounds or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, pulmonary, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other types of cancer 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, chondromatous hamartoma, mesothelioma; Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, Petition 870250110544, dated 02 / 12 / 2025, page 186 / 563 181 / 539 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 (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryo 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 chordoma of giant cell tumor, osteochondroma (osteocartilaginous exostoses), benign chondroma, 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); Petition 870250110544, dated 02 / 12 / 2025, page 187 / 563 182 / 539 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, 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 syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0173] 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 having 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 having cancer comprising a Rasamp (K-Rasamp, H-Rasamp, or N-Rasamp). In some embodiments, the cancer comprises a mutation of Petition 870250110544, dated 02 / 12 / 2025, page 188 / 563 183 / 539 Ras, as a mutation of RAs described in this document. In some modalities, the 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 K-Ras mutants: Q61R, G13R, Q61K, G12S, 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 K-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 foregoing. In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, Q61R, and Q61L. In some embodiments, the cancer comprises a K-Ras mutation that is Q61H. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a K-Ras mutation that is Q61H. In some embodiments, a compound of the present invention inhibits more than one Ras mutation. 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, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Petition 870250110544, dated 02 / 12 / 2025, p. 189 / 563 184 / 539 Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H or N-RasWT e H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H or N-RasWT e N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, ou A59T).In some embodiments, a compound of the present invention inhibits Rasampalem from one or more additional Ras mutations (e.g., K-, H- or N-Rasampe K-Ras 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; K, H or N-Rasampe H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H or NRasamp and N-Ras 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).

[0174] 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 (CE-IVD marked), for example, as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0175] In some forms, a cancer comprises a Ras Q61H mutation and a TP53 mutation, an STK11LOF, a CDKN2A, a KEAP1, a CDKN2B, an MTAP, an RBM10, a SMARCA4, an ATM, a MYC, an APC, a SMAD4, a PIK3CA, a SOX9, an FBXW7, a Petition 870250110544, dated 02 / 12 / 2025, p. 190 / 563 185 / 539 PTEN, FLT3, AMER1, CDK8, AKT2, RNF43, GATA6, SF381, IGH, CDKN2C, DNMT3A, RB1, TRAF3, N-Ras, TET2, FAF1, BRAF, KMT2A, RUNX1, PTPN11, ETV6, NPM1, or MYH11. In some modalities, the cancer is non-small cell lung cancer and comprises a K-Ras Q61H mutation and a TP53 mutation, an STK11LOF, a CDKN2A, a KEAP1, a CDKN2B, an MTAP, an RBM10, a SMARCA4, an ATM, or a MYC mutation. In some modalities, the cancer is colorectal cancer and comprises a K-Ras Q61H mutation and an APC, TP53, SMAD4, PIK3CA, SOX9, FBXW7, PTEN, FLT3, AMER1, or CDK8 mutation. In some modalities, the cancer is pancreatic cancer and comprises a K-Ras Q61H mutation and a TP53, CDKN2A, CDKN2B, MTAP, SMAD4, ATM, AKT2, RNF43, GATA6, or SF381 mutation. In some modalities, the cancer is multiple myeloma and comprises a K-Ras Q61H mutation and an IGH, TP53, CDKN2C, DNMT3A, RB1, TRAF3, N-Ras, TET2, FAF1, or BRAF mutation.In some forms, the cancer is acute myeloid leukemia and comprises a K-Ras Q61H mutation and an N-Ras, KMT2A, FLT3, DNMT3A, RUNX1, PTPN11, TP53, ETV6, NPM1, or MYH11 mutation. In some forms, the cancer is melanoma and the Ras mutation comprises an N-Ras mutation, such as N-Ras Q61R or N-Ras Q61K. In either of the above, a compound may inhibit RasWT (e.g., K-, H-, or N-RasWT) or Rasamp (e.g., K-, H-, or N-Rasamp) as well.

[0176] The invention also relates to a method of treating a hyperproliferative disorder in a subject comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. A method for inhibiting RAF-Ras binding, the method comprising contacting the cell with an effective amount of a compound. Petition 870250110544, dated 02 / 12 / 2025, pp. 191 / 563 186 / 539 of the present invention or a pharmaceutically acceptable salt thereof. The cell may be a cancer cell. The cancer cell may be of any type of cancer described herein. The cell may be in vivo or in vitro. Combination Therapy

[0177] 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 relative to standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0178] A compound of the present invention may be administered 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.

[0179] In some modalities, additional therapy is the administration of side-effect limiting agents (e.g., agents intended to decrease the occurrence or severity of treatment side effects. For example, in some modalities, the compounds of the present Petition 870250110544, dated 02 / 12 / 2025, page 192 / 563 The invention 187 / 539 can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used in the treatment of nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0180] In some modalities, one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy). 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 a non-drug treatment (e.g., surgery or radiation therapy) 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). In another modality, one or more additional therapies include two therapeutic agents. In yet another modality, one or more additional therapies include three therapeutic agents.In some modalities, one or more additional therapies include four or more therapeutic agents.

[0181] In this Combined Therapy section, all references are incorporated by reference to the agents described, whether explicitly stated as such or not. Non-drug therapies

[0182] 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 (ACT) therapy.

[0183] In some embodiments, the compounds of the invention Petition 870250110544, dated 02 / 12 / 2025, page 193 / 563 188 / 539 can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the invention can be used as neoadjuvant therapy before surgery.

[0184] Radiation therapy can be used to inhibit abnormal cell growth or treat a hyperproliferative disorder, such as cancer, in an individual (e.g., mammal (e.g., human)). Radiation therapy can be administered by one of several methods, or a combination of methods, including, without limitation, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, and permanent or temporary interstitial radiotherapy and brachytherapy. The term brachytherapy, as used in this document, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other site of proliferative tissue disease. The term is intended to include, without limitation, 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. By way of non-limiting example, the radiation source may be a radionuclide, such as 1-125, 1-131, Yb-169, 1r192 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may 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 may be produced using a suitable fluid substance containing small particles of solid radionuclides, such as Au-198, Y-90. Furthermore, the radionuclide(s) may be incorporated in the form of a gel or radioactive microspheres.

[0185] In some embodiments, the compounds of the present Petition 870250110544, dated 02 / 12 / 2025, page 194 / 563 189 / 539 invention can make abnormal cells more sensitive to radiation treatment for the purpose of killing or inhibiting the growth of such cells. Therefore, 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, the amount of 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 confirming 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.

[0186] In some embodiments, the non-drug treatment is an adoptive T-cell transfer (ACT) therapy. 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 (CART) 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, splenic 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 modalities, 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. Petition 870250110544, dated 02 / 12 / 2025, p. 195 / 563 190 / 539 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

[0187] 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 together with one or more non-drug therapies.

[0188] For example, a therapeutic agent may be a steroid. Steroids are well-known in the field. Consequently, in some modalities, one or more additional therapies include a steroid. 21acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidan acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate,Prednisolone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof. Petition 870250110544, dated 02 / 12 / 2025, page 196 / 563 191 / 539

[0189] 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 Patent Nos. 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.

[0190] A therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin, such as IL-2)) used in the treatment of cancer or symptoms associated with it. Biologics are 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 anti-cancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0191] 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 (by Petition 870250110544, dated 02 / 12 / 2025, page 197 / 563 192 / 539 example, 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 PDL2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, 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 & 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, 1-7F9 and KW-6002.

[0192] 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.

[0193] 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 the treatment of cancer or Petition 870250110544, dated 02 / 12 / 2025, page 198 / 563 193 / 539 symptoms associated with it, collectively, an anticancer agent). Anticancer agents can be, for example, chemotherapeutic agents or targeted therapy agents. Such agents are known in the art.

[0194] 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, epipodopilotoxines, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical suppressants, adrenocorticosteroids, progestogens, 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. Suitable dosage regimens for combination anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0195] Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesyldate); 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, triethylenethiophosphoramide and Petition 870250110544, dated 02 / 12 / 2025, p. 199 / 563 194 / 539 trimethylolmelamine; acetogenins (especially bulatacin and bulatacinone); 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; sarcodictin A; spongistatin; nitrogenous mustards, such as chlorambucil, chloranaphazene, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, fenesterin, prednimustine, trofosfamide, uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;antibiotics, such as enedine antibiotics (e.g., calicheamicin, such as calicheamicin gamma I and calicheamicin omega II (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynecin, including dynecin A; bisphosphonates, such as clodronate; esperamycin;as well as neocarzinostatin chromophore and related chromoprotein enedin antibiotic chromophores), aclacinomissins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophylline, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porphyromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, Streptozocin, tubercidine, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, tiamiprine, thioguanine;pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cotarabine; Petition 870250110544, dated 02 / 12 / 2025, page 200 / 563 195 / 539 dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglathine; aldofosfamide glycoside; aminolevulinic acid; enyluracil; amsacrine; bestrabucil; bisanthrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; epothilone; etoglucoside; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerin; pentostatin; fenamete; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydraniza; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxine; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''trichlorotriethylamine;Trichothecenes such as T-2 toxin, verracurine A, roridine A and anguidin; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobromane; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, for example, Taxol® (paclitaxel), Abraxane® (cremophor-free, engineered nanoparticle formulation with paclitaxel albumin), and Taxotere® (docetaxel); chlorambucil; tamoxifen (Nolvadex™); raloxifene; 4(5)-imidaze 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; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11);RFS 2000 topoisomerase inhibitor; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamycins (e.g., Xeloda®); and salts, acids and pharmaceutical derivatives; Petition 870250110544, dated 02 / 12 / 2025, page 201 / 563 196 / 539 acceptable from any of the above.

[0196] Additional, but not 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-17-demethoxygeldanamycin, alfaradine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell cycle nonspecific antineoplastic agents and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, briostatin, butionine sulfoximine, CBV (chemotherapy), caliculin, dichloroacetic acid, discodermolide, elsamitrucin, 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, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0197] 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 Petition 870250110544, dated 02 / 12 / 2025, page 202 / 563 197 / 539 do not have 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 abemiclib, 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), trazenosdacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogues, pyrimidine analogues (e.g., fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine inhibitors, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) (e.g., trichostatin, sodium butyrate, apicidan, 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., Array 520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors, such as PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), 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 luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibody (e.g., LY2127399), IK inhibitors, p38MAPK inhibitors, anti-IL-6, Petition 870250110544, dated 02 / 12 / 2025, page 203 / 563 198 / 539 (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., GSK-2141795), 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-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL2 antagonists.

[0198] In some embodiments, an anticancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or variant derived from the foregoing.

[0199] 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.

[0200] In some embodiments, the 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); Petition 870250110544, dated 02 / 12 / 2025, page 204 / 563 199 / 539 lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT707; TPX-0005 and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of document WO05016894.

[0201] In some embodiments, an anticancer agent is an inhibitor of a downstream member of a Receptor Tyrosine Kinase (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., BI1701963, BI-3406, SDR5, BAY-293, MRTX-0902 or RMC-5845), or a salt, solvate, isomer (e.g., stereoisomer), prodrug or pharmaceutically acceptable 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.

[0202] In some embodiments, the 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 2022219035, WO 2022214594, WO 2022199670, WO 2022146698, WO 2022081912, WO 2022058344, WO 2022026465, WO 2022017519, WO 2021173524, WO2021130731, WO2021127429, WO2021092115, WO2021105960, WO2021074227, WO2020180768, WO2020180770, 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.

[0203] In some modalities, an anticancer agent is a Petition 870250110544, dated 02 / 12 / 2025, page 205 / 563 200 / 539 additional Ras inhibitor or a Ras vaccine, or other 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 active state or bound to GDP. In some embodiments, the Ras inhibitor is, as a K-Ras G12C inhibitor, such as AMG 510, MRTX1257, MRTX849, JNJ74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-3312, JAB-21822, JAB-21000, IBI351, ERAS-3490, RMC-6291, BI 1823911, D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, IL-15293, BBO8520 (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255 or GDC-6036. In some embodiments, the Ras inhibitor is a K-Ras G12D inhibitor, such as MRTX1133, JAB-22000, MRTX282, ERAS-4, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835, RMC-9805, GFH375 (VS-7375), INCB161734, and KD-8. In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000. In some embodiments, the KRAS(OFF) inhibitor is a pan-KRAS(OFF) inhibitor. In specific modalities, the pan-KRAS(OFF) inhibitor is JAB-23400, JAB-23425, BI-2493, BI-2865, QTX-3034 (preferably G12D). QTX3544 (preferably G12V), ZG2001, BBO-a, BBO-B, or Pan KRas-IN-1. In some versions, the Ras inhibitor is JAB-23400. In some versions, the Ras inhibitor is RMC-6236. In some embodiments, the Ras inhibitor is selected from a Ras(ON) inhibitor (i.e., Ras in its GTP-bound state) disclosed below, incorporated herein by reference in its entirety, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof: WO 2022 / 235870, WO 2022 / 235864, WO 2022 / 060836, WO 2021091982, WO 2021091967, WO 2021091956, and WO 2020132597. Other examples of Ras inhibitors are Petition 870250110544, dated 02 / 12 / 2025, p. 206 / 563 201 / 539 known in the art, such as the following, incorporated herein by reference in sua totalidade: WO 2023287896 , WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280960, WO 2023280280, WO2023278600, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023274324, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023015559, WO 2023014979, WO 2023014006, WO 2023010121, WO 2023009716, WO 2023009572, WO 2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271923, WO 2022271823, WO 2022271810 WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO 2022216762, WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346,WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO, Petição 870250110544, de 02 / 12 / 2025, pág. 207 / 563 202 / 539 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 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807 WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524,WO 2015054572, WO, 2014152588, WO 2014143659 and WO 2013155223.

[0204] 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); Petition 870250110544, dated 02 / 12 / 2025, page 208 / 563 203 / 539 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.

[0205] 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; PKI-587; GSK2126458.

[0206] In some embodiments, an anticancer agent is a PD-1 or PD-L1 antagonist. Such agents are known in the art.

[0207] 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.

[0208] IGF-1R inhibitors are known in the art and include linsitinib or a pharmaceutically acceptable salt thereof.

[0209] 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. Petition 870250110544, dated 02 / 12 / 2025, page 209 / 563 204 / 539 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 completely block the activation of 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 having the same binding specificity.

[0210] 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, but not limited, 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 Patent No. 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; Petition 870250110544, dated 02 / 12 / 2025, page 210 / 563 205 / 539 WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; US Patent No. 5,789,427; US Patent No. 5,650,415; US Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Additional, non-limiting examples of small molecule EGFR inhibitors 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).

[0211] 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.

[0212] 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-[3-methyl2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]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-4-morpholinothieno[3,2d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-Petition 870250110544, dated 02 / 12 / 2025, page 211 / 563 206 / 539 morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl] phenol (available from Axon Medchem); PIK 75 (acid 2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3yl)methylene]-1-methyl-hydrazide-benzenesulfonic, monochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-di-hydro-imidazo[l,2-c]quinazolin-5yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2hydroxy-phenyl)-furan-2-yl]-met-(Z)-ylideno]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[ -(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrnidin-4-one (available from Axon Medchem XL-765 and XL-147) Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866; BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-13, 13 GNE-477, CUDC-907 and AEZS-136.

[0213] 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 its derivatives (e.g., U.S. Patent No. 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); lipid analogs of phosphatidylinositol ether (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).

[0214] mTOR inhibitors are known in the art and include, but are not limited to, competitive ATP inhibitors of mTORC1 / mTORC2, for example, PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also Petition 870250110544, dated 02 / 12 / 2025, page 212 / 563 207 / 539 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-epi-(tetrazolite)-rapamycin (also called ABT578); 32-desoxorapamycin; 16-pentiniloxy-32(S)dihydrorapamycin; derivatives disclosed in WO005 / 005434; derivatives disclosed in U.S. 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), as is RMC. 5552, having the structure

[0215] 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; Petition 870250110544, dated 02 / 12 / 2025, p. 213 / 563 208 / 539 D594H; F595L; G596D; G596R and A762E.

[0216] 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 tumor progression as well as resistance, not only to traditional chemotherapies but also to targeted therapies, including BCL-2 inhibitors such as ABT-263.

[0217] 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 several 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 binding network involving residues of the N-SH2 and PTP domains. Stimulation, for example, by cytokines or growth factors acting through receptor tyrosine kinases (RTKs), leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0218] SHP2 is involved in signaling via the mitogen-activated protein kinase Ras (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 Petition 870250110544, dated 02 / 12 / 2025, page 214 / 563 209 / 539 mutations destabilize the self-inhibited conformation of SHP2 and promote autoactivation or enhanced growth factor-driven activation of SHP2. 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., RMC4550 or SHP099) in combination with a RAS pathway inhibitor (e.g., a MEK inhibitor) has been shown to inhibit the proliferation of 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.

[0219] 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 orders: WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, 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 Petição 870250110544, de 02 / 12 / 2025, pág. 215 / 563 210 / 539 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 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584 , CN 115677661, CN 115677660, CN 115611869, CN 115521305, CN 115490697, CN 115466273, CN 115394612, CN 115304613, CN 115304612, CN 115300513,CN 115197225, CN 114957162, CN 114920759, CN 114716448, CN 114671879, CN 114539223, CN 114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN 113248521, CN 113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN 112409334,CN 112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN 110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US 11001561, US 10988466, US 10954243, US 10934302, or US 10858359, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer of the same, each of which is incorporated herein by reference.

[0220] 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 a site Petition 870250110544, dated 02 / 12 / 2025, p. 216 / 563 211 / 539 allosteric, 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 salt, solvate, isomer (e.g., stereoisomer), prodrug, or pharmaceutically acceptable tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC4550. In some embodiments, the SHP2 inhibitor is RMC-4630, with the structure: , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3068 having the 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 Petition 870250110544, dated 02 / 12 / 2025, page 217 / 563 212 / 539 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 structure or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601. In some embodiments, the SHP2 inhibitor is BBP-398.

[0221] 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 inhibitor of Petition 870250110544, dated 02 / 12 / 2025, page 218 / 563 213 / 539 SOS1. 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 lung cancer and the treatment comprises administering a Ras inhibitor 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 colorectal cancer and the treatment comprises the administration of a Ras inhibitor 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, a Ras inhibitor of the present invention is used in combination with immunotherapy, optionally in combination with a chemotherapeutic agent.

[0222] Proteasome inhibitors are known in the art and include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®) and oprozomib.

[0223] Immune 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 immunological therapies are known in the art.

[0224] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust responses Petition 870250110544, dated 02 / 12 / 2025, page 219 / 563 214 / 539 immunological) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide and apremilast).

[0225] Examples of 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.

[0226] FGFR inhibitors are known in the art, such as pemigatinib and erdafitinib, including FGFR2 inhibitors and FGFR4 inhibitors. See, for example, Cancers (Basel), 2021 Jun; 13(12) 2968.

[0227] BET inhibitors are known in the art, such as romidepsin, panobinostat, and belinostat. See, for example, British J. Cancer 124:1478 (2021).

[0228] PRMT5i inhibitors are known in the art, such as PF0693999, PJ-68 and MRTX1719. See, for example, Biomed. Pharmacotherapy 144:112252 (2021).

[0229] MAT2A inhibitors are known in the art, such as AG270 and IDE397. See, for example, Exp Opin Ther Patents (2022) DOI: 10.1080 / 13543776.2022.2119127.

[0230] GITR agonists 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. Patent No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or an anti-GITR antibody described, for example, in US Patent No. 7,025,962, EP 1947183, US Patent No. 7,812,135, US Patent No. 8,388,967, US Patent No. 8,591,886, US Patent No. 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. Petition 870250110544, dated 02 / 12 / 2025, page 220 / 563 215 / 539

[0231] 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., activation or inhibition of the receptor or enzyme) and thus promote cell death or halt cell growth. In some embodiments, one or more additional therapies include an antiangiogenic agent.

[0232] 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, EP100458 and US20090012085, and US Patents No. 5,863,949 and 5,861,510. Preferred inhibitors of MMP-2 and MMP-9 are those that have little or no activity inhibiting MMP-1. More 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. Petition 870250110544, dated 02 / 12 / 2025, page 221 / 563 216 / 539

[0233] Other exemplary anti-angiogenic agents include KDR (receptor kinase domain) inhibitors (e.g., antibodies and antigen-binding regions that bind specifically to the receptor kinase domain), 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, EGFR inhibitors (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 antigens). 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 antigen-binding regions or soluble antagonists of the TWEAK receptor; see US6,727,225), ADAM distintegrin domain to antagonize integrin binding to its ligands (US 2002 / 0042368), specifically binding to the anti-eph receptor or anti-ephrin antibodies or antigen-binding regions (US Patents Nos. 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 antagonists antiPDGF-BB (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 bind, Petition 870250110544, dated 02 / 12 / 2025, p. 222 / 563 217 / 539 specifically to the same). Additional antiangiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alfastatin (BioActa, UK); MPGA (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); alfa-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenic inhibitor (Trigen, UK); TBC1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA);Maspina (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); FR111142 (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); antiangiogenic derived from rBPI 21 and BPI (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; Petition 870250110544, dated 02 / 12 / 2025, p. 223 / 563 218 / 539 (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); VEGF-2 gene-based vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (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); plasminogen urokinase 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 Minnesota University, 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); Petition 870250110544, dated 02 / 12 / 2025, p. 224 / 563 219 / 539 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); irsogladine (Nippon Shinyaku, 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).

[0234] 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.

[0235] Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an inhibitor of Petition 870250110544, dated 02 / 12 / 2025, page 225 / 563 220 / 539 autophagy. 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, algal toxins, autophagy suppressive agents that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that elevate cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNAs that inhibit the expression of proteins 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.

[0236] Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an antineoplastic agent, already 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, dox or rubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine,issita, epirubicin, epoetin beta, etoposide phosphate, exemenenene, exeminide, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gentuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibadronic acid, idarubicin, Petition 870250110544, dated 02 / 12 / 2025, pp. 226 / 563 221 / 539 (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, 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 etidronate 186, RII retinamide, rituximab, romurtide, samarium (153 Sm), Lexidronam, Sargograma, sizofiran, sobuzoxaxan, Sonermin, sentox-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temosolomide, teniposide, tetrachloridecaoxide, thalidomide, timalfasin, 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 vaccine lysate, 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, gallocitabine, gastrin 17 immunogen, HLA-B7 gene therapy, Petition 870250110544, dated 02 / 12 / 2025, page 227 / 563 222 / 539 (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), Cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotypic MAb 105AD7 (CRC Technology), Idiotypic MAb CEA (Trilex), LYM-1-iodine 131 MAb (Clone Techni), yttrium polymorphic epithelial mucin 90 MAb (Antisoma), 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 tin, 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.,

[0237] 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 (Kadcila®); aflibercept (Eilea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (ADCETRIS®); canakinumab (Ilaris®); Certolizumab pegal (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab Petition 870250110544, dated 02 / 12 / 2025, page 228 / 563 223 / 539 (Prolia®); eculizumab (Soliris®); ephalizumab (Raptiva®); gentuzumabe ozogamycin (Milotarg®); golima (Symphony®); ibritumomabe thioxetane (Zevalin®); inflicts (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumuma (Arzerra®); omalizumab (Xolair®); palyvizumab (Synagis®); pertuzumab (Pearl®); pertuzuma (Pearl®); ranibizumab (Lucentis®); raxibacumabe (Abthrax®); tocilizumab (Actemra®); customers; tumorigenesis-131; toximab and toxoplasmomab-131 (Bexar®)); ustequinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0238] 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 being treated. Therefore, in some embodiments, one or more compounds of the disclosure 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, wherein both agents are present in separate formulations. In another alternative, a compound of the present disclosure may be administered and followed by any of the therapies described in this document, or vice versa. In some embodiments of the separate delivery protocol, a compound of the invention and any of the therapies... Petition 870250110544, dated 02 / 12 / 2025, p. 229 / 563 224 / 539 described in this document are administered with intervals of a few minutes, or a few hours, or a few days.

[0239] In some embodiments of any of the methods described in this document, the first therapy (for example, a compound of the 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 to 7, 1 to 14, 1 to 21 or 1 to 30 days before or after one or more additional therapies.

[0240] 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.

[0241] 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 Petition 870250110544, dated 02 / 12 / 2025, pp. 230 / 563 225 / 539 package with divided foil. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for the use of the separate components. The kit form 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. Examples

[0242] The disclosure is further illustrated by the following examples and summary examples, which should not be construed as limiting this disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that no limitation of the scope of this disclosure is intended hereby. It will also be understood that we may have recourse to 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 disclosure or the scope of the appended claims. Chemical Syntheses

[0243] The definitions used in the following examples and elsewhere here are: Table 3 CH2O2, DCM DCM dichloromethane or methylene chloride CH3CN, MeCN Acetonitrile CuI Copper(I) iodide DIPEA Diisopropylamine DMF N,N-Dimethylformamide EtOAc Ethyl acetate h hour H2O Water HCl Hydrochloric acid Petition 870250110544, dated 02 / 12 / 2025, pp. 231 / 563 226 / 539 K3PO4 Potassium phosphate (tribasic) MeOH Methanol Na2SO4 Sodium sulfate NMP N-methylpyrrolidone Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Instrumentation

[0244] Mass spectrometry data collection was performed using a Shimadzu LCMS-2020, an Agilent 1260LC-6120 / 6125MSD, a Shimadzu LCMS-2010EV, or a Waters Acquity UPLC, with a QDa or SQ Detector 2 detector. Samples were injected in their liquid phase into a C-18 reversed phase. Compounds were eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed using Agilent ChemStation, Shimadzu LabSolutions, or Waters MassLynx. NMR data were collected with a Bruker AVANCE III HD 400MHz, a Bruker Ascend 500MHz, or a Varian 400MHz instrument, and the raw data were analyzed with TopSpin or Mestrelab Mnova. Synthesis of Intermediates Intermediate 1. Synthesis of (2S)-2-{1-[(2S,3S)-1-(tert-butoxycarbonyl) 2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidin-3-yl]-N -methylformamido}-3methylbutanoic acid

[0245] Step 1. To a stirred solution of (benzyloxy)acetic acid Petition 870250110544, dated 02 / 12 / 2025, p. 232 / 563 227 / 539 (200 g, 1200 mmol) in DCM (2 L) was added to CDI (254 g, 1560 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. TEA (335 mL, 2410 mmol) and N,O-dimethylhydroxylamine hydrochloride (164 g, 1690 mmol) were then added at 0 °C and the reaction mixture was stirred for 1 h at room temperature. The resulting mixture was treated with 1M aqueous HCl solution (4 x 800 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(benzyloxy)-N-methoxy-N-methylacetamide (238 g, 85% yield) as a light yellow oil. LCMS (ESI) m / z: [M + H] calc. for C11H15NO3: 210.1; found 210.1.

[0246] Step 2. To a solution of dibenzylamine (177 g, 896 mmol) in DMF (500 mL) stirred at room temperature, tert-butyl 4-bromobutanoate (200 g, 896 mmol), K2CO3 (248 g, 1800 mmol) and KI (14.9 g, 90.0 mmol) were added. The resulting mixture was stirred for 2 hours at 80 °C. The reaction mixture was then cooled with H2O at room temperature, extracted with EtOAc (3 x 500 mL), treated with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield tert-butyl 4(dibenzylamino)butanoate (233 g, 71% yield) as a colorless oil. LCMS (ESI) m / z: [M + H] calc. for C11H15NO3: 340.2; found 340.2.

[0247] Step 3. To a stirred solution of DIPA (116 mL, 821 mmol) in dry THF (1.5 L) n-BuLi (328 mL, 821 mmol) was added dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C before being cooled again to -78 °C. Tert-Butyl 4(dibenzylamino)butanoate (186 g, 547 mmol) in dry THF (743 mL) was then added dropwise and the resulting mixture was stirred for 1 ha at -78 °C. 2(benzyloxy)-N-methoxy-N-methylacetamide (137 g, 657 mmol) in dry THF (550 mL) was then added dropwise and the resulting mixture was stirred for 1 ha at -78 °C. The reaction was then quenched with NH4Cl (500 mL), extracted with EtOAc (3 x 2 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Petition 870250110544, dated 02 / 12 / 2025, pp. 233 / 563 228 / 539 residue was purified by silica gel column chromatography to give tert-butyl 4-(benzyloxy)-2-[2-(dibenzylamino)ethyl]-3-oxobutanoate (168 g, 57% yield) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. for C31H37NO4: 488.3; found 488.3.

[0248] Step 4. To a solution of tert-butyl 4-(benzyloxy)-2-[2(dibenzylamino)ethyl]-3-oxobutanoate (168 g, 344 mmol) and Boc2O (90.1 g, 413 mmol) in THF (1.7 L) was added 10% Pd / C (83.9 g, 788 mmol). The mixture was hydrogenated at room temperature under 2.5 atm H2 for 18 hours, filtered through a Celite layer and concentrated under reduced pressure. The crude product (cis)-1,3-di-tert-butyl 2-[(benzyloxy)methyl]pyrrolidine-1,3-dicarboxylate (209 g, crude) was used in the next step directly without further purification. LCMS (ESI) m / z: [M + H] calc. for C22H33NO5: 392.2; found 392.2.

[0249] Step 5. To a stirred mixture of (cis)-1,3-di-tert-butyl 2[(benzyloxy)methyl]pyrrolidine-1,3-dicarboxylate (209 g, crude) in DMF (2 L) was added DBU (407 g, 2670 mmol) and the resulting mixture was stirred at 100 °C overnight. The reaction was quenched with H2O at room temperature, extracted with EtOAc (3 x 1 L), treated with brine (3 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (trans)-1,3-di-tert-butyl 2[(benzyloxy)methyl]pyrrolidine-1,3-dicarboxylate (109 g, 81% yield in 2 steps) as a light yellow oil. LCMS (ESI) m / z: [M + H] calc. for C22H33NO5: 392.2; found 392.2.

[0250] Step 6. To a solution of (trans)-1,3-di-tert-butyl-2[(benzyloxy)methyl]pyrrolidine-1,3-dicarboxylate (90 g, 230 mmol) in DCM (750 mL) was added TFA (250 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure and the residue was dissolved in a mixture of THF and H2O. To this mixture was added NaHCO3 (96.6 g, 1150 mmol) followed by Boc2O (100 g, 460 Petition 870250110544, dated 02 / 12 / 2025, pp. 234 / 563 229 / 539 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature before being concentrated under reduced pressure. The resulting aqueous mixture was washed with hexane (2 x 200 mL), acidified to pH = 6 with concentrated HCl, extracted with a 3:1 vol. DCM / i-PrOH mixture (3 x 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (trans)-2-[(benzyloxy)methyl]-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (109 g, crude) as a light red oil. LCMS (ESI) m / z: [M + H] calc. for C18H25NO5: 336.2; found 336.1.

[0251] Step 7. To a stirred mixture of (trans)-2[(benzyloxy)methyl]-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (109 g, crude) and HCl salt of methyl (2S)-3-methyl-2-(methylamino)butanoate (118 g, 650 mmol) in DMF (1 L) were added DIPEA (283 mL, 1630 mmol) and HATU (247 g, 650 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl trans-2-[(benzyloxy)methyl]3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (74 g, 70% yield in 2 steps) as a red oil. LCMS (ESI) m / z: [M + H] calc. for C25H38N2O6: 463.3; found 463.0.

[0252] Step 8. tert-Butyl trans-2-[(benzyloxy)methyl]-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (30.0 g, 65.0 mmol) was purified by prep-SFC to give tert-butyl (2S,3S)-2-[(benzyloxy)methyl]-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (13.0 g, 43% yield) as a yellow oil. LCMS (ESI) m / z: [M + H - 100] calc. for C25H38N2O6: 363.3; found 363.0.

[0253] Step 9. A mixture of tert-butyl (2S,3S)-2[(benzyloxy)methyl]-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (12.0 g, 25.9 mmol) and 10% Pd / C (12.0 Petition 870250110544, dated 02 / 12 / 2025, pages 235 / 563 230 / 539 g, 113 mmol) in a 9:1 vol. MeOH / AcOH mixture (100 mL) was stirred overnight at room temperature under a H2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the MeOH and the resulting mixture was basified to pH = 8 with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl(2S,3S)-2-(hydroxymethyl)-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (8.53 g, crude). LCMS (ESI) m / z: [M + H - Boc] calc. for C18H32N2O6: 272.2; found 272.9.

[0254] Step 10. To a stirred solution of tert-butyl(2S,3S)-2(hydroxymethyl)-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2yl](methyl)carbamoyl}pyrrolidine-1-carboxylate (8.53 g, crude), TEA (19.0 mL, 137 mmol) and DMAP (279 mg, 2.28 mmol) in DCM was added a solution of TsCl (19.6 g, 103 mmol) in DCM dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of H2O (50 mL) at 0 °C and then extracted with DCM (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2S,3S)-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (9.35 g, 69% yield in 2 steps) as a yellow solid. LCMS (ESI) m / z: [M + NH4] calc. for C25H38N2O8: 544.3; found 544.0.

[0255] Step 11. To a stirred solution of tert-butyl (2S,3S)-3{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (9.30 g, 17.7 mmol) in THF (75 mL) was added a solution of LiOH*H2O (2.22 g, 53.0 mmol) in H2O (15 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under pressure. Petition 870250110544, dated 02 / 12 / 2025, pp. 236 / 563 231 / 539 reduced to remove THF and the resulting mixture was diluted with H2O (10 mL), acidified to pH = 6 with aq. HCl, extracted with a 3:1 vol. DCM / i-PrOH mixture (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2S)-2-{1-[(2S,3S)-1-(tert-butoxycarbonyl)-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidin-3-yl]-N-methylformamido}-3-methylbutanoic acid (9.62 g, crude), which was used in the next step directly without further purification. LCMS (ESI) m / z: [M + NH4] calc. for C24H36N2O8: 530.3; found 530.3. Intermediate 1. Alternative Synthesis by Chiral Resolution Pd / C, H2MeOH, rt toluene, 140 °C to 25 °C HATU, MeCN / DMF, 0eC TsCI, TEA, DMAP DCM, rt Pd / C, H2THF, rt

[0256] Step 1. To a stirred solution of (cis)-1,3-di-tert-butyl 2[(benzyloxy)methyl]pyrrolidine-1,3-dicarboxylate (130 g, 332 mmol) in THF (570 mL) were added MeOH (260 mL) and LiOH^H2O (41.8 g, 996 mmol) in H2O (260 mL) at room temperature under a N2 atmosphere. The resulting mixture was stirred at 40 °C for 24 h. Four such reactions were carried out in parallel on the same scale. These four reaction mixtures were combined and extracted with petroleum ether (2 x 3 L), washed with 1M aq. LiOH (2 x 2 L), acidified to pH = 3 with aq. HCl. 1M, extracted with EtOAc (3 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-[(benzyloxy)methyl]-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (414 g, 93% yield) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C18H25NO5: 336.2; found 336.2.

[0257] Step 2. To a stirred solution of 2-[(benzyloxy)methyl acid] Petition 870250110544, dated 02 / 12 / 2025, pp. 237 / 563 232 / 539 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (207 g, 617 mmol) in MeOH (2 L) was added to 10 wt% Pd / C (80.1 g) in portions at room temperature. The resulting mixture was stirred for 16 hours at room temperature under a H2 atmosphere (10 atm). Two such reactions were carried out in parallel on the same scale. The two resulting mixtures were combined and then filtered. The filter cake was washed with MeOH (3 x 1 L) and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography to give 1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (266 g, 88% yield) as a white solid. LCMS (ESI) m / z: [2M + Na] calc. for C11H19NO5: 513.2; found 513.3.

[0258] Step 3. To a stirred mixture of 1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (26.6 g, 108 mmol) in toluene (1460 mL) was added (R)-[(2S,4R,5S)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl](6-methoxyquinolin-4-yl)methanol (35.2 g, 108 mmol) in portions at room temperature under a N2 atmosphere. The resulting mixture was stirred for 5 min at room temperature. The mixture was then heated to 140 °C and stirred under reflux for 1 min, and then cooled to 25 °C and stirred for 14 h. Ten of these reactions were carried out in parallel on the same scale. The ten resulting mixtures were then combined and filtered. The filtrate was concentrated under reduced pressure, dissolved in THF (1 L), basified to pH = 8 with 1N aqueous NaOH solution, extracted with n-hexane (1 x 1 L) and subsequently extracted with EtOAc (3 x 500 mL). The aqueous mixture was acidified to pH = 3 with 0.5M HCl and extracted with EtOAc (10 x 2 L).The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (2R,3R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (120 g, >99% ee, 45% yield) as a colorless oil. LCMS (ESI) m / z: [2M + Na] calc. for C11H19NO5:. Petition 870250110544, dated 02 / 12 / 2025, pp. 238 / 563 233 / 539 513.2; found 513.2.

[0259] The filter cake left over was washed with i-PrOAc (130 mL) and then diluted with ice water (300 mL). The resulting aqueous mixture was treated with 0.5M aq. HCl (700 mL), basified to pH 8 with 1 N aq. NaOH (1000 mL) and extracted with i-PrOAc (3 x 700 mL). The remaining aqueous mixture was acidified to pH = 3 with 0.5M aq. HCl, treated with NaCl (500 g), extracted with EtOAc (10 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2S,3S)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (120 g, 95.1% ee, 45% yield) as a colorless oil. LCMS (ESI) m / z: [2M + Na] calc. for C11H19NO5: 513.2; found 513.2.

[0260] Step 4. To a stirred mixture of (2S,3S)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (35.0 g, 143 mmol) and benzyl (2S)-3-methyl-2-(methylamino)butanoate (56.8 g, 257 mmol) in MeCN (500 mL) were added 2,6-lutidine (153 g, 1430 mmol) and a solution of HATU (81.4 g, 214 mmol) in MeCN (200 mL) and DMF (70 mL) at -5 °C under an argon atmosphere. The reaction mixture was stirred for 2 h at 0 °C before being cooled with H2O (3 L). The resulting mixture was extracted with EtOAc (3 x 1 L), washed with brine (3 x 1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give tert-butyl(2S,3S)-3-{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (42.0 g, 66% yield) as a light yellow oil. LCMS (ESI) m / z: [M + Na] calc. for C24H36N2O6: 471.3; found 471.3.

[0261] Step 5. To a stirred solution of tert-butyl(2S,3S)-3{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2(hydroxymethyl)pyrrolidine-1-carboxylate (73.0 g, 163 mmol) in DCM (600 mL) was added TEA (82.3 g, 814 mmol) followed by a solution of TsCl (40.3 g, 212 mmol) in DCM (100 mL) at -5 °C under an argon atmosphere. The mixture Petition 870250110544, dated 02 / 12 / 2025, p. 239 / 563 234 / 539 of the reaction was stirred for 16 hours at 25 °C and then quenched with H2O (1 L). The mixture was acidified to pH = 6 with 1 N aqueous HCl, extracted with DCM (3 x 700 mL), treated with brine (3 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(2S,3S)-3-{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine1-carboxylate (81.0 g, 78% yield) as a light yellow solid. LCMS (ESI) m / z: [M + Na] calc. for C31H42N2O8S: 625.3; found 625.3.

[0262] Step 6. To a stirred solution of tert-butyl (2S,3S)-3{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (87.0 g, 144 mmol) in THF (870 mL) was added 10 wt% of Pd / C (40 g) at room temperature. The reaction mixture was stirred for 16 h at 25 °C under a H2 atmosphere. The resulting mixture was then filtered and the filter cake was washed with MeOH (3 x 500 mL). The filtrate was concentrated under reduced pressure to give (2S)-2-{1-[(2S,3S)-1-(tert-butoxycarbonyl)-2{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidin-3-yl]-N-methylformamido}-3-methylbutanoic acid (71.0 g, 96% yield) as a whitish solid. LCMS (ESI) m / z: [2M + H] calc. for C24H36N2O8S: 1025.5; found 1025.3. Intermediate 1. Alternative Synthesis through the Use of Chiral Pool Starting Material Petition 870250110544, dated 02 / 12 / 2025, pp. 240 / 563 235 / 539

[0263] Step 1. To a solution of β-benzyl ester of N-(tert-butyloxycarbonyl)-L-aspartic acid (4.50 kg, 13.9 mol) in DCM (22.5 L) stirred at 0 °C under a N2 atmosphere, DIPEA (2.16 kg, 16.7 mmol) was added followed by TfOMe (2.74 kg, 16.7 mmol). The resulting mixture was stirred for 1 h at 20 °C. The reaction was quenched by the addition of 0.5M aq. HCl (11.2 L) and then washed with H2O (3 x 11.2 L). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting concentrated solution was treated with petroleum ether, stirred at 20 °C for 30 min, and filtered. The filter cake was washed with petroleum ether and then dried under reduced pressure to yield 1-methyl 4-(phenylmethyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-aspartate (4.76 kg, crude) as a white solid. LCMS (ESI) m / z: [M + Na] calc. for C17H23NO6: 360.1; found 359.9.

[0264] Step 2. To a solution of 1-methyl 4-(phenylmethyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-aspartate (1.50 kg, crude) in THF (12 L) stirred at -75 °C under a N2 atmosphere, KHMDS (11.1 L, 1 M in THF) was added, followed by HMPA (1.20 kg, 6.67 mol) and then 3-bromoprop-1-ene (807 g, 6.67 mol). The reaction mixture was stirred at -75 °C for 2 h. The mixture was then diluted with EtOAc, treated with a 30% aqueous citric acid solution, and stirred for 30 min at 20 °C. The aqueous layer was subsequently extracted with EtOAc, treated with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-methyl 4(phenylmethyl)-(3S)-N-[(1,1-dimethylethoxy)carbonyl]-3-(2-propen-1-yl)-L-aspartate (908 g, 85.1% purity, 47% yield in 2 steps) as a brown oil. LCMS (ESI) m / z: [M + H] calcd for C20H27NO6: 378.2; found 378.2.

[0265] Step 3. To a solution of 1-methyl 4-(phenylmethyl)-(3S)-N [(1,1-dimethylethoxy)carbonyl]-3-(2-propen-1-yl)-L-aspartate (2.00 kg, 5.30 mol) Petition 870250110544, dated 02 / 12 / 2025, pp. 241 / 563 236 / 539 in MeOH (20 L) and H2O (8 L) stirred at 15 °C under a N2 atmosphere were added K2OsO4*2H2O (19.5 g, 53.0 mmol) and NaIO4 (3.40 kg, 15.9 mol). The reaction mixture was stirred at room temperature for 12 h and then filtered. The filter cake was washed with MeOH and the filtrate was quenched with 1M aqueous HCl, treated with saturated aqueous Na2SO3 and concentrated under reduced pressure to remove MeOH. The resulting mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 3-benzyl-1-(tert-butyl)-2-methyl-(2S,3S)-5-hydroxypyrrolidine-1,2,3-tricarboxylate (1.79 kg, crude) as a brown oil. LCMS (ESI) m / z: [2M + Na] calc. for C19H25NO7: 781.3; found 781.4.

[0266] Step 4. To a solution of 3-benzyl-1-(tert-butyl)-2-methyl(2S,3S)-5-hydroxypyrrolidine-1,2,3-tricarboxylate (2.00 kg, crude) in DCM (20 L) stirred at room temperature, Et3SiH (919 g, 7.91 mol) was added under an N2 atmosphere. TFA (1.80 kg, 15.8 mol) was then added dropwise at 15 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction was then quenched by dropwise addition of saturated aqueous NaHCOa at 15 °C, and the resulting organic phase was washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to give 3-benzyl-1-(tert-butyl)-2-methyl-(2S,3S)-pyrrolidine-1,2,3-tricarboxylate (945 g, 69.4% purity, 44% yield in 2 steps) as a yellow oil. LCMS (ESI) m / z: [2M + Na] calc. for C19H25NO6: 749.3; found 749.3.

[0267] Step 5. A mixture of 20% Pd(OH)2 (12.0 g) in MeOH (500 mL) was added to a solution of 3-benzyl-1-(tert-butyl)-2-methyl(2S,3S)-pyrrolidine-1,2,3-tricarboxylate (120 g, 330 mmol) in MeOH (500 mL) under an argon atmosphere. The reaction was then placed under 45 psi of H2 and stirred at room temperature for 16 h. The mixture was then filtered through earth Petition 870250110544, dated 02 / 12 / 2025, pp. 242 / 563 237 / 539 diatomaceous earth and the filtered cake was washed with MeOH. The filtrate was concentrated under reduced pressure to yield (2S,3S)-1-(tert-butoxycarbonyl)-2(methoxycarbonyl)pyrrolidine-3-carboxylic acid (90 g, 78.0% purity, 78% yield) as a yellow oil. LCMS (ESI) m / z: [M - Boc + 2H] calc. for C12H19NO6: 174.1; found 174.1.

[0268] Step 6. To a solution of (2S,3S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (180 g, 659 mmol) in THF (1.8 L) stirred at 0 °C under a N2 atmosphere, LiBH4 (2 M in THF, 494 mL) was added. The reaction mixture was stirred at 50 °C for 13 h. The mixture was then cooled to 0 °C and tempered with H2O, adjusted to pH = 4 by the addition of 1 M aqueous HCl and diluted with brine. The aqueous layer was subsequently extracted with EtOAc and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2S,3S)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (135 g, crude) as a white solid. This material was taken directly to the next step without further purification.

[0269] Step 7. To a solution of (2S,3S)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3-carboxylic acid (285 g, 1.16 mol) in MeCN (2.3 L) and DMF (0.3 L) was added the HCl salt of the benzyl ester of N-methyl-L-valine (119 g, 0.465 mol). This mixture was cooled to 0 °C under a N2 atmosphere and 2,6-lutidine (622 g, 5.81 mol) was added, followed by HATU (442 g, 1.16 mol). The reaction mixture was stirred for 2 hours at 0 °C. The reaction was quenched by the addition of brine and the organic extract was subsequently treated with brine. Combined aqueous solutions were extracted with EtOAc, concentrated under reduced pressure, and purified by reversed-phase flash column chromatography to provide tert-butyl (2S,3S)-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2 Petition 870250110544, dated 02 / 12 / 2025, pp. 243 / 563 238 / 539 il](methyl)carbamoyl}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (120 g, 19% yield in 2 steps) as a white solid. LCMS (ESI) m / z: [M + Na] calc. for C24H36N2O6: 471.3; found 471.2.

[0270] Step 8. To a stirred solution of (2S,3S)-3-{[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (168 g, 375 mmol) in DCM (1.7 L) were added TEA (190 g, 1870 mmol) followed by a solution of TsCl (92.8 g, 487 mmol) in DCM (1.7 L) dropwise at -5 °C under an Ar gas atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was then diluted with water, acidified to pH = 6 with 1 M aqueous HCl, extracted with DCM, treated with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(2S,3S)-3-{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (216 g, 93% purity, 89% yield) as a light yellow solid. LCMS (ESI) m / z: [M + Na] calc. for C31H42N2O5S: 625.3; found 625.2.

[0271] Step 9. To a stirred solution of tert-butyl(2S,3S)-3{[(2S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl](methyl)carbamoyl}-2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (216 g, 93% purity, 333 mmol) in THF (2 L) was added 10% by weight of Pd / C (100 g) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature under an H2 gas atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain (2S)-2-{1-[(2S,3S)-1-(tert-butoxycarbonyl)-2{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidin-3-yl]-N-methylformamido}-3-methylbutanoic acid (170 g, 91.6% purity, 91% yield) as a whitish solid. LCMS (ESI) m / z: [M + Na] calc. for C31H42N2O5S: 535.2; Petition 870250110544, dated 02 / 12 / 2025, pp. 244 / 563 239 / 539 found 535.3. Intermediate 2. Synthesis of tert-butyl (2 S ,3 S )-2-ethynyl-3-(methyl(( S )-3-methyl-1 oxo-1-(2-(trimethylsilyl)ethoxy)butan-2-yl)carbamoyl)pyrrolidine-1-carboxylate BoczBoczBoczBocz BoczBocz

[0272] Step 1. To a solution of tert-butyl(2S,3S)-2((benzyloxy)methyl)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (9.0 g, 19 mmol) in MeOH (81 mL) and acetic acid (9.0 mL) at room temperature, Pd / C (9 g) was added. The resulting mixture was stirred overnight under an H2 atmosphere, filtered, and the filter cake washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (2S,3S)-2-(hydroxymethyl)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (6.8 g, crude), which was carried directly to the next reaction without further purification. LCMS (ESI) m / z: [M + Na] calculated for C18H32N2O6: 395.2; found 395.2.

[0273] Step 2. To a solution of tert-butyl(2S,3S)-2(hydroxymethyl)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (6.8 g, crude) in MeCN (70 mL) at 0 °C was added Dess-Martin periodinan (17.8 g, 41.9 mmol). The resulting mixture was stirred for 4 h at 0 °C and then cooled by the addition of an aqueous Na2S2O3 solution. The aqueous mixture was extracted with DCM (3 x 100 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide tert-butyl(2S,3S)-2-formyl-3(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate Petition 870250110544, dated 02 / 12 / 2025, pp. 245 / 563 240 / 539 (4.0 g, crude) which was used in the next reaction without further purification. LCMS (ESI) m / z: [M + H - 100] calc. for C18H30N2O6: 271.2; found 271.1.

[0274] Step 3. To a solution of tert-butyl(2S,3S)-2-formyl-3(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (3.8 g, crude) and K2CO3 (1.70 g, 12.3 mmol) in MeOH (40 mL) at 0 °C was added dimethyl(1-diazo-2-oxopropyl)phosphonate (1.97 g, 10.3 mmol). The resulting mixture was stirred for 3 hours at 0 °C and then quenched with an aqueous layer that was separated and extracted with H2O. The aqueous mixture was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reversed-phase chromatography yielded tert-butyl(2S,3S)-2-ethynyl-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.44 g, 33% yield in 3 steps) as a yellow solid. LCMS (ESI) m / z: [2M + NH4] calculated for C19H30N2O5: 750.4; found 750.5.

[0275] Step 4. To a solution of tert-butyl(R)-4-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-3-methylpiperazine-1-carboxylate (700 mg, 1.88 mmol) in THF (0.5 mL) and H2O (0.5 mL) at 0°C, LiOH*H2O (550 mg, 13.1 mmol) was added. The resulting mixture was stirred for 2 h at room temperature and then acidified to pH = 5 with 1M aqueous HCl. The aqueous mixture was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide N-((2S,3S)-1-(tert-butoxycarbonyl)-2-ethynylpyrrolidine-3-carbonyl)-N-methylL-valine (2.0 g, crude) which was used in the next reaction without further purification. LCMS (ESI) m / z: [M + H] calc. for C18H28N2O5: 353.2; found 353.1.

[0276] Step 5. To a solution of N-((2S,3S)-1-(tert-butoxycarbonyl)-2-ethynylpyrrolidine-3-carbonyl)-N-methylL-valine (1.98 g, crude) and 2-(trimethylsilyl)ethanol (1.33 g, 11.2 mmol) in DCM (20 mL) at 0 °C were added Petition 870250110544, dated 02 / 12 / 2025, pp. 246 / 563 241 / 539 EDCI (2.15 g, 11.2 mmol) and DMAP (690 mg, 5.61 mmol). The resulting mixture was stirred for 1 h at room temperature and then cooled to 0 °C by the addition of H2O. The aqueous mixture was extracted with DCM (3 x 30 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by reversed-phase chromatography yielded tert-butyl(2S,3S)-2-ethynyl-3-(methyl((S)-3-methyl-1-oxo-1-(2-(trimethylsilyl)ethoxy)butan-2yl)carbamoyl)pyrrolidine-1-carboxylate (1.95 g, 45% yield over 2 steps) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. for C23H40N2O5Si: 453.3; found 453.2. Intermediate 3. Synthesis of N-((2R,3S)-1-(tert-butoxycarbonyl)-2-vinylpyrrolidine-3-carbonyl)-N-methyl-L-valine / 0 / 0 Lindlar Catalyst ---'xJ / Pyridine,H2 O °Li0HO °” toluene, rt thf / h2o,oc Boc boczN

[0277] Step 1. To a solution of tert-butyl(2S,3S)-2-ethynyl-3-(((S)1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (7.0 g, 19.1 mmol) and pyridine (1.51 g, 19.1 mmol) in toluene (140 mL) was added Lindlar catalyst (7.0 g). The resulting mixture was stirred for 2 h at room temperature under an H2 atmosphere, filtered, and the solid retained on the filter was washed with MeOH (10 x 10 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl(2R,3S)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2yl)(methyl)carbamoyl)-2-vinylpyrrolidine-1-carboxylate (6.87 g, crude) which was used in the next reaction without further purification. LCMS (ESI) m / z: [M + NH4] calc. for C19H32N2O5: 368.2; found 368.3.

[0278] Step 2. To a solution of tert-butyl (2R,3S)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-vinylpyrrolidine-1-carboxylate (2.35 g, 6.38 mmol) in THF (30 mL) and H2O (10 mL) was added LiOH·H2O (540 mg, 12.8 mmol). The resulting mixture was stirred for 3 hours at 0 °C, concentrated Petition 870250110544, dated 02 / 12 / 2025, pp. 247 / 563 242 / 539 under reduced pressure and the concentrate acidified to pH = 5 with 1M aqueous HCl. The aqueous mixture was extracted with DCM (3 x 15 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide N-((2R,3S)-1-(tert-butoxycarbonyl)-2-vinylpyrrolidine-3carbonyl)-N-methyl-L-valine (2.36 g, crude) which was used in subsequent reactions without further purification. LCMS (ESI) m / z: [M + Na] calc. for C18H30N2O5: 377.2; found 377.2. Intermediate 4. Synthesis of tert-butyl (12S,13S,6S,9S)-45-iodo-9-isopropyl-6((S)-3-(methoxycarbonyl)hexahydropyridazine-1-carbonyl)-10-methyl-8,11dioxo-3-oxa-7,10-diaza-1(2,3)-pyrrolidine-4(1,3)-benzenecycloundecaphane-11-carboxylate

[0279] Step 1. To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-iodo-5-((triisopropylsilyl)oxy)phenyl)propanoate (5.0 g, 8.7 mmol) in DMF (50 mL) at 0 °C, CsF (6.58 g, 43.3 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature and cooled to 0 °C by the addition of H2O (50 mL). The aqueous mixture was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with brine (3 x 100 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(3-hydroxy-5-iodophenyl)propanoate (5.02 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C15H20INO5: 322.0; found 322.0.

[0280] Step 2. To a solution of methyl (S)-2-(( tert-) Petition 870250110544, dated 02 / 12 / 2025, page 248 / 563 243 / 539 butoxycarbonyl)amino)-3-(3-hydroxy-5-iodophenyl)propanoate (4.97 g, crude) in DCM (50 mL) at 0 °C was added TFA (10 mL). The resulting mixture was stirred for 1 h at room temperature and basified to pH 8 by the addition of saturated aqueous NaHCO3. The aqueous phase was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield methyl(S)-2-amino-3-(3-hydroxy-5-iodophenyl)propanoate (4.01 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C10H12INO3: 322.0; found 322.0.

[0281] Step 3. To a solution of methyl (S)-2-amino-3-(3-hydroxy-5-iodophenyl)propanoate (2.0 g, 6.2 mmol) in DMF (20 mL) at 0 °C were added DIPEA (43.4 mL, 249 mmol), N-((2S,3S)-1-(tert-butoxycarbonyl)-2((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl-L-valine (4.15 g, 8.10 mmol) and COMU (3.47 g, 8.10 mmol). The resulting mixture was stirred for 1 h at -10 °C, tempered to -10 °C by the addition of H2O (20 mL) and neutralized by the addition of 1M aq. HCl. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification by normal-phase chromatography yielded tert-butyl (2S,3S)-3-(((S)-1-(((S)-3-(3hydroxy-5-iodophenyl)-1-methoxy-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.60 g, 74% yield in 3 steps) as a yellow solid. LCMS (ESI) m / z: [M + NH4] calc.for C34H46IN3O10S: 833.2; found 833.2.

[0282] Step 4. To a solution of tert-butyl(2S,3S)-3-(((S)-1-(((S)3-(3-hydroxy-5-iodophenyl)-1-methoxy-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.83 g, 2.24 mmol) in DMF (183 mL), K2CO3 (3.10 g, 22.4 mmol) and KI (372 mg, 2.24 mmol) were added. The resulting mixture was stirred for 2 hours at 80 °C and cooled to 0 °C by the addition of H2O (100 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). Petition 870250110544, dated 02 / 12 / 2025, pp. 249 / 563 244 / 539 mL) and the combined organic extracts were washed with brine (3 x 400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by normal-phase chromatography yielded 11-(tert-butyl) 6-methyl(12S,13S,6S,9S)-45-iodo-9-isopropyl-10-methyl-8,11-dioxo-3-oxa-7,10-diaza1(2,3)-pyrrolidine-4(1,3)-benzenecycloundecaphane-11,6-dicarboxylate (1.04 g, 66% yield) as a yellow solid. LCMS (ESI) m / z: [M + NH4] calculated for C27H38IN3O7: 661.2; found 661.1.

[0283] Step 5. To a solution of 11-(tert-butyl) 6-methyl (12S,13S,6S,9S)-45-iodo-9-isopropyl-10-methyl-8,11-dioxo-3-oxa-7,10-diaza1-(2,3)-pyrrolidine-4(1,3)-benzenecycloundecaphane-11,6-dicarboxylate (1.04 g, 1.61 mmol) in THF (6.0 mL) at 0 °C was added a solution of LiOH*H2O (135 mg, 3.22 mmol) in H2O (6.0 mL). The resulting mixture was stirred for 1.5 h at 0 °C and acidified to pH 6 by the addition of 1M aqueous HCl. The aqueous mixture was extracted with EtOAc (3 x 50 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide (12S,13S,6S,9S)-11-(tert-butoxycarbonyl)-45-iodo-9-isopropyl-10-methyl-8,11-dioxo-3-oxa-7,10-diaza-1(2,3)-pyrrolidine-4(1,3)benzenecycloundecaphane-6-carboxylic acid (1.27 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + NH4] calc. for C26H36IN3O7: 647.2; found 647.1.

[0284] Step 6. To a solution of (12S,13S,6S,9S)-11-(tert-butoxycarbonyl)-45-iodo-9-isopropyl-10-methyl-8,11-dioxo-3-oxa-7,10-diaza-1(2,3)pyrrolidine-4(1,3)-benzenecycloundecaphane-6-carboxylic acid (1.15 g, crude) in DMF (15 mL) at 0 °C was added DIPEA (3.2 mL, 18.3 mmol), methyl(S)hexahydropyridazine-3-carboxylate bis(trifluoroacetate) (1.36 g, 3.65 mmol) and HATU (1.39 g, 3.65 mmol). The resulting mixture was stirred for 1 h at room temperature, cooled to 0 °C by the addition of H2O (20 mL), and acidified to pH 6 by the addition of 1M aqueous HCl. The aqueous mixture was extracted with EtOAc (3 x 20 mL) Petition 870250110544, dated 02 / 12 / 2025, pp. 250 / 563 245 / 539 mL), and the combined organic extracts were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by normal-phase chromatography yielded tert-butyl (12S,13S,6S,9S)-45-iodo-9-isopropyl-6-((S)-3(methoxycarbonyl)hexahydropyridazine-1-carbonyl)-10-methyl-8,11-dioxo-3-oxa-7,10diaza-1(2,3)-pyrrolidine-4(1,3)-benzenecycloundecaphane-11-carboxylate (1.10 g, 72% yield in 2 steps) as a light yellow solid. LCMS (ESI) m / z: [M + NH4] calc. for C32H46IN5O8: 773.3; found 773.3. Intermediate 5. Synthesis of tert-butyl ((63S,4S)-12-(5-(4cyclopropylpiperazin-1-yl)-2-((S )-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H 8-oxa-1 (5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundephane-4- yl)carbamate

[0285] Step 1. To a solution of benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1 carboxylate (60.0 g, 90.4 mmol) and methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3 Petition 870250110544, dated 02 / 12 / 2025, pp. 251 / 563 246 / 539 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((tri-isopropylsilyl)oxy)phenyl)propanoate (78.3 g, 136 mmol) in toluene (600 mL) were added K3PO4 (57.6 g, 271 mmol) and Pd(dppf)Cl2*CH2Cl2 (7.36 g, 9.04 mmol). The mixture was stirred overnight at 70 °C under a nitrogen atmosphere and then extracted with EtOAc (3 x 200 mL). The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzyl 4-(5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (92.8 g, 90%) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for CsgHsaNõOgSi: 1034.6; found 1034.7.

[0286] Step 2. A solution of benzyl 4-(5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (92.8 g, 89.7 mmol) and LiOH (3.87 g, 161 mmol) in H2O (1000 mL) and THF (1000 mL) was stirred overnight at 0 °C. The resulting mixture was concentrated under reduced pressure and acidified to pH = 5 with 1M HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (2S)-3-{3-[(2M)-2-(5-{4[(benzyloxy)carbonyl]piperazin-1-yl}-2-[(1S)-1-methoxyethyl]pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl]-5-[(tri-isopropylsilyl)oxy]phenyl}-2-[(tert-butoxycarbonyl)amino]propanoic acid (92.8 g, crude) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C58H81N5O9Si: 1020.6; found 1020.7.

[0287] Step 3. To a stirred solution of (2S)-3-{3-[(2M)-2-(5{4-[(benzyloxy)carbonyl]piperazin-1-yl}-2-[(1S)-1-methoxyethyl]pyridin-3-yl)-1-ethyl-3-(3hydroxy-2,2-dimethylpropyl)indol-5-yl]-5-[(triisopropylsilyl)oxy]phenyl}-2-[(tert-butoxycarbonyl)amino]propanoic acid (91.8 g, 90.0 mmol), DIPEA (116 g, 900 mmol) and methyl (S)-hexahydropyridazine-3-carboxylate (19.5 g, 135 mmol) in DMF (1000 mL) was added HATU (68.4 g, 180 mmol) in 0 portions °C. The resulting mixture was Petition 870250110544, dated 02 / 12 / 2025, pp. 252 / 563 247 / 539 was stirred for 2 h at room temperature and then diluted with deionized H2O (2 L). The resulting mixture was extracted with ethyl acetate (3 x 2 L), washed with brine (3 x 4 L) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound methyl (S)-1-((S)-3-(3-(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)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3carboxylate (94.6 g, 92%) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C64H9iN70ioSi: 1146.7; found 1146.9.

[0288] Step 4. A solution of (S )-1-(( S )-3-(3-(2-(5-(4((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy2,2-dimethylpropyl) -1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tertbutoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (110 g, 95.9 mmol) and LiOH (2.76 g, 115 mmol) in THF (900 mL) and H2O (300 mL) was stirred overnight at 0°C. The resulting mixture was concentrated under reduced pressure, acidified to pH = 5 with 1M HCl (aq.) and extracted with EtOAc (3 x 500 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (S)-1-((S)-3-(3-(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)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (106 g, crude) as a yellow solid. LCMS (ESI) m / z: [M + H] calc.for C63H89N7OwSi: 1132.6; found 1132.7.

[0289] Step 5. To a stirred solution of (S)-1-((S)-3-(3-(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)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (106 g, 93.2 mmol) and DIPEA (482 g, 3730 mmol) in DCM (10 L) were added HOBT (126 g, 932 Petition 870250110544, dated 02 / 12 / 2025, pp. 253 / 563 248 / 539 mmol) and EDCI (536 g, 2800 mmol) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure and diluted with DCM (3 L). The resulting solution was washed with brine and treated with 1M aqueous HCl (2 x 4 L), neutralized with saturated aqueous NaHCO3 (4 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzyl 4-(5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((tri-isopropylsilyl)oxy)61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphano-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (68.9 g, 63%) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C63H87N? O9Si: 1114.6; found 1115.0.

[0290] Step 6. A solution of benzyl 4-(5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (58.7 g, 52.7 mmol) and Pd(OH)2 / C (30.0 g, 214 mmol) in MeOH (500 mL) was stirred for 3 h at room temperature under an H2 atmosphere. The resulting mixture was filtered and the filtrate cake was washed with MeOH (3 x 200 mL). The filtrate was then concentrated under reduced pressure to give tert-butyl((63S,4S)11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7dioxo-25-((tri-isopropylsilyl)oxy)-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 (61.4 g, crude) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C55H8iN7O?Sí: 980.6; found 980.7.

[0291] Step 7. To a solution of tert-butyl ((63S,4S)-11-ethyl-12-(2((S)-1-methoxyethyl)-5-(piperazin-1 -yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-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 (25.2 g, 25.7 mmol), Petition 870250110544, dated 02 / 12 / 2025, pp. 254 / 563 249 / 539 (l-ethoxycyclopropoxy)trimethylsilane (11.4 g, 65.5 mmol) and AcOH (3.09 g, 51.4 mmol) in MeOH (250 mL) was added to NaBH3CN (3.23 g, 51.4 mmol) at 0 °C. The mixture was stirred overnight at 60 °C under a N2 atmosphere, basified to pH = 8 with saturated aqueous NaHCO3, and concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate (3 x 150 mL) and the combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to provide tert-butyl ((63S,4S)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((tri-isopropylsilyl)oxy)61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphano-4-yl)carbamate (19.3 g, 74% yield) as white solid. LCMS (ESI) m / z: [M + H] calc. for CõsHsõNyOySi: 1020.6; found 1021.3. Intermediate 6. Synthesis of tert-butyl (3a S ,6 S ,9 S ,15 S ,32a S )-21-(5-(4cyclopropylpiperazine-1-yl)-2-(( S )-1-methoxyethyl)pyridine-3-yl)-22-l9,ethylprop15-trimethy9,1-iso -4,7,10,16-tetraoxo2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1 H,12 H 11,15-epimino-23,25-ethene-9,28-methane-26,30-(methene)dipyrrole[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontine-1 -carboxylate Ok ek -zN.^O % N 1 H 1 Y^NHBoc MeO Jr— ,χΛχ, MeO V— r X Γ Í1 C«FN— / DMF, rt N—3 O-pju lips ç y—N / ~NN—' N—' <f <f Ox ,O 7 AaX —°x Jr Y N—< fY-íYÇA K2COS· Kl / / 'z DMF·80c )= / / r> N—'

[0292] Step 1. f''! °\\ ? o Not one. zN.(V ..kzN_x>O ΥΆ.-4, NNV HO NX_ 1 Η 1 ' Η 1 OY^NHBoc / ° r*NH2 I' N 1 1 2 T.0 Boc xjíYs, Meo jç- X— < \ rj] dipe |Γ] < X . Ζ·'-χ··ΖΖΐ:^ zl Λ I· XN—Z, rt N—γ JJ J 1,4-dioxane, rt / / V—]j J < N'''Y-ί^ y—N <( °γθν° 0 1 ηΑα ry> Uma p° / H—Bo\o tert-butyl solution ((63S,4S)-12-(5-(4- Petition 870250110544, dated 02 / 12 / 2025, pp. 255 / 563 250 / 539 cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7dioxo-25-((tri-isopropylsilyl)oxy)-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 (10.0 g, 9.80 mmol) in DMF (100 mL) was treated with CsF (7.44 g, 49.000 mmol) for 1 h at room temperature. The reaction was quenched with H2O at 0 °C. The resulting mixture was then extracted with EtOAc (3 x 150 mL), washed with brine (3 x 150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl((63S,4S)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-25-hydroxy-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)carbamate (8.68 g, crude) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C49H65N7O7: 864.5; found 854.4.

[0293] Step 2. To a stirred solution of tert-butyl ((63S,4S)-12(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-25-hydroxy-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 (8.68 g, crude) in 1,4-dioxane (40 mL) was added dropwise a solution of HCl (40 mL, 4.0 M in 1,4-dioxane) at 0 °C. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give (63S,4S)-4-amino-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3yl)-11-ethyl-25-hydroxy-10,10-dimethyl-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 (9.7 g, crude) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C44H57N7O5: 764.4; found 764.1.

[0294] Step 3. To a solution under stirring of (63S,4S)-4-amino12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-25hydroxy-10,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3) Petition 870250110544, dated 02 / 12 / 2025, page 256 / 563 251 / 539 pyridazine-2(1,3)-benzenecycloundecaphane-5,7-dione (5.66 g, crude) in DMF (60 mL) were added DIPEA (38.3 g, 296 mmol), N-((2S,3S)-1-(tert-butoxycarbonyl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-valine (3.80 g, 7.41 mmol) and COMU (4.76 g, 11.1 mmol) in 0 °C portions. The reaction mixture was stirred for 1 h at 0 °C. The reaction was then quenched with H2O at 0 °C and the resulting mixture was extracted with EtOAc (3 x 100 mL), washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography to obtain tert-butyl (2S,3S)-3-(((2S)-1-(((63S,4S)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-25-hydroxy-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (7.26 g, 99% yield over 3 steps) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C68H91N9O12S: 1257.7; found 1257.7.

[0295] Step 4. To a stirred solution of tert-butyl (2S,3S)-3(((2S)-1 -(((63S,4S)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1 -methoxyethyl)pyridin-3yl)-11-ethyl-25-hydroxy-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8oxa-1 (5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundephane-4-yl)amino)3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1carboxylate (7.26 g, 5.77 mmol) in DMF (700 mL) were added K2CO3 (7.97 g, 57.7 mmol) and KI (0.96 g, 5.77 mmol) in portions at 0 °C under a N2 atmosphere. The resulting mixture was stirred for an additional 3 h at 80 °C. The reaction was quenched with H2O at 0 °C. The resulting mixture was then extracted with EtOAc (3 x 300 mL), treated with brine (3 x 600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by reversed-phase flash column chromatography, resulting in: tert-butyl (3a S ,6 S ,9 S ,15 S ,32a S )-21-(5-(4-cyclopropylpiperazin-1-yl)-2-(( S )-1 Petition 870250110544, dated 02 / 12 / 2025, page 257 / 563. 252 / 539 methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosa-hydro-1H,12H11,15-epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c:3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontina-1-carboxylate (4.95 g, yield of 79%) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. for C61H83N9O9: 1086.6; found 1086.3. Intermediate 7. Synthesis of tert-butyl ((63S,4S)-12-(5-(1-cyclopropylpiperidin4-yl)-2-((S )-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2trifluoroethyl)-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa1 (5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundephane-4yl)carbamate

[0296] Step 1. To a solution of benzyl 4-oxopiperidine-1-carboxylate (25 g, 107 mmol) in MeOH (2.5 L) at room temperature, 4-methylbenzenesulfohydrazide (20 g, 107 mmol) was added. The resulting mixture was stirred for 2 hours at 40 °C and the precipitated solids were Petition 870250110544, dated 02 / 12 / 2025, pages 258 / 563 253 / 539 collected by filtration to provide benzyl 4-(2-tosylhydrazineylidene)piperidine-1-carboxylate (30 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C20H23N3O4S: 402.2; found 402.2.

[0297] Step 2. To a 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 (20 g, 40.1 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (20.3 g, 80.1 mmol) in THF (80 mL) at room temperature was added bis(1,5-cyclooctadiene)diiridium(I) dichloride (670 mg, 1.00 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (1.07 g, 4.01 mmol). The resulting mixture was stirred for 16 hours at 55 °C and then concentrated under reduced pressure to give (S)-3-(5-bromo-2-(2-(1-methoxyethyl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)1H-indol-3-yl)-2,2-dimethylpropan-1-ol (20.5 g, crude), which was used without further purification. LCMS (ESI) m / z: [M - C6H10+ H] calc. for C29H37BBrFaN2O4: 543.1; found 542.9.

[0298] Step 3. To a solution of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (20.0 g, crude) and benzyl 4-(2-tosylhydrazineylidene)piperidine-1-carboxylate (12.3 g, 30.7 mmol) in dioxane (200 mL) at room temperature, Cs2CO3 (19.9 g, 61.4 mmol) was added. The resulting solution was stirred for 10 h at 100 °C. The reaction was then filtered, the filter cake washed with EtOAc (3 x 50 mL) and the filtrate concentrated under reduced pressure. The residue was diluted with H2O (200 mL) and the aqueous layer extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by normal phase chromatography yielded benzyl (S)-4-(5-(5-bromo-3-(3-hydroxy-2,2-dimethylpropyl)-1. Petition 870250110544, dated 02 / 12 / 2025, page 259 / 563 254 / 539 (2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperidine-1-carboxylate (15 g, 61% yield in 2 steps) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C36H41BrF3N3O3: 716.2; found 716.2.

[0299] Step 4. To a solution of benzyl (S)-4-(5-(5-bromo-3-(3hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperidine-1-carboxylate (15 g, 20.9 mmol) and (3((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-((triisopropylsilyl)oxy)phenyl)boronic acid (12.7 g, 20.9 mmol) in toluene (90 mL), dioxane (30 mL) and H2O (30 mL) were added K3PO4 (8.89 g, 41.9 mmol) and Pd(dppf)Cl2*DCM (1.71 g, 2.09 mmol). The resulting mixture was stirred for 12 hours at 60 °C and diluted at room temperature by the addition of H2O (200 mL).The aqueous phase was extracted with ethyl acetate (2 x 100 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield methyl (S)-1-((S)-3(3-(2-(5-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (27.6 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C65H89F3N6OwSi: 1199.7; found 1199.7.

[0300] Step 5. To a solution of methyl (S)-1-((S)-3-(3-(2-(5-(1((benzyloxy)carbonyl)piperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-5((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (27.0 g, crude) in THF (135 mL) and H2O (135 mL) at 0 °C, LiOH (1.08 g, 45.0 mmol) was added. The resulting mixture was stirred for 4 hours at 0 °C and then acidified. Petition 870250110544, dated 02 / 12 / 2025, pp. 260 / 563 255 / 539 to pH 6 with 1M HCl. The aqueous phase was extracted with ethyl acetate (3 x 80 mL) and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide (S)-1-((S)-3-(3(2-(5-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (25.0 g (crude)), which was used without further purification. LCMS (ESI) m / z: [M + H] calc.

[0301] Step 6. To a solution of (S)-1-((S)-3-(3-(2-(5-(1((benzyloxy)carbonyl)piperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-5-((tri-isopropylsilyl)oxy)phenyl)-2((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (25.0 g, crude) and DIPEA (81.8 g, 632 mmol) in DCM (2.50 L) at 0 °C were added EDCI (115 g, 601 mmol) and HOBT (14.3 g, 105 mmol). The resulting solution was stirred overnight at room temperature, concentrated under reduced pressure, and the residue diluted with saturated aqueous NH4Cl (300 mL). The aqueous mixture was extracted with EtOAc (2 x 300 mL), and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure.Normal phase chromatography purification yielded benzyl 4-(5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)pyridazine-2(1,3)-benzenecycloundecaphano-12-yl)-6-((S)-1-methoxyethyl)pyridin-3yl)piperidine-1-carboxylate (10.0 g, 42% yield in 3 steps) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. for C64H85FaN6O9Si: 1167.6; found 1167.7.

[0302] Step 7. To a solution of benzyl 4-(5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-25-((tri Petition 870250110544, dated 02 / 12 / 2025, pp. 261 / 563 256 / 539 isopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)pyridazine-2(1,3)benzenecycloundecaphano-12-yl)-6-((S)-1-methoxyethyl)pyridin-3yl)piperidine-1-carboxylate (10 g, 8.57 mmol) in IPA (100 mL) was added Pd / C (5.0 g, 10% by weight of Pd). The resulting mixture was stirred overnight at room temperature under a H2 atmosphere, filtered, and the solid retained on the filter was washed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure to provide tert-butyl ((63S,4S)-12-(2-((S)-1-methoxyethyl)-5-(piperidin-4-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-25-((tri-isopropylsilyl)oxy)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 (9.70 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C56H79F3N6O?Si: 1033.6; found 1034.7.

[0303] Step 8. To a solution of tert-butyl ((63S,4S)-12-(2-((S)-1-methoxyethyl)-5-(piperidin-4-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-25-((tri-isopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphano-4-yl)carbamate (9.30 g, crude) in IPA (93 mL) at 0 °C were added (1-ethoxycyclopropoxy)trimethylsilane (4.71 g, 27.0 mmol) and AcOH (1.62 g, 27.0 mmol), followed by NaBH3CN (1.70 g, 27.0 mmol). The resulting mixture was stirred overnight at 60 °C and the reaction was then quenched by the addition of saturated NaHCO3 (200 mL). The aqueous mixture was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure.Normal phase chromatography purification yielded tert-butyl ((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-25-((tri-isopropylsilyl)oxy)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 (5.10 g, 58% yield in 2 steps) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. para. Petition 870250110544, dated 02 / 12 / 2025, pp. 262 / 563 257 / 539 C56H79F3N6O7Si: 1073.6; found 1074.7. Intermediate 8. Synthesis of tert-butyl (3aS,6S,9S,15S,32aS)-21-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-6-isopropyl-5,19,19trimethyl-4,7,10,16-tetraoxo-22-(2,2,2-trifluoroethyl)-2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H -11,15-epimino23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c:3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontina-1-carboxylate

[0304] Step 1. To a solution of tert-butyl ((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo11-(2,2,2-trifluoroethyl)-25-((tri-isopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecafano-4yl)carbamate (5.1 g, 4.75 mmol) in DMF (50 mL) was added CsF (3.61 g, 23.8 mmol). The resulting mixture was stirred for 1 h at room temperature and the reaction was then cooled to 0 °C by the addition of H2O. The aqueous mixture was extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure.Purification by normal phase chromatography yielded tert-butyl ((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-25-hydroxy-10,10-dimethyl-5,7-dioxo-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). Petition 870250110544, dated 02 / 12 / 2025, pp. 263 / 563 258 / 539 benzenecycloundecaphane-4-yl)carbamate (3.20 g, yield 73%) as a light yellow solid. LCMS (ESI) m / z: [M + H] calc. for C50H63F3N6O7: 917.5; found 917.5.

[0305] Step 2. To a solution of tert-butyl ((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-25-hydroxy-10,10-dimethyl5,7-dioxo-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)-benzenecycloundecafano-4-yl)carbamate (3.2 g, 3.50 mmol) in dioxane (15 mL) at 0 °C was added a 4 M HCl solution in dioxane (15 mL). The resulting mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and the resulting solution was alkalized to pH 8 with saturated aqueous NaHCO3.The aqueous mixture was extracted with DCM (3 x 30 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide (63S,4S)-4-amino-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)1-methoxyethyl)pyridin-3-yl)-25-hydroxy-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 (2.54 g, crude) which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C45H55F3N6O5: 817.4; found 817.3.

[0306] Step 3. For a solution of (63S,4S)-4-amino-12-(5-(1cyclopropylpiperidin-4-yl)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-25-hydroxy-10,10-dimethyl11-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1 (5,3)-indole6(1,3)-pyridazine-2(1,3)-benzenecycloundephane-5,7-dione (2.52 g, crude) and N ((2S,3S)-1-( tert -butoxycarbonyl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methylL-valine (2.37 g, 4.62 mmol) in DMF (20 mL) at -10 °C, DIPEA (21.5 mL, 123 mmol) and COMU (1.85 g, 4.32 mmol) were added. The resulting mixture was stirred for 1 h at -10 °C and the reaction was then cooled to 0 °C by the addition of cold H2O. The aqueous mixture was extracted with ethyl acetate (2 x 10 mL), and the Petition 870250110544, dated 02 / 12 / 2025, pp. 264 / 563 259 / 539 combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by normal-phase chromatography yielded tert-butyl (2S,3S)-3-(((2S)-1(((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-25hydroxy-10,10-dimethyl-5,7-dioxo-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)-benzenecycloundecaphano4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.90 g, 41% yield in 2 steps) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C69H89F3N8O12S: 1311.6; found 1311.5.

[0307] Step 4. To a solution of tert-butyl (2S,3S)-3-(((2S)-1(((63S,4S)-12-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-25hydroxy-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)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.33 g, 1.01 mmol) in DMF (130 mL) were added K2CO3 (1.40 g, 10.1 mmol) and KI (168 mg, 1.01 mmol). The resulting mixture was stirred for 4 hours at 80 °C and the reaction was then cooled to 0 °C by the addition of cold H2O. The aqueous mixture was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.Purification by reverse-phase chromatography yielded tert-butyl(3aS,6S,9S,15S,32aS)-21-(5-(1-cyclopropylpiperidin-4-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo-22-(2,2,2-trifluoroethyl)2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontina-1-carboxylate (600 mg, 42% yield) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C62H81F3N8O9: 1139.6; found 1139.9. Petition 870250110544, dated 02 / 12 / 2025, pp. 265 / 563 260 / 539 Synthesis of Exemplary Compounds Examples A25 and A26. Synthesis of (9 S ,15 S ,18 S ,22 S )-2-ethyl-18-isopropyl-3-(2((S )-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,5,19-trimethyl8,14,17,20-tetraoxo-2,4,5,6,9,10,11,12,14,15,16,17,18,19,20,21,22,23 octadecahidro-8H-9,13-epimino-1,30-etheno-15,27-methane-25,29 (metheno)pyrrolo[3,4-v][1,18]dioxa[6,9,12]triazacyclotriacontine-22 carbonitrila e (9 S ,15 S ,18 S ,22 R )-2-ethyl-18-isopropyl-3-(2-(( S )-1-methoxyethyl)-5 (4-methylpiperazin-1-yl)pyridin-3-yl)-5,5,19-trimethyl-8,14,17,20-tetraoxo 2,4,5,6,9,10,11,12,14,15,16,17,18,19,20,21,22,23-octadecahedron-8H-9,13epimino-1,30-etheno-15,27-methane-25,29-(metheno)pyrrolo[3,4v][1,18]dioxa[6,9,12]triazacyclotriacontine-22-carbonitrila TBDPSCI Imidazole MsCI, DIPEA DCM.rt NaCN DMSO, 60 'C DMF, rt

[0308] Step 1. To a solution of methyl(S)-3,4-dihydroxybutanoate (1.0 g, 7.5 mmol) and imidazole (1.02 g, 14.9 mmol) in DMF (10 mL) stirred at 0°C, TBDPSCl (2.05 g, 7.46 mmol) was added. The resulting mixture was stirred for 3 hours at room temperature and the reaction was cooled to 0°C by the addition of cold H2O. The aqueous mixture was extracted with EtOAc (3 x 50 mL), and the extracts Petition 870250110544, dated 02 / 12 / 2025, pages 266 / 563 261 / 539 combined organics were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by normal phase chromatography yielded methyl(S)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxybutanoate (2.4 g, 86% yield) as a clear oil. LCMS (ESI) m / z: [M + Na] calc. for C21H28O4Si: 395.2; found 395.2.

[0309] Step 2. To a solution of methyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxybutanoate (1.0 g, 2.7 mmol) and DIPEA (1.04 g, 8.05 mmol) in DCM (20 mL) at 0 °C, MsCl (461 mg, 4.03 mmol) was added. The resulting mixture was stirred for 1 hour at room temperature and the reaction cooled to 0 °C by the addition of cold H2O. The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic extracts were washed with H2O, dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methylsulfonyl)oxy)butanoate (1.38 g, crude) which was then carried to the next reaction without further purification. LCMS (ESI) m / z: [M + H] calc. for C22H30O6SSi: 451.2; found 451.2.

[0310] Step 3. To a solution of methyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methylsulfonyl)oxy)butanoate (1.38 g, crude) in DMSO (15 mL), under stirring at 55 °C, NaCN (750 mg, 15.3 mmol) was added. The resulting mixture was stirred for 2 hours at 60 °C and the reaction was cooled to 0 °C by the addition of cold H2O. The aqueous mixture was extracted with EtOAc (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by normal phase chromatography yielded methyl 4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoate (600 mg, 20% yield in 2 steps) as a brown solid. LCMS (ESI) m / z: [M + H] calc. for C22H27O3SL 382.2; found 382.2.

[0311] Step 4. To a solution of methyl 4-((tert-butyldiphenylsilyl)oxy)3-cyanobutanoate (600 mg, 1.57 mmol) in THF (6.0 mL) and MeOH (6.0 mL) at 0 Petition 870250110544, dated 02 / 12 / 2025, pp. 267 / 563 At 262 / 539 °C, a solution of LiOH*H2O (99.0 mg, 2.36 mmol) in H2O (6.0 mL) was added. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure to give 4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoic acid (620 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C21H25NO3Si: 368.2; found 368.2.

[0312] Step 5. To a solution of methyl N-methyl-L-valinate (558 mg, 3.84 mmol) and Et3N (971 mg, 9.60 mmol) in DMF (10 mL) at 0 °C, 4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoic acid (1.18 g, crude) and HATU (1.83 g, 4.80 mmol) were added. The resulting mixture was stirred for 1.5 h at room temperature and the reaction was then quenched by the addition of water. The aqueous mixture was extracted with EtOAc (3 x 20 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by normal phase chromatography yielded methyl N-(4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoyl)-N-methyl-L-valinate (770 mg, 99% yield over 2 steps) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C28H38N2O4Si: 495.3; found 495.4.

[0313] Step 6. To a solution of methyl N-(4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoyl)-N-methyl-L-valinate (100 mg, 0.202 mmol) in DCE (2.0 mL) at 80 °C was added trimethylstannol (292 mg, 1.62 mmol). The resulting mixture was stirred at 80 °C for 15 hours and concentrated under reduced pressure. Purification by normal-phase prep-TLC yielded N-(4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoyl)-N-methyl-L-valine (86 mg, 89% yield) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C27H36N2O4Si: 481.3; found 481.2.

[0314] Step 7. To a solution of (63S,4S)-4-amino-11-ethyl-12(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-25((tri-isopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole Petition 870250110544, dated 02 / 12 / 2025, page 268 / 563 263 / 539 6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-5,7-dione (210 mg, 0.235 mmol) and DIPEA (607 mg, 4.70 mmol) in DCM (2.0 mL) at 0 °C was added N-(4-((tert-butyldiphenylsilyl)oxy)-3-cyanobutanoyl)-N-methyl-L-valine (169 mg, 0.352 mmol) and COMU (151 mg, 0.352 mmol). The resulting mixture was stirred for 1 h at room temperature and the reaction was cooled to 0 °C by the addition of H2OFria. The aqueous mixture was extracted with DCM (3 x 5 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Normal-phase prep-TLC purification yielded 4-((tert-butyldiphenylsilyl)oxy)-3-cyano-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((tri-isopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N-methylbutanamide (180 mg yield of 57%) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C78H109N9O8Si2: 1356.8; found 1357.2.

[0315] Step 8. To a solution of 4-((tert-butyldiphenylsilyl)oxy)-3cyano-N -((2 S )-1 -(((63S,4 S )-11-ethyl-12-(2-(( S )-1 -methoxyethyl)-5-(4-methylpiperazin-1 yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66hexahydro-11H-8-oxa-1 (5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundephane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N methylbutanamide (180 mg, 0.133 mmol) in THF (2.0 mL) at 0 °C was added TBAF (69.4 mg, 0.266 mmol). The resulting mixture was stirred for 2 h at room temperature and concentrated under reduced pressure. Purification by preparative TLC of normal phase TLC (20% MeOH / DCM) afforded 3-cyano-N -((2S )-1(((63S ,4S)-11-ethyl-25-hydroxy-12-(2-(( S )-1 -methoxyethyl)-5-(4-methylpiperazin-1 il)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)-benzenecycloundephane-4-yl)amino)-3methyl-1-oxobutan-2-yl)-4-hydroxy-N-methylbutanamide (117 mg, yield of Petition 870250110544, dated 02 / 12 / 2025, pp. 269 / 563 264 / 539 92%) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C53H71N9O8: 962.6; found 962.5.

[0316] Step 9. To a solution of 3-cyano-N -((2 S )-1-(((63S,4S)11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1 -yl)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)-benzenecycloundephane-4-yl)amino)-3-methyl1-oxobutan-2-yl)-4-hydroxy-N -methylbutanamide (260 mg, 0.270 mmol) and PPh3 (354 mg, 1.35 mmol) in DCM DBAD (311 mg, 1.35 mmol) was added to 3.0 mL at 0 °C. The resulting mixture was stirred for 6 h at room temperature and then concentrated under reduced pressure. Normal-phase prep-TLC purification yielded a mixture of the desired products. The diastereoisomers were then separated by reverse-phase chromatography to obtain the final product.(9S ,15S ,18S ,22S )-2-ethyl-18-isopropyl-3-(2((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,5,19-trimethyl8,14,17,20-tetraoxo-2,4,5,6,9,10,11,12,14,15,16,17,18 ,19,20,21,22,23octadecahydro-8H-9,13-epimino-1,30-ethene-15,27-methane-25,29(methene)pyrrolo[3,4-v][1,18]dioxa[6,9,12]triazacyclotriacontine-22carbonitrile (11.8 mg, yield of 4.6%, assumed configuration) and (9S,15S,18S,22R)-2-ethyl-18-isopropyl-3-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,5,19-trimethyl-8,14,17,20-tetraoxo2,4,5,6,9,10,11,12,14,15,16,17,18,19,20,21,22,23-octadecahydro-8H-9,13epimino-1,30-etheno-15,27-methane-25,29-(metheno)pyrrolo[3,4v][1, 18]dioxa[6,9,12]triazacyclotriacontina-22-carbonitrile (13.0 mg, 5.1% yield, assumed configuration), each as a white solid.

[0317] Nuts for (9S,15S,18S,22S)-2-ethyl-18-isopropyl-3-(2-((S)1 -methoxyethyl)-5-(4-methylpiperazin-1 -yl)pyridin-3-yl)-5,5,19-trimethyl-8,14,17,20tetraoxo-2,4,5,6,9,10,11,12,14,15,16,17,18,19,20,21,22,23-octadecahidro-8H Petition 870250110544, 02 / 12 / 2025, pág. 270 / 563 265 / 539 9,13-epimino-1,30-etheno-15,27-methane-25,29-(metheno)pyrrolo[3,4v][1,18]dioxa[6,9,12]triazacyclotriacontina-22-carbonitrile: LCMS (ESI) m / z: [M + H] calculated for C53H69N9O7: 944.5; found 945.2;1H NMR (400 MHz, DMSO-d6) δ 9,33 (s, 1H), 9,28 (s, 1H), 8,72 (d, J = 8,2 Hz, 1H), 8,46 (d, J = 2,9 Hz, 2H), 8,27 (d, J = 7,8 Hz, 1H), 7,91 (d, J = 6,8 Hz, 2H), 7,58 (d, J = 8,6 Hz, 2H), 7,51 (d, J = 8,9 Hz, 2H), 7,33 - 7,21 (m, 6H), 7,18 (d, J = 1,6 Hz, 1H), 7,01 (d, J = 10,6 Hz, 2H), 6,50 (s, 2H), 5,37 (d, J = 11,0 Hz, 4H), 4,67 (d, J = 10,7 Hz, 1H), 4,30 (d, J = 12,0 Hz, 2H), 4,14 - 4,04 (m, 1H), 3,83 (d, J = 10,4 Hz, 2H), 3,65 (d, J = 10,7 Hz, 2H), 3,61 - 3,52 (m, 2H), 3,07 (d, J = 7,7 Hz, 6H), 2,87 (d, J = 14,2 Hz, 1H), 2,77 (d, J = 11,5 Hz, 6H), 2,70 (s, 1H), 2,46 (s, 4H), 2,22 (s, 6H), 2,01 (s, 1H), 1,95 (dd, J = 10,8, 1,5 Hz, 5H), 1,80 (s, 2H), 1,64 (s, 3H), 1,54 (d, J = 12,4 Hz, 2H), 1,35 (d, J = 6,1 Hz, 6H), 1,24 (s, 1H), 0,99 (t, J = 6,8 Hz, 6H), 0,90 (dd, J = 11,6, 6,5 Hz, 5H), 0,80 - 0,70 (m, 10H), 0,56 (d, J = 11,3 Hz, 6H).;

[0318] Dados for (9 S, 15 S, 18 S, 22 R)-2-etil-18-isopropil-3-(2-(( S )1 -metoxietil)-5-(4-metilpiperazin-1 -il)piridin-3-il)-5,5,19-trimetil-8,14,17,20tetraoxo-2,4,5,6,9,10,11,12,14,15,16,17,18,19,20,21,22,23-octadeca-hydro-8H9 ,13-epimino-1,30-eteno-15,27-metano-25,29-(meteno)pirrolo[3,4v][1,18]dioxa[6,9,12]triazaciclotriacontina-22-carbonitrila: LCMS (ESI) m / z: [M + H] calc. para C53H69N9O7: 944,5; encontrado 944,8.1H NMR (400 MHz, DMSOd6) δ 9,33 (s, 1H), 9,28 (s, 1H), 8,61 (d, J = 8,4 Hz, 1H), 8,45 (d, J = 2,9 Hz, 2H), 8,12 (d, J = 7,9 Hz, 1H), 7.91 (s, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.33 (s, 1H), 7.24 (s, 3H), 7.17 (s, 1H), 7.01 (s, 2H), 6.50 (s, 2H), 5,35 (s, 5H), 4,69 (d, J = 10,8 Hz, 1H), 4,29 (d, J = 12,9 Hz, 2H), 4,10 (dd, J = 12,4, 6.0 Hz, 2H), 3.90 (d, J = 10.0 Hz, 1H), 3.64 (s, 1H), 3.07 (d, J = 13.4 Hz, 6H), 2.88 (d, J = 13.7 Hz, 1H), 2.81 (s, 6H), 2.46 (s, 5H), 2.21 (d, J = 4.3 Hz, 9H), 2.11 (d, J = 1.7 Hz, 2H), 1.99 (s, 3H), 1.80 (s, 1H), 1.35 (d, J = 6.4 Hz, 5H), 1.24 (s, 3H), 0.98 (s, 1H), 0.99 - 0.88 (m, 5H), 0.81 - 0.74 (m, 10H), 0.58 (s, 2H), 0.53 Petition 870250110544, 02 / 12 / 2025, pág. 271 / 563 266 / 539 (s, 3H). Example A43. Synthesis of (9 S ,15 S ,18 S )-23-acetyl-2-ethyl-18-isopropyl-3-(2((S )-1-methoxyethyl)pyridin-3-yl)-5,5,19-trimethyl 2,4,5,6,9,10,11,12,15,16,18,19,22,23,24,25-hexadecahidro-8 H -9,13-epimino1,32-etheno-15,29-methane-27,31 -(metheno)pyrrole[3,4 MeOH, NaBH3CN, DIPEA x][1,20]dioxa[4,8,11,14]tetraazacyclodotriacontine-8,14,17,20(21 H )-tetraona AcCI, DIPEA TFA MeOH, 0 °C DCM. 0 °C DCM. rt Pd / C,H HCI COMMUNITY, DIPEA MeOH. 0 °C DMF, rt OH HATH, DIPEA CMBP DMF, rt Toluene 60 °C 1,4-dioxane 0 °C OH HO

[0319] Step 1. To a solution of 2-[( tert-1,4-dioxane 0 °C ' / 7 \ butyldimethylsilyl)oxy]acetaldehyde (2.00 g, 11.5 mmol), tert-butyl 3-aminopropanoate (2.50 g, 17.2 mmol) and DIPEA (2.97 g, 22.9 mmol) in MeOH (20 mL) NaBH3CN (2.16 g, 34.4 mmol) was added at 0 °C. The resulting mixture was stirred for 5 h at room temperature and then extracted with DCM, washed with brine (3 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)propanoate (2.00 g, crude), which was carried to the next reaction without further purification. LCMS (ESI) m / z: [M + H] calc. for C^HasNOeSi: 304.2; found 304.2.

[0320] Step 2. To a solution of tert-butyl 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)propanoate (2.00 g, crude) and DIPEA (1.70 g, 13.2 mmol) in DCM (20 mL) acetyl chloride (0.80 g, 9.88 mmol) was added in portions at 0 °C. The resulting mixture was stirred for 3 hours at room temperature and then cooled by the addition of H2O at 0 °C. The aqueous layer was extracted with DCM and the combined organic extracts were washed with Petition 870250110544, dated 02 / 12 / 2025, pp. 272 / 563 267 / 539 brine (3 x 50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase chromatography to give tert-butyl 3-(N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}acetamido)propanoate (2.10 g, 53% yield in 2 steps) as a yellow oil. LCMS (ESI) m / z: [M + H] calc. for Ci7H35NO4Si: 346.2; found 346.3.

[0321] Step 3. A solution of tert-butyl 3-(N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}acetamido)propanoate (3.00 g, 8.68 mmol) in DCM (24 mL) TFA (12 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature and then neutralized to pH 7 by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 3-[N-(2-hydroxyethyl)acetamido]propanoic acid (2.2 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C7H13NO4: 176.1; found 176.3.

[0322] Step 4. To a solution of tert-butyl ((63S,4S)-25(benzyloxy)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphano-4-yl)carbamate (2.70 g, 3.25 mmol) in MeOH (27 mL) was added 10% Pd / C at room temperature under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature under a H2 atmosphere. The resulting mixture was then filtered, the filter cake washed with DCM:MeOH in a 10:1 v / v ratio, and the filtrate concentrated under reduced pressure to give tert-butyl((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-4yl)carbamate (2.40 g, crude), which was used without further purification. LCMS (ESI) Petition 870250110544, dated 02 / 12 / 2025, pp. 273 / 563 268 / 539 m / z: [M + H] calc. for C42H53N5O7: 740.4; found 740.7.

[0323] Step 5. To a solution of tert-butyl ((63S,4S)-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphane-4-yl)carbamate (1.50 g, crude) in 1,4-dioxane (8 mL) was added HCl (8 mL, 4 M solution in 1,4-dioxane) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature and then neutralized to pH 8 by the addition of saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure to provide (63S,4S)-4-amino-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa1(5,3)-indole-6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-5,7-dione (1.00 g, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc.for C37H45N5O4: 640.3; found 640.3.

[0324] Step 6. To a solution of (63S,4S)-4-amino-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,1G-dimethyl-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 (1.00 g, crude) and DIPEA (8.08 g, 62.5 mmol) in DMF (10 mL) were added (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutanoic acid (0.54 g, 2.35 mmol) and COMU (80.0 g, 1.88 mmol) at 0°C. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere and neutralized by the addition of H2O. The aqueous mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by prep-TLC to provide tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3) Petition 870250110544, dated 02 / 12 / 2025, pp. 274 / 563 269 / 539 benzenecycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (800 mg, 46% yield in 3 steps) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C48H64N6O8: 853.5; found 853.6.

[0325] Step 7. To a solution of tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-Ao-pyridazine-2(1,3)benzenecycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (380 mg, 0.445 mmol) in 1,4-dioxane (2 mL) was added HCl (2 mL, 4 M solution in 1,4-dioxane) at 0 °C. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure. The residue was neutralized to pH 8 by the addition of saturated aqueous NaHCO3.The aqueous mixture was extracted with ethyl acetate (5 x 100 mL) and the combined organic extracts were washed with brine (3 x 50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to provide (2S)-N-((63S,4S)-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)-3-methyl-2-(methylamino)butanamide (250 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C43H56N6O4: 753.4; found 753.3.

[0326] Step 8. To a solution of (2S)-N-((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1-(5,3)-indol-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)-3-methyl-2-(methylamino)butanamide (200 mg, crude) and DIPEA (137 g, 10.6 mmol) in DMF (2 mL) were added 3-[N-(2-hydroxyethyl)acetamido]propanoic acid (69.8 mg, crude) and HATU (151 mg, (0.399 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of H2O. The aqueous mixture was extracted with EtOAc and the combined organic extracts were washed with brine. Petition 870250110544, dated 02 / 12 / 2025, pp. 275 / 563 270 / 539 dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC to give (2S)-N-((63S,4S)-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)-2-(3-(N-(2-hydroxyethyl)acetamido)-N-methylpropanamido)-3-methylbutanamide (60.0 mg, 19% yield in 2 steps) as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C50H67N7O9: 910.5; found 910.8.

[0327] Step 9. To a solution of (2S)-N-((63S,4S)-11-ethyl-25hydroxy-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo61,62,63,64,65,66-hexa-hydro-11H-8-oxa-1 (5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecafano-4-yl)-2-(3-(N-(2-hydroxyethyl)acetamido)-N-methylpropanamido)-3-methylbutanamide (35.0 mg, 0.038 mmol) in toluene (20 mL) was added CMBP (46.4 mg, 0.190 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours and then stirred overnight at 60 °C before being neutralized by the addition of H2O. The aqueous mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over sodium sulfate Na2SO4, filtered and concentrated under reduced pressure.The crude product was purified by reverse-phase chromatography to give (9S,15S,18S)-23-acetyl-2-ethyl-18-isopropyl-3-(2-((S)-1-methoxyethyl)pyridin-3-yl)-5,5,19-trimethyl2,4,5,6,9,10,11,12,15,16,18,19,22,23,24,25-hexadecahydro-8H-9,13-epimino1,32-etheno-15,29-methane-27,31-(metheno)pyrrolo[3,4x][1,20]dioxa[4,8,11,14]tetrazacyclodotriacontina-8,14,17,20(21H)-tetraone (1.1 mg, yield 3.0%) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C50H65N7O8: 892.5; found 892.8.1H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J = 4.8, 1.7 Hz, 1H), 8.61 - 8.38 (m, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.89 7.72 (m, 2H), 7.60 - 7.48 (m, 2H), 7.35 (s, 1H), 7.28 - 7.14 (m, 1H), 6.77 - 6.72. Petition 870250110544, dated 02 / 12 / 2025, pp. 276 / 563 271 / 539 (m, 1H), 5.35 - 5.10 (m, 2H), 4.80 (d, J = 11.0 Hz, 1H), 4.37 - 3.76 (m, 10H), 3.70 - 3.58 (m, 2H), 3.55 - 3.40 (m, 5H), 3.10 (d, J = 5.9 Hz, 3H), 3.00 - 2.70 (m, 7H), 2.70 - 2.61(m, 1H), 2.21 - 1.95 (m, 6H), 1.85 - 1.61 (m, 2H), 1.59 - 1.51 (m, 1H), 1.41 - 1.34 (m, 4H), 1,24 (br s, 1H), 1.11 - 0.62 (m, 14H), 0.61 - 0.33 (m, 3H). Example A62. Síntese de (9 S, 13 S, 16 S, 19 S, 25 S)-33-etil-16-isopropil-10-(3metoxiazetidina-1 -carbonil)-32-[2-[(1 S)-1 -metoxietil]-3-piridil]-15,29,29trimetil-7,27-dioxa-10,15,18,21,33,39hexazaheptaciclo[29.5.2.12'6.14'19.121'25.09'13.034'38]hentetraconta1(37),2(41) ),3,5,31,34(38),35-heptaeno-14,17,20,26-tetraona trifosgênio, TEA DCM, rt

[0328] Step 1. To a solution of (9S,13S,16S,19S,25S)-33-ethyl-16-isopropyl-32-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,29,29-trimethyl-7,27-dioxa-10,15,18,21,33,39-hexazaheptacyclo[29.5.2.12,6.14,19.121,25.09,13034,38]hentetraconta-1(37),2(41),3,5,31,34(38),35-heptaeno-14,17,20,26-tetarone (60.0 mg, 0.696 mmol) in DCM (1 mL) at 0 °C were added DIPEA (90.0 mg, 0.696 mmol) followed by triphosgene (8.26 mg, 0.028 mmol). The resulting mixture was stirred at room temperature for 1 h, 3-methoxyazetidine hydrochloride (7.74 mg, 0.063 mmol) was subsequently added at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then filtered, concentrated under reduced pressure, and the resulting crude material was purified by reverse-phase chromatography to provide (9S, 13S, 16S, 19S, 25S)-33-ethyl-16-isopropyl-10-(3-methoxyazetidine-1-carbonyl)-32-[2-[(1S)-1-methoxyethyl]-3. Petition 870250110544, dated 02 / 12 / 2025, page 277 / 563 272 / 539 piridil] -15,29,29-trimetil-7,27-dioxa-10,15,18,21,33,39-hexazaheptaciclo [29,5,2,12’6,14’19,121’25,09’13,034’38]hentetraconta-1(37),2(41),3,5,31,34(38),35heptaeno-14,17,20,26-tetraona (40 mg, 57% de rendimento) como um sólido branco. LCMS (ESI) m / z: [M + H] calc. para C54H70N8O9: 975,5; encontrado 975,9;1H NMR (400 MHz, DMSO-d6) δ = 8,76 (d, J = 4,0 Hz, 1H), 8,23 (d, J = 8,0 Hz, 1H), 8,02 (s, 1H), 7,86 - 7,79 (m, 1H), 7,76 - 7,70 (m, 1H), 7,61 - 7,44 (m, 2H), 7,42 - 7,31 (m, 1H), 7,27 - 7,13 (m, 1H), 6,83 - 6,72 (m, 1H), 5,37 - 5,08 (m, 2H), 4,72 (d, J = 12,0 Hz, 1H), 4,44 - 4,17 (m, 7H), 4,15 - 3,76 (m, 5H), 3,72 - 3,42 (m, 5H), 3,23 (s, 3H), 3,15 - 3,09 (m, 3H), 2,90 - 2,71 (m, 4H), 2,4 (s, 3H), 2,22 - 2,11 (m, 1H), 2,08 - 1,95 (m, 2H), 1,93 - 1,79 (m, 1H), 1,77 - 1,49 (m, 3H), 1,46 -1,36 (m, 3H), 1,30 - 1,12 (m, 1H), 1,00 - 0,64 (m, 12H), 0,50 - 0,44 (m, 3H). Example A80. Synthesis of (3aS,6S,9S,15S,32aS)-21-(5-(4cyclopropylpiperazin-1-yl)-2-((S )-1-methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl5,19,19-trimethyl-1-propionyl-3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1 H,12 H -11,15-epimino-23,25-ethene-9,28-methane-26,30(methene)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacyclotriacontin4,7,10,16(2 H,13 H )-tetraone

[0329] Step 1. To a stirred solution of tert-butyl (3a S ,6 S ,9 S ,15 S ,32a S )-21-(5-(4-cyclopropylpiperazin-1-yl)-2-(( S )-1 (methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosa-hydro-1 H ,12 H -11,15 epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontin-1-carboxylate (4.70 g, 4.33 mmol) in Petition 870250110544, dated 02 / 12 / 2025, pp. 278 / 563 273 / 539 DCM (20 mL) was added dropwise to TFA (4.00 mL, 35.1 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure to provide (3aS,6S,9S,15S,32aS)-21-(5(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl5,19,19-trimethyl-3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H11,15-epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontine-4,7,10,16(2H,13H)-tetraone (5.96 g, crude). LCMS (ESI) m / z: [M + H] calc. for C56H75N9O7: 986.6; found 986.5.

[0330] Step 2. To a stirred solution of (3a S ,6 S ,9 S ,15 S ,32a S )21-(5-(4-cyclopropylpiperazin-1-yl)-2-(( S )-1-methoxyethyl)pyridin-3-yl)-22-ethyl-6isopropyl-5,19,19-trimethyl-3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro1H ,12 H -11,15-epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3c To the solution of :3',4'-v][1,18]dioxa[6,9,12]triazacyclotriacontina-4,7,10,16(2H,13H)-tetraone (310 mg, crude) in DMF, DIPEA (406 mg, 3.14 mmol), propanoic acid (46.6 mg, 0.628 mmol) and HATU (239 mg, 0.628 mmol) were added. The reaction mixture was stirred for 30 min at 0 °C and then quenched by the addition of H2O (40 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL) and concentrated under reduced pressure.The residue was purified by reverse-phase prep-HPLC to give (3aS,6S,9S,15S,32aS)-21-(5-(4-cyclopropylpiperazin-1-yl)2-((S)-1-methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-1-propionyl3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontina-4,7,10,16(2H,13H)-tetraone (99 mg, 42% yield in 2 steps) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C59H79N9O8: 1042.6; found 1042.5.1H NMR (400 MHz,. DMSO- d6) δ 8.48 (s, 1H), 8.20 - 7.93 (m, 1H), 7.75 - 7.70 (m, 1H), 7.61 - 7.54 (m, 1H), 7.50 - 7.40 (m, 1H), 7.39 - 7.12 (m, 2H), 6.83 - 6.05 (m, 2H), 5.46 5.00 (m, 2H), 4.71 - 4.51 (m, 1H), 4.47 (s, 1H), 4.45 - 4.30 (m, 1H), 4.33 - 3.88 Petition 870250110544, dated 02 / 12 / 2025, pp. 279 / 563 274 / 539 (m, 5H), 3.90 - 3.60 (m, 4H), 3.23 (s, 3H), 3.10 - 2.95 (m, 5H), 2.90 - 2.71 (m, 7H), 2.69 - 2.60 (m, 1H), 2.39 (s, 3H), 2.32 - 2.16 (m, 4H), 2.10 - 1.90 (m, 3H), 1.90 - 1.79 (m, 2H), 1.77 - 1.55 (m, 4H), 1.50 - 1.15 (m, 6H), 1.10 - 0.90 (m, 6H), 0.91 - 0.43 (m, 16H). Example A126. Síntese de (3a S ,6 S ,9 S ,15 S ,32a S )-22-ethyl-6-isopropyl-21-(2((S )-1-methoxyetil)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,19,19-trimethyl-1 (thiazol-2-yl)-3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradeca-hydro-1 H,12 H 11,15-epimino-23,25-eteno-9,28-metano-26,30-(meteno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazaciclotriacontina-4,7,10,16(2 H,13 H )-tetraone Toluene, 80 °C FeCl3 DCM, ri TsCI, TEA, DMAP DCM, ft

[0331] Step 1. To a solution of tert-butyl(2S,3S)-2((benzyloxy)methyl)-3-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (3.0 g, 6.5 mmol) in DCM (24 mL) at °C was added TFA (8.0 mL). The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and the resulting solution was basified to pH 8 with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide N-methyl-N-((2S,3S)-1-(thiazole) 2-yl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-L-valinate (2.86 g, crude), which was Petition 870250110544, dated 02 / 12 / 2025, pp. 280 / 563 275 / 539 used without further purification. LCMS (ESI) m / z: [M + H] calc. for C20H30N2O4: 363.2; found 362.9.

[0332] Step 2. To a solution of methyl N-((2S,3S)-2((benzyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl-L-valinate (2.87 g, 7.91 mmol) and 2-bromothiazole (3.89 g, 23.7 mmol) in toluene (30 mL) were added CS2CO3 (7.74 g, 23.7 mmol), Pd(OAc)2 (1.07 g, 4.75 mmol) and BINAP (5.91 g, 9.45 mmol). The resulting mixture was stirred overnight at 80 °C and the reaction was then cooled to 0 °C by the addition of cold H2O. The aqueous phase was extracted with EtOAc (3 x 10 mL), and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reversed-phase chromatography yielded methyl N-((2S,3S)-2-((benzyloxy)methyl)-1-(thiazol-2yl)pyrrolidine-3-carbonyl)-N-methyl-L-valinate (923 mg, 26% yield) as a red oil. LCMS (ESI) m / z: [M + H] calc. for C23H31N3O4S: 446.2; found 446.2.

[0333] Step 3. To a solution of methyl N-((2S,3S)-2((benzyloxy)methyl)-1-(thiazol-2-yl)pyrrolidine-3-carbonyl)-N-methyl-L-valinate (821 mg, 1.84 mmol) in DCM (4.0 mL) at 0 °C, FeCl3 (1.20 g, 7.38 mmol) was added. The resulting mixture was stirred overnight at room temperature and the reaction was then cooled to 0 °C by the addition of saturated aqueous NaHCO3. The mixture was filtered and the aqueous layer extracted with DCM (3 x 5 mL). The filter cake was washed with DCM (3 x 5 mL) followed by MeOH (3 x 10 mL) and the combined organic extracts were concentrated under reduced pressure to yield methyl N((2S,3S)-2-(hydroxymethyl)-1-(thiazol-2-yl)pyrrolidine-3-carbonyl)-N-methyl-L-valinate (934 mg, crude) which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C15H25N3O4S: 356.2; found 356.2.

[0334] Step 4. To a solution of methyl N-((2S,3S)-2-(hydroxymethyl)-1-(thiazol-2-yl)pyrrolidine-3-carbonyl)-N-methyl-L-valinate (933 mg, crude) and Et3N (1.06 g, 10.5 mmol) in DCM (4.0 mL) at 0 °C, TsCl (1.50 g, Petition 870250110544, dated 02 / 12 / 2025, pp. 281 / 563 276 / 539 7.88 mmol) and DMAP (32 mg, 0.26 mmol). The resulting mixture was stirred for 2 h at room temperature and the reaction was then cooled to 0 °C by the addition of H2O. The aqueous phase was extracted with DCM (3 x 10 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by normal phase chromatography yielded methyl N-methyl-N-((2S,3S)-1-(thiazol-2-yl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-L-valinate (644 mg, 67% yield) as a brown oil. LCMS (ESI) m / z: [M + H] calc. for C23H31N3O6S2: 510.2; found 510.2.

[0335] Step 5. To a solution of methyl N-methyl-N-((2S,3S)-1(thiazol-2-yl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-L-valinate (320 mg, 0.628 mmol) in THF (5.0 mL) at 0 °C, LiOH*H2O (79 mg, 1.8 mmol) and H2O (1.0 mL) were added. The resulting mixture was stirred overnight at room temperature and the reaction solution was acidified to pH 6 with 2M aqueous HCl. The aqueous mixture was extracted with DCM (3 x 20 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide N-methyl-N-((2S,3S)-1-(thiazol-2-yl)-2((tosyloxy)methyl)pyrrolidine-3-carbonyl)-L-valine (355 mg, crude) which was used without further purification. LCMS (ESI) m / z: [M + H] calc. for C22H29N3O6S2: 496.2; found 496.1.

[0336] Step 6. To a solution of (63S,4S)-4-amino-11-ethyl-25hydroxy-12-(2-(( S )-1-methoxyethyl)-5-(4-methylpiperazin-1 -yl)pyridin-3-yl)-10,10-dimethyl61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(1,3)benzenecycloundecaphane-5,7-dione (264 mg, 0.358 mmol) and N -methyl-N -((2S,3S)1-(thiazol-2-yl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-L-valine (177 mg, crude) in DMF (4.0 mL) At 0 °C, DIPEA (1.85 g, 14.3 mmol) and COMU (230 mg, 0.537 mmol) were added. The resulting mixture was stirred for 1.5 h at 0 °C, and the reaction was then cooled to 0 °C by the addition of cold H2O. The aqueous mixture was extracted with EtOAc (3 x 10 mL), and the combined organic extracts were washed with Petition 870250110544, dated 02 / 12 / 2025, pp. 282 / 563 277 / 539 brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reversed-phase chromatography provided ((2S,3S)-3-(((2S)-1(((63S,4 S )-11-ethyl-25-hydroxy-12-(2-(( S )-1-methoxyethyl)-5-(4-methylpiperazin-1 il)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)-benzenecycloundecaphane-4-yl)amino)-3methyl-1 -oxobutan-2-yl)(methyl)carbamoyl)-1 -(thiazol-2-yl)pyrrolidin-2-yl)methyl 4methylbenzenesulfonate (187 mg, Yield of 43% as a yellow solid. LCMS (ESI) m / z: [M + H] calc. for C64H82N10O10S2: 1215.6; found 1215.2.

[0337] Step 7. To a solution of ((2 S ,3 S )-3-(((2 S )-1-(((63S ,4 S)11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1 (5,3)-indole6(1,3)-pyridazine-2(1,3)-benzenecycloundecaphane-4-yl)amino)-3-methyl-1 oxobutan-2-yl)(methyl)carbamoyl)-1-(thiazol-2-yl)pyrrolidin-2-yl)methyl 4methylbenzenesulfonate (185 mg, 0.152 mmol) in DMF (18.5 mL) were added K2CO3 (210 mg, 1.52 mmol) and KI (25.3 mg, 0.152 mmol). The resulting mixture was stirred for 2 hours at 80 °C and the reaction was then cooled to -78 °C with H2O. The aqueous mixture was extracted with EtOAc (3 x 20 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.Purification by reverse-phase chromatography yielded (3aS, 6S, 9S, 15S, 32aS)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,19,19-trimethyl-1-(thiazol-2-yl)3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3-c :3',4'v][1,18]dioxa[6,9,12]triazacyclotriacontina-4,7,10,16(2H,13H)-tetraone (24.2 mg, 15% yield) as a white solid. LCMS (ESI) m / z: [M + H] calc. for C57H74N10O7S: 1043.6; found 1043.4.1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.6 Hz, 1H), 8.39 - 8.17 (m, 1H), 8.11 - 7.95 (m, 1H),7.83 - 7.66 (m, 1H), 7.64 - 7.50 (m, 2H), 7.49 - 7.36 (m, 1H), 7.34 - 7.11 (m, 2H), 7.08 - 6.52 (m,. Petition 870250110544, dated 02 / 12 / 2025, pp. 283 / 563 278 / 539 2H), 5.46 - 5.06 (m, 2H), 4.83 - 4.66 (m, 1H), 4.64 - 4.46 (m, 1H), 4.44 -3.80 (m, 7H), 3.77 - 3.60 (m, 5H), 3.35 - 3.11 (m, 5H), 3.09 - 2.95 (m, 2H), 2.91 2.57 (m, 5H), 2.53 - 2.35 (m, 6H), 2.33 - 2.12 (m, 4H), 1.92 - 1.51 (m, 6H), 1.45 - 1.15 (m, 4H), 1.09 - 0.93 (m, 2H), 7,83 - 7.66 (m, 1H), 0.91 - 0.51 (m, 12H), 0.49 - 0.37 (m, 1H). Exemplo A130. Síntese de (3a S, 6 S, 9 S, 15 S, 32 a S)-21-(5-(4ciclopropilpiperazin-1-il)-2-((S) )-1-metoxietil)piridin-3-il)-22-etil-6-isopropil5,19,19-trimetil-1-(oxetan-3-ilmetil)-3,3a,5,6,8,9,14,15,18,19,20,22,32,32atetradeca-hydro-1 H,12 H -11,15-epimino-23,25-eteno-9,28-metano-26,30(meteno)dipirrolo[2,3-c :3',4'-v][1,18]dioxa[6,9,12]triazaciclotriacontina4,7,10,16(2 H,13 H)-tetraona

[0338] Step 1. To a stirred solution of (3a S ,6 S ,9 S, 15 S ,32a S )-21-(5-(4-cyclopropylpiperazin-1-yl)-2-(( S )-1-methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1 H ,12 H-11,15epimino-23,25-etheno-9,28-methane-26,30-(metheno)dipyrrolo[2,3- c :3',4'v ][1,

[18] dioxa[6,9,12]triazacyc...

Claims

CLAIMS 1. COMPOUND, characterized in that it has Formula Ia or Formula Ib: R1 Formula Ia Formula Ib 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; L is a ligand; R1 is optionally substituted 5- to 10-membered heteroaryl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; R4 is hydrogen or optionally substituted C1-C6 alkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl;Petition 870250110544, dated 02 / 12 / 2025, p. 546 / 563 2 / 15 t is 0, 1, 2 or 3; z is 0, 1 or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

2. COMPOUND, according to claim 1, characterized in that it has the structure of Formula Ia-1: 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; L is a ligand; R1 is optionally substituted 5- to 10-membered heteroaryl; R2 is optionally substituted C1-C6 alkyl; Petition 870250110544, dated 02 / 12 / 2025, p.547 / 563 3 / 15 R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; R4 is hydrogen or optionally substituted C1-C6 alkyl; each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2, or 3.

3. COMPOUND, according to claim 2, characterized in that it has the structure of Formula Ia-2: 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; L is a ligand; R1 is optionally substituted 5- to 10-membered heteroaryl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl; and R4 is hydrogen or optionally substituted C1-C6 alkyl.

4. COMPOUND, according to claim 1, characterized in that the compound has the structure of Formula IIa or Formula IIb: Formula IIa Formula IIb or a pharmaceutically acceptable salt thereof; where R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl.

5. COMPOUND, according to claim 4, characterized in that the compound has the structure of Formula IIa-1: ox I Formula IIa-1 Petition 870250110544, 02 / 12 / 2025, p. 549 / 563 5 / 15 or a pharmaceutically acceptable salt thereof; where R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl; each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3.

6. COMPOUND, according to claim 5, characterized in that the compound has the structure of Formula IIa-2: Formula IIa-2 or a pharmaceutically acceptable salt thereof; where R5 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, -OR5a, or optionally substituted C1-C6 heteroalkyl; and R5a is optionally substituted C1-C6 alkyl or optionally substituted 5- to 10-membered heteroaryl. Petition 870250110544, dated 02 / 12 / 2025, p. 550 / 563 6 / 15 7. COMPOUND, according to claim 4, characterized in that the compound has the structure of Formula IIIa or Formula IIIb: Formula IIIa Formula IIIb or a pharmaceutically acceptable salt thereof.

8. COMPOUND, according to claim 7, characterized in that the compound has the structure of Formula IIIa-1: Formula IIIa-1 or a pharmaceutically acceptable salt thereof.

9. COMPOUND, according to claim 8, characterized in that the compound has the structure of Formula IIIa-2: Petition 870250110544, dated 02 / 12 / 2025, p. 551 / 563 7 / 15 or a pharmaceutically acceptable salt thereof.

10. COMPOUND, according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that L has the structure of Formula IV: Aχΐ^ZA Formula IV X1 is O or CH2 and is attached to ring A; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

11. COMPOUND, according to claim 10, characterized in that the compound has the structure of Formula Va or Formula Vb: , . dL2 dL2 dL1 KK kX .0 / 0 v / ^nA-r3 —O IH r J-\ 1 RV nA Ao { Oi J * RS / <r83>- ou Fórmula Va o rvrL5 V\ X9 / ° H ] OV z\^Vr3 v \ irv / k— <f j] \t x xzz )=" / " ν'άζύ r5r4 (r33)t 1 k fórmula vb petição 870250110544, de 02 12 2025, pág. 552 563 8 15 ou um sal farmaceuticamente aceitável do mesmo; em que x1 é o ch2; e z heterocicloalquileno 3 a 6 membros opcionalmente substituído, c1-c6 alquileno heteroalquileno substituído.

12. COMPOUND, according to claim 11, characterized in that the compound has the structure of Formula Va-1: ο I r5r4 (R33)t Formula Va-1 or a pharmaceutically acceptable salt thereof; where X1 is O or CH2; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

13. COMPOUND, according to claim 12, characterized in that the compound has the structure of Formula Va-2: ox / / Formula Va-2 Petition 870250110544, dated 02 / 12 / 2025, p. 553 / 563 9 / 15 or a pharmaceutically acceptable salt thereof; where X1 is O or CH2; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

14. COMPOUND, according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that L has the structure of Formula VI: R6 Formula VI B is an optionally substituted 3- to 6-membered heterocycloalkyl; R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C10 aryl O | 11 0 R11 H;r8 r» h, optionally substituted, R , 0 , I , or 0 ; R7 and R8 are each independently H or optionally substituted C1-C6 alkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl;R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 Petition 870250110544, dated 02 / 12 / 2025, page 554 / 563 10 / 15 optionally substituted cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

15. COMPOUND, according to claim 14, or a pharmaceutically acceptable salt thereof, characterized in that L has the structure of Formula VIa: R6 Formula VIa 16. COMPOUND, according to claim 15, characterized in that the compound has the structure of Formula VIIa or Formula VIIb: Formula VIIa or Formula VIIb Petition 870250110544, 02 / 12 / 2025, p. 555 / 563 11 / 15 or a pharmaceutically acceptable salt thereof; wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C10 aryl O i HO d11 XRH-r8 r- Hr, R , O , I , or O ; R7 and R8 are each independently optionally substituted H or C1-C6 alkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl;R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is optionally substituted hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; C6-C10 aryl, or heteroaryl of 5 to 10 members optionally replaced.

17. COMPOUND, according to claim 16, characterized in that the compound has the structure of Formula VIIa-1: Petition 870250110544, dated 02 / 12 / 2025, p. 556 / 563 12 / 15 Formula VIIa-1 or a pharmaceutically acceptable salt thereof; wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C10 aryl OI 11 R 0 R11 H;rí Hr» r'« Kr, R , 0 , I , or 0 ; R7 and R8 are each independently H or optionally substituted C1-C6 alkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl;R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl. Petition 870250110544, dated 02 / 12 / 2025, page. 557 / 563 13 / 15 substituted, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

18. COMPOUND, according to claim 17, characterized in that the compound has the structure of Formula VIIa-2: Formula VIIa-2 or a pharmaceutically acceptable salt thereof; where R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C10 aryl O i HO d11 H; r8H-r8 r- Hr, optionally substituted, R, O, I, or O; R7 and R8 are each independently optionally substituted H or C1-C6 alkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl. Petition 870250110544, dated 02 / 12 / 2025, p.558 / 563 14 / 15 substituted, or optionally substituted 3- to 6-membered heterocyclyl; R10 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl; optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

19. COMPOUND, or a pharmaceutically acceptable salt thereof, characterized in that it is from Table 1 or Table 2.

20. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a compound, or a pharmaceutically acceptable salt thereof, of any of claims 1 to 19 and a pharmaceutically acceptable excipient.

21. A METHOD FOR TREATING CANCER IN A SUBJECT in need thereof, the method characterized in that it comprises administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of claims 1 to 19, or a pharmaceutical composition of claim 20.

22. METHOD FOR TREATING A RAS PROTEIN-RELATED DISORDER in a subject in need thereof, the method characterized in that it comprises administering to the subject a therapeutically effective amount of a compound of any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20.

23. METHOD FOR INHIBITING A RAS PROTEIN IN A CELL, the method characterized in that it comprises contacting the cell with an effective amount of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20.< / f>