Compounds for identifying pairs of protein-presenting proteins and target proteins: their use and pharmaceutical composition.

Description

Compounds for identifying pairs of protein-presenting proteins and target proteins: their use and pharmaceutical composition. Divided BR112019020967-0, filed on April 4, 2018. BACKGROUND

[001] The vast majority of small molecule drugs act by binding to a functionally important pocket in a target protein, thereby modulating that protein's activity. For example, cholesterol-lowering statin drugs bind to the active site of the HMG-CoA reductase enzyme, thus preventing the enzyme from engaging with its substrates. The fact that many of these drug / target interaction pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins with a reasonable amount of time, effort, and resources. This is far from the case. Current estimates hold that only about 10% of all human proteins are targetable by small molecules. The other 90% are currently considered refractory or intractable to small molecule drug discovery. These targets are commonly referred to as unruggable.These drug-unmodulated targets comprise a vast and largely unexplored reservoir of medically important human proteins. Therefore, there is considerable interest in discovering novel molecular modalities capable of modulating the function of these drug-unmodulated targets. SUMMARY

[002] Small molecules are limited in their targeting abilities due to the fact that their interactions with the target are driven by adhesive forces, the intensity of which is approximately Petition 870260070873, dated 07 / 16 / 2026, page 10 / 532 2 / 220 proportional to the contact surface area. Due to their small size, the only way for a small molecule to accumulate sufficient intermolecular contact surface area to effectively interact with a target protein is to be literally engulfed by that protein. In fact, a large body of both experimental and computational data supports the view that only those proteins that have a hydrophobic pocket on their surface have the capacity to bind small molecules. In those cases, binding is enabled by immersion.

[003] Nature has evolved a strategy that allows a small molecule to interact with target proteins at sites beyond hydrophobic pockets. This strategy is exemplified by naturally occurring immunosuppressive drugs cyclosporine A, rapamycin, and FK506. The biological activity of these drugs involves the formation of a high-affinity complex of the small molecule with a small presentation protein. The composite surface of the small molecule and the presentation protein engages the target. Therefore, for example, the binary complex formed between cyclosporine A and cyclophilin A targets calcineurin with high affinity and specificity, but neither cyclosporine A nor cyclophilin A alone binds calcineurin with measurable affinity.

[004] The present inventors have developed compounds and conjugates useful for identifying pairs of presenting proteins and target proteins, and probing the interfaces between them for use in the development of small molecules capable of modulating these interactions.

[005] Consequently, the present description provides useful methods and reagents for analyzing protein-protein interfaces such as interfaces between a presenting protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a Petition 870260070873, dated 07 / 16 / 2026, page 11 / 532 3 / 220 target protein. This analysis is useful in aiding the design of small molecules that have the capacity to bind simultaneously to both a presenting protein and a target protein, so that the resulting small molecule-protein complexes can bind to and modulate the activity of the target protein. In some embodiments, the target and / or presenting proteins are intracellular proteins. In some embodiments, the target and / or presenting proteins are mammalian proteins.

[006] In some respects, the disclosure provides compounds that can be used as crosslinking substrates. These compounds may include a protein-binding chemical moiety capable of covalent or non-covalent binding to a protein (e.g., a target protein or a presenter protein) and at least one crosslinking group capable of a chemoselective reaction with an amino acid of a protein other than the one that binds to the protein-binding chemical moiety. In some embodiments, the compounds include only a crosslinking group.

[007] Consequently, in one aspect, the disclosure provides a compound comprising a protein-binding chemical moiety (e.g., a presenting protein-binding chemical moiety or a target protein-binding chemical moiety) and a crosslinking group (e.g., a chemical moiety capable of chemoselective reaction with an amino acid of a protein other than the one that binds to the protein-binding chemical moiety). The protein-binding chemical moiety has the capacity to bind (covalently or non-covalently) to a protein (e.g., a presenting protein or a target protein, depending on whether it is a presenting protein-binding chemical moiety or a target protein-binding chemical moiety), while the crosslinking group has the capacity to form a covalent bond with a protein. Petition 870260070873, dated 07 / 16 / 2026, p. 12 / 532 4 / 220 (for example, a presenting protein, a target protein, or another compound that has the ability to bind this other protein). In some embodiments, when the compound includes a presenting protein-binding chemical moiety, the compound does not include a target protein-binding chemical moiety. In some embodiments, when the compound includes a target protein-binding chemical moiety, the compound does not include a presenting protein-binding chemical moiety.

[008] In some embodiments, the crosslinking group is a sulfhydryl-reactive crosslinking group (for example, the crosslinking group includes a mixed disulfide, a maleimide, a vinyl sulfone, a vinyl ketone, or an alkyl halide), an amino-reactive crosslinking group, a carboxyl-reactive crosslinking group, a carbonyl-reactive crosslinking group, or a triazole-forming crosslinking group.

[009] In some embodiments, the crosslinking group includes a mixed disulfide, for example, the crosslinking group includes the structure of Formula Ia: HS-S(O)a—ra. J Formula IA

[0010] wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound; and

[0011] a is 0.1 or 2;

[0012] RA is optionally substituted O1-O6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-Cw aryl or optionally substituted C2-C9 heteroaryl.

[0013] In some embodiments, RA is optionally substituted C2-C9 heteroaryl (e.g., pyridyl). In some embodiments, the crosslinking group includes the structure: Petition 870260070873, dated 07 / 16 / 2026, p. 13 / 532 5 / 220 where the wavy line illustrates the point where the crosslinking group attaches to the rest of the compound.

[0014] In some embodiments, RA is optionally substituted C1-C10 heteroalkyl (e.g., N,N-dimethylethyl). In some embodiments, the crosslinking group includes the structure: ch3

[0015] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound. In some embodiments, the crosslinking group includes the structure:

[0016] In some embodiments, RA is optionally substituted C1-C1 alkyl (e.g., methyl). In some embodiments, the crosslinking group includes the structure: c\zo X, XC s ch3J

[0017] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0018] In some embodiments, the crosslinking group includes a carbon-based crosslinking group (for example, a crosslinking group that forms a carbon-sulfide bond by reaction with a thiol).

[0019] In some embodiments, the crosslinking group includes a maleimide, for example, the crosslinking group includes the formula structure lb, Ic, Id, or le: Petition 870260070873, dated 07 / 16 / 2026, p. 14 / 532 6 / 220 Formula lb Formula lc Formula Id Formula le

[0020] wherein the wavy line illustrates the attachment point of the crosslinking group to the rest of the compound;

[0021] Xaé -C(O)- or -SO2-;

[0022] XBé -C(O)- or CRERF;

[0023] RBe Rcsão, independently, hydrogen, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C6 aryl, optionally substituted C6-C10 aryl, optionally substituted C2C6 heteroaryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl.

[0024] RD is hydrogen, hydroxyl, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; and

[0025] REe RFsão, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C10 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl Petition 870260070873, dated 07 / 16 / 2026, page 15 / 532 7 / 220 optionally substituted, Ce-Cw aryl optionally substituted, CeC10 aryl Ci-Ce alkyl optionally substituted, C2-C9 heteroaryl optionally substituted, C2-C9 heteroaryl Ci-Ce alkyl optionally substituted, C2-C9 heterocyclyl optionally substituted, or C2-C9 heterocyclyl C1-C6 alkyl optionally substituted.

[0026] In some embodiments, the crosslinking group includes the structure of Formula Ib. In some embodiments, Xa is -C(O)-. In some embodiments, XB is -C(O)-. In some embodiments, RBe Rc are hydrogen or optionally substituted C1-C1 alkyl (e.g., methyl).

[0027] In some forms, the crosslinking group includes the structure:

[0028] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0029] In some forms, the crosslinking group includes the structure:

[0030] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0031] In some forms, the crosslinking group includes the structure of the formula If, Ig, Ih or li: Formula If Formula Ig Formula Ih Formula li

[0032] where the wavy line illustrates the attachment point of the group Petition 870260070873, dated 07 / 16 / 2026, page 16 / 532 8 / 220 of crosslinking to the remainder of the compound;

[0033] Xcé -C(O)- or -SO2-;

[0034] XDestá ausente, NRJRK, ou ORL;

[0035] RG, RH, and R1 are, independently, hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C2 aryl, optionally substituted C1-C2 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; and

[0036] RJ, RK, and RL are, independently, absent, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl C1Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1Ce alkyl.

[0037] In some embodiments, the crosslinking group includes the structure of Formula If. In some embodiments, XD is absent. In some embodiments, RG, RH, and R1 are hydrogen. In some embodiments, X is -C(O)-. In some embodiments, X is -SO2-.

[0038] In some embodiments, the crosslinking group includes a vinyl sulfone, for example, the crosslinking group includes the structure Petition 870260070873, dated 07 / 16 / 2026, p. 17 / 532 9 / 220 ra: op

[0039] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0040] In some embodiments, the crosslinking group includes a vinyl sulfone, for example, the crosslinking group includes the structure: ÍO' 7O

[0041] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0042] In some embodiments, the crosslinking group includes a vinyl ketone, for example, the crosslinking group includes the following structures: the

[0043] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0044] In some embodiments, the crosslinking group includes vinyl ketone, for example, the crosslinking group includes the structure:

[0045] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0046] In some embodiments, the crosslinking group includes vinyl ketone, for example, the crosslinking group includes the structure: the Petition 870260070873, dated 07 / 16 / 2026, p. 18 / 532 10 / 220

[0047] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0048] In some embodiments, the crosslinking group includes an inone as a structure of formula Ij or Ik:

[0049] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound;

[0050] XE is absent, NRNR°, or ORP;

[0051] RMé hydrogen, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted O-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl C1-Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl O-Ce alkyl; and

[0052] RN, R°, and Rp are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl. Petition 870260070873, dated 07 / 16 / 2026, page 19 / 532 11 / 220

[0053] In some embodiments, the crosslinking group includes vinyl ketone, for example, the crosslinking group includes the structure: the rq

[0054] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0055] In some embodiments, the crosslinking group includes a structure of the formula lm or In: Y -xF-xG^—rqrr Formula lm Formula In

[0056] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound;

[0057] XF is absent, NRSRT, or ORU;

[0058] XG is absent or -C(O)-;

[0059] Y is an outgoing group;

[0060] RQe RRsão, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclil, optionally substituted C1-C6 aryl, optionally substituted C1-C6 aryl alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclil, or optionally substituted C2-C9 heterocyclil O1-O2 alkyl; and

[0061] Rs, RT, and Rusão, independently, absent, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1Ce alkyl, optionally substituted C2-C6 alkenyl Petition 870260070873, dated 07 / 16 / 2026, page 20 / 532 12 / 220 ide, optionally substituted C2-C6 alkynyl, optionally substituted C1-Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-C-io aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, Optionally substituted C2-C9 heteroaryl C1-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl O-Ce alkyl.

[0062] In some embodiments, Y is a halogen (e.g., fluoro, chlorine, bromine, or iodine), a mesylate, a tosylate, or a triflate. In some embodiments, Y is a nitrile. In some embodiments, XFe and XG are absent. In some embodiments, RQ and RR are hydrogen. In some embodiments, the crosslinking group includes an alkyl halide such as an alkyl chloride, for example, the crosslinking group includes the structure: A~-Clou^ Λ

[0063] wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound. In some embodiments, the crosslinking group includes an alkyl halide such as an alkyl chloride or alkyl fluoride, for example, the crosslinking group includes the structure: oo H or H;

[0064] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0065] In some embodiments, the crosslinking group includes an epoxide, for example, the crosslinking group includes a structure of formula Io: ÁRrvRx“Rw Petition 870260070873, dated 07 / 16 / 2026, p. 21 / 532 13 / 220 Formula I

[0066] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound;

[0067] Rv, Rw, and Rx are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C6 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heterocyclyl C1-C6 alkyl.

[0068] In some embodiments, the crosslinking group includes a structure of the Ip formula: IP Formula

[0069] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound;

[0070] the dotted lines represent optional double bonds included as necessary for the structure to be aromatic;

[0071] be 0, 1, or 2;

[0072] Y is an outgoing group;

[0073] RYe Rzsão, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, al Petition 870260070873, dated 07 / 16 / 2026, page 22 / 532 14 / 220 optionally substituted C2-C6 quinyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C6 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl;

[0074] each of XH, X1, XJ, XK and XL are, independently, absent, NRAA, or CRAB, wherein at least five of XH, X1, XJ, XK and XL are NRAA, or CRAB;

[0075] RAA is absent or hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; and

[0076] RAB is hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or C1-C9 heterocyclyl Petition 870260070873, dated 16 / 07 / 2026, page 23 / 532 15 / 220 Ce optionally substituted alkyl.

[0077] In some embodiments, at least one RAB is an electron-withdrawing group. In some embodiments, one to three RABs consist of electron-withdrawing groups.

[0078] In some embodiments, Y is a nitrile. In some embodiments, Y is a halogen (e.g., fluoro, chlorine, bromine, or iodine), a mesylate, a tosylate, or a triflate.

[0079] In some embodiments, the crosslinking group includes the structure: k 'N' 'N' n 'N*N'NII n N / N XI, ^Br, ^Cl, Y , OU Y

[0080] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0081] In some forms, the crosslinking group includes the structure: Tu 70 N^N CN OU CN

[0082] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0083] In some forms, the crosslinking group includes the structure:

[0084] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

[0085] In some forms, the crosslinking group is a Petition 870260070873, dated 07 / 16 / 2026, p. 24 / 532 16 / 220 internal crosslinking group, for example, the crosslinking group includes a structure of the formula Iq, Ir or Is: Iq Formula Ir Formula Is

[0086] where the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound;

[0087] XMé -C(O)- or -SO2-;

[0088] XNé absent, NRAEou O;

[0089] RACe RADsão, independently, hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; and

[0090] RAE is hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C2-C6 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl Petition 870260070873, dated 07 / 16 / 2026, p. 25 / 532 17 / 220 finally substituted, or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl;

[0091] In some embodiments, XN is NRAE, where RAE is hydrogen. In some embodiments, RAC and RAD are hydrogen. In some embodiments, XM is -C(O)-. In some embodiments, XM is -SO2-.

[0092] In some embodiments of any of the preceding compounds, the protein-binding chemical portion has the capacity for non-covalent interaction with a protein. In some embodiments of any of the preceding compounds, the protein-binding chemical portion has the capacity for covalent interaction with a protein.

[0093] In some aspects, the disclosure provides a compound that includes a chemical portion that binds the presenting protein and a crosslinking group. In some embodiments, the chemical portion that binds the protein and the crosslinking group are fixed via a ligand.

[0094] In some respects, the disclosure provides a compound that has the following structure: Petition 870260070873, dated 07 / 16 / 2026, p. 26 / 532 18 / 220 Petition 870260070873, dated 07 / 16 / 2026, p. 27 / 532 19 / 220

[0095] In some respects, the disclosure provides conjugates, methods for their synthesis, and uses thereof, including a chemical portion of a presenting protein capable of covalent or non-covalent binding to a presenting protein conjugated to a target protein via a ligand.

[0096] Consequently, in another aspect, disclosure provides a conjugate that includes a chemical-binding portion of a presenting protein conjugated to a target protein. In some embodiments, the chemical-binding portion of the presenting protein conjugate has the capacity for non-covalent interaction with a pro Petition 870260070873, dated 07 / 16 / 2026, p. 28 / 532 20 / 220 presenting protein. In some embodiments, the chemical-binding portion of the presenting protein conjugate has the capacity for covalent interaction with a presenting protein.

[0097] In some respects, the disclosure provides a method for producing a conjugate that includes a chemically binding presenter protein moiety conjugated to a target protein. This method involves reacting (a) a compound that includes a chemically binding presenter protein moiety and a crosslinking group with (b) a target protein under conditions that permit the production of the conjugate.

[0098] In some respects, the disclosure provides a method for producing a conjugate comprising a chemical-binding presenter protein moiety conjugated to a target protein. This method includes providing (a) a compound comprising a chemical-binding presenter protein moiety and a crosslinking group; (b) a target protein; and (c) a presenter protein; and reacting the compound with the target protein under conditions permitting the production of the conjugate.

[0099] In some respects, the disclosure provides complexes, methods for their production and uses thereof, including a presenter protein and a conjugate comprising a chemical-binding presenter protein moiety and a target protein.

[00100] Consequently, in another aspect, the disclosure provides a complex that includes (i) a conjugate that includes a chemical-binding presenter protein moiety conjugated to a target protein and (ii) a presenter protein.

[00101] In some respects, the disclosure provides a method for producing a complex that includes (i) a conjugate comprising a chemical-binding portion of a presenting protein conjugated to a target protein and (ii) a presenting protein. This method involves combining a conjugate comprising a chemical-binding portion of a presenting protein conjugated to a target protein and a protein Petition 870260070873, dated 07 / 16 / 2026, p. 29 / 532 21 / 220 presenter under conditions that permit production of the complex.

[00102] In some respects, the disclosure provides a method for producing a complex that includes (i) a conjugate comprising a presenter protein-binding chemical moiety conjugated to a target protein and (ii) a presenter protein. This method includes providing (a) a compound comprising a presenter protein-binding chemical moiety and a crosslinking group; (b) a target protein; and (c) a presenter protein; and reacting the compound with the target protein under conditions that permit production of the complex.

[00103] In some embodiments of the previous methods, the presenting protein binds to the compound in the absence of the target protein. In some embodiments of the previous methods, the presenting protein does not bind substantially to the compound in the absence of the target protein. In some embodiments of the previous methods, the compound and the target protein do not react substantially in the absence of the presenting protein. In some embodiments of the previous methods, the compound and the target protein react in the absence of the presenting protein. In some embodiments of the previous methods, the conditions do not include a reducing agent. In some embodiments of the previous methods, the conditions include an excess of presenting protein.

[00104] In some embodiments, detectable binding between the compound and the presenting protein is observed in the absence of the target protein. In some embodiments, however, detectable binding between the compound and the presenting protein is not observed (e.g., the presenting protein does not bind substantially to the compound) in the absence of the target protein. In some embodiments, significant reaction between the crosslinking group and the target protein (e.g., significant conjugate formation) is not observed in the absence of the presenting protein. In some embodiments, however Petition 870260070873, dated 07 / 16 / 2026, page 30 / 532 22 / 220 to, a significant reaction between the crosslinking group and the target protein can be observed even in the absence of the presenting protein. In some embodiments, the rate and / or extent of this reaction (e.g., rate and / or amount of conjugate formation) may differ in a given assay when the presenting protein is present compared to when it is absent (e.g., the rate and / or amount of conjugate formation is 2 times, 3 times, 4 times, 5 times, 10 times, or 100 times greater in the presence of the presenting protein).

[00105] In some embodiments, the production of conjugate as described herein is carried out under conditions that do not include (for example, are substantially free of) a reducing reagent.

[00106] In some embodiments, the present invention provides a complex comprising (i) a presenting protein; (ii) a compound as described herein (for example, a compound whose structure includes a presenting protein binding chemical moiety and a crosslinking group); and (iii) a target protein. In some embodiments, this complex is exposed to and / or maintained under conditions that allow the crosslinking chemical moiety to react with the target protein, so that a crosslink between them is formed. In some embodiments, the crosslink is with a heteroatom on an amino acid (for example, on an amino acid side chain) of the target protein. In some embodiments, the crosslink is with an -S- atom on a cysteine ​​in the target protein.In some embodiments, the target protein is a variant of a natural target protein; in some of these embodiments, the variant has an amino acid sequence that shows a high degree (e.g., 80%, 81%, 82%; 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or higher) of similarity to the natural target protein. Petition 870260070873, dated 07 / 16 / 2026, p. 31 / 532 23 / 220 but differs by substitution or addition of at least one amino acid susceptible to participation in a crosslinking with the crosslinking group (for example, whose amino acid side chain includes a heteroatom that can participate in this crosslinking).

[00107] In some respects, the disclosure provides conjugates, methods for their synthesis, and uses thereof, including a target protein-binding chemical moiety capable of covalent or non-covalent binding to a target protein conjugated to a presenter protein via a ligand.

[00108] Consequently, in another aspect, the disclosure provides a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein. In some embodiments, the target protein-binding chemical moiety of the conjugate has the capacity for non-covalent interaction with a target protein. In some embodiments, the target protein-binding chemical moiety of the conjugate has the capacity for non-covalent interaction with the target protein. In some embodiments, the target protein-binding chemical moiety and the presenting protein are conjugated through a ligand.

[00109] In some respects, the disclosure provides a method for producing a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein. This method involves reacting (a) a compound that includes a target protein-binding chemical moiety and a crosslinking group with (b) a presenting protein under conditions that permit the production of the conjugate.

[00110] In some respects, the disclosure provides a method for producing a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein. This method includes providing (a) a compound that includes a target protein-binding chemical moiety and a crosslinking group; (b) a protein Petition 870260070873, dated 07 / 16 / 2026, p. 32 / 532 24 / 220 presenting protein; and (c) a target protein; and react the compound with the presenting protein under conditions that allow conjugate production.

[00111] In some embodiments, detectable binding between the compound and the target protein is observed in the presence of the presenting protein. In some embodiments, however, detectable binding between the compound and the target protein is not observed (e.g., the presenting protein does not bind substantially to the compound) in the absence of the presenting protein. In some embodiments, significant reaction between the crosslinking group and the presenting protein (e.g., significant conjugate formation) is not observed in the absence of the target protein. In some embodiments, however, significant reaction between the crosslinking group and the presenting protein can be observed even in the absence of the target protein.In some embodiments, the rate and / or extent of this reaction (e.g., the rate and / or amount of conjugate formation) may differ in a given assay when the presenting protein is present compared to when it is absent (e.g., the rate and / or amount of conjugate formation is 2 times, 3 times, 4 times, 5 times, 10 times, 100 times greater in the presence of the presenting protein).

[00112] In some embodiments, the target protein binds to the compound in the absence of the presenting protein. In some embodiments, the target protein does not bind substantially to the compound in the absence of the presenting protein. In some embodiments, the presenting protein does not bind substantially to the compound in the absence of the target protein. In some embodiments, the reaction between the crosslinking group and the target protein (e.g., conjugate formation) is not observed in the absence of the presenting protein. In some embodiments, however, the reaction between the crosslinking group and the target protein is observed. Petition 870260070873, dated 07 / 16 / 2026, page 33 / 532 25 / 220 tion and the target protein is observed even in the absence of the presenting protein. In some embodiments, conjugate production as described herein is carried out under conditions that do not include (e.g., are substantially free of) a reducing agent.

[00113] In some embodiments, the present invention provides a complex comprising (i) a presenting protein; (ii) a compound as described herein (for example, a compound whose structure includes a presenting protein binding chemical moiety and a crosslinking group); and (iii) a target protein. In some embodiments, this complex is exposed to and / or maintained under conditions that allow the crosslinking chemical moiety to react with the target protein, so that a crosslink between them is formed. In some embodiments, the crosslink is with a heteroatom on an amino acid (for example, on an amino acid side chain) of the target protein. In some embodiments, the crosslink is with an -S- atom on a cysteine ​​in the target protein.In some embodiments, the target protein is a variant of a natural target protein; in some of these embodiments, the variant has an amino acid sequence that shows a high degree (e.g., 80%, 81%, 82%; 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or higher) of similarity to the natural target protein, but differs by substitution or addition of at least one amino acid susceptible to participation in a crosslinking with the crosslinking group (e.g., whose amino acid side chain includes a heteroatom that can participate in this crosslinking).

[00114] In some respects, disclosure provides complexes, methods for their production, and uses thereof, including a target protein and a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein via a li Petition 870260070873, dated 07 / 16 / 2026, p. 34 / 532 26 / 220 gante.

[00115] In some embodiments, the disclosure provides a complex that includes (i) a conjugate comprising a target protein-binding chemical moiety conjugated to a presenter protein; (ii) a target protein; and (iii) a presenter protein. In some embodiments, this complex is exposed and / or maintained under conditions that allow the crosslinking chemical moiety to react with the presenter protein, so that a crosslink between them is formed. In some embodiments, the crosslink is with a heteroatom on an amino acid (e.g., on an amino acid side chain) of the presenter protein. In some embodiments, the crosslink is with an -S- atom on a cysteine ​​in the presenter protein.In some embodiments, the presenting protein is a variant of a natural presenting protein; in some of these embodiments, the variant has an amino acid sequence that shows a high degree (e.g., 80%, 81%, 82%; 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or higher) of similarity to the natural presenting protein, but differs by substitution or addition of at least one amino acid susceptible to participation in a crosslinking with the crosslinking group (e.g., whose amino acid side chain includes a heteroatom that can participate in this crosslinking).

[00116] In some respects, the disclosure provides a method for producing a complex that includes (i) a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein and (ii) a target protein. This method involves combining a conjugate that includes a target protein-binding chemical moiety conjugated to a presenting protein and a target protein under conditions that allow production of the complex.

[00117] In some respects, the invention presents a method for Petition 870260070873, dated 07 / 16 / 2026, p. 35 / 532 27 / 220 to produce a complex that includes (i) a conjugate as described in this document (for example, a conjugate that includes a target protein-binding chemical moiety and a presenting protein) and (ii) a target protein. In some of these embodiments, a method provided includes combining the conjugate and target protein under conditions that permit the production of the complex. Alternatively or additionally, in some embodiments, these methods include, for example, (i) combining (a) a compound (for example, a compound whose structure includes a target protein-binding chemical moiety and a crosslinking group); (b) a target protein; and (c) a presenting protein with each other; and (ii) exposing the combination and / or maintaining the combination under conditions that permit the production of the complex. In some of these embodiments, the conditions permit the reaction of the crosslinking group with the presenting protein so that a conjugate is produced.

[00118] In some respects, the disclosure provides a method for producing a complex that includes (i) a conjugate comprising a target protein-binding chemical moiety conjugated to a presenting protein and (ii) a target protein. This method includes providing (a) a compound comprising a target protein-binding chemical moiety and a crosslinking group; (b) a presenting protein; and (c) a target protein; and reacting the compound with the presenting protein under conditions that permit production of the complex.

[00119] In some of these embodiments, the conditions are such that the compound, presenting protein, and / or target protein are characterized by the fact that detectable binding between the compound and the target protein is observed in the absence of the presenting protein. In some embodiments, however, detectable binding between the compound and the target protein is not observed (e.g., the target protein does not bind substantially to the compound) under the conditions in the au Petition 870260070873, dated 07 / 16 / 2026, page 36 / 532 28 / 220 presence of the presenting protein. In some embodiments, a significant reaction between the crosslinking group and the presenting protein is not observed in the absence of the target protein under the conditions. In some embodiments, however, a significant reaction between the crosslinking group and the presenting protein can be observed even in the absence of the target protein under the conditions. In some embodiments, the conditions do not include a reducing reagent. In some embodiments, the conditions include an excess of presenting protein.

[00120] In some embodiments, the target protein binds to the compound in the absence of the presenting protein. In some embodiments, the target protein does not bind substantially to the compound in the absence of the presenting protein. In some embodiments, the compound and the presenting protein do not react substantially in the absence of the target protein. In some embodiments, the compound and the presenting protein react in the absence of the target protein. In some embodiments, the conditions do not include a reducing reagent. In some embodiments, the conditions include an excess of target protein.

[00121] In some aspects, the disclosure provides compounds that include a presenter protein-binding chemical moiety capable of non-covalent interaction with a presenter protein and a target protein-binding chemical moiety capable of covalent or non-covalent interaction with a target protein. In some embodiments, the presenter protein-binding chemical moiety and the target protein-binding chemical moiety are fixed by means of a ligand.

[00122] Consequently, in some respects, the disclosure provides a compound that has the structure of Formula VII: Petition 870260070873, dated 07 / 16 / 2026, p. 37 / 532 29 / 220 ALB Formula VII

[00123] where A includes the Villa or Vlllb Formula structure: R4R4 Formula Villa Formula Vlllb

[00124] where bec are independently 0, 1, or 2;

[00125] d is 0, 1,2, 3, 4,5, 6 or 7;

[00126] X1 and X2 are, each independently, absent, CH2, O, S, SO, SO2 or NR13;

[00127] each R1 and R2 is independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl (e.g., optionally substituted C2-C9 heteroaryl), optionally substituted C2-C9 heterocyclyl C1-C1 alkyl (e.g., optionally substituted C2-C9 heteroaryl C1-C1 alkyl), or R1 and R2 combined with the carbon atom to which they are attached to form C=O or R1 and R2 combined to form an optionally substituted Cs-Cw carbocyclyl or optionally substituted C2-C9 heterocyclyl;

[00128] each R3 is independently hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C2 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl Petition 870260070873, dated 07 / 16 / 2026, page 38 / 532 30 / 220 optionally substituted, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl (e.g., optionally substituted C2-C9 heteroaryl), or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl (e.g., optionally substituted C2-C1 heteroaryl C1-C1 alkyl) or two R8s combined to form an optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C2-C9 heterocyclyl, e.g., optionally substituted C2-C9 heteroaryl;

[00129] R4 is optionally substituted Ci-Ce alkyl;

[00130] L is an optional binder; and

[00131] B is a target protein binding chemical moiety.

[00132] In some embodiments of a compound of Formula VII, the target protein-binding chemical portion, B, has the capacity for non-covalent interaction with a target protein. In some embodiments of a compound of Formula VII, the target protein-binding chemical portion, B, has the capacity for covalent interaction with a target protein. In some embodiments of a compound of Formula VII, the ligand, L, is present. In some embodiments of a compound of Formula VII, the ligand, L, is absent.

[00133] In some respects, the disclosure provides ternary complexes, methods for their production, and uses thereof, including a presenting protein, a target protein, and a compound that includes a chemical portion binding the presenting protein and a chemical portion binding the target protein.

[00134] Consequently, in another aspect, the disclosure provides a complex that includes (i) a compound of Formula VII; (ii) a Petition 870260070873, dated 07 / 16 / 2026, p. 39 / 532 31 / 220 target protein; and (iii) a presenting protein.

[00135] In some embodiments, the compounds, conjugates and complexes of the present invention may be useful for identifying conjugates that include a chemically binding portion of a presenting protein and a target protein that have the ability to form complexes with presenting proteins.

[00136] In some respects, the invention provides a method for identifying and / or characterizing a conjugate as described herein (for example, wherein a compound whose structure includes a chemical portion for binding a presenting protein and a crosslinking group, is conjugated to a target protein) that has the ability to form a complex with a presenting protein.In some embodiments, this method includes the steps of: (a) providing (i) this conjugate (for example, a compound whose structure includes a chemical portion of the presenting protein and a crosslinking group, conjugated to a target protein) and (ii) a presenting protein; (b) combining the conjugate and the presenting protein under suitable conditions to allow complex formation if the conjugate has the ability to form a complex with the presenting protein; and (c) determining whether a complex comprising the conjugate and the presenting protein is formed, wherein complex formation indicates that the conjugate is one that has the ability to form a complex with a presenting protein.

[00137] Consequently, in some respects, the disclosure provides a method for identifying and / or characterizing a conjugate that has the capacity to form a complex with a presenter protein. This method includes the steps of: (a) providing (i) a conjugate including a chemical-binding presenter protein moiety conjugated to a target protein and (ii) a presenter protein; (b) Petition 870260070873, dated 07 / 16 / 2026, page 40 / 532 32 / 220 combine the conjugate and the presenting protein under suitable conditions to allow complex formation if the conjugate has the capacity to form a complex with the presenting protein; and (c) determine whether a complex comprising the conjugate and the presenting protein is formed, wherein complex formation indicates that the conjugate is one that has the capacity to form a complex with a presenting protein.

[00138] In some embodiments, the compounds, conjugates and complexes of the present invention may be useful for identifying target proteins capable of forming covalent bonds to the compounds in the presence of a presenting protein.

[00139] Consequently, in another aspect, the disclosure provides a method for identifying and / or characterizing the target protein capable of reacting with a compound in the presence of a presenting protein, wherein the compound includes a chemical portion for binding to the presenting protein and a chemical portion for cross-linking.This method includes the steps of: (a) providing (i) a compound comprising a chemical portion for binding a presenting protein and a chemical portion for cross-linking; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the conjugate has the capacity to form a complex with the presenting protein; and (c) determining whether the target protein and the compound react during complex formation to form a conjugate, wherein if the target protein and the compound form a conjugate, the target protein is identified as having the capacity to react with the compound in the presence of a presenting protein.

[00140] In some embodiments, the compounds, conjugates and complexes of the invention may be useful for the identification of proteins. Petition 870260070873, dated 07 / 16 / 2026, p. 41 / 532 33 / 220 target proteins with the ability to form complexes with presenting proteins.

[00141] Consequently, in another aspect, the disclosure provides a method for identifying and / or characterizing a target protein that binds to a presenting protein. This method includes the steps of: (a) providing (i) a conjugate comprising a chemical binding moiety of a presenting protein conjugated to a target protein and (ii) a presenting protein; (b) combining the conjugate and the presenting protein under suitable conditions to allow complex formation if the conjugate has the ability to form a complex with the presenting protein; and (c) determining whether the target protein binds to the presenting protein in the complex, where if the target protein binds to the presenting protein, the target protein is identified as binding to the presenting protein.

[00142] In some respects, the disclosure provides a method for identifying and / or characterizing a target protein that binds to a presenting protein. This method includes the steps of: (a) providing (i) a compound comprising a chemical portion that includes a presenting protein binding moiety and a chemical portion that includes a cross-linking moiety; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the conjugate has the capacity to form a complex with the presenting protein; and (c) determining whether the target protein binds to the presenting protein in the complex, where if the target protein binds to the presenting protein, the target protein is identified as a target protein that binds to a presenting protein.

[00143] In some respects, disclosure provides a method for identifying and / or characterizing the target protein capable of forming a complex with a presenting protein. This method in Petition 870260070873, dated 07 / 16 / 2026, page 42 / 532 34 / 220 includes the steps of: (a) providing (i) a compound of Formula VII; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the conjugate has the capacity to form a complex with the presenting protein; and (c) determining whether the compound, the target protein, and the presenting protein form a complex, wherein if the compound, the target protein, and the presenting protein form a complex, the target protein is identified as a target protein capable of forming a complex with a presenting protein.

[00144] In some respects, the disclosure provides a method for identifying and / or characterizing a target protein that binds to a presenting protein. This method includes the steps of: (a) providing (i) a compound of Formula VII; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the compound has the ability to form a complex with the presenting protein; and (c) determining whether the target protein binds to the presenting protein in the complex, where if the target protein binds to the presenting protein, the target protein is identified as a target protein that binds to a presenting protein.

[00145] In some respects, disclosure provides a method for identifying a target protein capable of forming a complex with a presenting protein by (a) providing (i) one or more target proteins, (ii) any of the foregoing compounds; and (iii) a presenting protein that includes a tag (e.g., an affinity tag); (b) combining the compound with one or more target proteins and the presenting protein under suitable conditions to allow complex formation if one or more of the target proteins have the capacity to form a complex with the presenting protein. Petition 870260070873, dated 07 / 16 / 2026, p. 43 / 532 35 / 220 presenter; and (c) determine whether one or more target proteins form a complex with the compound and the presenting protein; wherein target proteins that form a complex with the presenting protein are identified as a target protein capable of forming a complex with a presenting protein.

[00146] In some embodiments, the determination step comprises using the tag of said presenting protein to selectively isolate target proteins that have formed a complex with the presenting protein (for example, by use in a pulldown experiment). In some embodiments, the complex includes a target protein, a presenting protein, and a compound of the invention. In some embodiments, the complex includes a conjugate comprising a target protein and a chemical binding moiety of the presenting protein (for example, a conjugate formed by the reaction between a crosslinking group of a compound of the invention and a reactive amino acid of a target protein) and a presenting protein. In some embodiments, the method further comprises (d) identifying the target protein (for example, determining the structure of the target protein) in a complex formed between one or more target proteins, the compound, and the presenting protein.In some embodiments, identifying the target protein structure involves performing mass spectrometry on the complex. In some embodiments, determining whether the target protein and presenting protein form a complex and / or whether the target protein binds to the presenting protein in the complex can be performed using pulldown experiments in which the target protein or the presenting protein is labeled (e.g., where a complex can be selectively pulldown-tested in the presence of target proteins and / or presenting proteins that are not in a complex).

[00147] In some respects, disclosure provides a method for Petition 870260070873, dated 07 / 16 / 2026, p. 44 / 532 36 / 220 identify a target protein capable of forming a complex with a presenting protein by (a) providing (i) two or more target proteins; (ii) any of the preceding compounds; and (iii) a presenting protein that includes an affinity tag; (b) combining the two or more target proteins, the compound, and the presenting protein under suitable conditions to allow complex formation if said target protein has the capacity to form a complex with the presenting protein; (c) selectively isolating one or more complexes of a target protein, the compound, and the presenting protein formed in step (b); and (d) identifying the target protein (e.g., determining the structure of the target protein) in one or more complexes isolated in step (c) by mass spectrometry; thus identifying a target protein capable of forming a complex with a presenting protein.

[00148] In some embodiments, the determination step comprises using the tag of said presenting protein to selectively isolate target proteins that have formed a complex with the presenting protein (for example, by use in a pulldown experiment). In some embodiments, the complex includes a target protein, a presenting protein, and a compound of the invention. In some embodiments, the complex includes a conjugate comprising a target protein and a chemical binding moiety of the presenting protein (for example, a conjugate formed by the reaction between a crosslinking group of a compound of the invention and a reactive amino acid of a target protein) and a presenting protein.In some embodiments, the determination of whether the target protein and presenting protein form a complex and / or whether the target protein binds to the presenting protein in the complex can be performed using pulldown experiments in which the target protein or the presenting protein is labeled (e.g., in which a complex can be subjected to pulldown). Petition 870260070873, dated 07 / 16 / 2026, p. 45 / 532 37 / 220 selectively downwards in the presence of target proteins and / or presenting proteins that are not in a complex).

[00149] In some embodiments, the compounds, conjugates and complexes of the present invention may be useful for identifying locations on target proteins to attach chemical binding moieties of the presenting protein, which may result in conjugates with the ability to form complexes with presenting proteins.

[00150] Consequently, in another aspect, the disclosure provides a method for identifying and / or characterizing a location on a target protein to form a conjugate with a chemical-binding portion of a presenting protein, which conjugate has the capacity to form a complex with a presenting protein.This method includes the steps of: (a) providing (i) a conjugate that includes a chemical binding moiety of a presenting protein conjugated to a target protein at a location and (ii) a presenting protein; (b) combining the conjugate and the presenting protein; (c) determining whether the conjugate and the presenting protein form a complex; and (d) optionally repeating steps (a) to (c) with the chemical binding moiety of the presenting protein conjugated at different locations on the target protein until a conjugate and the presenting protein form a complex, wherein a location on a target protein to form a conjugate with a chemical binding moiety of a presenting protein, a conjugate which has the capacity to form a complex with a presenting protein is identified if the conjugate and the presenting protein form a complex. In some embodiments, the presenting protein is a variant of a naturally occurring target protein.

[00151] In some respects, disclosure provides a method for identifying and / or characterizing a location on a target protein to form a conjugate with a protein-binding chemical moiety. Petition 870260070873, dated 07 / 16 / 2026, p. 46 / 532 38 / 220 presenter, conjugate which has the capacity to form a complex with a presenter protein. This method includes the steps of: (a) providing (i) a compound that includes a presenter protein-binding chemical moiety and a crosslinking group; (ii) a target protein; and (iii) a presenter protein; (b) combining the compound with the target protein in the presence of the presenter protein under conditions that allow the formation of a conjugate that includes a presenter protein-binding chemical moiety conjugated to a target protein at one location; (c) determining whether the conjugate and the presenter protein form a complex; and (d) optionally repeating steps (a) to (c) in which the presenter protein-binding chemical moiety is conjugated at different locations on the target protein until a conjugate and the presenter protein form a complex;in which a location on a target protein to form a conjugate with a chemical-binding moiety of a presenting protein, which has the capacity to form a complex with a presenting protein, is identified if the conjugate and the presenting protein form a complex, thus identifying a location on a target protein to form a conjugate with the capacity to form a complex with a presenting protein. In some embodiments, the target protein is a variant of a naturally occurring target protein.

[00152] In some embodiments, the compounds, conjugates, and complexes of the present invention may be useful for identifying compounds capable of forming covalent bonds to target proteins in the presence of presenting proteins. In some embodiments, the selectively identified compounds form covalent bonds with target proteins in the presence of presenting proteins.

[00153] Consequently, in another aspect, disclosure provides Petition 870260070873, dated 07 / 16 / 2026, p. 47 / 532 39 / 220 is a method for identifying and / or characterizing a compound capable of covalently binding to a target protein in the presence of a presenting protein. This method includes the steps of: (a) providing a sample including (i) a compound comprising a presenting protein-binding chemical moiety and a crosslinking group; (ii) a target protein; and (iii) a presenting protein; and (b) determining whether the compound and the target protein form a covalent bond through the crosslinking group in said compound in the sample, wherein a compound is identified as covalently binding to a target protein in the presence of a presenting protein if the compound and the target protein react in the sample.

[00154] In some respects, disclosure provides a method for identifying and / or characterizing a compound with the capacity for selective and covalent binding to a target protein in the presence of a presenting protein.This method includes the steps of: (a) providing a first sample including (i) a compound that includes a chemical portion of a protein-presenting host and a crosslinking group; (ii) a target protein; and (iii) a protein-presenting host and a second sample that includes (i) the same compound that includes a chemical portion of a protein-presenting host and a crosslinking group as in the first sample and (ii) the same target protein as in the first sample; and (b) determining the extent to which the compound and the target protein react in the first sample compared to the second sample, wherein a compound is identified as selectively covalently binding to a target protein in the presence of a protein-presenting host if the compound and the target protein react in the first sample more than in the second sample.

[00155] In some embodiments, a compound is identified as selectively covalently binding to a target protein in the presence of a protein-presenting compound if the compound and the protein Petition 870260070873, dated 07 / 16 / 2026, p. 48 / 532 40 / 220 target proteins react in the first sample at least 5 times more than in the second sample. In some embodiments, a compound is identified as selectively binding covalently to a target protein in the presence of a presenting protein if the compound and the target protein react in the first sample but do not react substantially in the second sample.

[00156] In some embodiments, the compounds, conjugates, and complexes of the present invention may be useful in identifying conjugates that include a target protein and a chemical-binding portion of a presenting protein capable of forming complexes with presenting proteins.

[00157] Consequently, in another aspect, the disclosure provides a method for identifying and / or characterizing a conjugate capable of forming a complex with a presenting protein. This method includes the steps of: (a) providing (i) a conjugate including a chemical-binding portion of a presenting protein conjugated to a target protein and (ii) a presenting protein; and (b) combining the conjugate and the presenting protein under suitable conditions to form a complex; (c) determining whether the conjugate and the presenting protein form a complex, wherein a conjugate is identified as capable of forming a complex with a presenting protein if the conjugate and the presenting protein form a complex, thus identifying a conjugate capable of forming a complex with a presenting protein.

[00158] In some embodiments, the binding between a conjugate and a protein can be determined by a method that includes a ternary-time resolved fluorescence energy transfer assay, a ternary amplified luminescent proximity homogeneous assay, an isothermal titration calorimetry, surface plasmon resonance, or nuclear magnetic resonance. Petition 870260070873, dated 07 / 16 / 2026, page 49 / 532 41 / 220

[00159] In some embodiments, the compounds, conjugates, and complexes of the present invention may be useful for determining the structure of protein-protein interfaces between presenting proteins and target proteins.

[00160] Consequently, in another aspect, the disclosure provides a method for determining the structure of and / or evaluating one or more structural features of an interface in a complex that includes a presenting protein and a target protein. This method includes the steps of: (a) providing (i) a conjugate that includes a chemical binding moiety of a presenting protein conjugated to a target protein and (ii) a presenting protein; (b) contacting the conjugate with a presenting protein to form a complex (e.g., in a flask); and (c) determining the crystal structure of the complex, wherein the interface structure includes at least the portion of the crystal structure between the presenting protein and the target protein, thereby determining the structure of an interface in a complex that includes a presenting protein and a target protein.

[00161] In some respects, the disclosure provides a method for determining the structure of and / or evaluating one or more structural features of an interface in a complex that includes a presenting protein and a target protein. This method includes the steps of: (a) providing (i) a compound that includes a presenting protein-binding chemical moiety and a cross-linking chemical moiety; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to form a conjugate between the compound and the target protein and to form a complex between said conjugate and said presenting protein (e.g., in a flask); and (c) determining the crystal structure of the complex, wherein the interface structure includes at least the portion of the crystal structure between the protein Petition 870260070873, dated 07 / 16 / 2026, p. 50 / 532 42 / 220 presenting protein and the target protein, thus determining the structure of an interface in a complex that includes a presenting protein and a target protein.

[00162] In some respects, the disclosure provides a method for determining the structure of and / or evaluating one or more structural features of an interface in a complex that includes a presenting protein and a target protein. This method includes the steps of: (a) providing (i) a compound of Formula VII; (ii) a target protein; and (iii) a presenting protein; (b) forming a complex that includes the compound, the target protein, and the presenting protein (e.g., in a flask); and (c) determining the crystal structure of the complex, wherein the interface structure includes at least the portion of the crystal structure between the presenting protein and the target protein, thereby determining the structure of an interface in a complex that includes a presenting protein and a target protein.

[00163] In some respects, the disclosure provides a method for determining the structure of and / or evaluating one or more structural features of a protein-protein interface in a complex that includes a presenting protein and a target protein. This method includes the steps of: (a) providing a crystal of any of the aforementioned complexes; and (b) determining the structure of the crystal, in which the interface structure includes at least the portion of the crystal structure between the presenting protein and the target protein, thereby determining the structure of a protein-protein interface in a complex that includes a presenting protein and a target protein.

[00164] In some respects, disclosure provides a method for identifying and / or characterizing compounds with the ability to modulate the biological activity of a target protein. This method includes the steps of: (a) providing the structure of a protein-protein interface in a complex that includes a presenting protein and a protein Petition 870260070873, dated 07 / 16 / 2026, p. 51 / 532 43 / 220 target (for example, a structure determined by any of the previous methods); and (b) determine the structure of compounds capable of binding at the interface, thus identifying compounds capable of modulating the biological activity of a target protein. In some embodiments, the structure of compounds capable of binding at the interface is determined using computational methods. In some embodiments, the structure of compounds capable of binding at the interface is determined by screening compounds that include a presenting protein-binding chemical moiety described in this document for complex formation in the presence of a target protein and a presenting protein.

[00165] In some respects, the disclosure provides a method for obtaining X-ray crystal coordinates for a complex. This method includes the steps of: (a) providing (i) a conjugate that includes a chemical-binding presenter protein moiety conjugated to a target protein and (ii) a presenter protein; (b) combining the conjugate and the presenter protein under suitable conditions to allow complex formation if the conjugate has the capacity to form a complex with the presenter protein; and (c) determining the crystal structure of the complex, thereby obtaining the X-ray crystal coordinates for the complex.

[00166] In some respects, the disclosure provides a method for obtaining X-ray crystal coordinates for a complex. This method includes the steps of: (a) providing (i) a compound comprising a presenting protein-binding chemical moiety and a cross-linking chemical moiety; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the compound has the capacity to form a complex. Petition 870260070873, dated 07 / 16 / 2026, p. 52 / 532 44 / 220 with the presenting protein; and (c) determine the crystal structure of the complex, thereby obtaining X-ray crystal coordinates for the complex.

[00167] In some respects, the disclosure provides a method for obtaining X-ray crystal coordinates for a complex. This method includes the steps of: (a) providing (i) a compound of the invention; (ii) a target protein; and (iii) a presenting protein; (b) combining the compound, the target protein, and the presenting protein under suitable conditions to allow complex formation if the compound has the ability to form a complex with the presenting protein; and (c) determining the crystal structure of the complex, thereby obtaining the X-ray crystal coordinates for the complex.

[00168] In some respects, the disclosure provides a method for determining the residues in a target protein that participate in binding with a presenting protein. This method includes the steps of: (a) providing X-ray crystal coordinates of a complex obtained by a method for the invention; (b) identifying the residues of the target protein that include an atom within 4 Å of an atom in the presenting protein; thus determining the residues in a target protein that participate in binding with a presenting protein. In some respects, the disclosure provides a method for determining biochemical and / or biophysical properties of any of the presenting protein / target protein complexes described in this document.This method includes the steps of: (a) providing X-ray crystal coordinates of a complex described herein obtained by a method described herein; (b) calculating a biochemical and / or biophysical property of the complex; thereby determining biochemical and / or biophysical properties of a complex presenting protein / target protein.

[00169] In some forms, the biochemical properties Petition 870260070873, dated 07 / 16 / 2026, page 53 / 532 45 / 220 and / or biophysical properties include the binding free energy of a complex, the Kd of a complex, the K of a complex, the Kinata of a complex, and / or the Ki / Kinata of a complex. In some embodiments, the biochemical and / or biophysical properties are determined by isothermal titration calorimetry, surface plasmon resonance, and / or mass spectrometry.

[00170] In some embodiments, the interface in a complex including a presenting protein and a target protein is or comprises a binding pocket.

[00171] In some respects, the disclosure provides compositions that include any of the above compounds, a target protein, and a presenting protein in solution.

[00172] In some respects, the disclosure provides a pharmaceutical composition including any of the compounds, conjugates or complexes of the invention and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in unit dosage form.

[00173] In some respects, the disclosure provides a method for modulating a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). In some embodiments, this method includes the steps of contacting the target protein with a modulating amount (e.g., positive or negative modulation) of any of the compounds (e.g., in the presence of a presenting protein), conjugates including a target protein-binding chemical moiety, or compositions of the invention.

[00174] In some respects, disclosure provides a method for modulating (e.g., modulating positively or negatively) a target protein (e.g., a eukaryotic target protein such as Petition 870260070873, dated 07 / 16 / 2026, pp. 54 / 532 46 / 220 a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). In some embodiments, this method includes the steps of contacting a cell expressing the target protein and a presenting protein with an effective amount of a compound or composition of the invention under conditions in which the compound can form a complex with a presenting protein and the resulting complex can bind to the target protein, thus modulating (e.g., positively or negatively modulating) the target protein.

[00175] In some aspects, the disclosure provides a method for modulating (e.g., positively or negatively modulating) a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). In some embodiments, this method includes the steps of contacting the target protein with the conjugate of the invention including a target protein-binding chemical moiety, thereby modulating the target protein.

[00176] In some respects, the disclosure provides a method for inhibiting prolyl isomerase activity. In some embodiments, this method includes contacting a cell expressing prolyl isomerase with a compound or composition of the invention under conditions that allow the formation of a complex between the compound and prolyl isomerase, thereby inhibiting prolyl isomerase activity.

[00177] In some respects, the disclosure provides a method for forming a presenting protein / compound complex in a cell. In some embodiments, this method includes the steps of contacting a cell expressing the presenting protein with a compound or composition of the invention under conditions that allow the formation of a complex between the compound and the presenting protein.

[00178] In some embodiments of any of the compounds Petition 870260070873, dated 07 / 16 / 2026, p. 55 / 532 47 / 220 previous, conjugated, complexed, composed, or method-based embodiments, the presenting protein binding chemical moiety has the capacity to bind a protein encoded by any of the genes in Table 1. In some embodiments of any of the previous compounds, conjugated, combined, composed, or method-based embodiments, the presenting protein binding chemical moiety is a prolyl isomerase binding chemical moiety. In some embodiments of any of the previous compounds, conjugated, combined, composed, or method-based embodiments, the presenting protein binding chemical moiety is an FKBP binding chemical moiety (e.g., the presenting protein binding chemical moiety has the capacity to bind FKBP12, FKBP12).6, FKBP13, FKBP25, FKBP51, or FKBP52), a cyclophilin-binding chemical moiety (for example, the presenting protein-binding chemical moiety has the capacity to bind PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1), or a PIN 1-binding chemical moiety. In some embodiments of any of the foregoing methods, the presenting protein is known to bind to the presenting protein-binding chemical moiety.

[00179] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the presenting protein binding chemical moiety is an FKBP binding chemical moiety (e.g., a selective FKBP binding chemical moiety or a non-selective FKBP binding chemical moiety). In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the FKBP binding chemical moiety includes the structure of Formula Ha or llb: Petition 870260070873, dated 07 / 16 / 2026, p. 56 / 532 48 / 220 Formula Ha Formula lib

[00180] wherein Z1 and Z2 are each independently optionally substituted C1-C1 alkyl, optionally substituted C1-C1 heteroalkyl, or Z1 and Z2 combined to form, with the atoms to which they are attached, an optionally substituted 10 to 40 membered macrocycle; and wherein at least one of Z1 or Z2 includes an attachment point to the crosslinking group;

[00181] bec are, independently, 0, 1, or 2;

[00182] d is 0, 1,2, 3, 4, 5, 6 or 7;

[00183] X1 and X2 are, each independently, absent, CH2, O, S, SO, SO2 or NR4;

[00184] each R1 and R2 is independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl (e.g., optionally substituted C2-C9 heteroaryl), optionally substituted C2-C9 heterocyclyl C1-C1 alkyl (e.g., optionally substituted C2-C9 heteroaryl C1-C1 alkyl), or R1 and R2 combined with the carbon atom to which they are attached to form C=O or R1 and R2 combined to form an optionally substituted Cs-Cw carbocyclyl or optionally substituted C2-C9 heterocyclyl; Petition 870260070873, dated 07 / 16 / 2026, p. 57 / 532 49 / 220

[00185] each R3 is independently a hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl (e.g., optionally substituted C2-C9 heteroaryl), or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl (e.g., optionally substituted C2-C1 heteroaryl C1-C1 alkyl) or two R8s combined to form an optionally substituted C3-C10 carbocyclyl, aryl Ce-Cw optionally substituted, for example, C2-C9 heteroaryl optionally substituted; and

[00186] each R4 is independently hydrogen, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, C3-C7 carbocyclyl, optionally substituted C1-C6 aryl C1-C1 alkyl, and optionally substituted C3-C7 carbocyclyl C1-C1 alkyl.

[00187] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the chemical portion of the presenting protein includes the following structure: Petition 870260070873, dated 07 / 16 / 2026, p. 58 / 532 50 / 220

[00188] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the presenting protein binding moiety is a cyclophilin binding moiety (e.g., a selective cyclophilin binding moiety or a non-selective cyclophilin binding moiety). In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the cyclophilin binding moiety includes the structure of Formula III or IV: Petition 870260070873, dated 07 / 16 / 2026, p. 59 / 532 51 / 220 Formula III Formula IV

[00189] wherein Z3, Z4, Z5, and Z6 are each independently hydroxyl, optionally substituted C1-C1 alkyl, optionally substituted C1-C1 heteroalkyl, or Z3 and Z4 or Z5 and Z6 combine to form, with the atoms to which they are attached, an optionally substituted 10 to 40 membered macrocycle;

[00190] at least one of Z3, Z4, Z5, Z6, or R5 includes an attachment point to the crosslinking group;

[00191] eéO, 1,2, 3, or 4;

[00192] R5e R7são, independently, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl Ci-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl Ci-Ce alkyl;

[00193] R6é alkylates optionally substituted Ci-Ce; and

[00194] R8 is hydrogen, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, C3-C7 carbocyclyl, optionally substituted C1-C1 aryl C1-C1 alkyl, and optionally substituted C3-C7 carbocyclyl C1-C1 alkyl.

[00195] In some embodiments of any of the compounds Petition 870260070873, dated 07 / 16 / 2026, p. 60 / 532 52 / 220 previous, conjugated, complex, compositions, or methods, the chemical binding moiety of cyclophilin includes the structure of Formula IVa: Formula IVa

[00196] wherein each R7 is independently hydroxyl, cyano, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C6 aryl, optionally substituted C2-C9 heterocyclyl (e.g., optionally substituted C2-C9 heteroaryl), or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl (e.g., optionally substituted C2-C9 heteroaryl C1-C6 alkyl).

[00197] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the chemical portion of the presenting protein includes the following structure: Petition 870260070873, dated 07 / 16 / 2026, page 61 / 532 53 / 220

[00198] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, a target protein is a GTPase, GTPase-activating protein, guanine nucleotide exchange factor, a heat shock protein, an ion channel, a coiled-coil protein, a kinase, a phosphatase, a ubiquitin ligase, a transcription factor, a chromatin modifier / remodeler, or a protein with classical protein-protein interaction motifs and domain. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the target protein includes a non-drug targetable surface. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the target protein does not have a traditional binding pocket.

[00199] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the target protein has been modified to replace at least one native amino acid with a reactive amino acid (by Petition 870260070873, dated 07 / 16 / 2026, p. 62 / 532 54 / 220 For example, a natural amino acid such as cysteine, lysine, tyrosine, aspartic acid, glutamic acid, or serine, or a non-natural amino acid). In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the target protein has been modified to replace at least one native reactive amino acid (e.g., cysteine, lysine, tyrosine, aspartic acid, glutamic acid, or serine) with a non-reactive amino acid (e.g., a natural amino acid such as serine, valine, alanine, isoleucine, threonine, tyrosine, aspartic acid, glutamic acid, or leucine, or a non-natural amino acid). In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the at least one native reactive amino acid is a solvent-exposed amino acid.In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the target protein is modified to replace all reactive amino acids with a non-reactive amino acid. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the substitution is a conservative substitution. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the target protein includes only one amino acid exposed to a reactive solvent.

[00200] In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the presenting protein is a protein encoded by any of the genes in Table 1. In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the presenting protein is a prolyl isomerase. In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the prolyl isomerase is a membrane Petition 870260070873, dated 07 / 16 / 2026, p. 63 / 532 55 / 220 bromide of the FKBP family (e.g., FKBP12, FKBP12.6, FKBP13, FKBP25, FKBP51, or FKBP52), a member of the cyclophilin family (e.g., PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, or PPWD1), or PIN1.

[00201] In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the presenting protein has been modified to replace at least one native amino acid with a reactive amino acid (for example, a natural amino acid such as cysteine, lysine, tyrosine, aspartic acid, glutamic acid, or serine or a non-natural amino acid). In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the presenting protein has been modified to replace at least one native reactive amino acid (for example, a cysteine, lysine, tyrosine, aspartic acid, glutamic acid, or serine) with a non-reactive amino acid (for example, a natural amino acid such as serine, valine, alanine, isoleucine, threonine, tyrosine, aspartic acid, glutamic acid, or leucine or a non-natural amino acid).In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, at least one native reactive amino acid is a solvent-exposed amino acid. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the amino acid sequence of the presenting protein is modified to replace all reactive amino acids with a non-reactive amino acid. In some embodiments of any of the foregoing compounds, conjugates, complexes, compositions, or methods, the substitution is a conservative substitution.

[00202] In some embodiments of any of the compounds Petition 870260070873, dated 07 / 16 / 2026, p. 64 / 532 In some embodiments of any of the previous compounds, conjugates, complexes, compositions, or methods, the ligand is 1 to 20 atoms long. In some embodiments of any of the previous compounds, conjugates, complexes, compositions, or methods, the ligand is 1.5 to 30 angstroms long.

[00203] In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the ligand has the structure of Formula V: A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2 Formula V

[00204] where A1 is a linkage between the ligand and the protein-binding chemical portion; A2 is a linkage between the crosslinking group and the ligand; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, O, S, and NRN; RN is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, l, j, and k are each independently 0 or 1;and D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkyl, or a chemical linkage connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k-A2;

[00205] In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the ligand includes the structure of Formula VI: Petition 870260070873, dated 07 / 16 / 2026, p. 65 / 532 57 / 220 Formula VI

[00206] where A1 is a link between the ligand and the chemical binding portion of the protein;

[00207] A2 is a link between the crosslinking group and the ligand;

[00208] I is 0, 1, 2, or 3;

[00209] m is 0 or 1;

[00210] néO, 1,ou2;e

[00211] X3, X4, and X5 are each independently absent, O, S, -CeC-, CR9R10 or NR11; and

[00212] Each R9, R10, and R11 are independently hydrogen, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, C3-C7 carbocyclyl, optionally substituted C1-C6 aryl C1-C1 alkyl, and optionally substituted C3-C7 carbocyclyl O-C1 alkyl. In some embodiments, each R9, R10, and R11 are independently hydrogen, unsubstituted C1-C1 alkyl, unsubstituted C2-C6 alkenyl, unsubstituted C2-C6 alkynyl, unsubstituted aryl, C3-C7 carbocyclyl, unsubstituted C1-C6 aryl C1-C1 alkyl, and unsubstituted C3-C7 carbocyclyl C1-C6 alkyl.

[00213] In some embodiments of any of the preceding compounds, conjugates, complexes, compositions, or methods, the ligand includes the structure: Petition 870260070873, dated 07 / 16 / 2026, page 66 / 532 58 / 220 οjqU. CHEMICAL TERMS

[00214] Those skilled in the art will understand that certain compounds described herein may exist in one or more isometric (e.g., stereoisomers, geometric isomers, tautomers) and / or isotopic forms (e.g., where one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium). Unless otherwise indicated or free from context, a depicted structure may be understood to represent any of these isomeric or isotopic forms, individually or in combination.

[00215] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, as well as enantiomers and diastereomers, are intended unless otherwise indicated. The compounds of this description containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by solving 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 description. The cis and trans geometric isomers of the compounds of this description are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[00216] In some embodiments, one or more compounds depicted in this document may exist in different tau forms. Petition 870260070873, dated 07 / 16 / 2026, p. 67 / 532 59 / 220 tautomeric forms. As it will be context-free unless explicitly excluded, references to these compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the exchange of a single bond for an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state that has the same empirical formula and total charge as a reference form. Examples of prototropic tautomeric chemical moieties include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms in which 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 locked in a form by suitable substitution. In certain embodiments, the tautomeric forms result from an acetal interconversion, for example, the interconversion illustrated in the diagram below:.

[00217] Those skilled in the art will understand that, in some embodiments, the isotopes of compounds described in this document can be prepared and / or used in accordance with the present invention. Isotopes refers to atoms that have the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, an isotopic substitution (e.g., substitution of hydrogen for deuterium) Petition 870260070873, dated 07 / 16 / 2026, p. 68 / 532 60 / 220 can alter the physicochemical properties of molecules, such as metabolism and / or the racemization rate of a chiral center.

[00218] 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, these entities can be used in any form, including in any solid form. In some embodiments, these entities are used in a particular form, for example, in a particular solid form.

[00219] In some embodiments, the compounds described and / or depicted in this document may be supplied and / or used in salt form.

[00220] In certain embodiments, the compounds described and / or depicted in this document may be supplied and / or used in the form of hydrate or solvate.

[00221] In several places in this descriptive report, the substituents of compounds of this description are described in groups or in ranges. It is specifically intended that this description includes each and every individual subcombination of the members of these groups and ranges. For example, the term C1-E alkyl is specifically intended to individually reveal methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C1-E alkyl. Furthermore, when a compound includes a plurality of positions in which the substituents are described in groups or in ranges, unless otherwise indicated, this description is intended to cover groups and individual compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.

[00222] In the present document a sentence of the optional form X Petition 870260070873, dated 07 / 16 / 2026, p. 69 / 532 61 / 220 optionally substituted (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 particularity X (e.g., alkyl) itself is optional.

[00223] The term alkyl, as used herein, refers to saturated hydrocarbon groups 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., linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted by one, two, three, or, in the case of alkyl groups of two or more carbons, four substituents independently selected from the group consisting of: (1) alkoxy C1e; (2) alkylsulfinyl C1w; (3) amino, as defined in this document (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2, where RN1 is as defined for amino); (4) Ce-io aryl-Ci-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy;(8) hydroxyl, optionally replaced by a protecting group; (9) nitro; (10) OxO (e.g., carboxaldehyde or acyl); (11) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO2Ra, optionally replaced by a protecting group O and wherein RA is selected from the group consisting of (a) C1-6 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C1-10 aryl, (d) hydrogen, (e) C1-6 aq-C1-10 aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of (CH2)s2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10). 10), and R' is H or C1-20 alkyl; Petition 870260070873, dated 07 / 16 / 2026, p. 70 / 532 62 / 220 alkyl, and (h) amino-polyethylene glycol of NRn1(CH2)s2(CH2CH2O)si(CH2)s3NRn1, wherein s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; (15) -C(O)NRB'RC', wherein each of RB' and Rc' is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, θ (d) C1-6 alq-Ce-w aryl; (16) -SO2RD, wherein RD is selected from the group consisting of (a) C16 alkyl, (b) Ce-w aryl, (c) C1-6 alq-Ce-w aryl, and (d) hydroxyl; (17) -SO2NRE'RF, wherein each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, θ (d) C1-6 alq-Ce-w aryl;(18) -C(O)RG', wherein RG' is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) Ce-w aryl, (d) hydrogen, (e) C1-6 alq-Ce-w aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10). 10), and R' is H or C1-20 alkyl, θ(h) amino-polyethylene glycol of NRN1(CH2)s2(CH2CH2O)si(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-20 alkyl;(19) -NRH'C(O)R', where RH is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and R1 is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1w alkyl); Petition 870260070873, dated 07 / 16 / 2026, p. 71 / 532 63 / 220 (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) Ce-io aryl, (d2) hydrogen, (e2) C1-6 alq-Ce-w aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', where s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, θ (h2) amino-polyethylene glycol of NRN1(CH2)s2(CH2CH2O)si(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; (20) -NRJC(O)ORK, wherein RJ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl,θ RK is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) Ce-w aryl, (d2) hydrogen, (e2) C1-6 alq-Ce-w aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of -(OH2)S2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, θ(h2) amino-polyethylene glycol of NRn1(OH2)s2(CH2CH2O)si(CH2)s3NRni, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; (21) amidine; and (22) silyl groups such as trimethylsilyl,t-butyldimethylsilyl and tri-isopropylsilyl. In some embodiments, each of these groups may be further substituted as described herein. Petition 870260070873, dated 07 / 16 / 2026, p. 72 / 532 64 / 220 document. For example, the alkylene group of a C1 alkyl group can be further replaced by an oxo group to provide the respective aryl substituent.

[00224] The term alkylene and the prefix alq-, as used herein, represent a saturated divalent hydrocarbon group derived from a branched or straight-chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term Cx.yalkylene and the prefix Cx.yalq- represent alkylene groups having between x and y carbons. 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 (e.g., C1-6, C1-10, C2-20, C2-6, C2-10, or C2-20 alkylene). In some embodiments, the alkylene may be further replaced by 1, 2, 3 or 4 substituent groups as defined herein for an alkyl group.

[00225] The term alkenyl, as used herein, represents monovalent branched or straight chain groups of, unless otherwise specified, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Alkenyls include both cis and trans isomers. The alkenyl groups may optionally be substituted by 1, 2, 3, or 4 substituent groups which are independently selected from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

[00226] The term alkynyl, as used in this document, represents monovalent branched or straight chain groups of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10). Petition 870260070873, dated 07 / 16 / 2026, p. 73 / 532 65 / 220 carbons) containing a carbon-carbon triple bond, exemplified by ethynyl, 1-propynyl, and the like. The alkynyl groups may optionally be replaced by 1, 2, 3, or 4 substituent groups selected independently from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

[00227] The term amino, as used herein, represents -N(RN1)2, wherein each RN1 is independently H, OH, NO2i N(RN2)2i SO2ORN2, SO2RN2, SORN2, a / V-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any other described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any other described herein), heterocyclyl (e.g., heteroaryl), or alkylheterocyclyl (e.g., alqheteroarila), where each of these cited RN1 groups may be optionally substituted, as defined in this document for each group;or two RN1s combine to form a heterocycline or a / V-protecting group, wherein each RN2 is independently H, alkyl or aryl. The amino groups of the invention may be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2). In a preferred embodiment, amino is NH2 or -NHRn1, wherein RN1 is independently OH, NO2, NH2, NRN22, SO2ORN2, SO2RN2, SORN2, alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl or others described herein), alkoxycarbonylalkyl (e.g., t; Petition 870260070873, dated 07 / 16 / 2026, p. 74 / 532 66 / 220 butoxycarbonylalkyl) or aryl, and each RN2 may be H, C1-20 alkyl (e.g., Ci-e alkyl), or Ce-io aryl.

[00228] The term amino acid, as described herein, refers to a molecule that has a side chain, an amino group, and an acid group (e.g., a carboxy group of CO2H or a sulfo group of -SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). As used herein, the term amino acid in its broader sense refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide linkages. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; In some embodiments, an amino acid is a D-amino acid; In some embodiments, an amino acid is an L-amino acid.Standard amino acid refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Non-standard amino acid refers to any amino acid other than the standard amino acids, regardless of whether it is synthetically prepared or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, may undergo a structural modification compared to the overall structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, and / or substitution compared to the overall structure. In some embodiments, this modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid compared to one containing an otherwise identical unmodified amino acid. Petition 870260070873, dated 07 / 16 / 2026, p. 75 / 532 67 / 220 In some embodiments, this modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, compared to one containing an otherwise identical unmodified amino acid. As will become evident from the context, in some embodiments, the term amino acid is used to refer to a free amino acid; in some embodiments it is used to refer to an amino acid residue of a polypeptide. In some embodiments, the amino acid is attached to the parent molecular group by a carbonyl group, in which the side chain or amino group is attached to the carbonyl group. In some embodiments, the amino acid is an α-amino acid. In certain embodiments, the amino acid is a β-amino acid. In some embodiments, the amino acid is a γ-amino acid. Exemplary side chains include an alkyl, aryl, heterocyclyl, alkaryl, alkylheterocyclyl, aminoalkyl, carbamoylalkyl, and optionally substituted carboxyalkyl.Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.The amino acid groups may be optionally replaced by one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents selected independently from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined in this document (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2, where RN1 is as defined for amino); (4) C1-I aryl-C1-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxyl; (9) nitro; (10) OxO (e.g., carboxaldehyde or acyl); (11) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO2RA, where RA is selected from the group consisting of (a) C1-20 alkyl (e.g., al. Petition 870260070873, dated 07 / 16 / 2026, p. 76 / 532 68 / 220 C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C1-6 aryl, (d) hydrogen, (e) C1-6 alkyl-C1-20 aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', where s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, and (h) amino-polyethylene glycol of NRn1(CH2)s2(CH2CH2O)si(CH2)s3NRn1, wherein s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl;(15) -C(O)NRB'RC', wherein each of RB' and Rc' is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-io aryl, θ (d) C1-6 alq-Ce-w aryl; (16) -SO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) Ce-w aryl, (c) C1-6 alq-Ce-w aryl, and (d) hydroxyl; (17) -SO2NRE'RF, wherein each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-io aryl, θ (d) C1-6 alq-Ce-w aryl;(18) -C(O)RG', wherein RG' is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-θ alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C1-w aryl, (d) hydrogen, (e) C1-6 alq-C1-w aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10). 10), and R' is H or C1-20 alkyl, and (h) amino-polyethylene glycol of NRN1(CH2)s2(CH2CH2O)si(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each from s2 and s3; Petition 870260070873, dated 07 / 16 / 2026, p. 77 / 532 69 / 220 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; (19) -NRH'C(O)Rr, where RH' is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and Rr is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C1-10 aryl, (d2) hydrogen, (e2) C1-6 alkyl-C1-20 aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, θ(h2) amino-polyethylene glycol of NRN1(CH2)s2(CH2CH2O)si(CH2)s3NRN1, where s1 is an integer from 1 to 10 (for example,from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; (20) -NRJC(O)ORK, wherein RJ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and RK' is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) Ce-w aryl, (d2) hydrogen, (e2) C1-6 alq-Ce-w aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of -(CH2)s2(OCH2CH2)si(CH2)s3OR', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of NRn1(CH2)s2(CH2CH2O)si(CH2)s3NRn1,where s1 is an integer from 1 to 10 (for example, from 1 to 6 or from 1 to 4), each of s2 and s3, Petition 870260070873, dated 07 / 16 / 2026, p. 78 / 532 70 / 220 is independently an integer from 0 to 10 (for example, from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is independently hydrogen or optionally substituted C1-6 alkyl; and (21) amidine. In some embodiments, each of these groups may be further substituted as described in this document.

[00229] The term N-alkylated amino acids as used herein refers to amino acids containing an optionally substituted O to C₆ alkyl group on the nitrogen of the amino acid that forms the peptide bond. N-alkylated amino acids include, without limitation, N-methyl amino acids such as N-methylalanine, N-methylthreonine, N-methylphenylalanine, N-methylaspartic acid, N-methylvaline, N-methylleucine, N-methylglycine, N-methylisoleucine, N(a)-methyllysine, N(a)-methylasparagine, and N(a)-methylglutamine.

[00230] The term aryl, as used in this document, represents a mono-, bi- or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted by 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of: (1) C1-7 acyl (e.g., carboxaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxyC1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) Ce-w aryl; (6) amino; (7) C1-6 alk-Ce-w aryl; (8) azide; (9) C3-8 cycloalkyl;(10) C1-6 alq-Cs-8 cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C1-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy; (14) hydroxyl; (15) nitro; (16) C1-20 thioalkoxy (e.g.; Petition 870260070873, dated 07 / 16 / 2026, p. 79 / 532 71 / 220 pio, C1-6 thioalkoxy); (17) -(CH2)qCO2RA, where q is an integer from zero to four, and RA' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce-w aryl, (c) hydrogen, and (d) C1-6 alq-Ce-w aryl; (18) -(CH2)qCONRB'Rc', where q is an integer from zero to four and where RBe and Rc are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, and (d) C1-6 alq-Ce-io aryl; (19) -(CH2)qSO2RD, where q is an integer from zero to four and where RD is selected from the group consisting of (a) alkyl, (b) Ce-w aryl, (c) alq-Ce-w aryl; (20) (CH2)qSO2NRE'RF, where q is an integer from zero to four and where each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, (d) C1-6 alq-Ce-w aryl; (21) thiol; (22) Ce-w aryloxy; (23) C3-8 cycloalkoxy; (24) Ce-w aryl-C1-6 alkoxy;(25) C1-6 alq-C1-12 heterocyclyl (e.g., C1-6 alq-C1-12 heteroaryl); (26) C2-20 alkenyl; and (27) C2-20 alkynyl. In some embodiments, each of these groups may be further substituted as described in this document. For example, the alkylene group of a C1-alkaryl or a C1alqheterocyclyl may be further substituted by an oxo group to provide the respective aryl and (heterocyclyl) substituent groups.

[00231] The arylalkyl group, as used herein, represents an aryl group, as defined herein, attached to the parent molecular group via an alkylene group, as defined herein. Unsubstituted arylalkyl groups of 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C1-6 alq-Ce-war aryl, C1-w alq-Ce-war aryl, or C1-20 alq-Ce-war aryl). In some embodiments, each of the alkylene and aryl groups may be further substituted by 1, 2, 3, or 4 substituent groups as defined herein for the Petition 870260070873, dated 07 / 16 / 2026, p. 80 / 532 72 / 220 respective groups. Other groups preceded by the prefix alq- are defined in the same way, where alq refers to a C1-6 alkylene, unless otherwise indicated, and the fixed chemical structure is as defined in this document.

[00232] The term azide represents a group -N3, which can be represented as -N=N=N.

[00233] The terms carbocyclic and carbocyclyl, as used in this document, refer to a non-aromatic, monocyclic, bicyclic or tricyclic C3-12 ring structure optionally substituted in which the rings are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl and cycloalkynyl groups.

[00234] The carbocyclylalkyl group, as used herein, represents a carbocyclic group, as defined herein, attached to the parent molecular group via an alkylene group, as defined herein. Exemplary unsubstituted carbocyclylalkyl groups are 7 to 30 carbons long (e.g., 7 to 16 or 7 to 20 carbons, such as C1-6 alq-Ce-io carbocyclyl, C1-10 alq-Ce-w carbocyclyl, or C1-20 alq-Ce-w carbocyclyl). In some embodiments, each of the alkylene and carbocyclyl groups may be further substituted by 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. Other groups preceded by the prefix alq- are defined in the same way, where alq refers to a C1-6 alkylene, unless otherwise indicated, and the fixed chemical structure is as defined in this document.

[00235] The term carbonyl, as used in this document, represents a C(O) group, which can also be represented as C=O.

[00236] The term carboxy, as used in this document, Petition 870260070873, dated 07 / 16 / 2026, page 81 / 532 73 / 220 means -CO2H.

[00237] The term cyan, as used in this document, represents a -CN group.

[00238] The term cycloalkyl, as used herein, represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl and the like. When the cycloalkyl group includes a carbon-carbon double bond, the cycloalkyl group may be referred to as a cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl and the like. The cycloalkyl groups of this invention may optionally be replaced by: (1) C1-7 acyl (e.g., carboxaldehyde);(2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxyC1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) arila Ce-w! (6) amino; (7) C1-6 alk-Ce-w aryl; (8) azide; (9) C3-8 cycloalkyl; (10) C1-6 alq-Cs-e cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C1-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy; (14) hydroxyl; (15) nitro; (16) C1-20 thioalkoxy (e.g., C1-6 thioalkoxy); (17) -(CH2)qCO2RA, where q is an integer from zero to four, and RA is selected from the group consisting of (a) C1-6 alkyl, (b) Ce-w aryl, (c) hydrogen, and (d) C1-6 alq-Ce-w aryl;(18) -(CH2)qCONRB'Rc', where q is an integer from zero to four and where RBe Rc' are independently selected from the group consisting of (a) hydrogen, (b) Ce-w alkyl, (c) Ceio aryl, and (d) C1-6 alkyl-Ce-w aryl; (19) -(CH2)qSO2RD, where q is an integer from zero to four and where RD is selected from the group; Petition 870260070873, dated 07 / 16 / 2026, p. 82 / 532 74 / 220 consisting of (a) Ce-io alkyl, (b) Ce-w aryl, and (c) C1-6 alq-Ce-w aryl; (20) -(CH2)qSO2NRE'RF, where q is an integer from zero to four and where each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) Ce-io alkyl, (c) Ce-io aryl, (d) C1-6 alq-Ce-w aryl; (21) thiol; (22) Ce-w aryloxy; (23) C3-8 cycloalkoxy; (24) Ce-w aryl-C1-6 alkoxy; (25) C1-6 alq-C1-12 heterocyclyl (e.g., C1-6 alq-C1-12 heteroaryl); (26) oxo; (27) C2-20 alkenyl; and (28) C2-20 alkynyl. In some embodiments, each of these groups may be further substituted as described in this document. For example, the alkylene group of a C1-alkaryl or a C1-alqheterocyclyl may be further substituted by an oxo group to provide the respective aryl and (heterocyclyl)oyl substituent groups.

[00239] The cycloalkyl group, as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group via an alkylene group, as defined herein (for example, an alkylene group of 1 to 4, 1 to 6, 1 to 10, or 1 to 20 carbons). In some embodiments, the alkylene and cycloalkyl may each be optionally substituted by 1, 2, 3, or 4 substituent groups as defined herein for the respective group.

[00240] The term diastereomer, as used in this document, means stereoisomers that are not mirror images of each other and are not superimposable on each other.

[00241] The term enantiomer, as used in this document, means each individual optically active form of a compound of the invention, which has an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of an enantiomer and at most Petition 870260070873, dated 07 / 16 / 2026, page 83 / 532 75 / 220 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[00242] The term halo, as used in this document, represents a halogen selected from bromine, chlorine, iodine, or fluorine.

[00243] The term heteroalkyl, as used herein, refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further replaced by 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. The terms heteroalkenyl and heteroalkynyl, as used herein, refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups may be further replaced by 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.

[00244] The term heteroaryl, as used herein, represents that subset of heterocyclyls, as defined herein, which are aromatic: that is, they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiments, the heteroaryl is substituted by 1, 2, 3, or 4 substituent groups as defined for a heterocyclyl group.

[00245] The term heteroarylalkyl refers to a heteroaryl group, Petition 870260070873, dated 07 / 16 / 2026, p. 84 / 532 76 / 220 as defined herein, attached to the parent molecular group by means of an alkylene group, as defined herein. Exemplary unsubstituted heteroarylalkyl groups are 2 to 32 carbons long (e.g., 2 to 22, 2 to 18, 2 to 17, 2 to 16, 3 to 15, 2 to 14, 2 to 13, or 2 to 12 carbons, such as C1-6 alq-C1-12 heteroaryl, C-mo alq-C1-12 heteroaryl, or C1-20 alqC1-12 heteroaryl). In some embodiments, the alkylene and heteroaryl may each be further substituted by 1, 2, 3, or 4 substituent groups as defined herein for the respective group. Heteroarylalkyl groups consist of a subset of heterocyclylalkyl groups.

[00246] The term heterocyclyl, as used herein, represents a 5-, 6-, or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- to 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclyl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term heterocyclyl also represents a heterocyclic compound having a multicyclic bridged structure in which one or more carbons and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, for example, a quinuclidinyl group.The term heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings are fused to one, two, or three carbocyclic rings, for example, an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like. Examples of fused heterocyclyls include... Petition 870260070873, dated 07 / 16 / 2026, page 85 / 532 77 / 220 em tropanos e 1,2,3,5,8,8a-hexa-hidroindolizina. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl (for example, 1,2,3-oxadiazolyl), purinyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl), tetra-hidrofuranila, di-hidrofuranila, tetrahydrotienila, di-hidrotienila, di-hidroindolila, di-hidroquinolila, tetrahydroquinolila, tetra-hidroisoquinolila, di-hidroisoquinolila,Pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like, including the dihydro and tetrahydro forms thereof, in which one or more double bonds are reduced and replaced by hydrogens. Other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g. 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1Himidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g. 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1 / 7-triazolyl (e.g. 4,5-dihydro-3-methyl-4-amino 5-oxo-1 / 7-triazolyl); 1,2,3,4tetrahydro-2,4-dioxopyridinyl (e.g. 1,2,3,4-tetrahydro-2,4dioxo-3,3-diethylpyridinyl); 2,6-dioxo-piperidinyl (e.g. 2,6-dioxo3-ethyl-3-phenylpiperidinyl); 1,6-dihydro-6-oxopiridiminyl; 1,6-dihydro-4oxopyrimidinyl (e.g., 2-(methylthio)-1,6-di-hydro-4-oxo-5methylpyrimidin-1-yl); 1,2,3,4-tetra-hydro-2,4-dioxopyrimidinyl (e.g., 1,2,3,4-tetra-hydro-2,4-dioxo-3-ethylpyrimidinyl); 1,6-dihydro-6-oxo, Petition 870260070873, of 16 / 07 / 2026, p. 86 / 532 78 / 220 pyridazinyl (e.g., 1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl (e.g., 1,6-dihydro-5-isopropyl-6-oxo1,2,4-triazinyl); 2,3-di-hydro-2-oxo-1 / - / -indolyl (e.g., 3,3-dimethyl2,3-di-hydro-2-oxo-1 / - / -indolyIa and 2,3-di-hydro-2-oxo-3,3'-spiropropano1 / - / -indole-1 -i I); 1,3-d ih id ro-1 -oxo-2 / - / -iso-i n dol i Ia; 1,3-d ih id rho-1,3-dioxo2 / - / -iso-indolyl; 1 / - / -benzopyrazolyl (e.g., l-(ethoxycarbonyl)- 1 / - / benzopyrazolyl); 2,3-di-hydro-2-oxo-1 / - / -benzimidazolyl (e.g., 3ethyl-2,3-di-hydro-2-oxo-1 / - / -benzimidazolyl); 2,3-dihydro-2-oxobenzoxazolyl (e.g., 5-chloro-2,3-di-hydro-2-oxo-benzoxazolyl); 2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H-benzopyranyl; 1,4benzodioxanyl; 1,3-benzodioxanyl; 2,3-di-hydro-3-oxo,4 / - / -1,3benzothiazinyl; 3,4-dihydro-4-oxo-3 / 7-quinazolinyl (e.g., 2-methyl3,4-dihydro-4-oxo-3 / - / -quinazolinyl);1,2,3,4-tetra-hidro-2,4-dioxo-3 / 7quinazolil (for example, 1-etil-1,2,3,4-tetra-hidro-2,4-dioxo-3 / 7quinazolil); 1,2,3,6-tetra-hidro-2,6-dioxo-7-H-purinil (for example, 1,2,3,6-tetra-hidro-1,3-dimetil-2,6-dioxo-7H-purinil); 1,2,3,6-tetrahydro-2,6-dioxo-1H-purinil (for example, 1,2,3,6-tetra-hidro-3,7dimethyl-2,6-dioxo-1H-purinil); 2-oxobenz[c,c / ]indolila; 1,1-dioxo-2Hnaft[1,8-c,c / ]isothiazolila; e 1,8-naphthylenodicarboxamido. These additional heterocyclics include 3,3a,4,5,6,6a-hexahido-pyrrolo[3,4-b]pyrrol-(2H)-ila, and 2,5-diazabicyclo[2.2.1]heptan-2-ila, homopiperazinila (or diazepanila), tetra-hidropiranila, ditiazolila, benzofuranila, benzotienila, oxepanila, tiepanila, azocanila, oxecanila and tiocanila. These heterocyclic groups also include formula groups;

[00247] em que

[00248] E' is selected from the group consisting of -N- and CH-; F' is selected from the group consisting of -N=CH-, -NHCH2-, -NH-C(O)-, -NH-, -CH=N-, -CH2-NH-, -C(O)-NH-, -CH=CH-, Petition 870260070873, dated 07 / 16 / 2026, page 87 / 532 79 / 220 CH2-, -CH2CH2-, -CH2O-, -OCH2-, -O-, and -S-; and G' is selected from the group consisting of -CH- and -N-. Any of the heterocyclyl groups mentioned in this document may optionally be replaced by one, two, three, four, or five substituents selected independently from the group consisting of: (1) Ci7 acyl (e.g., carboxaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) Ce-w aryl; (6) amino; (7) C1-6 alk-Ce-io aryl; (8) azide; (9) C3-8 cycloalkyl; (10) C1-6 alk-Cs-e cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C2-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy;(14) hydroxyl; (15) nitro; (16) C1-20 thioalkoxy (e.g., C1-6 thioalkoxy); (17) -(CH2)qCO2RA, where q is an integer from zero to four, and RA is selected from the group consisting of (a) C1-6 alkyl, (b) Ce-w aryl, (c) hydrogen, and (d) C1-6 alq-Ce-w aryl; (18) -(CH2)qCONRB'Rc', where q is an integer from zero to four and where RBe and Rc are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, and (d) C1-6 alq-Ce-w aryl; (19) -(CH2)qSO2RD, where q is an integer from zero to four and where RD is selected from the group consisting of (a) C1-6 alkyl, (b) Ce-w aryl, and (c) C1-6 alq-Ce-w aryl; (20) -(CH2)qSO2NRE'RF, wherein q is an integer from zero to four and wherein each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce-w aryl, and (d) C1-6 alq-Ce-w aryl; (21) thiol; (22) Ce-w aryloxy; (23) C3-8 cycloalkoxy;(24) arylalkoxy; (25) C1-6 alk-C1-12 heterocyclyl (e.g., C1-6 alk-C1-12 heteroaryl); (26) oxo; (27) (C112 heterocyclyl)imino; (28) C2-20 alkenyl; and (29) C2-20 alkynyl. In al; Petition 870260070873, dated 07 / 16 / 2026, p. 88 / 532 80 / 220 In some embodiments, each of these groups may be further substituted as described in this document. For example, the alkylene group of a C1-alkaryl or a C1-alphaheterocyclyl may be further substituted by an oxo group to provide the respective aryl and (heterocyclyl)oyl substituent groups.

[00249] The heterocyclylalkyl group, as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group via an alkylene group, as defined herein. Exemplary unsubstituted heterocyclylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alq-C12 heterocyclyl, C1-10 alq-C12 heterocyclyl, or C1-20 alq-C12 heterocyclyl). In some embodiments, the alkylene and heterocyclyl groups may each be further substituted by 1, 2, 3, or 4 substituent groups as defined in this document for the respective group.

[00250] The term hydrocarbon, as used in this document, represents one that consists of carbon and hydrogen atoms.

[00251] The term hydroxyl, as used herein, represents an -OH group. In some embodiments, the hydroxyl group may be replaced by 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl group.

[00252] The term isomer, as used herein, means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is known that the compounds of the invention may have one or more chiral centers and / or double bonds and therefore exist as stereoisomers, such as Petition 870260070873, dated 07 / 16 / 2026, page 89 / 532 81 / 220 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 depicted herein, 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 diastereometrically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. The 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 phase gas chromatography, chiral phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[00253] The term amino / V-protected, as used herein, refers to an amino group, as defined herein, to which one or two / V-protecting groups are attached, as defined herein.

[00254] The term / V-protective group, as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protective groups are described in Greene, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. / V-protective groups include acyl, aryl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t Petition 870260070873, dated 07 / 16 / 2026, page 90 / 532 82 / 220 butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D,L-amino acids or D,L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, nitrobenzyloxycarbonyl, dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 23,42,4dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(pbiphenylyl)-1-methylethoxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy α,α-dimethylcarbonyl, tbutyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like, alkaryl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like, and silyl groups such as trimethylsilyl and the like. The preferred / V-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[00255] The term nitro, as used in this document, represents a -NO2 group.

[00256] The term O-protecting group, as used in this document, represents those groups intended to protect an oxygen-containing group (e.g., phenol, hydroxyl, or carbonyl) against undesirable reactions during synthetic procedures. Commonly used O-protecting groups are described in Greene, Protective Petition 870260070873, dated 07 / 16 / 2026, page 91 / 532 83 / 220 Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, E-butyldimethylsilyl, tri- / iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl, pivaloyl, and the like; optionally substituted arylcarbonyl groups, such as benzoyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), and the like;ether-forming groups such as hydroxyl, such as methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, trityl, and the like; alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, methyloxycarbonyl, and the like; alkoxyalkoxycarbonyl groups, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, 3-methyl-2-butenoxycarbonyl, and the like; haloalkoxycarbonyls, such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and the like;optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, fluorenylmethyloxycarbonyl, and the like; and optionally substituted aryloxycarbonyl groups, such as phenoxycarbonyl, p; Petition 870260070873, dated 07 / 16 / 2026, page 92 / 532 84 / 220 nitrophenoxycarbonyl, o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methylphenoxycarbonyl, m-methylphenoxycarbonyl, obromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, pchlorophenoxycarbonyl, 2-chloro-4-nitrophenoxycarbonyl, and similar); substituted alkyl, aryl and alkaryl ethers (for example, trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,-trichloroethoxymethyl; tetra-hydropyranyl; tetra-hydrofuranyl; ethoxyethyl; 1-[2(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, pmethoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, e nitrobenzyl); silyl ethers (eg, trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; e diphenymethylsilyl); carbonaceous (eg methyl, methoxymethyl, 9fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl;3,4-dimethoxybenzyl; and nitrobenzyl); carbonyl-protective groups (for example, acetal and ketal groups, such as dimethyl acetal, 1,3-dioxolane, and the like; acyl groups; and dithiane groups, such as 1,3-dithianes, 1,3-dithiolane, and the like); carboxylic acid-protective groups (for example, ester groups, such as methyl ester, benzyl ester, t-butyl ester, orthoesters, and the like; and oxazoline groups.

[00257] The term oxo as used herein, represents =0.;

[00258] The prefix perfluoro, as used herein, represents an anyl group, as defined herein, in which each hydrogen radical attached to the alkyl group has been replaced by a fluoride radical. For example, perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.

[00259] The term protected hydroxyl, as used in this document, refers to an oxygen atom bonded to a protecting O group. Petition 870260070873, dated 07 / 16 / 2026, p. 93 / 532 85 / 220

[00260] The term spirocyclyl, as used in this document, represents a C2-7 alkylene diradical, both ends of which are attached to the same carbon atom of the parent group to form a spirocyclic group, and also a C1-6 heteroalkylene diradical, both ends of which are attached to the same atom. The heteroalkylene radical forming the spirocyclyl group may contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the spirocyclyl group includes from one to seven carbons, excluding the carbon atom to which the diradical is attached. The spirocyclyl groups of the invention may optionally be replaced by 1, 2, 3, or 4 substituents provided in this document as optional substituents for cycloalkyl and / or heterocyclyl groups.

[00261] The term stereoisomer, as used herein, refers to all possible different isomers as well as conformational forms that a compound may possess (for example, a compound of any formula described herein), in particular all possible stereochemically and conformationally 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 the foregoing being included within the scope of the present invention.

[00262] The term sulfonyl, as used in this document, represents an -S(O)2- group.

[00263] The term thiol, as used in this document, represents an -SH group. DEFINITIONS

[00264] In this application, unless otherwise evident from Petition 870260070873, dated 07 / 16 / 2026, page 94 / 532 86 / 220 of the context, (i) the term "a" can be understood to mean at least one; (ii) the term "or" can be understood to mean both and / or; (iii) the terms "comprising" and "including" can be understood to encompass itemized components or steps whether presented alone or together with one or more additional components or steps; and (iv) the terms "about" and "approximately" can be understood to allow for standard variation as understood by those individuals of common skill in the technique; and (v) where ranges are provided, endpoints are included.

[00265] As is known in the art, affinity is a measure of the closeness with which a particular ligand binds to its partner. Affinities can be measured in different ways. In some embodiments, affinity is measured by a quantitative assay. In some of these embodiments, the binding partner concentration may be fixed so that it is in excess of the ligand concentration to mirror physiological conditions. Alternatively or additionally, in some embodiments, the ligand partner concentration and / or ligand concentration may be varied. In some of these embodiments, affinity may be compared to a reference under comparable conditions (e.g., concentrations).

[00266] As used in this document, the terms approximately and about are each intended to encompass normal statistical variation as would be understood by those individuals of ordinary skill in the technique as appropriate to the relevant context. In certain embodiments, the terms approximately or about each refer to a range of values ​​covered 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 either direction (greater than or less than) of a stated value. Petition 870260070873, dated 07 / 16 / 2026, p. 95 / 532 87 / 220 rado, unless stated otherwise or evident otherwise from the context (for example, where this number would exceed 100% of a possible value).

[00267] It will be understood that the term linkage, as used herein, typically refers to the association (e.g., covalent or non-covalent) between or among two or more entities. Direct linkage involves physical contact between entities or chemical moieties; indirect linkage involves physical interaction through physical contact with one or more intermediate entities. The linkage between two or more entities can typically be evaluated in any one of a variety of contexts – including where the interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a cell or biological system).

[00268] The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described in this document. Illustrative and exemplary embodiments for measuring binding affinity are described below. The term Kd, as used herein, is intended to refer to the dissociation equilibrium constant of a particular compound-protein interaction or protein complex. Typically, the compounds of the invention bind to presenting proteins with a dissociation equilibrium constant (Kd) less than about 10⁻⁶ M, such as less than approximately 10⁻⁷ M, 10⁻⁸ M, 10⁻⁹ M, or 10⁻¹⁰ M, or even lower, for example, when determined by surface plasmon resonance (SPR) technology using the presenting protein as the analyte and the compound as the ligand. The presented protein complexes Petition 870260070873, dated 07 / 16 / 2026, p. 96 / 532 The 88 / 220 ra / compound of the invention binds to target proteins (for example, a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein) with a dissociation equilibrium constant (Kd) less than about 10-6M, such as less than approximately 10'7M, 10'8M, 10'9M, or 10'10M or even lower, for example, when determined by surface plasmon resonance (SPR) technology using the target protein as the analyte and the complex as the ligand.

[00269] As used in this document, the term crosslinking group refers to a group comprising a reactive functional group capable of chemically attaching to specific functional groups (e.g., primary amines, sulfhydryls) in proteins or other molecules. A chemical moiety capable of chemoselective reaction with an amino acid, as used in this document, refers to a chemical moiety comprising a reactive functional group capable of chemically attaching to a functional group of a natural or non-natural amino acid (e.g., primary and secondary amines, sulfhydryls, alcohols, carboxyl groups, carbonyls, or triazole-forming functional groups such as azides or alkynes).Examples of crosslinking groups include sulfhydryl-reactive crosslinking groups (e.g., groups comprising maleimides, haloacetyls, pyridyl disulfides, thiosulfonates, or vinyl sulfones), amine-reactive crosslinking groups (e.g., groups comprising esters such as NHS esters, imidoesters, and pentafluorophenyl esters, or hydroxymethylphosphine), carboxyl-reactive crosslinking groups (e.g., groups comprising primary or secondary amines, alcohols, or thiols), carbonyl-reactive crosslinking groups (e.g., groups comprising hydrazides or alkoxyamines), and triazole-forming crosslinking groups (e.g., Petition 870260070873, dated 07 / 16 / 2026, page 97 / 532 89 / 220 example, groups comprising azides or alkynes).

[00270] As used in this document, the term complex refers to a group of two or more compounds and / or proteins that are linked together through a binding interaction (e.g., a non-covalent interaction, such as a hydrophobic effect interaction, an electrostatic interaction, a van der Waals interaction, or a π-effect interaction). Examples of complexes are presenter protein / conjugate complex and target protein / conjugate complex which include a conjugate of the invention linked to a presenter protein or a target protein.

[00271] As used in this document, the term conjugate refers to one formed by the union (for example, by means of a covalent bond-forming reaction) of two or more chemical compounds (for example, a compound that includes a crosslinking group and a protein such as a target protein or a presenting protein).

[00272] As used in this document, the term electron-withdrawing group refers to a functional group that removes electron density from a π system. Examples of electron-withdrawing groups include, without limitation, halide groups (e.g., fluoride, chloride, bromide, iodide), aldehydes, ketones, carboxylic acids, acyl chlorides, esters, amides, trihalides (e.g., trifluoromethyl, trichloromethyl), nitriles, sulfonates, and nitro.

[00273] As used in this document, the term leaving group refers to a molecular fragment that leaves with an electron pair in a heterolytic bond cleavage. Examples of leaving groups include, but are not limited to, halides (e.g., fluoride, chloride, bromide, iodide), carboxylates, tosylates, mesylates, perfluoroalkylsulfonates (e.g., triflate), nitrates, and phosphates.

[00274] As used in this document, an atom that Petition 870260070873, dated 07 / 16 / 2026, p. 98 / 532 90 / 220 participates in the bonding, is within 4 Å of the entity to which they are bonded, or connects to an atom that is within 4 Å of the entity to which they are bonded.

[00275] The term protein-presenting protein refers to a protein that binds to a small molecule to form a complex that binds to and modulates the activity of a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein, or a prokaryotic target protein such as a bacterial target protein). In some embodiments, the protein-presenting protein is a relatively abundant protein (e.g., the protein-presenting protein is sufficiently abundant that participation in a tripartite complex does not substantially impact the biological role of the protein-presenting protein in a cell and / or cell viability or other cell attributes). In certain embodiments, the protein-presenting protein is a protein that has chaperone activity within a cell. In some embodiments, the protein-presenting protein is a protein that has multiple natural interaction partners within a cell.In certain embodiments, the presenting protein is one that is known to bind a small molecule to form a binary complex that is known or suspected to bind and modulate the biological activity of a target protein.

[00276] The term presenting protein binding chemical moiety refers to a group of atoms and the chemical moieties attached to it (e.g., atoms within 20 atoms, atoms within 15 atoms, atoms within 10, atoms within 5 atoms) that participate in binding to a presenting protein such that the compound binds specifically to said presenting protein, for example, with a Kd less than 10 μM (e.g., less than 5 μM, less than 1 pM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, Petition 870260070873, dated 07 / 16 / 2026, p. 99 / 532 91 / 220 less than 50 nM, less than 25 nM, less than 10 nM) or inhibits the peptidyl-prolyl isomerase activity of the presenting protein, for example, with an IC50 less than 1 μM (e.g., less than 0.5 μM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM). It will be understood that the chemical portion of the presenting protein does not necessarily encompass all atoms in the compound that interact with the presenting protein. It will also be understood that one or more atoms of the presenting protein's binding chemical portion may be within the target protein's binding chemical portion (e.g., eukaryotic target protein binding chemical portion as a mammalian target protein binding chemical portion or fungal target protein binding chemical portion or prokaryotic target protein binding chemical portion as a bacterial target protein binding chemical portion).

[00277] As used herein, FKBP binding chemical moiety refers to a presenting protein binding chemical moiety that is selective for presenting proteins in the FKBP family of proteins (e.g., FKBP12, FKBP12.6, FKBPP13, FKBP25, FKBP51, or FKBP52). A selective FKBP binding chemical moiety, as used herein, refers to a binding chemical moiety that is specific for one or more (e.g., two, three, four, five) members of the FKBP family relative to all other members of the FKBP family. A non-selective FKBP binding chemical moiety, as used herein, refers to a binding chemical moiety that has comparable affinity (within 2 times, within 3 times, within 4 times, within 5 times, within 10 times) for all members of the FKBP family.

[00278] The term protein-binding chemical moiety refers to Petition 870260070873, dated 07 / 16 / 2026, p. 100 / 532 92 / 220 a group of atoms and the chemical moieties attached to it (e.g., atoms within 20 atoms, atoms within 15 atoms, atoms within 10, atoms within 5 atoms) that participate in binding to a protein (e.g., a presenting protein or a target protein) such that the compound binds specifically to said protein, for example, with a Kd less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM) or inhibits the peptidylprolyl isomerase activity of the presenting protein, for example, with an IC50 less than 1 μM (e.g., less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM). It will be understood that the protein-binding chemical portion does not necessarily encompass all atoms in the compound that interacts with the protein.

[00279] As used in this document, the term react refers to a process in which atoms of the same or different elements rearrange to form a new substance. For example, the formation of a covalent bond between two atoms, such as the reaction between a reactive amino acid in a protein and a crosslinking group to form a covalent bond. A reaction can be measured by any method known in the art, for example, the formation of a reaction product can be determined by LC-MS or NMR.

[00280] As used in this document, the term reactive amino acid refers to a natural or non-natural amino acid comprising a functional group (e.g., a nucleophilic functional group) with the ability to chemically attach to specific functional groups (e.g., a crosslinking group). Examples of reactive amino acids include cysteine, lysine, serine, and amino acids. Petition 870260070873, dated 07 / 16 / 2026, p. 101 / 532 93 / 220 acids that have azides in the side chain. The term non-reactive amino acids refers to natural or non-natural amino acids that do not contain a functional group capable of chemically binding to specific functional groups. Examples of non-reactive amino acids include valine, alanine, isoleucine, threonine, and leucine.

[00281] The term reference is frequently used in this document to describe a standard or control compound, individual, population, sample, sequence, or value against which a compound, individual, population, sample, sequence, or value of interest is compared. In some embodiments, a reference compound, individual, population, sample, sequence, or value is tested and / or determined substantially simultaneously with the testing or determination of the compound, individual, population, sample, sequence, or value of interest. In some embodiments, a reference compound, individual, population, sample, sequence, or value is a historical reference, optionally embodied in a tangible medium.Typically, as would be understood by those skilled in the art, a reference compound, individual, population, sample, sequence, or value is determined or characterized under conditions comparable to those used to determine or characterize the compound, individual, population, sample, sequence, or value of interest.

[00282] As used in this document, the term solvent-exposed amino acid refers to an amino acid that is accessible to the solvent surrounding the protein. In some embodiments, a solvent-exposed amino acid is an amino acid that, when substituted, does not substantially change the three-dimensional structure of the protein.

[00283] As used in this document, the terms specific linking or specific to or specific for refer to an interaction between a linking agent and a target entity. As Petition 870260070873, dated 07 / 16 / 2026, page 102 / 532 94 / 220 will be understood by those individuals of common ability; an interaction is considered specific if it is favored in the presence of alternative interactions, for example, binding with a Kd less than 10 μM (e.g., less than 5 μM, less than 1 pM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM). In many modalities, specific interaction is dependent on the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is understood that specificity need not be absolute. In some modalities, specificity can be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some modalities, specificity is evaluated in relation to that of a specific reference binding agent.In some modalities, specificity is evaluated in relation to that of a non-specific reference binding agent.

[00284] The term specific, when used with reference to a compound that has activity, is understood by those skilled in the art to mean that the compound discriminates between potential target entities or states. For example, in some embodiments, a compound is said to bind specifically to its target if it preferentially binds to that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent on the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is understood that specificity need not be absolute. In some embodiments, specificity can be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., Petition 870260070873, dated 07 / 16 / 2026, p. 103 / 532 95 / 220 competitors). In some modes, specificity is evaluated relative to that of a specific reference binding agent. In some modes, specificity is evaluated relative to that of a non-specific reference binding agent. In some modes, the agent or entity does not bind detectably to the alternative competitor target under conditions of binding to its target entity. In some modes, the binding agent binds with a higher on-rate, lower off-rate, higher affinity, lower dissociation, and / or greater stability to its target entity compared to the alternative competitor target(s).

[00285] The term substantially refers to the qualitative condition of exhibiting a full or near-full degree or extent of a property or characteristic of interest. A person of ordinary skill in biological technique will understand that biological and chemical phenomena are rarely, if ever, completed and / or advance toward completion or reach or avoid an absolute result. The term substantially is therefore used in the present document to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[00286] The term does not substantially link to a particular protein as used in this document; it may, for example, be displayed by a molecule or portion of a molecule that has a Kd for the target of 10⁻⁴ M or greater, alternatively 10⁻⁵ M or greater, alternatively 10⁻⁶ M or greater, alternatively 10⁻⁷ M or greater, alternatively 10⁻⁸ M or greater, alternatively 10⁻⁹ M or greater, alternatively 10⁻¹⁰ M or greater, alternatively 10⁻¹¹ M or greater, alternatively 10⁻¹² M or greater, or a Kd in the range of 10⁻⁴ M to 10⁻¹² M. M or IO'6M to 10-10M or 10'7M to 10'9M.

[00287] The term target protein refers to any protein that participates in a biological pathway associated with a disease or disorder. Petition 870260070873, dated 07 / 16 / 2026, p. 104 / 532 96 / 220 or condition. In some embodiments, the target protein is not mTOR or calcineurin. In some embodiments, the target protein has the ability to form a tripartite complex with a presenting protein and a small molecule. In some embodiments, a target protein is a naturally occurring protein; in some of these embodiments, a target protein is naturally found in certain mammalian cells (e.g., a mammalian target protein), fungal cells (e.g., a fungal target protein), bacterial cells (e.g., a bacterial target protein), or plant cells (e.g., a plant target protein). In some embodiments, a target protein is characterized by natural interaction with one or more natural presenting protein / natural small molecule complexes.In some embodiments, a target protein is characterized by natural interactions with a plurality of different natural presenting protein / natural small molecule complexes; in some of these embodiments, some or all of the complexes use the same presenting protein (and different small molecules). In some embodiments, a target protein does not bind substantially to a cyclosporine, rapamycin, or FK506 complex and a presenting protein (e.g., FKBP). The target proteins may be naturally occurring, for example, wild-type. Alternatively, the target protein may vary from the wild-type protein but still retain biological function, for example, as an allelic variant, a splicing mutant, or a biologically active fragment.Mammalian target proteins include GTPases, GTPase-activating proteins, guanine nucleotide exchange factor, heat shock proteins, ion channels, coiled-coil proteins, kinases, phosphatases, ubiquitin ligases, transcription factors, chromatin modifiers / remodelers, proteins with classic protein-protein interaction motifs and domains, or any others. Petition 870260070873, dated 07 / 16 / 2026, page 105 / 532 97 / 220 proteins that participate in a biological pathway associated with a disease, disorder, or condition.

[00288] In some embodiments, a target protein is a modified target protein. A modified target protein may include an insertion, deletion, or substitution of an amino acid, conservative or non-conservative (e.g., D-amino acids, desamino acids) in the protein sequence (e.g., where such changes do not substantially alter the biological activity of the polypeptide). In particular, the addition of one or more cysteine ​​residues to the amino or carboxy terminus of any of the polypeptides of the invention may facilitate the conjugation of these proteins by, for example, disulfide linkage. In some embodiments, one or more reactive amino acid residues (e.g., cysteines) are removed to decrease the number of possible conjugation sites on the protein.Amino acid substitutions can be conservative (i.e., where one residue is replaced by another of the same type or general group) or non-conservative (i.e., where a residue is replaced by an amino acid of a different type). Furthermore, a naturally occurring amino acid can be substituted by a non-naturally occurring amino acid (i.e., conservative non-naturally occurring amino acid substitution or non-conservative non-naturally occurring amino acid substitution).

[00289] The term target protein binding chemical moiety refers to a group of ring atoms and the chemical moieties attached thereto (e.g., atoms within 20 atoms, atoms within 15 atoms, atoms within 10 atoms, atoms within 5 atoms) that participate in binding to a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein) when the compound is in a complex with a presenting protein. It will be understood that the chemical moiety Petition 870260070873, dated 07 / 16 / 2026, p. 106 / 532 The 98 / 220 target protein binding moiety does not necessarily encompass all atoms in the compound that interact with the target protein. It will also be understood that one or more atoms from the presenting protein binding moiety may also be present in the target protein binding moiety.

[00290] The term traditional binding pocket refers to cavities or pockets in a protein structure with physicochemical and / or geometric properties comparable to proteins whose activity has been modulated by one or more small molecules. In some embodiments, a traditional binding pocket is a well-defined pocket with a volume greater than 1000 A3. Those of common skill in the art are familiar with the concept of a traditional binding pocket and, moreover, are aware of its relationship to pharmacoactivity. In certain embodiments, a protein is considered not to have a traditional binding pocket if it is not susceptible to drug modulation, as defined herein.

[00291] The term not susceptible to drug modulation refers to proteins that are not members of a protein family that is known to be targeted by drugs and / or do not possess a binding site that is suitable for high-affinity binding to a small molecule. Methods for determining whether a target protein is not susceptible to drug modulation are known in the art. For example, whether a target protein is not susceptible to drug modulation can be determined using a structure-based algorithm, such as those used by the DOGSITESCORER® program (Universität Hamburg, Hamburg, Germany) which assesses pharmacoactivity based on computed parameters for binding pockets in a protein that include volume, surface area, lipophilic surface area, depth, and / or hydrophobic ratio. BRIEF DESCRIPTION OF THE DRAWINGS Petition 870260070873, dated 07 / 16 / 2026, page 107 / 532 99 / 220

[00292] Figure 1 is an image illustrating the SDS-PAGE analysis of KRASgtp / s39c lite / C2-FK506 conjugates. Lane 1: KRASgtp / ssqc lite; Lane 2: reaction mixture of KRASgtp / s39c lite / C2-FK506; Lane 3: Reaction mixture of KRASgtp / s39c lite / C2-FK506 + 100 mM DTT.

[00293] Figure 2 is an image illustrating the SDS-PAGE analysis of the KRASgtp / gwc lite / SFAX9DS conjugates.

[00294] Figures 3A and 3B are images illustrating the SEC and SDS-PAGE analysis of the KRASgtp / s39c lite / C2Holt / FKBP12 Complex Formation. Figure 3A) SEC purification profile. The dashed blue lines indicate the peak corresponding to the elution of the ternary complex KRASgtp / s39c lite / C2Holt / FKBP12; Figure 3B) SDS-PAGE analysis of SEC elution peaks. The dashed blue lines correspond to the fractions collected for the elution peak of KRASgtp / s39c lite / C2Holt / FKBP12.

[00295] Figure 4 is an image illustrating the SEC profile and SDS-PAGE analysis of the elution peaks confirms the formation of the KRASgdp / s39C lite / SFAC4DS / CypAc52S complex.

[00296] Figures 5A and 5B are images illustrating the SEC profile and SDS-PAGE analysis of the free PTPIBswzc lite and FKBP12 proteins and the PTPIBswc lite / C3SLF / FKBP12 complex.

[00297] Figure 6 is an image that illustrates the effectiveness of C3 and C4SLF crosslinking by SDS-PAGE.

[00298] Figures 7A and 7B consist of an image illustrating the crystal structure of the FKBP12-Compound 1-KRASgtp / s39c complex. Figure 7A) Loop representation showing FKBP12, KRASgtp / s39c and the ligand. The Fo-Fc electron density at 3 σ is shown for the ligand in close-up view. Figure 7B) Surface representation of the complex with atoms within the 4 Å proximity to ligand or partner protein colored in the third.

[00299] Figure 8 is an image that illustrates the crystal structure. Petition 870260070873, dated 07 / 16 / 2026, p. 108 / 532 100 / 220 of CypAc52s-SFAC4DS-KRASGDP / s39c·

[00300] Figures 9A and 9B are images illustrating the crystal structure of FKBP12-C3SLF-PTP1Bsi87c. Figure 9A illustrates that the crystal contains two molecules of the FKBP12-C3SLFPTP1Bsi87c complex in the asymmetric unit. Figure 9B illustrates that the buried surface area of ​​PTPIBswzc is 427 A2 and the buried surface area of ​​C3SLF is 615 A2.

[00301] Figure 10 is an image illustrating the crystal structure of MCL1s245c / C3SLF / FKBP52.

[00302] Figure 11 is an image illustrating the W21487-dependent complex formation binding curve of the ternary complex CYPA-W21487-KRASgwc-gtp.

[00303] Figure 12 is an image illustrating the W21487-dependent complex formation binding curve of the ternary complex CYPA-W21487-KRASgwc-gtp.

[00304] Figure 13 is an image illustrating ITC measurements for the binding of binary complexes FKBP12-Compound 1 and FKBP12Compound 2 at CEP250.

[00305] Figure 14 is an image illustrating SPR sensorgrams for the connection of FKBP12 / Compound 1 to CEP250n.4 and CEP250292.

[00306] Figure 15 is an image illustrating the sensorgram and continuous-state fitting curves for CYPA / Compound 3 binding to KRASgwc-gtp.

[00307] Figure 16 is an image illustrating fluorescence polarization curves for the formation of the CypA:C3DS:KRAS complex.

[00308] Figures 17A-17C are images illustrating the 2D 1H-15N TROSY-HSQC spectrum of KRASgwc-gtp (Figure 17A), the addition of a stoichiometric amount of CYPA (Figure 17B), and KRAS and CYPA alone (Figure 17C). Petition 870260070873, dated 07 / 16 / 2026, p. 109 / 532 101 / 220 DETAILED DESCRIPTION OF CERTAIN MODALITIES

[00309] Small molecules are limited in their targeting abilities due to the fact that their interactions with the target are driven by adhesive forces, the intensity of which is approximately proportional to the contact surface area. Due to their small size, the only way for a small molecule to accumulate sufficient intermolecular contact surface area to effectively interact with a target protein is to be literally engulfed by that protein. In fact, a large body of both experimental and computational data supports the view that only those proteins that have a hydrophobic pocket on their surface have the capacity to bind small molecules. In those cases, binding is enabled by immersion.

[00310] Nature has evolved a strategy that allows a small molecule to interact with target proteins at sites beyond hydrophobic pockets. This strategy is exemplified by naturally occurring immunosuppressive drugs cyclosporine A, rapamycin, and FK506. The biological activity of these drugs involves the formation of a high-affinity complex of the small molecule with a small presentation protein. The composite surface of the small molecule and the presentation protein engages the target. Therefore, for example, the binary complex formed between cyclosporine A and cyclophilin A targets calcineurin with high affinity and specificity, but neither cyclosporine A nor cyclophilin A alone binds calcineurin with measurable affinity.

[00311] Many important therapeutic targets exert their function by complexing with other proteins. The protein / protein interaction surfaces in many of these systems contain an inner core of hydrophobic side chains surrounded by a broad ring of polar residues. The hydrophobic residues contribute almost Petition 870260070873, dated 07 / 16 / 2026, page 110 / 532 102 / 220 all energetically favorable contacts and, consequently, this cluster has been designated as a hotspot for engagement in protein-protein interactions. Importantly, in the aforementioned complexes of naturally occurring small molecules with small presenting proteins, the small molecule provides a hydrophobic functional cluster similar to a hotspot, and the protein provides the ring of mostly polar residues. In other words, the small molecule presented systems mimic the surface architecture widely employed in natural protein / protein interaction systems.

[00312] Nature has demonstrated the ability to reprogram the target specificity of small presented molecules—portable hotspots—through evolutionary diversification. In the best-characterized example, the complex formed between the FK506 binding protein (FKBP) and FK506 targets calcineurin. However, FKBP can also form a complex with the related molecule rapamycin, and that complex interacts with a completely different target, TorC1. To date, no methodology has been developed to reprogram the binding and modulation capacity of presenter / ligand protein interfaces so that they can interact with and modulate other target proteins that were previously considered not susceptible to drug modulation.

[00313] Furthermore, it is well established that some drug candidates fail because they modulate the activity of both the intended target and other unintended proteins as well. The problem is particularly alarming when the drug binding site of the target protein is similar to the binding sites of non-target proteins. The insulin-like growth factor receptor (IGF-1R), whose ATP binding pocket is structurally similar to the binding pocket of the non-target insulin receptor (IR), is an example. Petition 870260070873, dated 07 / 16 / 2026, p. 111 / 532 103 / 220 Small molecule drug development candidates designed to target IGF-1R typically have unacceptable side effects from also modulating the insulin receptor. However, structural dissimilarities exist between these two proteins in the regions surrounding the ATP-binding pocket. Despite this knowledge, no methodology currently exists to take advantage of those differences and develop drugs that are specific to IGF-1R as opposed to IR.

[00314] This description provides methods and reagents useful for analyzing protein-protein interfaces such as the interface between a protein-presenting protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein. In some embodiments, the target and / or presenting proteins are intracellular proteins. In some embodiments, the target and / or presenting proteins are mammalian proteins. In some embodiments, these methods and reagents may be useful for identifying target proteins that are favorable to inhibition or activation by forming a complex with a protein-presenting protein and a small molecule. In some embodiments, these methods and reagents may be useful in identifying compounds capable of inhibiting or activating target proteins by forming a complex with a protein-presenting protein and the target protein. COMPOUNDS AND CONJUGATES

[00315] The disclosure provides compounds that include a protein-binding chemical moiety (e.g., a presenter protein-binding chemical moiety or a target protein-binding chemical moiety) and a crosslinking group. The invention also discloses conjugates that include a protein-binding chemical moiety conjugated to a protein, for example, a presenter protein-binding chemical moiety conjugated to a target protein or Petition 870260070873, dated 07 / 16 / 2026, p. 112 / 532 104 / 220 a target protein-binding chemical moiety conjugated to a presenting protein.

[00316] The invention also features the compounds of Formula VII: ALB Formula VII where A comprises the structure of Formula VIII: R4 Formula Vlllb

[00317] In some embodiments, the compound of the invention is: Petition 870260070873, dated 07 / 16 / 2026, page 113 / 532 105 / 220 Petition 870260070873, dated 07 / 16 / 2026, page 114 / 532 106 / 220 RETICULATION GROUPS

[00318] In some embodiments, the compounds of the invention include a crosslinking group. A crosslinking group refers to a group comprising a reactive functional group capable of chemically attaching to specific functional groups (e.g., primary amines, sulfhydryls) in proteins or other molecules.Examples of crosslinking groups include sulfhydryl-reactive crosslinking groups (e.g., groups comprising maleimides, haloacetyls, pyridyl disulfides, thiosulfonates, or vinyl sulfones), amine-reactive crosslinking groups (e.g., groups comprising esters such as NHS esters, imidoesters, and pentafluorophenyl esters, or hydroxymethylphosphine), carboxyl-reactive crosslinking groups (e.g., groups comprising primary or secondary amines, alcohols, or thiols), carbonyl-reactive crosslinking groups (e.g., groups comprising hydrazides or alkoxyamines), and triazole-forming crosslinking groups (e.g., groups comprising azides or alkynes).

[00319] Exemplary crosslinking groups include 2' Petition 870260070873, dated 07 / 16 / 2026, page 115 / 532 107 / 220 pyridyl disulfide, 4'-pyridyl disulfide iodoacetyl, maleimides, thioesters, alkyl disulfides, alkylamine disulfides, nitrobenzoic acid disulfide, anhydrides, NHS esters, aldehydes, alkyl chlorides, alkynes, Michael acceptor groups (e.g., unsubstituted α,β-ketones or sulfones), epoxides, heteroaryl nitriles, and azides. PRESENTING PROTEIN BINDING CHEMICAL MONOMETRY

[00320] In some embodiments, the compounds of the invention include a chemical portion that binds to a presenting protein.In some embodiments, a presenting protein binding chemical moiety includes a group of atoms (e.g., 5 to 20 atoms, 5 to 10 atoms, 10 to 20 atoms) and may include any chemical moieties attached to it (e.g., atoms within 20 atoms, atoms within 15 atoms, atoms within 10 atoms, atoms within 5 atoms) that participates in binding to a presenting protein such that a supplied compound binds specifically to said presenting protein, for example, with a Kd less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM) or inhibits the peptidyl-prolyl isomerase activity of the presenting protein, for example, with an IC50 less than 1 μM (e.g., less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM).In some embodiments, the chemical binding moiety of the presenting protein does not encompass all atoms in a given compound that interact with the presenting protein. In certain embodiments, one or more atoms of the chemical binding moiety of the presenting protein do not interact with the presenting protein.

[00321] In some embodiments, a chemical bonding portion Petition 870260070873, dated 07 / 16 / 2026, p. 116 / 532 The 108 / 220 presenting protein includes a chemical moiety of N-acyl proline, a chemical moiety of N-acyl-pipecolic acid, a chemical moiety of N-acyl 3-morpholinocarboxylic acid, and / or a chemical moiety of N-acyl piperizic acid (e.g., with acylation at any nitrogen atom). In certain embodiments, a chemical moiety of the presenting protein includes a chemical moiety of N-acyl-pipecolic acid. In some embodiments, a chemical moiety of the presenting protein includes a chemical moiety of N-acyl proline. In certain embodiments, a chemical moiety of the presenting protein includes a chemical moiety of N-acyl 3-morpholinocarboxylic acid. In some embodiments, a chemical moiety of the presenting protein includes a chemical moiety of N-acyl piperizic acid.

[00322] In some embodiments, at least one atom of a chemical-binding portion of a presenting protein participates in binding with one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) of Tyr 27, Phe 37, Asp 38, Arg 41, Phe 47, Gin 54, Glu 55, Vai 56, Lie 57, Trp 60, Ala 82, Try 83, His 88, Lie 92, and / or Phe 100 of FKBP12. In some embodiments, at least one of a chemical-binding portion of a presenting protein participates in binding with at least one (e.g., two, three, or four) of Arg 41, Gin 54, Glu 55, and / or Ala 82 of FKBP12.

[00323] In some embodiments, a chemical portion of the presenting protein has a structure according to Formula I l-IV: z2 Formula Ha Petition 870260070873, dated 07 / 16 / 2026, p. 117 / 532 109 / 220 z2 Formula lib z5 Formula IV

[00324] In some embodiments, a chemical binding moiety of a presenting protein includes or consists of the following structure: Petition 870260070873, dated 07 / 16 / 2026, p. 118 / 532 110 / 220 Petition 870260070873, dated 07 / 16 / 2026, p. 119 / 532 111 / 220 OMe OH OMe OMe Petition 870260070873, dated 07 / 16 / 2026, p. 120 / 532 112 / 220 Petition 870260070873, dated 07 / 16 / 2026, p. 121 / 532 113 / 220 or a stereoisomer thereof.

[00325] A presenting protein can bind to an atom in a chemical portion of the presenting protein binding. Alternatively or additionally, a presenting protein can bind to two or more atoms in a chemical portion of the presenting protein binding. In another alternative, a presenting protein binding can be to a substituent attached to one or more atoms in a chemical portion of the presenting protein binding. Furthermore, in some embodiments, a presenting protein can bind to an atom in a chemical portion of the presenting protein binding and to a substituent attached to one or more atoms in a chemical portion of the presenting protein binding. In some embodiments, a presenting protein binds to a group that mimics a natural ligand of a presenting protein, and wherein the group that mimics a natural ligand of a presenting protein is attached to a chemical portion of the presenting protein binding.In some embodiments, a presenting protein binds to another presenting protein, and the affinity of a presenting protein for another presenting protein in the binary complex is increased relative to the affinity of a presenting protein for another presenting protein in the absence of the complex. The binding in these examples is typically, but not limited to, non-covalent interactions of a presenting protein to a chemical binding moiety of a presenting protein. TARGET PROTEIN BINDING CHEMICAL MONITIONS

[00326] In some embodiments, the compounds of the invention include a target protein-binding chemical moiety (for example, a eukaryotic target protein-binding chemical moiety such as a mammalian target protein-binding chemical moiety or a fungal target protein-binding chemical moiety or a prokaryotic target protein-binding chemical moiety such as a chemical moiety). Petition 870260070873, dated 07 / 16 / 2026, p. 122 / 532 114 / 220 of bacterial target protein binding). In some embodiments, the target protein binding chemical moiety includes a group of atoms (e.g., 5 to 20 atoms, 5 to 10 atoms, 10 to 20 atoms) and may include any chemical moieties attached to it (e.g., atoms within 20 atoms, atoms within 15 atoms, atoms within 10 atoms, atoms within 5 atoms) that specifically bind to a target protein. In some embodiments, a target protein binding chemical moiety comprises a plurality of the atoms in the compound interacting with the target protein. In certain embodiments, one or more atoms of a target protein binding chemical moiety do not interact with the target protein.

[00327] A target protein can bind to an atom in a target protein binding chemical portion. Alternatively or additionally, a target protein can bind to two or more atoms in a target protein binding chemical portion. In another alternative, a target protein binding can be to a substituent attached to one or more atoms in a target protein binding chemical portion. In another alternative, a target protein can bind to an atom in a target protein binding chemical portion and to a substituent attached to one or more atoms in a target protein binding chemical portion. In another alternative, a target protein binds to a group that mimics a natural ligand of a target protein, wherein the group that mimics a natural ligand of a target protein is attached to a target protein binding chemical portion.In yet another alternative, a target protein binds to a presenting protein, and the affinity of a target protein for a presenting protein in the binary complex is increased relative to the affinity of a target protein for a presenting protein in the absence of the complex. The binding in these examples is typically through, but not limited to, non-covalent interactions of a target protein to a chemical binding moiety of the presenting protein. Petition 870260070873, dated 07 / 16 / 2026, p. 123 / 532 115 / 220 on target.

[00328] In some embodiments, the target protein-binding chemical portion includes a crosslinking group (e.g., an internal crosslinking group). BINDERS

[00329] The compounds of the invention include a linker (e.g., a linker chemical moiety that links a protein-binding chemical moiety (e.g., a presenter protein-binding chemical moiety or a target protein-binding chemical moiety) to a crosslinking group or a linker that links a protein-binding chemical moiety to a protein (e.g., a presenter protein or target protein). The linker component of the invention is, in its simplest form, a linkage, but it can also provide a linear, cyclic, or branched molecular backbone that has pendant groups that covalently link two chemical moieties.

[00330] In some embodiments, at least one atom of a ligand participates in binding to the presenting protein and / or the target protein. In certain embodiments, at least one atom of a ligand does not participate in binding to the presenting protein and / or the target protein.

[00331] Therefore, a ligand, when included in a compound and / or conjugate as described in this document, achieves the linking of two (or more) chemical moieties through covalent means, involving the formation of a bond with one or more functional groups located in any chemical moiety. Examples of chemically reactive functional groups that can be used for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate, vicinal diols, thioethers, 2-amino alcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups. Petition 870260070873, dated 07 / 16 / 2026, p. 124 / 532 116 / 220

[00332] In some embodiments, this covalent bonding of two (or more) chemical moieties can be effected using a ligand that contains reactive chemical moieties capable of reacting with these functional groups present in any chemical moiety. For example, an amine group of a chemical moiety can react with a carboxyl group of the ligand, or an activated derivative thereof, resulting in the formation of an amide linking the two.

[00333] Examples of chemical moieties capable of reacting with sulfhydryl groups include α-haloacetyl compounds of the type XCH2CO- (where X=Br, Cl, or I), which show particular reactivity for sulfhydryl groups, but which can also be used to modify imidazolyl, thioether, phenol, and amino groups as described by Gurd, Methods Enzymol. 11:532 (1967). NMaleimide derivatives are also considered selective for sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions. Reagents such as 2-iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through the conversion of an amino group, can be considered as sulfhydryl reagents if the linkage occurs through the formation of disulfide bridges.

[00334] Examples of reactive chemical moieties capable of reacting with amino groups include, for example, alkylating and acylating agents. Representative alkylating agents include:

[00335] (i) α-haloacetyl compounds, which show specificity for amino groups in the absence of reactive thiol groups and are of the type XCH2CO- (where X=Br, Cl, or I), for example, as described by Wong Biochemistry 24:5337 (1979);

[00336] (ii) N-maleimide derivatives, which can react with amino groups via a Michael-type reaction or via acylation by addition to the ring carbonyl group, for example, as Petition 870260070873, dated 07 / 16 / 2026, page 125 / 532 117 / 220 described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91:589(1964);

[00337] (iii) aryl halides as reactive nitrohaloaromatic compounds;

[00338] (iv) alkyl halides, as described, for example, by McKenzie et al., J. Protein Chem. 7:581 (1988);

[00339] (v) aldehydes and ketones with the capacity to form Schiff bases with amino groups, wherein the adducts formed are generally stabilized by reduction to generate a stable amine;

[00340] (vi) epoxide derivatives such as epichlorohydrin and bisoxiranes, which can react with amino, sulfhydryl, or phenolic hydroxyl groups;

[00341] (vii) derivatives containing chlorine of s-triazines, which are very reactive to nucleophiles such as amino, sulfhydryl and hydroxyl groups;

[00342] (viii) aziridines based on s-triazine compounds detailed above, for example, as described by Ross, J. Adv. Cancer Res. 2:1 (1954), which react with nucleophiles as amino groups by ring opening;

[00343] (ix) diethyl esters of squaric acids as described by Tietze, Chem. Ber. 124:1215(1991); and

[00344] (x) α-haloalkyl ethers, which are more reactive alkylating agents than normal alkyl halides due to activation caused by the ether oxygen atom, as described by Benneche et al., Eur. J. Med. Chem. 28:463 (1993).

[00345] Representative amino-reactive acylating agents include:

[00346] (i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives, respectively; Petition 870260070873, dated 07 / 16 / 2026, p. 126 / 532 118 / 220

[00347] (ii) sulfonyl chlorides, which were described by Herzig et al., Biopolymers 2:349 (1964);

[00348] (iii) acid halides;

[00349] (iv) active esters such as nitrophenyl esters or N-hydroxysuccinimidyl esters;

[00350] (v) acid anhydrides as mixed, symmetrical or N-carboxyanhydrides;

[00351] (vi) other reagents useful for amide bond formation, for example, as described by M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, 1984;

[00352] (vii) acylazides, for example, wherein the azide group is generated from a pre-formed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974);

[00353] (viii) imidoesters, which form stable amidines by reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962); and

[00354] (ix) halo-heteroaryl groups such as halopyridine or halopyrimidine.

[00355] Aldehydes and ketones can be reacted with amines to form Schiff bases, which can be advantageously stabilized through reductive amination. Alkoxylamino chemical moieties react readily with ketones and aldehydes to produce alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1:96 (1990).

[00356] Examples of reactive chemical moieties capable of reacting with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947). Modifying reagents of Petition 870260070873, dated 07 / 16 / 2026, p. 127 / 532 119 / 220 carboxyl groups, such as carbodiimides, which react via the formation of an oacylurea followed by the formation of an amide bond, can also be used.

[00357] It will be understood that functional groups in any chemical moiety can, if desired, be converted into other functional groups before the reaction, for example, to confer additional reactivity or selectivity. Examples of useful methods for this purpose include the conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylmocysteine ​​thiolactone, sacetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as α-haloacetates; conversion of thiols to amines using reagents such as ethyleneimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.

[00358] So-called zero-length ligands, involving the direct covalent bonding of a reactive chemical group from one chemical moiety to a reactive chemical group from another without introducing additional bonding material, can, if desired, be used according to the invention.

[00359] More commonly, however, the ligand includes two or more reactive chemical moieties, as described above, connected by a spacer element. The presence of this spacer allows bifunctional ligands to react with specific functional groups within any chemical moiety, resulting in a covalent bond between the two. The reactive chemical moieties in a ligand can be the same (homobifunctional ligand) or different (heterobifunctional ligand). Petition 870260070873, dated 07 / 16 / 2026, page 128 / 532 120 / 220 te, or, in which several similar reactive chemical moieties are present, heteromultifunctional ligand), providing a diversity of potential reagents that can cause covalent bonding between the two chemical moieties.

[00360] The spacers in the linker typically consist of linear or branched chains and may include a C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkyl, C3-10 alkylheterocyclyl, C2-C100 polyethylene glycol or C1-10 heteroalkyl.

[00361] In some cases, the ligand is described by Formula V.

[00362] Examples of homobifunctional ligands useful in the preparation of conjugates of the invention include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.

[00363] In some embodiments, the linker is a linear chain or linkage of up to 10 atoms, independently selected from carbon, nitrogen, oxygen, sulfur, or phosphorus atoms, wherein each atom in the chain is optionally replaced by one or more substituents independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, chlorine, iodine, bromine, fluoro, hydroxyl, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamide, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and wherein any two atoms in the chain may be taken together with the substituents attached to them to form a ring, wherein the ring may be further substituted and / or fused to one or more optionally carbocyclic, heterocyclic, aryl, or heteroaryl rings. replaced.

[00364] In some forms, a ligand has the structure of Formula XIX: Petition 870260070873, dated 07 / 16 / 2026, p. 129 / 532 121 / 220 A1-(B1)a-(C1)b-(B2)c-(D)-(B3)d-(C2)e-(B4)^A2Formula XIX

[00365] wherein A1 is a linkage between the ligand and the chemical binding portion of the presenting protein; A2 is a linkage between the chemical interaction portion of the mammalian target and the ligand; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, O, S, and NRN; Rn is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl or optionally substituted C1-7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1;and D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol or optionally substituted C1-10 heteroalkyl, or a chemical linkage linking A1-(B1)a-(C1)b-(B2)c-a (B3)d-(C2)e-(BVA2.; PROTEINS PRESENTING PROTEINS

[00366] Presenter proteins can bind a small molecule to form a complex, which can bind to and modulate the activity of a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein, or a prokaryotic target protein such as a bacterial target protein). In some embodiments, the presenter protein is a mammalian presenter protein (e.g., a human presenter protein). In some embodiments, the presenter protein Petition 870260070873, dated 07 / 16 / 2026, p. 130 / 532 122 / 220 The presenting protein is a fungal presenting protein. In certain embodiments, the presenting protein is a bacterial presenting protein. In some embodiments, the presenting protein is a plant presenting protein. In some embodiments, the presenting protein is a relatively abundant protein (e.g., the presenting protein is sufficiently abundant that participation in a tripartite complex does not materially negatively impact the biological role of the presenting protein in a cell and / or cell viability or other attributes). In some embodiments, the presenting protein is more abundant than the target protein. In certain embodiments, the presenting protein is a protein that has chaperone activity within a cell. In some embodiments, the presenting protein has multiple natural interaction partners within a cell.In certain embodiments, the presenting protein is one that is known to bind a small molecule to form a binary complex that is known or suspected to bind and modulate the biological activity of a target protein. Immunophilins are a class of presenting proteins that are known to have these functions and include FKBPs and cyclophilins. In some embodiments, the reference presenting protein exhibits peptidyl prolyl isomerase activity; in some embodiments, a presenting protein shows activity comparable to the reference presenting protein. In certain embodiments, the presenting protein is a member of the FKBP family (e.g., FKBP12, FKBP12).6, FKBP13, FKBP19, FKBP22, FKBP23, FKBP25, FKBP36, FKBP38, FKBP51, FKBP52, FKBP60, FKBP65, and FKBP133), a member of the cyclophilin family (e.g., PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G), or PIN1. The FKBP family is a... Petition 870260070873, dated 07 / 16 / 2026, page 131 / 532 The 123 / 220 family of proteins has prolyl isomerase activity and functions as protein folding chaperones for proteins containing proline residues. Genes encoding proteins in this family include AIP, AIPL1, FKBP1A, FKBP1B, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9, FKBP9L, FKBP10, FKBP11, FKBP14, FKBP15, and LOC541473.

[00367] The cyclophilin family is a family of proteins that bind to cyclosporine. Genes encoding proteins in this family include PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH, SDCCAG-10, PPIL1, PPIL2, PPIL3, PPIL4, P270, PPWD1, and COAS-2. Exemplary cyclophilins include PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, and PPIAL4G.

[00368] In some embodiments, a presenting protein is a chaperone protein such as GRP78 / BIP, GRP94, GRP170, calnexin, calreticulin, HSP47, ERp29, protein disulfide isomerase (PDI), and ERp57.

[00369] In some embodiments, a presenting protein is an allelic variant or splicing variant of an FKBP or cyclophilin disclosed in this document.

[00370] In some embodiments, a presenting protein is a polypeptide whose amino acid sequence i) shows significant identity with that of a reference presenting protein; ii) includes a portion that shows significant identity with a corresponding portion of a reference presenting protein; and / or iii) includes at least one characteristic sequence found in the presenting protein. In many embodiments, identity is considered significant for the purposes of defining a presenting protein if it is above 80%, 81%, 82%, 83%, 84%, 85%, 86%, Petition 870260070873, dated 07 / 16 / 2026, page 132 / 532 124 / 220 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher. In some modalities, the portion that shows significant identity has a length of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 350, 450, 500, 550, 600 amino acids or more.

[00371] Representative presenting proteins are encoded by the genes or homologs thereof listed in Table 1; in some embodiments, a reference presenting protein is encoded by a gene presented in Table 1. In addition, those individuals of ordinary skill in the technique, referring to Table 1, can readily identify sequences that are characteristic of presenting proteins generally and / or of particular subsets of presenting proteins. TABLE 1. GENES THAT CODE SELECTED PRESENTING PROTEINS Gene Name Accession Number Uniprot AIP 000170 AIPL1 Q9NZN9 FKBP1A P62942 FKBP1B P68106 FKBP2 P26885 FKBP3 Q00688 FKBP4 Q02790 FKBP5 Q13451 FKBP6 075344 FKBP7 Q9Y680 FKBP8 Q14318 FKBP9 095302 Petition 870260070873, dated 07 / 16 / 2026, page 133 / 532 125 / 220 Gene Name Uniprot Accession Number FKBP9L Q75LS8 FKBP10 Q96AY3 FKBP11 Q9NYL4 FKBP14 Q9NWM8 FKBP15 Q5T1M5 LOC541473 - PPIA Q567Q0 PPIB P23284 PPIC P45877 PPID Q08752 PPIE Q9UNP9 PPIG Q13427 PPIH 043447 PPIL1 Q9Y3C6 PPIL2 Q13356 PPIL3 Q9H2H8 PPIL4 Q8WUA2 PPIL5 Q32Q17 PPIL6 Q8IXY8 PPWD1 Q96BP3 TARGET PROTEINS

[00372] A target protein (for example, a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein) is a protein that mediates a disease condition or a symptom of a disease condition. As such, a desirable therapeutic effect can be achieved by modulating (inhibiting or enhancing) its activity. Useful target proteins in the complexes and methods of the invention include those that do not naturally associate with a presenting protein, for example, those that have an affinity for a presenting protein in the absence of a binary complex. Petition 870260070873, dated 07 / 16 / 2026, p. 134 / 532 126 / 220 with a compound of the invention larger than 1 μM, preferably larger than 5 μM, and more preferably larger than 10 μM. Alternatively, target proteins that do not naturally associate with a presenting protein are those that have an affinity for a compound of the invention in the absence of a binary complex larger than 1 μM, preferably larger than 5 μM, and more preferably larger than 10 μM. In another alternative, target proteins that do not naturally associate with a presenting protein are those that have an affinity for a binary complex of cyclosporine, rapamycin, or FK506 and a presenting protein (e.g., FKBP) larger than 1 μM, preferably larger than 5 μM, and more preferably larger than 10 μM. Alternatively, target proteins that do not naturally associate with a presenting protein are those that are different from calcineurin or mTOR.The selection of suitable target proteins for the complexes and methods of the invention may depend on the presenting protein. For example, target proteins that have low affinity for a cyclophilin may have high affinity for an FKBP and would not be used together with the former.

[00373] Target proteins can be naturally occurring, for example, wild-type. Alternatively, a target protein can vary from the wild-type protein but still retain biological function, for example, as an allelic variant, a splicing mutant, or a biologically active fragment.

[00374] In some embodiments, a target protein is a transmembrane protein. In some embodiments, a target protein has a coiled-coil structure. In certain embodiments, a target protein is a protein of a dimeric complex.

[00375] In some embodiments, a target protein of the invention includes one or more surface sites (for example, a super site Petition 870260070873, dated 07 / 16 / 2026, p. 135 / 532 127 / 220 flat surface) characterized by the fact that, in the absence of the formation of a presenting protein / compound complex, small molecules typically demonstrate low or undetectable binding to the site (or sites). In some embodiments, a target protein includes one or more surface sites (e.g., a flat surface site) to which, in the absence of the formation of a presenting protein / compound complex, a particular small molecule (e.g., the compound) shows low or undetectable binding (e.g., binding at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100 times, or more, lower than that observed with a presenting protein / compound complex involving the same compound).In some embodiments, a target protein has a surface characterized by one or more sites (and, in some embodiments, an entire surface) that lacks any traditional binding pocket, for example, a cavity or pocket in the protein structure with physicochemical and / or geometric properties comparable to proteins whose activity has been modulated by one or more small molecules. In certain embodiments, a target protein has a traditional binding pocket and a site for a protein-protein interaction. In some embodiments, a target protein is a target not susceptible to drug modulation, for example, a target protein is not a member of a protein family that is known to be targeted by drugs and / or does not possess a binding site that is expected (e.g., according to the accepted understanding of the art, as discussed herein) to be suitable for binding to a small molecule.In some forms, the protein includes at least one reactive cysteine.

[00376] In some embodiments, the target protein is a GTPase such as DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, Petition 870260070873, dated 07 / 16 / 2026, p. 136 / 532 128 / 220 RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB4A, RAB4B, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RAB10, RAB11A, RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL RAB40B, RAB40C, RAB41, RAB42, RAB43, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6, ARL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B, ARL10C, ARL11, ARL13A, ARL13B, ARL14, ARL15, ARL16, ARL17, TRIM23, ARL4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1,RIT2, RHOT1, or RHOT2. In some modalities, the target protein is a GTPase-activating protein such as NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1, or ASAP3. In some embodiments, the target protein is a guanine nucleotide exchange factor such as CNRASGEF, RASGEF1A, RASGRF2, RASGRP1, RASGRP4, SOS1, RALGDS, RGL1, RGL2, RGR, ARHGEF10, ASEF / ARHGEF4, ASEF2, DBS, ECT2, GEF-H1, LARG, NET1, OBSCURIN, P-REX1, P-REX2, PDZRHOGEF, TEM4, TIAM1, TRIO, VAV1, VAV2, VAV3, DOCK1, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C3G, BIG2 / ARFGEF2, EFA6, FBX8, or GEP100. In certain embodiments, the target protein is... Petition 870260070873, dated 07 / 16 / 2026, p. 137 / 532 129 / 220 a protein with a protein-protein interaction domain such as ARM; BAR; BEACH; BH; BIR; BRCT; BROMO; BTB; C1; C2; CARD; CC; CALM; CH; CHROMO; CUE; DEATH; DED; DEP; DH; EF-hand; EH; ENTH; EVH1; F-box; FERM; FF; FH2; FHA; FYVE; GAT; GEL; GLUE; GRAM; GRIP; GYF; HEAT; HECT; IQ; LRR; MBT; MH1; MH2; MIU; NZF; PAS; PB1; PDZ; PH; POLO-Box; PTB; PUF; PWWP; PX; RGS; RING; SAM; SC; SH2; SH3; SOCS; SPRY; START; SWIRM; TIR; TPR; TRAF; SNARE; TUBBY; TUDOR; UBA; UEV; UIM; VHL; VHS; WD40; WW; SH2; SH3; TRAF; Bromodomain; or TPR. In some modalities, the target protein is a heat shock protein such as Hsp20, Hsp27, Hsp70, Hsp84, crystalline alpha B, TRAP-1, hsf1, or Hsp90. In certain modalities, the target protein is an ion channel such as Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1, NAv1.7, Nav1.8, Nav1.9, P2X3, or P2X4.In some embodiments, the target protein is a coiled-coil protein such as geminin, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, Vimentin, ATF4, Nemo, SNAP25, Syntaxin 1a, FYCO1, or CEP250. In certain modalities, the target protein is a kinase such as Cyclin D1, ABL, ALK, AXL, BTK, EGFR, FMS, FAK, FGFR1, 2, 3, 4, FLT3, HER2 / ErbB2, HER3 / ErbB3, HER4 / ErbB4, IGF1R, INSR, JAK1, JAK2, JAK3, KIT, MET, PDGFRA, PDGFRB, RET RON, ROR1, ROR2, ROS, SRC, SYK, TIE1, TIE2, TRKA, TRKB, KDR, AKT1, AKT2, AKT3, PDK1, PKC, RHO, ROCK1, RSK1, RKS2, RKS3, ATM, ATR, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, ERK1, ERK2, ERK3, ERK4, GSK3A, GSK3B, JNK1, JNK2, JNK3, AurA, AurB, PLK1, PLK2, PLK3, PLK4, IKK, KIN1, cRaf, PKN3, c-Src, Fak, PyK2, or AMPK. In some modalities, the target protein is a phosphatase such as WIP1, SHP2, SHP1, PRL-3, PTP1B, or STEP.In certain modalities, the target protein is a ubiquitin or ubiquitin-like protein (such as NEDD8, ATG8 proteins, SUMO proteins, etc.). Petition 870260070873, dated 07 / 16 / 2026, page 138 / 532 130 / 220 ISG15), activating enzyme (E1s such as UBA1, UBA2, UBA3, UBA5, UBA6, UBA7, ATG7, NAE1, SAE1), conjugating enzyme (E2s such as UBE, ATG3, BIRC6 proteins), binding enzyme (E3s such as BMI-1, MDM2, NEDD4-1, Beta-TRCP, SKP2, E6AP, CBL-B, or APC / C), and ubiquitin or ubiquitin-like protease protein. In some embodiments, the target protein is a chromatin modifier / remodeler such as a chromatin modifier / remodeler encoded by the BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, or CREBBP gene. In some modalities, the target protein is a transcription factor such as a transcription factor encoded by the genes EHF, ELF1, ELF3, ELF4, ELF5, ELK1, ELK3, ELK4, ERF, ERG, ETS1, ETV1, ETV2, ETV3, ETV4, ETV5, ETV6, FEV, FLI1, GAVPA, SPDEF, SPI1, SPIC, SPIB, E2F1, E2F2, E2F3, E2F4, E2F7, E2F8, ARNTL, BHLHA15, BHLHB2, BHLBHB3, BHLHE22, BHLHE23, BHLHE41, CLOCK, FIGLA, HAS5, HES7, HEY1, HEY2, ID4, MAX, MESP1, MLX, MLXIPL, MNT, MSC, MYF6, NEUROD2, NEUROG2,NHLH1, OLIG1, OLIG2, OLIG3, SREBF2, TCF3, TCF4, TFAP4, TFE3, TFEB, TFEC, USF1, ARF4, ATF7, BATF3, CEBPB, CEBPD, CEBPG, CREB3, CREB3L1, DBP, JHLF2, MAFK, MAFK, MAFK, MAFK, MAFK NFE2, NFIL3, TEF, XBP1, PROX1, TEAD1, TEAD3, TEAD4, ONECUT3, ALX3, ALX4, ARX, BARHL2, BARX, BSX, CART1, CDX1, CDX2, DLX1, DLX2, DLX3, DLX1, DLX1, DLX1, MB, 65 DPRX, DRGX, DUXA, EMX1, EMX2, EN1, EN2, ESX1, EVX1, EVX2, GBX1, GBX2, GSC, GSC2, GSX1, GSX2, HESX1, HMX1, HMX2, HMX3, HNF1, HNF1, HMX1, HMX1, HMX1 HOXA10, HOXA13, HOXA2, HOXAB13, HOXB2, HOXB3, HOXB5, HOXC10, HOXC11, HOXC12, HOXC13, HOXD11, HOXD12, HOXD13, HOXD8, IRX2, IRX5, ISLX2, LXXX2, LXX2, LXXXXX, LLB2, HOXD11, HOXD12 LHX9, LMX1A, LMX1B, MEIS1, MEIS2, MEIS3, MEOX1, MEOX2, MIXL1, MNX1, MSX1, MSX2, NKX2-3, NKX2-8, NKX3-1, NKX3-2, NKX6-1, NKX3-2, NOXTO6, Petition 870260070873, of 16 / 07 / 2026, p. 139 / 532 131 / 220 ONECUT1, ONECUT2, OTX1, OTX2, PDX1, PHOX2A, PHOX2B, PITX1, PITX3, PKNOX1, PROP1, PRRX1, PRRX2, RAX, RAXL1, RHOXF1, SHOX, SHOX2, TGIF1, TGIF2, TGIF2LX, UNCX, VAX1, VAX2, VENTX, VSX1, VSX2, CUX1, CUX2, POU1F1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3, POU3F4, POU4F1, POU4F2, POU4F3, POU5F1P1, POU6F2, RFX2, RFX3, RFX4, RFX5, TFAP2A, TFAP2B, TFAP2C, GRHL1, TFCP2, NFIA, NFIB, NFIX, GCM1, GCM2, HSF1, HSF2, HSF4, HSFY2, EBF1, IRF3, IRF4, IRF5, IRF7, IRF8, IRF9, MEF2A, MEF2B, MEF2D, SRF, NRF1, CPEB1, GMEB2, MYBL1, MYBL2, SMAD3, CENPB, PAX1, PAX2, PAX9, PAX3, PAX4, PAX5, PAX6, PAX7, BCL6B, EGR1, EGR2, EGR3, EGR4, GLIS1, GLIS2, GLI2, GLIS3, HIC2, HINFP1, KLF13, KLF14, KLF16, MTF1, PRDM1, PRDM4, SCRT1, SCRT2, SNAI2, SP1, SP3, SP4, SP8, YY1, YY2, ZBED1, ZBTB7A, ZBTB7B, ZBTB7C, ZIC1, ZIC3, ZIC4, ZNF143, ZNF232, ZNF238, ZNF282, ZNF306, ZNF410, ZNF435, ZBTB49, ZNF524, ZNF713, ZNF740, ZNF75A, ZNF784, ZSCAN4, CTCF, LEF1, SOX10, SOX14, SOX15, SOX18, SOX2, SOX21, SOX4, SOX7, SOX8, SOX9, SRY, TCF7L1,FOXO3, FOXB1, FOXC1, FOXC2, FOXD2, FOXD3, FOXG1, FOXI1, FOXJ2, FOXJ3, FOXK1, FOXL1, FOXO1, FOXO4, FOXO6, FOXP3, EOMES, MGA, NFAT5, NFATC1, NFKB2, NFKB3, NTP6 RUNX2, RUNX3, T, TBR1, TBX1, TBX15, TBX19, TBX2, TBX20, TBX21, TBX4, TBX5, AR, ESR1, ESRRA, ESRRB, ESRRG, HNF4A, NR2C2, NR2E1, NR2F1, NR2F1, NR2F1, NR316 NR3C2, NR4A2, RARA, RARB, RARG, RORA, RXRA, RXRB, RXRG, THRA, THRB, VDR, GATA3, GATA4, or GATA5; or C-myc, Max, Stat3, Stat4, Stat6, androgen receptor, C-Jun, C-Fox, NMyc, L-Myc, MITF, Hif-lalpha, Hif-2alpha, Bcl6, E2F1, NF-kappaB, Stat5, or ER(coact). In certain modalities, the target protein is TrkA, P2Y14, mPEGS, ASK1, ALK, Bcl-2, BCL-XL, mSIN1, RORyt, IL17RA, elF4E, TLR7 R, PCSK9, IgE R, CD40, CD40L, Shn-3, TNFR1, TNFR2, Petition 870260070873, of 16 / 07 / 2026, p. 140 / 532 132 / 220 IL31RA, OSMR, IL12beta1,2, Tau, FASN, KCTD 6, KCTD 9, Raptor, Rictor, RALGAPA, RALGAPB, Annexin family members, BCOR, NCOR, beta catenin, AAC 11, PLD1, PLD2, Frizzled?, RaLP1, Myb12, ELL, ELL. RhoGD12, EGFR, CTLA4R, GCGC (coact), Adiponectin R2, GPR 81, IMPDH2, IL-4R, IL-13R, IL-1R, IL2-R, IL-6R, IL-22R, TNF-R, TLR4, MyD88, Keapl3, or Nr. PROTEIN VARIANTS

[00377] A protein or polypeptide variant, as described in this document, generally has an amino acid sequence that shows significant identity (e.g., 80% or more, i.e., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with that of a reference polypeptide (e.g., a presenting protein or target protein as described in this document as, for example, a mammalian presenting protein or target protein), but includes a limited number of particular amino acid changes (e.g., insertions, deletions, or substitutions, conservative or non-conservative and / or including one or more amino acid variants or analogs (e.g., D-amino acids, (desamino acids) in relation to the reference polypeptide.In certain embodiments, a variant shares a relevant biological activity (e.g., binding to a particular compound or chemical portion thereof) with the reference polypeptide; in some of these embodiments, the variant exhibits this activity at a level that is not less than about 50% of that of the reference polypeptide and / or is not less than about 0.5 times below that of the reference polypeptide.

[00378] In some embodiments, a polypeptide variant has an amino acid sequence that differs from that of a reference polypeptide at least (or only) where the variant has a Petition 870260070873, dated 07 / 16 / 2026, p. 141 / 532 133 / 220 a greater number of cysteine ​​residues and / or has one or more cysteine ​​residues in a position corresponding to a non-cysteine ​​residue in the reference polypeptide. For example, in some embodiments, the addition of one or more cysteine ​​residues to the amino or carboxy terminal of any of a polypeptide (e.g., of a presenter protein and / or a target protein) as described herein may facilitate the conjugation of this polypeptide by, for example, disulfide linkage. In some embodiments, amino acid substitutions may be conservative (i.e., where a residue is substituted by another of the same general type or group) or non-conservative (i.e., where a residue is substituted by an amino acid of another type).In some embodiments, a naturally occurring amino acid can be substituted for a non-naturally occurring amino acid (i.e., non-naturally occurring conservative amino acid substitution or non-naturally occurring non-conservative amino acid substitution), or vice versa.

[00379] Synthetically produced polypeptides may include substitutions of amino acids encoded unnaturally by DNA (e.g., unnaturally occurring or non-naturally occurring amino acids). Examples of unnaturally occurring amino acids include D-amino acids, an amino acid having an azide-containing side chain, an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine, a pegylated amino acid, the omega amino acids of the formula NH2(CH2)nCOOH where n is 2 to 6, neutral nonpolar amino acids such as sarcosine, t-butylalanine, t-butylglycine, N-methylisoleucine, and norleucine. Phenylglycine may be substituted for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic. Proline may be substituted for hydroxyproline and retains conformational-conferring properties. Petition 870260070873, dated 07 / 16 / 2026, p. 142 / 532 134 / 220

[00380] Analogs can be generated by substitutional mutagenesis and retain the structure (e.g., a local structure or global structure) of the original protein. Examples of substitutions identified as conservative substitutions are shown in Table 2. If these substitutions result in an undesired change, then another type of substitutions, termed exemplary substitutions in Table 2, or as further described in this document in reference to amino acid classes, are introduced and the products tested.

[00381] Substantial modifications in immunological function or identity are achieved by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the protein backbone in the area of ​​the substitution, for example, as a sheet or helical conformation. (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side chain properties:

[00382] (1) hydrophobic: norleucine, methionine (Met), Alanine (Ala), Valine (Vai), Leucine (Leu), Isoleucine (Ile), Histidine (His), Tryptophan (Trp), Tyrosine (Tyr), Phenylalanine (Phe),

[00383] (2) hydrophilic neutral: Cysteine ​​(Cys), Serine (Ser), Threonine (Thr)

[00384] (3) acid / negatively charged: Aspartic acid (Asp), Glutamic acid (Glu)

[00385] (4) basic: Asparagine (Asn), Glutamine (Gin), Histidine (His), Lysine (Lys), Arginine (Arg)

[00386] (5) residues that influence chain orientation: Glycine (Gly), Proline (Pro);

[00387] (6) aromatic: Tryptophan (Trp), Tyrosine (Tyr), Phenylalanine (Phe), Histidine (His), Petition 870260070873, dated 07 / 16 / 2026, page 143 / 532 135 / 220

[00388] (7) polar: Ser, Thr, Asn, Gin

[00389] (8) positively charged basic: Arg, Lys, His and;

[00390] (9) loaded: Asp, Glu, Arg, Lys, His

[00391] Other amino acid substitutions are listed in Table 2. TABLE 2. AMINO ACID SUBSTITUTIONS Original Residue Exemplary Substitution Conservative Substitution Ala (A) Vai, Leu, lie Vai Arg (R) Lys, Gin, Asn Lys Asn (N) Gin, His, Lys, Arg Gin Asp (D) Glu Glu Cys (C) Ser Ser Gin (Q) Asn Asn Glu (E) Asp Asp Gly (G) Pro Pro His (H) Asn, Gin, Lys, Arg Arg He O) Leu, Vai, Met, Ala, Phe, norleucine Leu Leu (L) Norleucine, lie, Vai, Met, Ala, Phe lie Lys (K) Arg, Gin, Asn Arg Met (M) Leu, Phe, lie Leu Phe (F) Leu, Vai, lie, Ala Leu Pro (P) Gly Gly Ser (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr Tyr Tyr (Y) Trp, Phe, Thr, Ser Phe Vai (V) lie, Leu, Met, Phe, Ala, norleucine Leu PROTEIN VARIANTS WITH REA- AMINO ACID PROFILES ALTERED ASSETS Petition 870260070873, dated 07 / 16 / 2026, page 144 / 532 136 / 220

[00392] In some embodiments, a variant protein or polypeptide may include the addition of one or more reactive amino acid residues (e.g., cysteines) to a protein (e.g., at the amino or carboxy terminus of any of the proteins described in this document) which may facilitate the conjugation of these proteins by, for example, disulfide bonding. In some embodiments, one or more reactive amino acids (e.g., cysteines) may be removed to reduce the number of possible conjugation sites in a protein. Amino acid substitutions may be conservative (i.e., where one residue is replaced by another of the same type or general group) or non-conservative (i.e., where one residue is replaced by an amino acid of a different type).Furthermore, a naturally occurring amino acid can be replaced by a non-naturally occurring amino acid (i.e., non-naturally occurring conservative amino acid substitution or non-naturally occurring non-conservative amino acid substitution).

[00393] As is known in the art, for example, as described in Chin, JW, Expanding and Reprogramming the Genetic Code of Cells and Animals, Annual Review of Biochemistry, Vol. 83: 379 to 408, non-natural amino acids can be incorporated into proteins produced in vitro. For example, in one system, amber UAG (termination) codons were used to incorporate pyrrolysine via an archaeal tRNA synthetase and tRNA, and these can also be used to incorporate azides and alkynes via feeding. Other non-natural amino acid side chains that have been demonstrated in the technique include cyclopropene, trans-cyclooctene, bicyclo[6.1.0]noninalysine, coumarins, p-azidophenylalanine, N6-[(2-propynyloxy)carbonyl]-L-lysine, bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN), N-5-norbornene-2-yloxycarbonyl-L-lysine, N-tert-butyloxycarbonyl-L-lysine, N-2-azidoethyloxycarbonyl-L-lysine, NL-tiaprolyl-L-lysine, ND-cysteinyl-L-lysine, Petition 870260070873, dated 07 / 16 / 2026, p. 145 / 532 137 / 220 NL-cysteinyl-L-lysine, N6-[(2-propynyloxy)carbonyl]-L-lysine, N6-[(2azidoethoxy)carbonyl]-L-lysine, benzophenone, 4-(6-methyl-s-tetrazine-3yl)aminophenylalanine, and cyclo-octynes. COMPLEX

[00394] In naturally occurring protein-protein interactions, binding events are typically triggered largely by hydrophobic residues on planar surface sites of the interacting proteins, in contrast to many small molecule-protein interactions that are triggered by interactions between the small molecule in a cavity or pocket in the protein. Commonly, hydrophobic residues on a planar surface site of the protein form a hydrophobic hotspot where most binding interactions between or among interacting proteins are van der Waalss interactions. In some situations, a small molecule may provide a portable hotspot (or portion thereof) where it participates in or generates a hydrophobic interaction site on a protein (e.g., a presenting protein) where this does not exist in the absence of the small molecule; aspects of the present description are particularly applicable to these situations.For example, in some embodiments, a compound (and / or a labeled form thereof) as described in this document forms a complex with a protein (e.g., a presenter protein / compound complex) and participates in pseudoprotein-protein interactions (e.g., forming a tripartite complex with a target protein).

[00395] Many mammalian proteins have the capacity to bind to any one of a plurality of different partners; in some cases, these alternative binding interactions contribute to the biological activity of the proteins. Many of these proteins adapt the inherent variability of the protein's hotspot regions to present the same residues in different contexts. Petition 870260070873, dated 07 / 16 / 2026, p. 146 / 532 138 / 220 structural. More specifically, protein-protein interactions can be mediated by a class of natural products produced by a select group of fungal and bacterial species. These molecules exhibit both a common structural organization and resulting functionality that provides the ability to modulate protein-protein interaction. These molecules may contain a highly conserved presenting protein-binding chemical portion and a target protein-interaction chemical portion that exhibits a high degree of variability among the different natural products.The presenting protein-binding chemical moiety confers specificity for the presenting protein and allows the molecule to bind to the presenting protein to form a complex; the mammalian target protein-binding chemical moiety confers specificity for the target protein and allows the binary complex to bind to the target protein, typically modulating (e.g., positively or negatively modulating) its activity. In the present invention, a binary complex (e.g., between a compound and a presenting protein or a compound and a target protein) is simulated by conjugating a presenting protein-binding chemical moiety to a target protein or a target protein-binding chemical moiety to the presenting protein. The resulting conjugates of the invention can then bind to a presenting protein or target protein, forming a complex that simulates the tripartite complex.These complexes can be used, for example, to determine the structure of the interface between the presenting protein and the target protein. Furthermore, by simplifying the formation of the complex, for example, by conjugating a chemical binding moiety of the presenting protein to a target protein, the compounds of the invention can be used, for example, to identify target proteins capable of binding to presenting proteins. Petition 870260070873, dated 07 / 16 / 2026, page 147 / 532 139 / 220 USES IDENTIFICATION OF TARGET PROTEINS

[00396] In some embodiments, the compounds, conjugates, complexes, compositions and / or methods of the present invention may be useful for identifying target proteins capable of forming complexes with presenting proteins (for example, in the presence of a small molecule). The target proteins can be identified by forming conjugates that include a chemical binding moiety of a presenting protein conjugated to a chemical target moiety and determining whether the conjugate forms a complex with a presenting protein.

[00397] Most target proteins known in the art to form ternary complexes with presenting proteins and small molecules were identified fortuitously during the determination of the small molecule's mechanism of action. The present methods allow the rational identification of target proteins capable of forming complexes with presenting proteins in the presence of small molecules by covalent conjugation of a chemical binding moiety of the presenting protein to the target molecule, allowing the formation of a complex before identifying a compound capable of binding both the presenting protein and the target protein simultaneously.

[00398] Testing small molecules for their ability to facilitate complex formation between the presenting protein and the identified target protein could then be performed to identify potential therapeutics capable of modulating the biological activity of the target protein.

[00399] In some embodiments, the compounds of the invention can be used to identify target proteins capable of forming complexes with presenter proteins. For example, the Petition 870260070873, dated 07 / 16 / 2026, page 148 / 532 140 / 220 target proteins can be identified by combining one or more target proteins with a labeled presenting protein (e.g., labeled with biotin) in the presence of a compound of the invention under suitable conditions to allow the formation of a presenting protein / target protein complex. Target proteins that do not form complexes with presenting proteins can then be removed (e.g., washed) and target proteins that do form complexes can then be subjected to pulldown using the label on the presenting protein and analyzed. In some embodiments, the target proteins subjected to pulldown can be analyzed by mass spectrometry in order to determine their identity. COMPOSITE DESIGN

[00400] In some embodiments, the compounds, conjugates, complexes, compositions and / or methods of the present invention may be useful for the design of compounds capable of modulating the biological activity of target proteins for use in the treatment of disease.

[00401] For example, the formation of complexes of presenting proteins and conjugates of the invention can facilitate the determination of the protein-protein interface structure between a presenting protein and a target protein by crystallization and determination of the crystal structure of the complex. Once the crystal structure of a complex of the invention is determined, methods known in the art for rational drug design can be used to develop small molecules capable of facilitating complex formation between the presenting protein and the target protein, such as computational chemistry methods to construct de novo structures and / or fragment-based drugs using methods such as fragment embedding of the crystals of complexes of the invention and determining the resulting structure. Petition 870260070873, dated 07 / 16 / 2026, page 149 / 532 141 / 220

[00402] The compounds designed as described above can then be tested to determine their ability to modulate the biological activity of the target protein and modified using medicinal chemistry techniques, as needed, to produce therapeutically useful compounds. IDENTIFICATION OF SMALL COVALENT MOLECULE THERAPEUTICS

[00403] In some embodiments, the compounds, conjugates, complexes, compositions and / or methods of the present invention may be useful for identifying compounds capable of modulating the biological activity of target proteins through covalent interaction.

[00404] For example, the compounds of the inventions can be tested for their ability to covalently bind to target proteins in the presence and absence of presenting proteins to identify compounds capable of selectively binding to target proteins only in the presence of a presenting protein. These compounds can then be tested for their ability to modulate the biological activity of the target protein and modified using medicinal chemistry techniques, as needed, to produce therapeutically useful compounds. DETERMINATION OF BIOCHEMICAL AND / OR BIOPHYSICAL PROPERTIES

[00405] In some embodiments, the compounds, conjugates, complexes, compositions and / or methods of the invention may be useful for determining biochemical and / or biophysical properties of a protein or complex.

[00406] For example, the binding free energy between a conjugate that includes a chemical-binding moiety of a presenting protein and a target protein and a presenting protein can be determined, for example, by isothermal titration calorimetry. The Kd of a Petition 870260070873, dated 07 / 16 / 2026, page 150 / 532 The 142 / 220 conjugate that includes a chemically binding portion of a presenting protein and a target protein for a presenting protein can be determined, for example, by surface plasmon resonance. The Ki, Kinact, and / or Ki / Kinact for a compound and a presenting protein for a target protein can be determined, for example, by mass spectrometry. TREATMENT OF DISEASES OR DISORDERS

[00407] The compounds, conjugates, and complexes described in this document may be useful in methods for treating diseases and disorders related to the target proteins described in this document, and, while not limited by theory, are believed to exert their desirable effects through their ability to modulate (e.g., positively or negatively modulate) the activity of a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein), through interaction with presenting proteins and the target protein. KITS

[00408] In some embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods according to the present invention. In general, the pharmaceutical kit or package comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. These kits are specifically suitable for the delivery of solid oral dosage forms such as tablets or capsules. This kit preferably includes a number of unit dosages, and may also include a card that has the dosages arranged in the order of their intended use. If desired, for example, if the individual suffers from Alzheimer's disease, a memory aid may be provided, for example, in the form of Petition 870260070873, dated 07 / 16 / 2026, p. 151 / 532 143 / 220 numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule on which dosages may be administered. Alternatively, placebo dosages, or calcium dietary supplements, in a form similar to or distinct from the dosages of the pharmaceutical compositions, may be included to provide a kit in which one dosage is taken every day. An optional warning associated with this container (or containers) in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical products, which warning reflects the agency's approval for manufacture, use, or sale for human administration. PHARMACEUTICAL COMPOSITIONS

[00409] For use as treatment of human and animal subjects, the compounds and conjugates of the invention may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired—for example, prevention, prophylaxis, or therapy—the compounds are formulated in forms consistent with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[00410] The compounds described in this document may be present in amounts totaling 1 to 95% by weight of the total weight of the composition. The composition may be supplied in a dosage form that is suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, ​​intrathecal, epidural, aural, or ocular administration, or by injection, inhalation. Petition 870260070873, dated 07 / 16 / 2026, p. 152 / 532 144 / 220 tion, or direct contact with the nasal, genitourinary, reproductive or oral mucosa. Therefore, 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, tube (drenches), osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for inotophoretic delivery, or aerosols. The compositions may be formulated in accordance with conventional pharmaceutical practice.

[00411] In general, for use in treatment, the compounds described herein may be used alone or in combination with one or more other active agents. An example of other pharmaceuticals to combine with the compounds described herein would include pharmaceuticals for the treatment of the same indication. Another example of a potential pharmaceutical to combine with compounds described herein would include pharmaceuticals for the treatment of different, but associated or related, symptoms or indications. Depending on the route of administration, the compounds are formulated in compositions suitable for easy delivery. Each compound in a combination therapy may be formulated in a variety of forms known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately.Ideally, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents.

[00412] The compounds of the invention can be prepared and used as pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable vehicle or excipient, as is well known in the art. In some embodiments, a composition includes at least Petition 870260070873, dated 07 / 16 / 2026, page 153 / 532 145 / 220 minus two pharmaceutically different carriers or excipients.

[00413] 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 generally includes diluents and, in some cases, adjuvants, buffers, preservatives, and the like. Compounds may also be administered in liposomal compositions or as microemulsions.

[00414] For injection, formulations may be prepared in conventional forms as liquid solutions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline solution, dextrose, glycerol and the like. 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, sorbitan monolaurate and so forth.

[00415] Several extended-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677, which is incorporated herein by reference.

[00416] Systemic administration may also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the invention. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[00417] Each component of a combination therapy, as Petition 870260070873, dated 07 / 16 / 2026, page 154 / 532 The 146 / 220 described in this document can be formulated in several ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or separately.

[00418] Individually or separately formulated agents may be packaged together as a kit. Non-limiting examples include, without limitation, 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 individuals, such as ampoules for reconstituting powder forms, syringes for injection, customized delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for preparing and administering the compositions. The kit may be manufactured as a single-use unit dose for one individual, multiple uses for a particular individual (at a constant dose or where the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple individuals (bulk packaging).The kit components can be assembled into cardboard boxes, blister packs, bottles, tubes, and similar containers.

[00419] Oral formulations include tablets containing the active ingredient (or ingredients) in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may be, for example, inert fillers and diluents (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., sa Petition 870260070873, dated 07 / 16 / 2026, page 155 / 532 147 / 220 carose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating, glidant, 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.

[00420] Two or more compounds may be mixed together in a tablet, capsule or other vehicle or may be partitioned. In one example, the first compound is contained inside the tablet, and the second compound is outside, so that a substantial portion of the second compound is released before the release of the first compound.

[00421] 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 kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, for example, a mixer, a fluid bed apparatus or a spray drying apparatus.

[00422] Controlled diffusion dissolution or release can be achieved by suitably coating a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into a suitable matrix. A release coating Petition 870260070873, dated 07 / 16 / 2026, page 156 / 532 Controlled coatings 148 / 220 may include one or more of the coating substances mentioned above and / or, for example, shellac, beeswax, glycol wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate, and / 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 and / or halogenated fluorocarbon.

[00423] The liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, suitable flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[00424] In general, when administered to a human, the oral dosage of any of the compounds in the combination of the invention depends on the nature of the compound, and can be readily determined by an individual skilled in the art. Typically, this dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be required.

[00425] The administration of each drug in a combination therapy, as described in this document, may, independently Petition 870260070873, dated 07 / 16 / 2026, p. 157 / 532 149 / 220 fearfully, it can be one to four times a day for one day to a year, and may even be for the life of the individual. Chronic long-term administration may be indicated. EXAMPLES EXAMPLE 1: SYNTHESIS OF CERTAIN CROSSLINKING REAGENTS Synthesis of cyclosporine analogs containing acrylamide. R4, R6, R7, RT are amino acid side chains on reactive warhead-type electrolytes {e.g., acrylamide or vinyl sulfonamide}.

[00426] All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd. Amino acids Fmoc, HATU, HOAT, H-Ala-2-CI-(Trt) resin (0.36 mmol / g), H-Leu-2-CI-(Trt) resin (0.30 mmol / g), H-Phe-2-CI-(Trt) resin (0.35 mmol / g) and HThr(tBu)-2-CI-(Trt) resin (0.36 mmol / g) were purchased from GL Biochem. Petition 870260070873, dated 07 / 16 / 2026, page 158 / 532 150 / 220 (Shanghai) Ltd.

[00427] The coupling of linear peptides was performed using SPSS procedure in standard Fmoc on an automated synthesizer.

[00428] General Method A: Linear peptides were synthesized using a TETRAS™ synthesizer with a 0.025 mmol resin scale. A general protocol is as follows: 2 x NMP solution, 30 s; 1 x 20% (vol / vol) piperidine in NMP, 15 min; 5 x NMP, 30 s; amino acids (3 eq) in NMP were added to the vessel containing resin followed by the addition of a HATU and DIEA solution in DMF respectively, coupling for 45 min; 3 x NMP, 30 s. A double coupling strategy was applied for all amino acids.

[00429] General Method B: Boc-7mer fixation

[00430] The coupling was performed on the TETRAS™ synthesizer using the same general protocol as for amino acid coupling except that the amount of Boc-7mer is 1.5 equivalent. Only one coupling was necessary.

[00431] General Method C: Removal of protective group ivDde.

[00432] The removal of the ivDde protecting group in the Dap side chain was performed on the TETRAS™ synthesizer. General Protocol: A 20% (v / v) solution of hydrazine monohydrate in NMP was added to the vessel containing the resin. The vessel was shaken for 30 min. The resin was drained and rinsed with 5 x 5 ml (30 s) of NMP.

[00433] General Method D: fixation of acrylic acid to the amino group of the Dap side chain.

[00434] The coupling was performed on the TETRAS™ synthesizer using the same general protocol as amino acid coupling. A double coupling strategy was applied.

[00435] General Method E: Deprotection of side chain protective groups and final resin splitting. Petition 870260070873, dated 07 / 16 / 2026, page 159 / 532 151 / 220

[00436] Deprotection and cleavage of the resin was performed using TFA cocktails for 1 to 2 hours at room temperature. Cleavage cocktails (TFA / TIPS / H2O, 95 / 2.5 / 2.5) or (TFA / DCM / TIPS, 40:60:1) can be used for final cleavage. More solvent was removed under reduced pressure and the residue was concentrated under vacuum to remove trace solvent. The resulting residue was used in the next cyclization directly without further purification.

[00437] General Method F: Cyclization of linear peptides

[00438] The crude linear peptide was dissolved in dry DCM to generate a final concentration of 0.1 M. Then HATU (3eq), HOAt (3eq) and DIEA (6eq) were added. The reaction mixture was stirred overnight and then monitored by ESI-LCMS. The solvent was concentrated under reduced pressure and the residue was dissolved in NMP and purified by preparative HPLC. Cyclopeptides were identified by ESI-LCMS.

[00439] Reverse-Phase HPLC. An Accucore C18 column (2.6 µm, 2.1 mm x 50 mm) with a flow rate of 1 ml / min was used for analytical RP-HPLC. An Xselect Peptide CSH column (5 µm, 19 mm x 150 mm) was used for preparative RP-HPLC. Mobile phase A: water (0.1% formic acid), Mobile phase B: ACN; Flow rate: 20 ml / min; Gradient: 25% B to 95% B in 16 min. Synthesis of cycle[7mer-NMALA-Dap-d-nmala-LEU]: Me

[00440] The linear peptide chain assembly was performed using the general methods described above with 850 mg of H2 resin. Petition 870260070873, dated 07 / 16 / 2026, page 160 / 532 152 / 220 Leu-2-CI-(Trt) (0.3 mmol / g, scale of 0.025 mmol). DN-methyl Ala, Dap, and LN-methyl Ala residue were fixed using general method A. Then Boc-7mer was assembled using general method B. Side chain protecting group removal was performed using general method C. Then acrylic acid was fixed to the free amino group on the Dap side chain using general method D. After global deprotection and resin cleavage in one step (general method E), the crude linear peptide was subjected to cyclization (general method F). After final preparative HPLC, 17 mg of final compound was obtained as a white solid (56.6% calculated by resin loading). ESI-MS: [M+1]+= 1202, [M+Na]+=1224, [M / 2 + 1]+=602. Synthesis of cycle[7mer-NMALA-Dap-d-nmala-PHE]: Me

[00441] 2.8 mg of final compound was obtained as a white solid (9.1% calculated by resin loading) using a method similar to the synthesis of cyclo[7mer-NMALA-Dap-d-nmala-LEU]. ESI-MS: [M+1 ]+=1236, [M+Na]+=1258, [M / 2 + 1 ]+=619. Synthesis of cycle[7mer-NMALA-Dap-d-nmala-THR]: Me

[00442] 3.4 mg of the final compound was obtained as a white solid. Petition 870260070873, dated 07 / 16 / 2026, p. 161 / 532 153 / 220 (11.4% calculated by resin loading) with a similar method as the cyclo[7mer-NMALA-Dap-d-nmala-LEU] synthesis. ESI-MS: [M+1]+=1190, [M+Na]+=1212, [M / 2 + 1]+=596. Synthesis of FKBP12 ligands containing acrylamide

[00443] All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd. Fmoc-amino acids, HATU, HOAT, 2-CI-(Trt)-CI resin (0.9 mmol / g based on active site) and Ala-loaded 2-CI-(Trt)-CI resin (0.36 mmol / g) were purchased from GL Biochem (Shanghai) Ltd.

[00444] To fix the first amino acid in the 2-CI-(Trt)-CI resin.

[00445] In an SPSS container, 5 g of resin were expanded in 50 ml of dry NMP for 40 minutes. Drain the resin and rinse it with DCM (5 x 30 ml) then with 2% NMM / DCM (3 x 30 ml). A solution of Fmoc-Dap(ivDde)-OH (3.0 mmol, 1.6 g) with NMM (4 mmol, 400 mg) in 50 ml of DCM was added. The container was shaken overnight. Then 2 ml of a 25% NMM / MeOH solution was added and the container was shaken for another hour. A Petition 870260070873, dated 07 / 16 / 2026, page 162 / 532 154 / 220 resin was drained and rinsed with DCM, NMP, MeOH, and EtOH (3 x 50 ml each). The resin was then vacuum dried at room temperature.

[00446] The load was measured by photometric measurement of Fmoc splitting (0.32 mmol / g).

[00447] The coupling of linear peptides was performed using the standard Fmoc SPSS procedure on an automated synthesizer.

[00448] General Method A: Linear peptides were synthesized using a TETRAS™ synthesizer with a 0.025 mmol resin scale. A general protocol was as follows: 2 x NMP solution, 30 s; 1 x 20% (vol / vol) piperidine in NMP, 15 min; 5 x NMP, 30 s; amino acids (3 eq) in NMP were added to the vessel containing resin followed by the addition of a HATU and DIEA solution in DMF respectively, coupling for 45 min; 3 x NMP, 30 s. A double coupling strategy was applied for all amino acids.

[00449] General Method B: Boc-3mer fixation

[00450] The coupling was performed on the TETRAS™ synthesizer using the same general protocol as for amino acid coupling except that the amount of Boc-3mer is 1.5 equivalent. Coupling was only necessary once.

[00451] General Method C: Removal of protective group ivDde.

[00452] The removal of the ivDde protecting group in the Dap side chain was performed on the TETRAS™ synthesizer. General Protocol: A 20% (v / v) solution of hydrazine monohydrate in NMP was added to the vessel containing the resin. The vessel was shaken for 30 min. The resin was drained and rinsed with 5 x 5 ml (30 s) of NMP.

[00453] General Method D: fixation of acrylic acid to the amino group of the Dap side chain.

[00454] The coupling was performed on the TETRAS™ synthesizer. Petition 870260070873, dated 07 / 16 / 2026, page 163 / 532 155 / 220 using the same general protocol as for amino acid coupling. A double coupling strategy was applied.

[00455] General Method E: Deprotection of side chain protective groups and final resin splitting.

[00456] Deprotection and cleavage of the resin was performed using TFA cocktails for 1 to 2 hours at room temperature. Cleavage cocktails (TFA / TIPS / H2O, 95 / 2.5 / 2.5) or (TFA / DCM / TIPS, 40:60:1) can be used for final cleavage. More solvent was removed under reduced pressure and the residue was concentrated under vacuum to remove trace solvent. The resulting residue was used in the next cyclization directly without further purification.

[00457] General method F: cyclization of linear peptides

[00458] The crude linear peptide was dissolved in dry DCM to generate a final concentration of 0.1 M. Then HATU (3eq), HOAt (3eq) and DIEA (6eq) were added. The reaction mixture was stirred overnight and then monitored by ESI-LCMS. The solvent was concentrated under reduced pressure and the residue was dissolved in NMP and purified by preparative HPLO. Cyclopeptides were identified by ESI-LCMS.

[00459] Reverse-Phase HPLC. An Accucore C18 column (2.6 µm, 2.1 mm x 50 mm) with a flow rate of 1 ml / min was used for analytical RP-HPLC. An Xselect Peptide CSH column (5 µm, 19 mm x 150 mm) was used for preparative RP-HPLC. Mobile phase A: water (0.1% formic acid), Mobile phase B: ACN; Flow rate: 20 ml / min; Gradient: 25% B to 95% B in 16 min. Synthesis of cycle[diamine-Dap-ALA-ALA]: Petition 870260070873, dated 07 / 16 / 2026, page 164 / 532 156 / 220

[00460] The linear peptide chain assembly was performed using the general methods above with 700 mg of H-Ala-2-CI-(Trt) resin (0.025 mmol scale). Ala and Dap residue were fixed using general method A. Then Boc-3mer was assembled using general method B. Removal of the ivDde side chain protecting group was performed using general method C. Then acrylic acid was fixed to the free amino group on the Dap side chain using general method D. After global deprotection and resin cleavage in one step (general method E), the crude linear peptide was subjected to cyclization (general method F). After final preparative HPLC, 3.1 mg of final compound was obtained as a white solid (14.5% calculated by resin loading). ESI-MS: [M+1]+=857, [M+Na]+=879. Synthesis of cycle[diamine-ALA-ALA-Dap] Petition 870260070873, dated 07 / 16 / 2026, page 165 / 532 157 / 220

[00461] 2.2 mg of final compound were obtained as a white solid (10.3% calculated by resin loading) using a method similar to the synthesis of cyclo[diamine-Dap-ALA-ALA]. ESI-MS: [M+1]+=857, [M+Na]+=879. Synthesis of cycle[diamine-Dap-ALA]:

[00462] 2.7 mg of final compound were obtained as a white solid (12.6% calculated by resin loading) using a method similar to the synthesis of cyclo[diamine-Dap-ALA-ALA]. ESI-MS: [M+1]+=786. Synthesis of sanglefehrin analogs:

[00463] Method A can be used to prepare the compounds of Formula IV as shown below in Diagram 1. SCHEME 1 where R7, R8, Z5, and Z6 are as defined previously, PG1 is a Petition 870260070873, dated 07 / 16 / 2026, p. 166 / 532 158 / 220 suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc, and X is OH, Cl, F, or some other group suitable for displacement or activation followed by displacement.

[00464] In a typical procedure, protected amine IV is reacted with a suitable reagent familiar to those skilled in the art to remove the protecting group PG1. The isolated crude product can be reacted with acylating agent Z5C(O)X in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and amine coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DLPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature.

[00465] Alternatively, the unprotected amine can be directly reacted with the acylating reagent Z5C(O)X when X is a halogen in a suitable solvent (including, without limitation, DMF, dichloromethane, DME, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, pyridine, DIPEA, triethylamine, and NMM) in the temperature range of -78 °C to about 120 °C, preferably between -20 °C and 50 °C.

[00466] The compounds of Formula IVb from Scheme 1 can be prepared as shown below in Scheme 2. SCHEME 2 1) Remove PS2 fn.pg1IV» where R7, R8, and Z6 are as defined previously and PG1 and PG2 Petition 870260070873, dated 07 / 16 / 2026, page 167 / 532 159 / 220 are each independently amine protecting groups including, without limitation, Boc, Cbz, Alloc and Fmoc.

[00467] In a typical procedure, protected amine IVc is reacted with a suitable reagent familiar to those skilled in the art to remove the PG2 protecting group to produce the corresponding amine, which is then reacted with the appropriate amino acid in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and amine coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature to deliver the compounds of Formula IVb.

[00468] The compounds of Formula IVc from Scheme 2 can be prepared as shown below in Scheme 3. SCHEME 3 IVd IVc where R7 and Z6 are as defined above and PG2 is a suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc.

[00469] In a typical procedure, the protected amine IVd is reacted with the piperazic acid derivative IVe in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and amine coupling partners Petition 870260070873, dated 07 / 16 / 2026, page 168 / 532 160 / 220 are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile and tetrahydrofuran) in the presence of a base (including, without limitation, DLPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature.

[00470] Alternatively, compounds of Formula IVb can be synthesized from compounds of formula ll-B as described in Scheme 4. SCHEME 4 1) remove PG3, 2) intrdicir HN'PÜ' IVb wherein R7, R8, and Z6 are as defined above, PG1 is a suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc, and PG3 is an alkyl or aryl group including, but not limited to, methyl, ethyl, benzyl, allyl, phenyl, and the like which can be removed by methods known to those skilled in the art.

[00471] In a typical procedure, compound IVe is reacted at room temperature under hydrolysis conditions using a base (e.g., lithium hydroxide, sodium hydroxide, sodium carbonate) in an organic solvent system (e.g., methanol, THF, dioxane) with or without water. It will be understood by those skilled in the art that, depending on the identity of PG3, removal of PG3 may also occur under hydrogenolysis using a suitable catalyst, or under desalination conditions using a palladium catalyst, e.g., Pd(PPh3)4, and a basic scavenger (e.g., piperidine, morpholine, piperidine). After deprotection to generate the resulting carboxylic acid, Z6 may be introduced. Petition 870260070873, dated 07 / 16 / 2026, page 169 / 532 161 / 220 in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The carboxylic acid and coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature to generate product IVb.

[00472] Alternatively, compounds of Formula IVb can be synthesized as shown below in Scheme 5. SCHEME 5 IVf hn.pg1 IVb where R7, R8, and Z6 are as defined above and PG1 is a suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc.

[00473] In a typical procedure, the protected amine VI is reacted with reagent V in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and amine coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, NMM) at room temperature or slightly elevated temperature. Synthesis of Intermediate I-8 Petition 870260070873, dated 07 / 16 / 2026, page 170 / 532 162 / 220 I-3 I-7

[00474] To a room temperature solution of Intermediate 1-1 (2.00 g, 7.11 mmol) in DMF (13 ml) cesium carbonate (4.75 g, 14.58 mmol) and benzyl bromide (2.49 g, 14.58 mmol, 1.73 ml) were added at 25°C. The reaction mixture was stirred for two hours and then diluted with ethyl acetate (100 ml) and washed with brine (50 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude residue. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate^ 20:1 to 10:1) to provide Intermediate I-2 (3.20 g, 96% yield) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 7.45 - 7.30 (m, 10 H), 7.20 - 7.10 (m, 1 H), 6.95 - 6.85 (m, 1 H), 6.74 (s, 1 H), 6.70 - 6.60 (m, 1 H), 5.20 - 5.10 (m, 2 H), 4.99 (s, 2 H), 4.70 - 4.60 (m, 1 H), 3.15 - 3.05 (m, 2 H), 1.43 (s, 9 H). ESI-MS m / z = 484.1 [M+Na]+; Calculated MW: 461.55.

[00475] Lithium hydroxide (1 M in water, 10 ml) at 0°C was added to a solution of Intermediate I-2 (3.20 g, 6.93 mmol) in tetrahydrofuran (15 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH~6 with HCl (1 M) Petition 870260070873, dated 07 / 16 / 2026, p. 171 / 532 163 / 220 in water) at 0°C and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude residue. The crude product was dissolved in aqueous sodium bicarbonate (7 ml) and extracted with MTBE (100 ml x 3). The aqueous layer was adjusted to pH~6 with hydrochloric acid (1 M in H2O) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield Intermediate I-3 (2.27 g, 88% yield) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 7.45 - 7.30 (m, 5 H), 7.25 - 7.18 (m, 1 H), 6.90 - 6.85 (m, 1 H), 6.83 6.75 (m, 2 H), 5.05 (s, 2 H), 4.94 (d, 7=8.00 Hz, 1H), 4.60 - 4.50 (m, 1H), 3.20 - 3.12 (m, 1H), 3.10 - 3.00 (m, 1H), 1.43 (s, 9H).ESI-MS m / z = 394.3 [M+Na]+; MW Calculated: 371.43.

[00476] To a solution of Intermediate I-3 (888 mg, 2.39 mmol) in dichloromethane (15 ml) was added / V-methyl morpholine (967 mg, 9.56 mmol), HOBt (65 mg, 478 µmol), (S)-methyl hexahydropyridazine-3-carboxylate as the TFA salt (890 mg, 2.39 mmol), and EDCI (917 mg, 4.78 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with dichloromethane (50 ml) and adjusted to pH~6 with 5% aqueous citric acid. The aqueous layer was extracted with dichloromethane (20 ml x 2). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate^ 10:1, 5:1 to 3:1) to provide Intermediate I-4 (910 mg, 77% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.50 - 7.35 (m, 5 H), 7.20 - 7.13 (m, 1 H), 6.90 - 6.80 (m, 3 H), 5.60. Petition 870260070873, dated 07 / 16 / 2026, page 172 / 532 164 / 220 5.50 (m, 1 Η), 5.30 - 5.20 (m, 1 Η), 5.05 - 5.00 (m, 2 Η), 4.40 - 4.30 (m, 1 Η), 3.65 (s, 3 Η), 3.55 (d, J=11.20 Hz, 1 Η), 3.00 - 2.93 (m, 1 Η), 2.90 - 2.80 (m, 1 Η), 2.75 - 2.65 (m, 1 Η), 2.35 - 2.25 (m, 1 Η), 1.80 - 1.72 (m, 2 Η), 1.42 (s, 9 H). ESI-MS m / z = 520.1 [M+Na]+. Calculated MW: 497.58.

[00477] To a solution of Intermediate I-4 (450 mg, 904 µmol) in ethyl acetate (4 ml) hydrochloric acid in ethyl acetate (4 M, 8.00 ml) at 0°C was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to provide the HCl salt of Intermediate I-5 (390 mg, 100% yield) as a light yellow solid and used for the next step without purification. ESI-MS m / z = 398.0 [M+H]+, 420.0 [M+Na]+, Calculated MW: 397.47.

[00478] To a solution of Intermediate I-5 (195 mg, 899 µmol) in dichloromethane (5.00 ml) was added / V-methylmorpholine (273 mg, 2.70 mmol), HOBt (24.29 mg, 179.75 µmol), the HCl salt of 1-((S)-2-amino3-(3-(benzyloxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (S)-methyl (390 mg, 899 µmol) and EDCI (345 mg, 1.80 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml) and adjusted to pH~6 with 5% aqueous citric acid. The aqueous layer was extracted with dichloromethane (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate—> 5:1, 2:1, 1:1) to provide Intermediate I-6 (750 mg, 70% yield) as a white solid.RMN de1H (400 MHz, CDCh) δ 7,50 - 7,35 (m, 5 H), 7,23 - 7,15 (m, 1 H), 6,90 - 6,80 (m, 3 H), 6,13 - 6,08 (m, 1 H), 5,83 - 5,73 (m, 1 H), 5,10 - 5,00 (m, 3 H), 4,30 - 4,20 (m, 1 H), 4,00 Petição 870260070873, de 16 / 07 / 2026, pág. 173 / 532. 165 / 220 3,90 (m, 1 Η), 3,65 (s, 3 Η), 3,50 (d, J=1 1,20 Hz, 1H), 3,05 - 2,97 (m, 1 H), 2,93 - 2,83 (m, 1 H), 2,80 - 2,70 ( m, 1 H), 2,35 - 2,25 (m, 1 H), 2,15 - 2,10 (m, 1 H), 1,75 - 1,65 (m, 4 H), 1,45 (s, 9 H), 0,94 (d, J=6,80 Hz, 3H), 0,88 (d, J=6,80 Hz, 3H). ESI-MS m / z = 597,1 [M+H]+. MW Calculado: 596,71.

[00479] Palladium on carbon (2 grams, 10% loading) was added to a solution of Intermediate I-6 (3.00 g, 6.03 mmol) in methanol (300 ml) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas, and the mixture was stirred under hydrogen (1 atm) at 20°C for 3 hours. The mixture was filtered and concentrated under reduced pressure to yield Intermediate I-7 (2.3 g, 5.64 mmol, 94% yield) as a white solid. ESI-MS m / z = 430.1 [M+Na]+. Calculated MW: 407.46

[00480] To a mixture of Intermediate I-7 (2.3 g, 5.64 mmol) in dioxane (10 ml) was added hydrochloric acid in dioxane (4 M, 30 ml) in a portion at 20°C. The mixture was stirred at 20°C for 3 hours. The mixture was adjusted to pH ~7-8 with saturated aqueous NaHCO3 and extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield Intermediate I-8 (1.3 g, 3.63 mmol, 64% yield, 86% purity) as a light yellow solid. 1H NMR (400 MHz, CDCh) δ 7.157.02 (m, 1 H), 6.75-6.5 (m, 3 H), 4.90-4.77 (m, 1 H), 4.50-4.37 (m, 1 H), 4.00-3.90 (m, 1 H), 3.80-3.70 (m, 1 H), R H), 1.42-1.28 (m, 1 H). ESI-MS m / z = 308.2 [M+Na]+. Calculated MW: 307.34. Synthesis of Intermediate 1-11 Petition 870260070873, dated 07 / 16 / 2026, page 174 / 532 166 / 220 1-91-10

[00481] To a solution of 2-(dimethylamino)ethanethiol I-9 (500 mg, 3.53 mmol) in methanol (10 ml) was added a solution of 1,2di(pyridin-2-yl)disulfide (1.17 g, 5.3 mmol) in methanol (10 ml) at 0°C. The mixture was stirred at 25°C for 15 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate —> 3:1, 1:1, then dichloromethane / ethyl acetate^ 2:1, then dichloromethane / methanol —> 10:1) which was combined with a previous batch to provide Intermediate 1-10 (1.05 g, 58% yield) as a light yellow solid. Ή NMR (400 MHz, CD3OD) δ 8.56 (d, J=4.0 Hz, 1 H), 7.85-7.75 (m, 1 H), 7.69 (d, J=8.0 Hz, 1 H), 7.36-7.26 (m, 1 H), 3.48-3.40 (m, 2 H), 3,283.20 (m, 2 H), 2.93 (s, 6 H). ESI-MS m / z = 214.9 [M+H]+. Calculated MW: 214.35.

[00482] A solution of 4-mercaptobutanoic acid (50 mg, 416 µmol) in methanol (1 ml) was added to a solution of Intermediate 1-10 (125 mg, 499 µmol) in methanol (1.5 ml) at 25°C. The mixture was stirred at 25°C for 15 hours. The reaction mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate—> 2:1, 1:1, then dichloromethane / methanol—> 10:1) to give Intermediate 1-11 (80 mg, 86% yield) as a white gum. 1H NMR (400 MHz, CD3OD) δ 3.55-3.45 (m, 2 H), 3.08-3.00 (m, 2 H), 2.93 (s, 6H), 2.83 (t, J=7.2 Hz, 2 H), 2.43 (t, J=7.2 Hz, 2 H), 2.05-1.94 (m, 2 H). Synthesis of Intermediate 1-15 Petition 870260070873, dated 07 / 16 / 2026, p. 175 / 532 167 / 220 1-15

[00483] To a solution of tert-butyl 2-mercaptoacetate 1-12 (800 mg, 5.4 mmol) in Λ / , / V-dimethylformamide (15 ml) were added potassium carbonate (1.49 g, 10.8 mmol) and 1-bromo-2-chloroethane (2.32 g, 16.2 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with ethyl acetate (100 ml) and washed with water (50 ml x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield Intermediate 1-13 (1.00 g, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) δ 3.64 - 3.71 (m, 2 H), 3.14 - 3.17 (m, 2 H), 2.95 - 3.01 (m, 2 H), 1.47 (s, 9 H).

[00484] A solution of Intermediate 1-13 (1.00 g, 4.75 mmol) in dichloromethane (10 ml) was added to a solution of m-CPBA (4.61 g, 21.4 mmol, 80% purity) in dichloromethane (10 ml) at 0°C. The mixture was heated to room temperature and stirred for 2 hours. The mixture was diluted with dichloromethane (80 ml) and washed with saturated aqueous sodium sulfide (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield a crude residue which was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate^ 5 / 1) to yield Intermediate 1-14 (700 mg, 60% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 2 H), 3.90 - 3.95 (m, 2 H), 3.69 - 3.75 (m, 2 H), 1.50 - 1.53 (m, 9 H).

[00485] To a solution of Intermediate 1-14 (650 mg, 2.68 mmol) Petition 870260070873, dated 07 / 16 / 2026, page 176 / 532 168 / 220 in dichloromethane (12 ml) was added to trifluoroacetic acid (6.00 ml). The mixture was stirred at 45 °C for 2 hours. Then the mixture was concentrated to yield Intermediate 1-15 (360.00 mg, 72% yield) as a white solid. 1H NMR (400 MHz, DMSO-1H) δ 4.34 (s, 2H), 3.89 - 4.01 (m, 2H), 3.71 - 3.81 (m, 2H). Synthesis of Compound-1 i Compound-1

[00486] To a solution of HCl salts of Intermediate I-8 (31 mg, 119 µmol) and Intermediate I-11 (44 mg, 99 µmol) in dichloromethane (1.5 ml) was added HOBt (1.34 mg, 9.9 µmol), / V-methylmorpholine (38.2 µl) and EDCI (27 mg, 139 µmol). The mixture was stirred at 25°C for one hour. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (5 ml). The aqueous layer was extracted with dichloromethane (5 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse-phase HPLC (HCl additive) and repurified using reverse-phase HPLC (HCOOH additive) and lyophilized to provide Compound-1 (5.8 mg, 9% yield) as a light yellow oil. 1H NMR (400 MHz, MeOD) δ 8.53 (br,s., 1 H), 7.12-7.04 (m, 1 H), 6.72-6.62 (m, 3H), 5.75 -5.65 (m, 1 H), 4.20-4.10 (m, 2H), 3.70 (s, 3H), 3.08- 3.00 (m, 2H), 2.95-2.76 (m, 5 H), 2.76-2.70 (m, 2 H), 2.60 (s, 6 H), 2.42-2.32 (m, 3 H), 2.10-1.98 (m, 3 H),1.85-1.70 (m, 2 H), 1.55-1.40 (m, 2 H), 1.02-0.85 (m, 6 H). ESI-MS m / z = 612.1 [M+H]+, 634.5 [M+Na]+. Calculated MW: 611.82. Synthesis of Compound-2 (SFAC4DS) Petition 870260070873, dated 07 / 16 / 2026, p. 177 / 532 169 / 220 Compound-2 (SFAC4DS)

[00487] A solution of Intermediate I-8 (27 mg, 60 µmol) in dichloromethane was treated with Λ / , / V-diisopropylethylamine (24 mg, 180 µmol), Intermediate 1-16 (14 mg, 60 µmol), HOBt (1.6 mg, 2 µmol), and then finally EDCI (18 mg, 90 µmol). After stirring for 15 hours, the solution was poured into water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and the solvent removed was vacuum-sealed. Purification by reverse-phase HPLC (acetonitrile in water with 0.1% formic acid) and lyophilization yielded Compound-2 (SFAC4DS) (16 mg, 42% yield) as a white solid.1H NMR (400 MHz, CDCfi) 8.47 (d, 1H), 8.16 (brs, 1H), 7.69-7.66 (m, 1H), 7.63-7.60 (m, 1H), 7.13 (app t, 1H), 7.09-7.05 (m, 1H), 5.85-5.79 (m, 1H), 4.72 (m, 1H), 4.31 (br s, 1H), 3.70 (s, 3H), 3.42 (d, 1H), 3.00 (dd, 1H), 2.87-2.78 (m, 3H), 2,522.43 (m, 2H), 2.28 (br s, 1H), 2.14 -2.04 (m, 3H), 1.83-1.73 (m, 2H), 1.62-143 (m, 5H), 0.95 (d, 3H), 0.90 (d, 3H). ESI-MS m / z = 617.9 [M+H]+. Calculated MW: 617.78. Synthesis of Compound-3 CompüstD-3

[00488] A solution of the HCl salt of Intermediate 1-15 (31.8 mg, 0.17 mmol), HOBt (2.3 mg, 0.017 mmol) and NMM (54 pl, 0.54 mmol) Petition 870260070873, dated 07 / 16 / 2026, page 178 / 532 170 / 220 in DCM (0.75 ml) was added to the HCl salt of I-8 (86 mg, 0.17 mmol) and EDCI (76 mg, 0.34 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (2 ml), washed with citric acid (pH~3, 2 ml), saturated aqueous sodium bicarbonate (2 ml), and saturated aqueous sodium chloride (2 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 15°C to yield a yellow oil-like product. The residue was purified by preparative TLC with silica gel (eluent: DCM / MeOH —> 10:1) followed by preparative HPLC (column: Phenomenex Gemini C18 250 x 50 10u; mobile phase: [water (0.225% FA)-ACN]; B%: 26% to 56%, 11.2 min) to provide Compound-3 (8.5 mg, 8% yield) as a white solid.Ή NMR (400 MHz, CDCh) δ 9.02 (s, 1 H), 8.80 (s, 1 H), 8.42 (s, 1 H), 7.01 - 7.08 (m, 1 H), 6.82 (dd, J=16.3, 9.9 Hz, 1 H), 6.74 (d, J=7.5 Hz, 1 H), 6.64 - 6.70 (m, 2 H), 6.36 (d, J=16.5 Hz, 1 H), 6.12 - 6.16 (m, 2 H), 4.81 - 4.85 (m, 1 H), 4.40 - 4.46 (m, 2 H), 4.21 4.25 (m, 1 H), 4.09 - 4.13 (m, 1 H), 3.57 (s, 3 H), 2.81 - 3.08 (m, 2 H), 2.63-2.65 (m, 1 H), 2.15-2.19 (m, 1 H), 1.21 - 1.60 (m, 4 H), 0.880.92 (m, 6 H). ESI-MS m / z = 539.1 [M+H]+. Calculated MW: 538.61. Synthesis of Compound-4. Intermediate i-9 Compound-4

[00489] Compound-4 was prepared as described in the preparation of Compound-3 using the HCl salt of Intermediate I-8 (34 mg, 77 µmol) and 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid 1-17 (13 mg, 77 µmol) as starting materials. The resulting crude product was combined with previously synthesized and purified crude material to generate Compound-4 (29.0 mg, 51.28 µmol, Petition 870260070873, dated 07 / 16 / 2026, p. 179 / 532 171 / 220 45% yield) as a white solid after freeze-drying. Ή NMR (400 MHz, CDCh) δ 8.55-8.40 (s, 1 H), 8.20-8.07 (m, 1 H), 7.106.97 (m, 2 H), 6.80-6.73 (m, 1 H), 6.73-6.63 (m, 1H), 6.63-6.50 (m, 1 H), 6.47-6.37 (m, 1 H), 5.90-5.75 (m, 1 H), 4.80-4.67 (m, 1 H), 4.354.15 (m, 3 H), 3.70-3.57 (m, 3 H), 3.45-3.30 (d, 1 H), 3.10-3.00 (m, 1 H), 3.00-2.70 (m, 2 H), 2.20-2.00 (m, 5 H), 1.85-1.60 (m, 2 H), 1.601.45 (m, 1 H), 1.45-1.30 (m, 1 H), 1.05-0.80 (m, 6 H). ESI-MS m / z = 558.3 ​​[M+H]+; Calculated MW: 557.60. Synthesis of Compound-5 Intermediary Compost 0-5

[00490] Compound-5 was prepared as described in the preparation of Compound-3 using the HCl salt of Intermediate I-8 (34 mg, 77 µmol) and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1yl)acetic acid 1-18 (13 mg, 77 µmol) as starting materials to generate Compound-5. ESI-MS m / z = 544.0 [M+H]+; Calculated MW: 543.58.

[00491] Synthesis of (S)-1-((S)-3-(3-hydroxyphenyl)-2-((S)-3-methyl-2-(3(2-(pyridin-2-yldisulfanyl)ethoxy)propanamido)butanamido)propanoyl)hexahydropyridazine-3-carboxylate methyl (SFAX6):

[00492] Carboxylic acid 2 (70 mg, 0.270 mmol) and HBTU (204 mg, 0.540 mmol, 2.00 eq) were mixed in 3 ml of acetonitrile, and the resulting suspension was stirred at room temperature for 15 minutes. After this period, amine 1 (Intermediate I-8) (110 mg, 0.270 mmol, 1.00 eq) was added followed by triethylamine (113 ml, 0.810 mmol, Petition 870260070873, dated 07 / 16 / 2026, page 180 / 532 172 / 220 3.00 eq) and the mixture was stirred at room temperature for 18 hours. The mixture was then treated with 20 ml of saturated sodium bicarbonate and extracted with 2 x 30 ml portions of ethyl acetate. The pooled organic extracts were washed with 2 x 20 ml portions of brine, dried over saturated sodium sulfate, filtered, and concentrated under vacuum. The residue was purified using silica gel chromatography, eluting with dichloromethane:MeOH, 100:1 to 50:1, yielding 70 mg (40%) of the product as a colorless oil. Ri = 0.31 (dichloromethane:MeOH, 20:1). MS (ESI) calc = 648.2 (M+H), obs = 648.2. Synthesis of SFAX9DS: O OY O

[00493] SFAX9DS was synthesized according to a common procedure similar to that described above for the synthesis of SFAX6. Synthesis of Compound-6 Compound O-6

[00494] Compound-6 was prepared starting with Intermediate 1-19 to generate Compound-6. ESI-MS m / z = 631.0 [M+H]+; MW Petition 870260070873, dated 07 / 16 / 2026, page 181 / 532 173 / 220 Calculated: 630.82. Synthesis of Compounds of Formula IVf

[00495] Compounds of Formula IVf can be synthesized as shown below in Scheme 6. SCHEME 6 IVq Remove PCS'1 wherein R7, R8, and Z6 are as defined above, PG1 is a suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc, and PG4 is an alkyl or aryl group including, but not limited to, methyl, ethyl, benzyl, allyl, and phenyl that can be removed by methods known to those skilled in the art.

[00496] In a typical procedure, compound IVd is reacted with reagent IVg in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) familiar to those skilled in the art. The acid and amine coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature. After amide formation, the protecting group PG4 is then removed using conditions described for removing PG3 from the compound of formula IVe (Scheme 4). z2lia Petition 870260070873, dated 07 / 16 / 2026, page 182 / 532 174 / 220

[00497] Method B can be used to prepare compounds from Formula Ha as shown now in Diagram 7. SCHEME 7 z2llc H-X2, lld where R1, R2, R3, X1, X2, Z1 and Z2 are as defined above.

[00498] In a typical procedure, the carboxylic acid llc is reacted with intermediate XI in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The llc acid and coupling partner are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, DCE, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature.

[00499] Compounds of formula llc can be synthesized as shown below in Scheme 8. SCHEME 8 He 2) Remove -Fü5 wherein R1, R2, R3, X1 and Z2 are as defined above, PG5 is an alkyl or aryl group including, but not limited to, methyl, ethyl, benzyl, allyl, and phenyl which can be removed by methods known to those skilled in the art, and LG1 is a group such as Petition 870260070873, dated 07 / 16 / 2026, p. 183 / 532 175 / 220 OH which can be activated and displaced by the amine of compound He. Alternatively, LG1 can be a suitable halide (such as F, Cl, and Br) that can be displaced by a nucleophile.

[00500] In a typical procedure, He is reacted with Hf (LG1 = halide) in the presence of a suitable base (including, without limitation, pyridine, triethylamine, DIPEA, and NMM) in a suitable solvent (including, without limitation, THF, DCM, and DMF) at temperatures in the range of -78°C to 120°C, but ideally -20°C to 50°C. Alternatively, if LG1 is OH, XII is reacted with the reagent Hf in the presence of standard coupling agents (e.g., EDC / HOBT, DCC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and amine coupling partners are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature.It will be understood by those skilled in the art that the compound Hf (LG1 = halide) can be readily produced from the corresponding carboxylic acid by treatment with a suitable halogenating reagent. After amide formation between He and Hf, the protecting group PG5 is then removed using conditions described for removing PG3 from compound IVe (scheme 4) to generate compound Hc.

[00501] Method B-2 can be used to prepare the compounds of Formula Ha as shown below in Scheme 9. SCHEME 9 Petition 870260070873, dated 07 / 16 / 2026, page 184 / 532 176 / 220 where R1, R2, R3, X1, X2, Z1 and Z2 are as defined previously. The reaction can be carried out under the conditions described to couple the reaction between compound IIg and compound llf (scheme 8).

[00502] The compounds of Formula llg can be prepared as shown below in Scheme 11. SCHEME 11 1) Enter X^Z1 2) Remove 13 <Ssllh llg where R3, X1, X2, Z1 are as defined above and PG6 is a suitable amine protecting group including, without limitation, Boc, Cbz, Alloc, and Fmoc.

[00503] In a typical procedure, carboxylic acid llg is reacted with a suitable coupling partner containing a -X2-Z1 chemical moiety in the presence of standard coupling agents (e.g., EDC / HOBT, DOC, PyBOP, PyBROP, HATU, HBTU, COMU) known to those skilled in the art. The acid and coupling partner are combined with the coupling agent in an organic solvent (including, without limitation, DMF, dichloromethane, acetonitrile, and tetrahydrofuran) in the presence of a base (including, without limitation, DIPEA, triethylamine, and NMM) at room temperature or slightly elevated temperature. PG6 is then removed by reacting the resulting intermediate with a suitable reagent familiar to those skilled in the art. Petition 870260070873, dated 07 / 16 / 2026, page 185 / 532 177 / 220 Synthesis of Compound-7 (C3SLF)

[00504] To a solution of Intermediate I-24 (18 mg, 0.085 mmol) in tetrahydrofuran (1.2 ml) was added / V-methylmorpholine (10 pl, 0.085 mmol). The solution was cooled to -20°C and then isobutylchloroformate (11 pl, 0.085 mmol) was added dropwise. The solution was immediately heated to 0°C. After stirring for 45 minutes at 0°C, the TFA salt of Intermediate I-23 (37 mg, 0.057 mmol) was mixed with / V-methylmorpholine (7 pl, 0.057 mmol) in anhydrous tetrahydrofuran (0.5 ml) and added dropwise to the 0°C mixed anhydride solution over the course of 5 minutes. The resulting solution was stirred for 1.5 hours at 0°C, at which point methanol (1 ml) was added, and the solution was immediately heated to room temperature and stirred for 5 minutes. The solution was diluted with dichloromethane (75 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 30 ml).The organics were combined, washed with brine (20 ml), dried over magnesium sulfate, filtered, and the solvent was removed under vacuum. Purification by silica gel chromatography (0 to 80% ethyl acetate in hexanes) yielded Compound 7 (C3SLF) as a white foam (20 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.55 (d, 1H), 7.77 (app t, 1H), 7.71-7.65 (m, 2H), 7.60-7.58 (m, 1H), 7.20-7.17 (m, 1H), 7.01 (d, 1H) (dt, 1H), 2.92 (t, 2H), 2.64-2.50 (m, 2H), 2.38 (d, 1H), 2.29-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.78-1.63 (m, 3H), 1.53-1.37 (m, 3H), 1.22 (s, 6H), 0.89 (t, 3H, rotamer 1), 0.80 (t, 3H, rotamer 2). ESI-MS m / z =. Petition 870260070873, dated 07 / 16 / 2026, page 186 / 532 178 / 220 722.0 [M+H]+, 744.0 [M+Na]+; Calculated MW: 721.93. Synthesis of Compound-8

[00505] To a solution of Compound 7 (22 mg, 0.031 mmol) in dichloromethane (0.5 ml) was added triethylamine (62 pl, 0.55 mmol) followed by 2-(dimethylamino)ethanethiol (0.0500 mmol) (4.8 mg, 0.046 mmol). After stirring at room temperature for 30 minutes, the solution was poured into dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The organics were dried over magnesium sulfate, filtered, and the solvent was removed under vacuum. Purification by silica gel chromatography (0 to 10% methanol in dichloromethane) yielded impure material which was repurified by reverse phase HPLC (acetonitrile in water with 0.1% formic acid) to generate the formic acid salt of Compound-8 (7.1 mg, 21% yield) as a white solid.RMN de Ή (400 MHz, CDCI3) δ 12,53 (br s, 1H), 9,50 (s, 1H), 8,00 (s, 1H), 7,75 (d, 1H), 7,68 (s, 1H), 7,29 (t, 1H), 7,02 (d, 1H), 6,79-6,77 (m, 1H), 6,70-6,67 (m, 2H), 5,76 (dd, 1H), 5,29 (d, 1H), 3,86 (s, 3H), 3,85 (s, 3H), 3,36-3,27 (m, 2H), 3,23-3,11 (m, 4H), 2,90 (t, 2H), 2,79-2,71 (m, 8H), 2,62-2,50 (m, 2H), 2,55 (d, 1H), 2,28-2,17 (m, 1H), 2,12-2,03 (m, 1H), 1,72-1,61 (m, 3H), 1,49-1,36 (m, 3H), 1,22 (s, 3H), 1,21 (s, 3H), 0,88 (t, 3H, rotâmero 1), 0,79 (t, 3H, rotâmero 2). ESI-MS m / z = 716,1 [M+H]+; Calculado MW: 715,97. Síntese do Composto-9 Petição 870260070873, de 16 / 07 / 2026, pág. 187 / 532 179 / 220 Composto-ü

[00506] To a solution of Intermediate I-23 at room temperature (15 mg, 0.029 mmol), 3-(2,5-dioxopyrrol-1-yl)propanoic acid (5.8 mg, 0.034 mmol), and DMAP (0.4 mg, 0.003 mmol) in dichloromethane, Λ / ,Λ / '-dicyclohexylcarbodiimide (9.4 mg, 0.046 mmol) was added. After stirring at room temperature for 15 hours, the resulting solids were filtered through a syringe filter and washed with dichloromethane. The solvent was removed under vacuum and the resulting residue was lifted on ethyl acetate. After cooling to -20 °C, the suspension was filtered through a syringe filter and washed with cold ethyl acetate. The filtrate was diluted with ethyl acetate (30 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml). The organics were dried over magnesium sulfate, filtered, and the solvent was removed under vacuum.Purification by silica gel chromatography (0 to 90% ethyl acetate in hexanes) yielded Compound-9 (11 mg, 60% yield) as an oil. 1H NMR (400 MHz, CDCh) δ 8.25 (br s, 1H), 7.79 (d, 1H), 7.38 (s, 1H), 7.29 (t, 1H), 6.98 (d, 1H), 6.82 (s, 2H), 6.78-6.76 (m, 1H), 6.70-6.66 (m, 2H), 5.83 (dd, 1H), 5.37 (d, 1H), 4.43 (d, 1H), 4.37 (d, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.32 (d, 1H), 2.96 (t, 1H), 2.55 (t, 2H), 2.35 (d, 1H), 2.29-2.15 (m, 1H), 2,112.01 (m, 1H), 1.81-1.60 (m, 4H), 1.49-1.42 (m, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 0.93 (t, 3H, rotamer 1), 0.82 (t, 3H, rotamer 2). ESI-MS m / z = 662.0 [M+H]+; Calculated MW: 661.75. Synthesis of (R)-3-(3,4-dimethoxyphenyl)-1-(3-(4-(pyridin-2yldisulfanyl)butanamido)phenyl)propyl (S)-1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carboxylate (C4-SLF): Petition 870260070873, dated 07 / 16 / 2026, p. 188 / 532 180 / 220

[00507] To a solution of Aniline 1 (90 mg, 172 pmol, 1 eq), disulfide 2 (79 mg, 343 pmol, 2 eq) and diisopropylethylamine (149 pL, 111 mg, 858 pmol, 5 eq) in DMF (3 ml) HATU (130 mg, 343 pmol, 2 eq) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The organic extracts were washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by silica gel gradient elution (20% ethyl acetate: 80% heptane -> 100% ethyl acetate) to provide the titrant compound C4-SLF (98 mg, 77%). MS (ESI) calc=736.3 (M+H), obs=736.3. EXAMPLE 2: SYNTHESIS OF CERTAIN CONJUGATES

[00508] General Protocol: This protocol describes a method for the formation of target protein-compound conjugates.

[00509] Reagents: Composed of 100% DMSO (internal) and mammalian target protein (internal)

[00510] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad)

[00511] Experimental Protocol: A 1:2 molar ratio of target protein and compound are mixed together in 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. Crosslinking effectiveness is evaluated by SDS-PAGE gel. Conjugates migrate more slowly than uncrosslinked target protein. For thiol-reactive compounds, specific Cys binding of the compound to the target protein may Petition 870260070873, dated 07 / 16 / 2026, p. 189 / 532 181 / 220 was further confirmed by SDS-PAGE after the addition of 100 mM DTT to the reaction mixture, which reduced the conjugate back to its components. A. FORMATION OF KRASgtp / s39c LITE / C2-FK506 CONJUGATES

[00512] Reagents: C2-FK506 in 100% DMSO (internal), KRASgtp / s39c life (internal; residues 1 to 169 containing G12V / S39C / C51S / C80L / C118S). C2-FK506

[00513] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad)

[00514] Experimental Protocol: A 1:2 molar ratio of KRASgtp / s39c lite and C2-FK506 are mixed together in 12.5 mM HEPES pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. Crosslinking effectiveness is assessed by SDS-PAGE gel. Binding of C2-FK506 to Cysteine ​​39 in KRASgtp / s39c lite is also evaluated by incubating the reaction mixture with 100 mM DTT.

[00515] Results: C2-FK506 crosslinks effectively with KRASgtp / s39c lite and is specific for Cysteine ​​39 (Figure 1). B. FORMATION OF KRASgtp / gi2C LITE / SFAX9DS CONJUGATES

[00516] Reagents: SFAX9DS in 100% DMSO (internal), KRASgtp / gi2c lite (internal; residues 1 to 169 containing G12C / C51S / C80L / C118S).

[00517] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad)

[00518] Experimental Protocol: A 1:2 molar ratio of KRASGTP / G12C lite and SFAX9DS are mixed together in 12.5 mM HEPES. Petition 870260070873, dated 07 / 16 / 2026, p. 190 / 532 182 / 220 pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. Crosslinking efficacy is assessed by SDS-PAGE gel. Wild-type CypA also crosslinked with the compound. Cysteine ​​52, as a reactive cysteine ​​in CypA, was mutated to serine in order to revoke presenter crosslinking.

[00519] Results: SFAX9DS crosslinks effectively with KRASgtp / gwc lite protein and CypAcs2s does not crosslink with SFAX9DS (Figure 2). EXAMPLE 3: FORMATION OF CERTAIN COMPLEXES

[00520] General Protocol: This protocol describes two methods for the formation and isolation of complexes comprising a presenting protein, compound, and mammalian target protein.

[00521] Reagents: Composed of 100% DMSO (internal), presenting protein (internal) and mammalian target protein (internal)

[00522] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad), Superdex 75 (GE Healthcare, CV 120 ml) EXPERIMENTAL PROTOCOL A: PROTEIN AND PRECONJUGATED COMPOUND

[00523] A 1:2 molar ratio of conjugate and presenting protein are mixed together in 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. The pure complex is isolated by Size Exclusion Chromatography (SEC) purification. The reaction mixture is directly injected onto a pre-equilibrated Superdex 75 column (CV 120 ml) containing 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer. The complex elutes at a higher molecular weight than the unreacted target protein and presenting protein. For Petition 870260070873, dated 07 / 16 / 2026, page 191 / 532 183 / 220 to confirm the presence of a complex at the elution peak, samples are evaluated by SDS-PAGE. EXPERIMENTAL PROTOCOL B: CROSSLINKING REAGENT, PROTEIN PRESENTING AND TARGET PROTEIN

[00524] A molar ratio of 1:2:2 of the compound, presenting protein, and target protein are mixed together in 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. The pure complex is isolated by Size Exclusion Chromatography (SEC) purification. The reaction mixture is directly injected onto a pre-equilibrated Superdex 75 column (CV 120 ml) containing 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer. The complex elutes at a higher molecular weight than the unreacted target protein and presenting protein. To confirm the presence of the complex at the elution peak, samples are evaluated by SDS-PAGE. A. FORMATION OF TERNARY COMPLEX KRASGtp / s39c LlTE / C2HOLT / FKBP12

[00525] Reagents: C2Holt in 100% DMSO (internal), KRASgtp / s39c lite (internal; residues 1 to 169 containing G12V / S39C / C51S / C80L / C118S) and FKBP12 (internal). C2Holt

[00526] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad), Superdex 75 (GE Healthcare, CV 120 ml)

[00527] Experimental Protocol: A 1:2:2 molar ratio of C2-Holt, FKBP12, and KRASgtp / s39c lite are mixed together in 12.5 mM HEPES pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an incubation Petition 870260070873, dated 07 / 16 / 2026, p. 192 / 532 The reaction mixture is heated overnight at room temperature from 184 / 220°C. The pure complex is isolated by Size Exclusion Chromatography (SEC) purification. The reaction mixture is directly injected onto a pre-equilibrated Superdex 75 column (CV 120 ml) containing 12.5 mM HEPES buffer at pH 7.4 and 75 mM NaCl. The complex elutes approximately 69 ml post-injection, and unreacted KRASgtp / s39c lite and FKBP12 elute approximately 75 ml and 87 ml post-injection, respectively. To confirm the presence of KRASgtp / ssqc lite and FKBP12 in the elution peak, the samples are also evaluated by SDS-PAGE.

[00528] Results: The SEC profile and SDS-PAGE analysis of the elution peaks confirm the formation of the KRASgtp / s39c lite / C2Holt / FKBP12 complex (Figures 3A and 3B). B. Formation of the ternary complex KrasGdp / s39c Ll- TE / SFAC4DS / CYPAc52s

[00529] Reagents: SFAC4DS in 100% DMSO (internal), KRASgdp / s39c lite (internal; residues 1 to 169 containing G12V / S39C / C51S / C80L / C118S), and CypAC52s (internal).

[00530] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad), Superdex 75 (GE Healthcare, CV 120 ml)

[00531] Experimental Protocol: A 1:2:2 molar ratio of SFAC4DS, CypAc52s, and KRASgdp / s39c lite are mixed together in 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer containing 2% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. The pure complex is isolated by Size Exclusion Chromatography (SEC) purification. The reaction mixture is directly injected into a pre-equilibrated Superdex 75 column (CV 120 ml) containing 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer. The complex elutes approximately 69 ml post-injection, and unreacted KRASgdp / s39c lite and CypAc52s elute approximately 75 ml and 80 ml post-injection, respectively. Petition 870260070873, dated 07 / 16 / 2026, page 193 / 532 185 / 220 To confirm the presence of KRASgdp / s39c lite and CypAcs2s in the elution peak, the samples are also evaluated by SDS-PAGE.

[00532] Results: The SEC profile and SDS-PAGE analysis of the elution peaks confirm the formation of the KRASgdp / ssqc lite / SFAC4DS / CypAc52s complex (Figure 4). C. FORMATION OF TERNARY COMPLEX PTP1Bsi87c LlTE / C3SLF / FKBP12

[00533] Reagents: C3SLF in 100% DMSO (internal), PTP1Bei86c lite (internal; residues 1 to 293 containing C32S / C92V / C121S / S187C) and FKBP12 (internal).

[00534] Equipment: Mini-PROTEAN TGX Gel (Bio-Rad), Superdex 75 (GE Healthcare, CV 120 ml)

[00535] Experimental Protocol: A 1:3:3 molar ratio of C3SLF, FKBP12, and PTPIBswzc lite are mixed together in 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer containing 4% DMSO. The reaction is incubated at 37°C for 30 minutes, followed by an overnight incubation at room temperature. The pure complex is isolated by Size Exclusion Chromatography (SEC) purification. The reaction mixture is directly injected into a pre-equilibrated Superdex 75 column (CV 120 ml) containing 12.5 mM HEPES at pH 7.4, 75 mM NaCl buffer. The complex elutes approximately 62 ml post-injection, and unreacted FKBP12 elutes approximately 75 ml (Dimer) and 90 ml (Monomer) post-injection, respectively. To confirm the presence of PTPIBswzc lite and FKBP12 at the elution peak, samples are also evaluated by SDS-PAGE. The mixture of free PTPIBswzc lite and FKBP12 is subjected to a Superdex 75 column under the same conditions to determine its elution time.

[00536] Results: The SEC profile and SDS-PAGE analysis of free PTPIBswzc lite and FKBP12 proteins (Figure 5A) confirm that free PTPIBswzc lite elutes around 64 to 65 ml. The SEC profile and Petition 870260070873, dated 07 / 16 / 2026, page 194 / 532 186 / 220 SDS-PAGE analysis of the elution peaks confirms the formation of the PTPIBs-iezc lite / C3SLF / FKBP12 complex, which elutes approximately 61 ml (Figure 5B). EXAMPLE 4: CONJUGATE FORMATION WHEN THE PRESENTING PROTEIN IS PRESENT, BUT NOT WHEN IT IS ABSENT

[00537] This protocol describes methods for analyzing crosslinking effectiveness using mass spectrometry and gel displacement assay in an effort to evaluate the presenter dependence of conjugate formation.

[00538] Reagents: 100% DMSO compound (internal), FKBP12 (internal), KRASgtp / gizc (internal, residues 1 to 169).

[00539] Experimental Protocol. In order to follow the kinetics of disulfide crosslinking reactions, Agilent 6230 TOFLC / MS and Agilent 1260 HPLC instruments employing an AdvanceBio RP-mAb C4 column (2.1 x 1...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that it comprises: a chemically binding portion of a presenting protein that binds to an FKPB protein or a cyclophilin, and a crosslinking group, wherein said crosslinking group has a structure selected from: a) Formula I: HS-S(O)a—ra. Formula I wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound; and a is 0, 1 or 2; RA is optionally substituted C1-C1 alkyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C1-C1 aryl or optionally substituted C2-C9 heteroaryl; b) Formula Ib, Ic, Id or le: Formula Ib Formula Ic Formula Id Formula le wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound; Xa is -C(O)- or -SO2-; XB is -C(O)- or CRERF;RB and Rc are, independently, hydrogen, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C10 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 carbocyclyl, optionally substituted C1-C6 aryl Petition 870260070873, dated 07 / 16 / 2026, page 230 / 532 2 / 10 ida, optionally substituted C1-C6 aryl C1-C10 alkyl, optionally substituted C2-C1 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl;RD is hydrogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl C1-Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1Ce alkyl;RE and RF are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; c) If, Ig, Ih or li formula: If formula Ig formula Ih formula li formula where the wavy line illustrates the attachment point of the crosslinking group to the rest of the compound; Xc is -C(O)- or -SO2-;XD is absent, NRJRK, or ORL; RG, RH, and R1 are, independently, hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl C1-Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-Ce alkyl;and RJ, RK, and RL are, independently, absent, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3C10 carbocyclyl, optionally substituted Ce-Cw aryl, optionally substituted Ce-Cw aryl C1Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1Ce alkyl; d) Im or In Formula: Y Im Formula In Formula where the wavy line illustrates the attachment point of the crosslinking group to the rest of the compound; Petition 870260070873, dated 07 / 16 / 2026, p. 232 / 532 4 / 10 XF is absent, NRSRT, or ORU; XG is absent or -C(O)-;Y is a leaving group selected from the halogen and nitrile group; RQ and RR are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl;and Rs, RT, and Ru are, independently, absent, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1Ce heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3Cw carbocyclyl, optionally substituted C3Cw aryl, optionally substituted C3Cw aryl, optionally substituted C3Cw aryl C1Ce alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C2-Ce alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C2-Ce alkyl; e) Formula Io / o Rv RX^RW Formula Io where the wavy line illustrates the attachment point of the crosslinking group to the rest of the compound; Petition 870260070873, dated 07 / 16 / 2026, p. 233 / 532 5 / 10Rv, Rw, and Rx are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted O-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; f) Formula Ip: RY Formula Ip wherein the wavy line illustrates the attachment point of the crosslinking group to the rest of the compound; The dashed lines represent optional double bonds included as necessary for the structure to be aromatic; b is 0, 1, or 2;Y is a leaving group; RY and Rz are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, C2-C6 carbocyclyl. Petition 870260070873, dated 07 / 16 / 2026, page 1. 234 / 532 6 / 10 optionally substituted, Ce-Cw aryl optionally substituted, CeC10 Ci-Ce aryl alkyl optionally substituted, C2-C9 heteroaryl optionally substituted, C2-C9 heteroaryl Ci-Ce alkyl optionally substituted, C2-C9 heterocyclyl optionally substituted, C2-C9 heterocyclyl C1-C6 heterocyclyl optionally substituted; each of XH, X1, XJ, XK and XL are independently absent, NRAA, or CRAB, wherein at least five of XH, X1, XJ, XK and XL are NRAA, or CRAB;RAA is absent or hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl O-C1 alkyl;RAB is hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C2-C9 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; g) Formula Iq, Ir or Is: Petition 870260070873, dated 16 / 07 / 2026, p. 235 / 532 7 / 10 Formula lq Formula Ir Formula Is in which the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound; XM is -C(O)- or -SO2-; XN is absent, NRAE or O;RAC and RAD are, independently, hydrogen, nitrile, halogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl;RAE is hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl; and Petition 870260070873, dated 07 / 16 / 2026, p. 236 / 532 8 / 10 h)-CH(O).; 2. Compound according to claim 1, characterized in that the crosslinking group has the structure: so J wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

3. Compound according to claim 1, characterized in that the crosslinking group has the structure: OO O oo wherein the wavy line illustrates the point of attachment of the crosslinking group to the rest of the compound.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that the crosslinking group forms a covalent bond with a cysteine ​​or lysine residue of a target protein.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that the chemically binding portion of the presenting protein binds to an FKBP protein.

6. A compound or a pharmaceutically acceptable salt thereof, according to claim 5, characterized in that the FKBP protein is FKBP12.

7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that the chemically binding portion of the presenting protein binds to a cyclophilin protein.

8. A pharmaceutically acceptable compound or salt of Petition 870260070873, dated 07 / 16 / 2026, page 237 / 532 9 / 10, according to claim 7, characterized in that the cyclophilin protein is cyclophilin A.

9. A compound according to any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof, characterized in that the target protein is KRAS, HRAS, MRAS or NRAS.

10. Compound characterized by having the structure of Formula VII: ALB Formula VII wherein A is a protein-binding chemical moiety FKPB comprising the structure of Formula Villa: Formula Villa wherein b and c are independently 0, 1, or 2; d is O, 1, 2, 3, 4, 5, 6, or 7; X1 and X2 are each independently absent, CH2, O, S, SO, SO2, or NR13;Each R1 and R2 are independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C6 aryl, optionally substituted C1-C6 aryl alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heterocyclyl. Petition 870260070873, dated 07 / 16 / 2026, page. 238 / 532 10 / 10 substituted, or R1 and R2 combine with the carbon atom to which they are attached to form C=O or R1 and R2 combine to form an optionally substituted C3-C10 carbocyclyl or optionally substituted C2-C9 heterocyclyl;and each R3 is independently a hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C1-C1 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C1 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C1-C1 aryl C1-C1 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C1 alkyl or two R8 combine to form an optionally substituted C3-C10 carbocyclyl, optionally substituted C1-C1 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; R4 is an optionally substituted C1-C1e alkyl group; L is an optional ligand; and B is a target protein-binding chemical moiety.

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