Compounds, pharmaceutical composition, methods of cancer treatment and treatment of a disorder related to the ras protein and method of inhibiting a ras protein in a cell

Description

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

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

[0002] It is well established in the literature that Ras proteins (KRas, H-Ras, and N-Ras) play an essential role in several human cancers and are therefore appropriate targets for anticancer therapy. In fact, mutations in Ras proteins are responsible for approximately 30% of Petition 870250111477, dated 04 / 12 / 2025, page 9 / 545 2 / 499 of all cancer cases in humans in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by inhibiting the intrinsic and GTP-dependent GTPase activator protein (GAP) hydrolysis rates of GTP, significantly shifting the population of mutant Ras proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers.

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

[0004] Ras inhibitors are provided in this document. The approach described in this document involves the formation of a high-affinity, three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenting protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described in this document induce a novel binding pocket in Ras leading to the formation of a high-affinity tri-complex, or Petition 870250111477, dated 04 / 12 / 2025, page 10 / 545 3 / 499 conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA). Without being limited by theory, the inventors believe that one way in which the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, that they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF and PI3K, which are necessary to propagate the oncogenic signal.

[0005] As such, in one aspect, the disclosure provides a compound with the structure of Formula Ia or Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is attached to X, and a second ring in Q is attached to A; X is a connection; a linear chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)0-2; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, where “*” represents a portion of X attached to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl )-; Petition 870250111477, dated 04 / 12 / 2025, p. 11 / 545 4 / 499 A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl or optionally substituted C1-C3 heteroalkyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8 is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 combine to form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 is a ring atom in Q, the carbon atom to which R7 is attached, and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3; Each R5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 12 / 545 5 / 499 p is 0, 1, 2, or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6, join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0006] In one aspect, the invention provides a compound with the structure of Formula IIa or Formula IIb: Formula IIa Formula IIb or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene. Petition 870250111477, dated 04 / 12 / 2025, p. 13 / 545 6 / 499 optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently hydrogen or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y5 is CRx, CH, CH2 or N; Y6é CRz, C(O), CH, CH2 or N; Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, page 14 / 545 7 / 499 Rzé hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached. Petition 870250111477, dated 04 / 12 / 2025, page 15 / 545 8 / 499 linked to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. Petition 870250111477, dated 04 / 12 / 2025, p. 16 / 545 9 / 499 replaced; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; R21 is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6, join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0007] In one aspect, the invention provides a compound with the structure of Formula IIa-1: Formula IIa-1 Petition 870250111477, dated 04 / 12 / 2025, p. 17 / 545 10 / 499 or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is, independently, either hydrogen or C1-C4 alkyl. Petition 870250111477, dated 04 / 12 / 2025, p. 18 / 545 11 / 499 optionally replaced; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are independently C or N; Y 5 is CRx, CH, CH2 or N; Y 6 is CRz, C(O), CH, CH2 or N; Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13e and R2se combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group; R2 is absent, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached. Petition 870250111477, dated 04 / 12 / 2025, page 19 / 545 12 / 499 linked to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl Petition 870250111477, dated 04 / 12 / 2025, page 20 / 545 13 / 499 substituted, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; and R21 is hydrogen or optionally substituted C1-C3 alkyl.

[0008] In one aspect, the invention provides a compound with the structure of Formula IIIa or Formula IIIb: Formula IIIa Formula IIIb Petition 870250111477, dated 04 / 12 / 2025, p. 21 / 545 14 / 499 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O). , -NHC(O)NH- , -NHC(O)NCH3- , -NHC(O)O- , -NHC(S)- -NHC(S)NH- , -NHS(O)2- or -NHS(O)2NH·. L is a ligand; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from F or Petition 870250111477, dated 04 / 12 / 2025, page 22 / 545 15 / 499 CH3, or R7e R8se combine with the atoms to which they are attached to form a 3-membered cycloalkyl group; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6, join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0009] In one aspect, the invention provides a compound with the structure of Formula IIIa-1: Formula IIIa-1 or a pharmaceutically acceptable salt thereof, where A is Petition 870250111477, dated 04 / 12 / 2025, p. 23 / 545 16 / 499 optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O). , -NHC(O)NH- , -NHC(O)NCH3- , -NHC(O)O- , -NHC(S)- -NHC(S)NH- , -NHS(O)2- or -NHS(O)2NH·; L is a ligand; X4 and X5 are, each independently, CH2, CH(CH3) or NH; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from F or Petition 870250111477, dated 04 / 12 / 2025, p. 24 / 545 17 / 499 CH3, or R7e R8se combine with the atoms to which they are attached to form a 3-membered cycloalkyl group; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0010] In one aspect, the invention provides a compound with the structure of Formula IVa or Formula IVb: or a pharmaceutically acceptable salt thereof, where A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or C1-C3 heteroalkyl Petition 870250111477, dated 04 / 12 / 2025, page 25 / 545 18 / 499 optionally replaced; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2, or 3.

[0011] In one aspect, the invention provides a compound with the structure of Formula Va or Formula Vb: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; Petition 870250111477, dated 04 / 12 / 2025, page 26 / 545 19 / 499 R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0012] In one aspect, the invention provides a compound having the structure of Formula VIIa or Formula VIIb: Formula VIIa Formula VIIb Petition 870250111477, dated 04 / 12 / 2025, page 27 / 545 20 / 499 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; X6, X7 and X8 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form a C3-C8 Petition 870250111477, dated 04 / 12 / 2025, p. 28 / 545 21 / 499 optionally substituted cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0013] In one aspect, the invention provides a compound having the structure of Formula XI: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene or optionally substituted C2-C4 alkenylene; W is optionally substituted heterocycloalkyl with 3 to 10 members or optionally substituted cycloalkyl with 3 to 10 members; X4e CH2 or NH; R1 is C1-C6 optionally substituted alkyl, C1-C6 optionally substituted alkenyl, C1-C6 optionally substituted alkynyl, C1-C6 optionally substituted heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally 3- to 6-membered cycloalkenyl Petition 870250111477, dated 04 / 12 / 2025, page 29 / 545 22 / 499 substituted, optionally substituted 3 to 15 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R3 is hydrogen; or R2e R3se combine with the atoms to which they are attached to form an optionally substituted 8- to 14-membered heterocycloalkyl; Each of R4, R5, R6, and R7 is hydrogen; or R4 and R6 are hydrogen and R5 and R7 combine with the atoms to which they are attached to form an optionally substituted four-membered cycloalkyl group; or R5 and R7 are hydrogen and R4 and R6 combine with the atoms to which they are attached to form an optionally substituted four-membered cycloalkyl group; R10 is -OR11 or -NR12R13; R11, R12 and R13 are each independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12 and R13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0014] In one aspect, the invention provides a compound, or a pharmaceutically acceptable salt thereof, of Table 1. Petition 870250111477, dated 04 / 12 / 2025, page 30 / 545 23 / 499

[0015] Pharmaceutical compositions are also provided including a compound, or a pharmaceutically acceptable salt thereof, of any of the above aspects and embodiments, and a pharmaceutically acceptable excipient.

[0016] A method is also provided for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, a method is provided for treating a Ras protein-related disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0018] A method is further provided for inhibiting a Ras protein in a cell, the method comprising bringing the cell into contact with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0019] It is specifically contemplated that any limitation discussed in relation to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention and any method of the invention may be used to produce or utilize any compound or composition of the invention. Chemical Definitions and Terms

[0020] In this solicitation, unless otherwise indicated by the context, (i) the term “the” means “one or more”; (ii) the term “or” is used to mean “and / or”, unless explicitly indicated to refer only to alternatives or to mutually exclusive alternatives, although disclosure supports a Petition 870250111477, dated 04 / 12 / 2025, p. 31 / 545 24 / 499 definition which refers only to alternatives and “and / or”; (iii) the terms “comprising” and “including” are understood as encompassing discriminated components or steps, presented by themselves or in conjunction with one or more additional components or steps; and (iv) where ranges are provided, outcomes are included.

[0021] As used in this document, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater or less than) of a stated value, unless otherwise indicated or evident from the context (for example, when such a number exceeds 100% of a possible value).

[0022] As used in this document, the term “adjacent” in the context of describing adjacent atoms refers to divalent atoms that are directly connected by a covalent bond.

[0023] A “compound of the present invention” and similar terms as used in this document, whether explicitly mentioned or not, refer to Ras inhibitors described in this document, including compounds of Formula I, subformulas thereof, and compounds of Table 1, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0024] The expression “wild type” refers to an entity with a structure or activity as found in nature in a normal state or context (as opposed to mutant, diseased, altered, etc.). Those of common skill in the technique will appreciate that wild-type genes and polypeptides generally exist in multiple different forms (e.g., Petition 870250111477, dated 04 / 12 / 2025, p. 32 / 545 25 / 499 alleles).

[0025] Those skilled in the art will appreciate that certain compounds described in this document may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., where one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium) forms. Unless otherwise indicated or clear from the context, a represented structure may be understood as representing any isomeric or isotopic form, individually or in combination.

[0026] The compounds described in this document may be asymmetric (e.g., with one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are considered unless otherwise indicated. The compounds of this disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of 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 in this document, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[0027] In some embodiments, one or more compounds represented in this document may exist in different tautomeric forms. As will become clear from the context, unless explicitly stated otherwise. Petition 870250111477, dated 04 / 12 / 2025, page 33 / 545 26 / 499 excluded, references to such compounds encompass all these tautomeric forms. In some embodiments, the 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, the tautomeric form may be a prototropic tautomer, which is an isomeric protonation state with the same empirical formula and total charge as the reference form. Examples of fractions with prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms, where a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or sterically blocked in a form by appropriate substitution.In certain forms, tautomeric shapes result from acetal interconversion.

[0028] Unless otherwise indicated, structures depicted in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds (e.g., those labeled with 3H and 14C) may be useful in composite tissue or substrate distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes may be useful for their ease of preparation and detectability.Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some modalities, one. Petition 870250111477, dated 04 / 12 / 2025, p. 34 / 545 27 / 499 or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by carbon enriched with 13C or 14C. Positron-emitting isotopes, such as 15O, 13N, 11C, and 18F, are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labeled compounds are known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared following procedures analogous to those disclosed for the compounds of the present invention described herein, replacing an isotopically labeled reagent with a non-isotopically labeled reagent.

[0029] Non-limiting examples of fractions that may contain one or more deuterium substitutions in compounds of the present invention, where any “R” position may be deuterium (D), include rR R \TRR r3co r-Vt )^CR3 NV / / VL· 1 RH •'Y' \ / 1 J Vo )=^ R-7\ V e R CR3

[0030] Additional examples include R R01· RVV RA—nr R-η ¥--rn—Ar \^-R d—K / R—AV—RK RTn4^r / bn R 1 RA hK R3C r K R3C Rr rr ·< Η <. < < >1- rR>M5 / / A 3XA k RL· ro * T~RAR ) <R r by r e by R e ^TV . frações tais como . 0- R^“N\Z_R rV *rr \Lr R , deuteração de frações Petition 870250111477, dated 04 / 12 / 2025, p. 35 / 545 28 / 499 similar, for example, in compounds of Formula I, II, III, IV, V and VI, and subformulas thereof). Furthermore, the deuteration of available positions in any fraction A of compounds of the Formulas described in this document is also contemplated, as RRR R and R. Furthermore, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as Furthermore, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as

[0031] Furthermore, deuterium substitution can also occur in compounds of the present invention in the ligand position, such as ox IS %

[0032] In an additional embodiment, substitution by silylation0I / sk ° is also contemplated, such as in the ligand as follows: l .

[0033] As is known in the art, many chemical entities can adopt a variety of different solid forms, such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any of these forms, including in Petition 870250111477, dated 04 / 12 / 2025, page 36 / 545 29 / 499 any solid form. In some embodiments, compounds described or represented in this document may be supplied or used in the form of a hydrate or solvate.

[0034] In several places in this descriptive report, the substituents of compounds in this disclosure are disclosed in groups or in bands. It is specifically intended that this disclosure includes any and all individual subcombinations of the members of these groups and bands. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions in which substituents are disclosed in groups or in bands, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members in each position.

[0035] The term “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described in this document, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are substituted by a suitable substituent, for example, any of the substituents or groups described in this document.Unless otherwise indicated, an "optionally substituted" group may have a suitable substitute at each replaceable position in the group, and when more than one position in any given structure can be replaced with more than one substitute selected from a specified group, the substitute may... Petition 870250111477, dated 04 / 12 / 2025, p. 37 / 545 30 / 499 may also be the same or different in each position. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl”, the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents provided for in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. The term “stable”, as used in this document, refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection and, in certain embodiments, their recovery, purification and use for one or more of the purposes disclosed in this document.

[0036] Suitable monovalent substituents on a replaceable carbon atom of an “optionally substituted” group may independently be deuterium; halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o4Ro; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted for R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted for R°; -CH=CHPh, which may be substituted for R°; -(CH2)0-4O(CH2)0-1-pyridyl, which may be substituted for R°; saturated or unsaturated 4- to 8-membered heterocycloalkyl (e.g., pyridyl); saturated or unsaturated cycloalkyl groups with 3 to 8 members (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)o-4N(R°)C(O)NR°2; N(R°)C(S)NR°2; -(CH2)o-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(O)R°; -C(S)R°; -(CH2)o4C(O)OR°; -(CH2)o-4-C(0)-N(R0)2; -(CH2)o-4-C(0)-N(R0)-S(0)2-R0; -C(NCN)NR°2; -(CH2)o-4C(0)SR°; -(CH2)o-4C(O)OSiR°3;-(CH2)o-40C(0)R°; -OC(0)(CH2)o-4SR°; -SC(S)SR°; -(CH2)o-4SC(0)R°; -(CH2)o-4C(0)NR°2; -C(S)NR°2; -C(S)SR°; (CH2)o-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; C(NOR°)R°; -(CH2)o-4SSR°; -(CH2)o-4S(0)2R°; -(CH2)o-4S(0)20R°; -(CH2)o4OS(O)2R°; -S(O)2NR°2; -(CH2)o-4S(0)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; Petição 870250111477, de 04 / 12 / 2025, pág. 38 / 545 31 / 499 OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°; -SiR°3; -(Ci-4 linear or branched alkylene)ON(R°)2; or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)o-iPh, -CH2-(5- to 6-membered heteroarylene ring), or a saturated or partially saturated 3- to 6-membered aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R° join to their intervening atoms, forming a saturated or partially unsaturated 3- to i2-membered mono- or bicyclic aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as below.

[0037] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) may independently be halogen, -(CH2)o-2R·, (haloR·), -(CH2)o-2OH, -(CH2)o-2OR·, -(CH2)o-2CH(OR')2; -O(haloR·), -CN, -N3, (CH2)o-2C(O)R·, -(CH2)o-2C(O)OH, -(CH2)o-2C(O)OR·, -(CH2)o-2SR·, -(CH2)o-2SH, -(CH2)o-2NH2, -(CH2)o-2NHR·, -(CH2)o-2NR% -NO2, -SiR^e, -OSiR^e, C(O)SR·, -(C1-4 linear or branched alkylene)C(O)OR· or -SSR·, wherein each R· is unsubstituted or when preceded by “halo” is substituted only by one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)o-iPh or a saturated or partially unsaturated aryl ring 5 to 6 members with o-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S. [oo38] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =nr*, =nor*, Petition 870250111477, dated 04 / 12 / 2025, p. 39 / 545 32 / 499 O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or a 5- to 6-membered unsubstituted saturated or partially unsaturated aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are attached to vicinal replaceable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or a 5- to 6-membered unsubstituted saturated or partially unsaturated aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents in the aliphatic group of R* include halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR·), -CN, -C(O)OH, -C(O)OR·, NH2, -NHR·, -NR^2 or -NO2, wherein each R· is unsubstituted or when preceded by “halo” is substituted by only one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)c-1Ph, or a saturated or partially unsaturated aryl ring of 5 to 6 members with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0040] Suitable substituents on a replaceable nitrogen of an “optionally substituted” group include -Rt -NR^2, -C(O)Rt, -C(O)ORt, C(O)C(O)Rt -C(O)CH2C(O)Rt, -S(O)2Rt -S(O)2NRt2, -C(S)NR^, -C(NH)NR^ or -N(Rt)S(O)2Rf wherein each Rt is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh or an unsubstituted saturated or partially unsaturated 3- to 6-membered aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Rt taken together with their atoms. Petition 870250111477, dated 04 / 12 / 2025, page 40 / 545 33 / 499 intervening elements form a saturated or partially unsaturated 3- to 12-membered unsubstituted mono- or bicyclic aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] Suitable substituents on an aliphatic group of Rt are independently halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR·), -CN, C(O)OH, -C(O)OR·, -NH2, -NHR·, -NR^2 or -NO2, wherein each R· is unsubstituted or when preceded by “halo” is substituted only by one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph or a saturated or partially unsaturated aryl ring of 5 to 6 members with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of Rt include =O and =S.

[0042] The term “acetyl”, as used in this document, refers to the -C(O)CH3 group.

[0043] The term “alkoxy”, as used in this document, refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the rest of the compound via an oxygen atom.

[0044] The term “alkyl”, as used in this document, refers to a saturated, linear or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., it is linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0045] The term “alkylene”, as used in this document, represents a saturated divalent hydrocarbon group derived from a saturated linear or branched chain hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and Petition 870250111477, dated 04 / 12 / 2025, page 41 / 545 34 / 499 similar. The term “Cx-Cy alkylene” represents alkylene groups with x and y carbons between them. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene). In some embodiments, the alkylene may be further substituted by 1, 2, 3, or 4 substituent groups, as defined in this document.

[0046] The term “alkenyl”, as used in this document, represents monovalent linear or branched chain groups of, unless otherwise specified, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyls include cis and trans isomers. The term “alkenylene”, as used in this document, represents divalent linear or branched chain groups of, unless otherwise specified, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0047] The term “alkynyl”, as used in this document, represents monovalent linear or branched chain groups of 2 to 20 carbon atoms (for example, 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0048] The term “alkynyl sulfone”, as used herein I_r document, represents a group comprising the structure « , where R is any chemically viable substituent described in this document.

[0049] The term “amino”, as used in this document, represents -N(Rt)2, for example, -NH2 and -N(CH3)2.

[0050] The term “aminoalkyl”, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with Petition 870250111477, dated 04 / 12 / 2025, p. 42 / 545 35 / 499 one or more amino fractions.

[0051] The term “amino acid,” as described in this document, refers to a molecule with a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). As used in this document, the term “amino acid,” in its broadest sense, refers to any compound or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid."Standard amino acid" refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0052] The term “aryl”, as used in this document, represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, in which the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring may be attached to its pendant group on any heteroatom or carbon ring atom that results in a stable structure, and any of the ring atoms may optionally be substituted unless otherwise specified.

[0053] The term “C0”, as used in this document, represents Petition 870250111477, dated 04 / 12 / 2025, p. 43 / 545 36 / 499 a bond. For example, part of the term -N(C(O)-(Co-C5 alkylene-H)- includes N(C(O)-(Co alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0054] The terms “carbocyclic” and “carbocyclyl”, as used in this document, refer to an optionally substituted, monovalent C3-C12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused, or spirocyclic, in which all rings are formed from carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can optionally be substituted unless otherwise specified.

[0055] The term “carbonyl”, as used in this document, represents a C(O) group, which can also be represented as C=O.

[0056] The term “carboxyl”, as used in this document, means -CO2H, (C=O)(OH), COOH or C(O)OH or the non-protonated counterparts.

[0057] The term “cyan”, as used in this document, represents a -CN group.

[0058] The term “cycloalkyl”, as used in this document, represents a monovalent saturated cyclic hydrocarbon group that may be bridged, fused or spirocyclic with three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0059] The term “cycloalkenyl”, as used in this document, represents a saturated, non-aromatic, monovalent cyclic hydrocarbon group that may be bridged, fused, or spirocyclic with three to eight Petition 870250111477, dated 04 / 12 / 2025, page 44 / 545 37 / 499 ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0060] 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.

[0061] The term “enantiomer”, as used in this document, means each individual optically active form of a compound of the invention, with an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0062] The term “guanidinil” refers to a group with the following structure: where each R is, independently, any chemically viable substituent described in this document.

[0063] The term “guanidinoalkyl alkyl”, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with one or more guanidinyl moieties.

[0064] The term “haloacetyl”, as used in this document, refers to an acetyl group in which at least one of the hydrogens has been replaced by a halogen.

[0065] The term “haloalkyl”, as used in this document, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same different halogen moieties.

[0066] The term “halogen”, as used in this document, represents a halogen selected from bromine, chlorine, iodine or fluorine.

[0067] The term “heteroalkyl”, as used in this document, if Petition 870250111477, dated 04 / 12 / 2025, page 45 / 545 38 / 499 refers to an “alkyl” group, as defined in this document, in which at least one carbon atom has been replaced by a heteroatom (for example, an O, N, or S atom). The heteroatom may appear in the middle or at the end of the radical.

[0068] The term “heteroaryl”, as used in this document, represents a monovalent, monocyclic or polycyclic ring structure containing at least one fully aromatic ring: that is, they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O or S in that aromatic ring. Exemplary unsubstituted heteroaryl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9) carbons. The term “heteroaryl” includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more aryl or carbocyclic rings, for example, a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl.A heteroaryl ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted by 1, 2, 3, or 4 substituent groups.

[0069] The term “heterocycloalkyl”, as used in this document, represents a monovalent monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic, in which at least one ring is non-aromatic and in which the non-aromatic ring contains one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has from zero to two double bonds, and the 6- and 7-membered rings have from zero to three double bonds. Petition 870250111477, dated 04 / 12 / 2025, p. 46 / 545 39 / 499 double bonds. Exemplary unsubstituted heterocycloalkyl groups are 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heterocycloalkyl” also represents a heterocyclic compound with a bridged multicyclic structure in which one or more carbons or heteroatoms bridge to two non-adjacent members of a monocyclic ring, for example, a quinuclidinyl group. The term “heterocycloalkyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, for example, an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphtiridine.A heterocycloalkyl ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can optionally be substituted unless otherwise specified.

[0070] The term “hydroxy”, as used in this document, represents an -OH group.

[0071] The term “hydroxyalkyl”, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms by one or more -OH moieties.

[0072] The term “isomer,” as used in this document, means any tautomer, stereoisomer, atropiomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention may have one or more chiral centers or double bonds and therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the Petition 870250111477, dated 04 / 12 / 2025, page 47 / 545 40 / 499 invention, the chemical structures represented in this document and, therefore, the compounds of the invention, encompass all corresponding stereoisomers, i.e., the stereomerically (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) form and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallizing the compound as a chiral salt complex or crystallizing the compound in a chiral solvent. The enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0073] As used in this document, the term “ligand” refers to a divalent organic moiety that connects a first moiety (e.g., a fraction of a macrocycle) to a second moiety (e.g., a second portion of the same macrocycle). In some embodiments, the ligand results in a compound capable of achieving an IC50 of 2 μM or less in the Ras-RAF breakthrough assay protocol provided here: The aim of this biochemical assay is to measure the ability of the test compounds to facilitate the formation of ternary complexes between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFrbd construct, inhibiting Ras signaling through a RAF effector.

[0074] In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl2, unlabeled cyclophilin A, His6-K-Ras-GMPPNP (or another Ras variant) and GST Petition 870250111477, dated 04 / 12 / 2025, page 48 / 545 41 / 499 BRAFrBds are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compound is present in the plate wells as a 10-point dilution series in 3-fold increments starting with a final concentration of 30 μM. After incubation at 25°C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin is then added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction is incubated for a further 1.5 hours. The TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate the disruption of a Ras:RAF complex are identified as those that cause a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0075] This assay can also be used to evaluate selectivity. In some embodiments, a compound of the present invention is selective for one or more particular Ras mutants relative to other Ras mutants or to the wild type, compared to what is known in the art. For example, a compound of Formula Ia and subformulas thereof may be more selective for K-Ras G12C or K-Ras G13C compared to wild-type K-Ras. For example, a compound of Formula IIa-1 and Formula IIa-2 may be more selective for K-Ras G12C, K-Ras G13C, K-Ras G12D, or K-Ras G12V compared to wild-type K-Ras. For example, a compound of Formula IIIa-1 and Formula IIIa-2 may be more selective for K-Ras G12D or K-Ras G12V compared to wild-type K-Ras. For example, a compound of Formula IVa and its subformulas may be more selective for K-Ras G12C or K-Ras G13C compared to wild-type K-Ras.For example, a compound of Formula VIa and subformulas thereof may be more selective for G12D K-Ras compared to wild-type K-Ras. For example, a compound of Formula VIIa and subformulas thereof may be more selective for G12D K-Ras compared to wild-type K-Ras. Petition 870250111477, dated 04 / 12 / 2025, p. 49 / 545 42 / 499 wild.

[0076] Without being limited by theory, the inventors postulate that the non-covalent interactions of “L” and the chaperone protein (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. For example, van der Waals, hydrophobic, hydrophilic, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. The inventors also postulate that “L” also confers structural rigidity to the compounds, which can optimize these non-covalent interactions, thus contributing to the inhibition of Ras activity.

[0077] In some embodiments, the ligand comprises 20 or fewer linear atoms. In some embodiments, the ligand comprises 15 or fewer linear atoms. In some embodiments, the ligand comprises 10 or fewer linear atoms. In some embodiments, the ligand has a molecular weight less than 500 g / mol. In some embodiments, the ligand has a molecular weight less than 400 g / mol. In some embodiments, the ligand has a molecular weight less than 300 g / mol. In some embodiments, the ligand has a molecular weight less than 200 g / mol. In some embodiments, the ligand has a molecular weight less than 100 g / mol. In some embodiments, the ligand has a molecular weight less than 50 g / mol.

[0078] As used in this document, a “monovalent organic fraction” is less than 500 kDa. In some embodiments, a “monovalent organic fraction” is less than 400 kDa. In some embodiments, a “monovalent organic fraction” is less than 300 kDa. In some embodiments, a “monovalent organic fraction” is less than 200 kDa. In some embodiments, a “monovalent organic fraction” is less than 100 kDa. In some embodiments, a “monovalent organic fraction” is less than 50 kDa. In some embodiments, a “monovalent organic fraction” is less than 25 Petition 870250111477, dated 04 / 12 / 2025, page 50 / 545 43 / 499 kDa. In some embodiments, a “monovalent organic fraction” is less than 20 kDa. In some embodiments, a “monovalent organic fraction” is less than 15 kDa. In some embodiments, a “monovalent organic fraction” is less than 10 kDa. In some embodiments, a “monovalent organic fraction” is less than 1 kDa. In some embodiments, a “monovalent organic fraction” is less than 500 g / mol. In some embodiments, a “monovalent organic fraction” varies between 500 g / mol and 500 kDa.

[0079] The term “stereoisomer,” as used in this document, refers to all the different possible isomeric and conformational forms that a compound may possess (for example, a compound of any formula described in this document), in particular all possible stereochemical and conformational isomeric forms, all diastereomers, enantiomers, or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0080] The term “sulfonyl”, as used in this document, represents an -S(O)2- group.

[0081] The term “thiocarbonyl”, as used in this document, refers to a -C(S)- group.

[0082] The term “vinyl ketone”, as used in this document, refers to a group comprising a carbonyl group directly connected to a carbon-carbon double bond.

[0083] The term “vinyl sulfone”, as used in this document, refers to a group comprising a sulfonyl group directly connected to a carbon-carbon double bond.

[0084] The term “inona”, as used in this document, if Petition 870250111477, dated 04 / 12 / 2025, page 51 / 545 44 / 499 refers to a group comprising the structure , where R is any chemically viable substituent described in this document.

[0085] Those skilled in the art, upon reading this disclosure, will appreciate that certain compounds described herein may be supplied or utilized in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a specific form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form.In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing one conformational isomer ((Z) or (E)) of a double bond may be considered a different form from that containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope from that present in a reference preparation may be considered a different form. Detailed Description of Compounds

[0086] Ras inhibitors are provided in this document. The approach described in this document involves the formation of a high-affinity, three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a Petition 870250111477, dated 04 / 12 / 2025, page 52 / 545 45 / 499 widely expressed cytosolic chaperone (presenting protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described in this document induce a novel binding pocket in Ras leading to the formation of a high-affinity tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA). Without being limited by theory, the inventors believe that one way in which the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, that they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF, which are necessary to propagate the oncogenic signal.

[0087] Without being limited by theory, the inventors postulate that covalent, non-covalent interactions, or combinations of covalent and non-covalent interactions of a compound of the present invention with Ras and the chaperone protein (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. In some embodiments, a compound of the present invention forms a covalent adduct with a side chain of a Ras protein (e.g., a histidine side chain at position 61 of a mutant Ras protein). Covalent adducts can also be formed with other Ras side chains. Additionally or alternatively, non-covalent interactions may be involved: for example, van der Waals, hydrophobic, hydrophilic, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors.

[0088] Consequently, a variety of Ras proteins can be inhibited by a compound of the present invention (for example, K-Ras, N-Ras, H-Ras and mutants thereof at positions 12, 13 and 61, such as G12C, G12D, Petition 870250111477, dated 04 / 12 / 2025, p. 53 / 545 46 / 499 G12V, G12S, G13C, G13D, Q61H, Q61K, Q61R and Q61L, and others described in this document, or a combination thereof).

[0089] Methods for determining covalent adduct formation are known in the art. One method for determining covalent adduct formation is to perform a “crosslinking” test, as under these conditions; Note - the following protocol describes a procedure for monitoring the crosslinking of K-Ras G12C (GMP-PNP) to a compound of the invention. This protocol can also be performed by substituting other Ras proteins or nucleotides.

[0090] The aim of this biochemical assay is to measure the ability of test compounds to covalently label nucleotide-loaded K-Ras isoforms. In assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl and 1 mM MgCl2, 1 mM BME (if studying a cysteine ​​Ras mutant, such as K-Ras G12C or G13C), 5 pM cyclophilin A and 2 pM of the test compound, a 5 pM stock of GMP-PNP-loaded KRas (1-169) G12C is diluted 10 times to produce a final concentration of 0.5 pM; with the final sample volume being 100 pL.

[0091] The sample is incubated at 25 °C for up to 24 hours before suppression by the addition of 10 pL of 5% formic acid. Suppressed samples are centrifuged at 15000 rpm for 15 minutes in a benchtop centrifuge before injecting a 10 pL aliquot onto a C4 reversed-phase column and eluting into the mass spectrometer with an increasing gradient of acetonitrile in the mobile phase. Raw data analysis can be performed using Waters MassLynx MS software, with % binding calculated from deconvolved protein peaks for labeled and unlabeled K-Ras.

[0092] Consequently, a Petition 870250111477, dated 04 / 12 / 2025, p. 54 / 545 47 / 499 compound with the structure of Formula Ia or Formula Ib: or Formula Ia Formula Ib or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is attached to X, and a second ring in Q is attached to A; X is a connection; a linear chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)o-2; *-CH2-O-; *-CH2-S(O)o-2-; *-O-CH2-; or *-CH2-S(O)o-2-, where “*” represents a portion of X attached to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl )-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. Petition 870250111477, dated 04 / 12 / 2025, page 55 / 545 48 / 499 optionally replaced; L is a ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl or optionally substituted C1-C3 heteroalkyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8 is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 combine to form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 is a ring atom in Q, the carbon atom to which R7 is attached, and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3; Each R5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, C2-C6 Petition 870250111477, dated 04 / 12 / 2025, p. 56 / 545 49 / 499 optionally substituted alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5 and RL6, join to the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0093] In some embodiments, the compound has the structure of Formula Ia-1: (R5)p Formula Ia-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is attached to X, and a second ring in Q is attached to A; X is a connection; a linear chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *CH2-O-; *-CH2-S(O)o-2-; *-O-CH2-; or *-CH2-S(O)o-2-, where “*” represents a portion of X attached to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl )-; Petition 870250111477, dated 04 / 12 / 2025, p. 57 / 545 50 / 499 A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 hydroxyalkyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8 is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 combine to form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 joins with a ring atom at Q, the carbon atom to which R7 is attached, and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3; Each R5 is independently a halogen, C1-C3 alkyl Petition 870250111477, dated 04 / 12 / 2025, page 58 / 545 51 / 499 optionally substituted or C1-C3 haloalkyl optionally substituted; ep is 0, 1, 2 or 3.

[0094] In some embodiments, the compound has the structure of formula Ia-2 Formula Ia-2, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. where: X is a bond, -O-, -CH2-, -CH(CH3)-, *-CH2-O- or -CH2-CH2-, where “*” represents a portion of X bonded to C(R4)(R5); Y is -O- or -NH-; L is a ligand; R3 is -C1-C4 alkyl, -(CH2)hi-(C3-C6 cycloalkyl) or -C4-C6 cycloalkyl; R7 is hydrogen, halo, or C1-C3 alkyl; R8 is hydrogen, halo, -OH, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkylene-O-C1-C3 alkyl, C1-C3 haloalkyl, -(CH2)o-C3-C6 cycloalkyl, C1-C3 cyanoalkyl or -(CH2)o-1-aryl (benzyl) or R7 and R8 combine to form =CH2 or a C3-C6 cycloalkyl or R8 joins with an atom of the Q ring, the carbon atom to which it is attached, and X to form a saturated 5- to 7-membered heterocycle; Q is a bicyclic arylene, a bicyclic heteroarylene, or a bicyclic heterocyclylene, where: A first ring in Q is connected to X and a second ring in Q Petition 870250111477, dated 04 / 12 / 2025, page 59 / 545 52 / 499 is connected to Z; and Q is optionally replaced by one or more substituents selected independently from =O; -CN; halogen; -C1-C5 alkyl optionally replaced by one or more halos independently selected, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl) or a saturated 4- to 7-membered heterocyclyl; -O-(C1-C3 alkyl) optionally replaced by one or more halos independently selected; C2-C5 alkenyl optionally replaced by one or more -CN or -OH independently selected; C2-C3 alkynyl; -S(O)2-C1-C3 alkyl; (CH2)oi-C3-C6 cycloalkyl optionally substituted by one or more independently selected halos, =O, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl or -O-aryl;-(CH2)0-1-heteroaryl optionally substituted by one or more independently selected halos, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, saturated -C(O)-heterocyclyl, saturated -O-heterocyclyl, O-cycloalkyl or -O-aryl; -(CH2)0-1-heterocyclyl optionally substituted by one or more independently selected halos, =O, -CN, C1-C3 alkyl optionally substituted by -CN or -OC1-C3 alkyl, saturated -C(O)-heterocyclyl, saturated -O-heterocyclyl, O-cycloalkyl or -O-aryl; -(CH2)0-1-aryl optionally substituted by one or more independently selected halos, -CN, -C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl or -O-aryl; -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene=NO-(C1-C3 alkyl) optionally substituted by C3-C6 cycloalkyl;or two substituents on the same ring atom or on adjacent Q atoms combine to form a 5- to 7-membered monocyclic ring or a 6- to 12-membered bicyclic ring, optionally substituted by one or; Petition 870250111477, dated 04 / 12 / 2025, p. 60 / 545 53 / 499 plus independently selected halos, =O, -CN, C1-C3 alkyl or -O-C1-C3 alkyl; and fused to Q.

[0095] In some embodiments, the compound has the structure of formula Ia-3: Formula Ia-3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein.

[0096] In some embodiments, the compound has the structure of formula (Ic): (Ic), or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0097] In some embodiments, Q is a 5,6-bicyclic heteroarylene, a 5,6-bicyclic heterocyclylene, a 6,6-bicyclic heteroarylene, or a 6,6-bicyclic heterocyclylene; and where Q is optionally substituted. In some embodiments, Q is a 5,6-bicyclic heteroarylene, where Q is optionally substituted. In some embodiments, Q is a 5,6-bicyclic heterocyclylene, where Q is optionally substituted. In some embodiments, Q is a Petition 870250111477, dated 04 / 12 / 2025, page 61 / 545 54 / 499 6,6-bicyclic heteroarylene, in which Q is optionally substituted. In some embodiments, Q is a 6,6-bicyclic heterocyclylene, in which Q is optionally substituted.

[0098] In some modalities, Q is selected from the group consisting of: in which: RQ1 Each of Vi, V2, V3, and V4 is, independently, C, CH, CF, or N; RQ1 is -S(O)2-RQ11, -C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 14-membered heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted; or RQ1se bonds to the nitrogen atom to which it is attached and an atom Petition 870250111477, dated 04 / 12 / 2025, p. 62 / 545 55 / 499 of adjacent ring to form an optionally replaced 4 to 8 member ring, which is optionally additionally fused to a 5 to 6 member ring; Each of RQ11 and RQ12 is independently a C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl or heteroaryl, wherein each of RQ11 and RQ12 is optionally substituted; or RQ11 and RQ12 combine with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RQ11 and RQ12 together is optionally fused to another 5- to 6-membered ring.

[0099] In some embodiments, Q is optionally further replaced by 1 to 4 substituents independently selected from =O; halo; -OH; -CN; -C1-C5 alkyl optionally replaced by one or more independently selected halos, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -OC(O)-N(C1-C3 alkyl)2, -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl), a 5- to 6-membered heteroaryl optionally replaced by one or more C1-C3 alkyl or a 4- to 7-membered saturated heterocyclyl; -O-(C1-C3 alkyl) optionally replaced by one or more independently selected halos; -C2-C5 alkenyl optionally replaced by one or more independently selected -CN or -OH; C2-C3 alkynyl optionally substituted by a heteroaryl; -S(O)2-Ci-C3 alkyl;-(CH2)o-C3-C6 cycloalkyl optionally substituted by one or more independently selected halos, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, saturated -C(O)heterocyclyl, saturated -O-heterocyclyl, O-cycloalkyl or -O-aryl; -(CH2)o-iheteroaryl optionally substituted by one or more independently selected halos, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, saturated -C(O)-heterocyclyl, saturated -O-heterocyclyl, O-cycloalkyl or -O-aryl; -(CH2)o-1-heterocyclyl optionally substituted by one or more halos; Petition 870250111477, dated 04 / 12 / 2025, page 63 / 545 56 / 499 independently selected, =O, -CN, C1-C3 alkyl optionally substituted by -CN or -O-C1-C3 alkyl, -C(O)-heterocyclyl saturated, -O-heterocyclyl saturated, O-cycloalkyl or -O-aryl; -(CH2)0-1-aryl optionally substituted by one or more halos independently selected, -CN, -C1-C3 alkyl optionally substituted by -CN, -C(O)-O-C1-C3 alkyl, -C1-C3 alkylene-O-C1C3 alkyl, -O-C1-C3 alkyl, NO2, -C(O)-heterocyclyl saturated, -CH2-heterocyclyl saturated, -O-heterocyclyl saturated, O-cycloalkyl or -O-aryl; -CH2-O-heteroaryl, C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene=NO-(C1-C3 alkyl) optionally substituted by C3-C6 cycloalkyl; or two substituents on Q join to form a 5- to 7-membered monocyclic ring or a 6- to 12-membered bicyclic ring, optionally substituted by one or more independently selected halo groups, =O, -CN, C1C3 alkyl or -O-C1-C3 alkyl and fused to Q; and “**” represents a portion of Q that is attached to ring Z.

[0100] In some modalities, Q is N v^2. In f Ϊ X some modalities, Q is V3 In some modalities, Q is In some modalities, Q is Q1 V23. In some V1 modalities,V <v23. Em algumas modalidades, Q é ,N-^VK / N^V»V2 . In some modalities, Q is Q1. In Petition 870250111477, dated 04 / 12 / 2025, p. 64 / 545 57 / 499 some modalities, Q is In some modalities, Q is In some modalities, Q is In some modalities, Q is In some modalities, Q is In some modalities, Q is RQ1. In some In some modalities, Q is modalities, Q In some modalities, Q is In some modalities, Q is

[0101] In some embodiments, Q is optionally further replaced by 1 to 4 substituents independently selected from chlorine, fluoro, -CN, -CH3, -CF3, -CHF2, -CH2CH3, -CH2-CN, (CH2)2-CN, -OCH3, -CH2-O-CH3, -(CH2)2-O-CH3, -CH2-O-CH2-CN, -CH(CN)-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -C(O)-CH3, -S(O)2CH3, -C(CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -CEC-CH3, -CECH, -CH=CH-CN, -CH2-O-CH2-CeCH, C(CH3)(CN)CH2CN, -CH2-OC(O)-N(CH3)2, 1-(cyclopentyl)-1-cyanoetan-1-yl, 1(tetrahydrofuran-3-yl)-1-cyanoetan-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoetan-1-yl, 1,3-dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1Petition 870250111477, of 12 / 04 / 2025, p. 65 / 545 58 / 499 cyanocyclopropyl, 1-cyanocylopentil, 1-methyl-1,2,3,6-tetra-hydropyridin-4-yl, 1-methylpiperidin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, (1-methylpyrazol-4yl)cyanomethyl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2methoxyethane-1 -yl)phenyl, 3-(1,1 -dioxothiomorpholin-1 -ylmethyl)phenyl, 2-(tetra-hydropyran-4yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2-chlorophenyl, 2-cyano-2-tetrahydrofuran-3-ylpropanyl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-methoxybutan-2yl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5(methoxymethyl)phenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-bromophenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-(tetra-hydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxiphenyl, 2methoxycarbonylphenyl,2-(Methoxymethyl)phenyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2phenoxyphenyl, 3-(2-methoxyethan-1-yl)phenyl, 3-methoxycarbonylphenyl, 3,5-difluoro-4(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl, 3-cyanophenyl, 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1yn-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxyphenyl, 3-methoxymethyl-5-methylisoxazol4-yl, 3-oxo-2-methylbutan-2-yl, 3-(tetrahydropyran-4-yl)-2-cyanopropan-2-yl, 4cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, morpholin-4-ylmethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyrazol-1-ylmethyl, pyridin2-yl, pyridin-2-ylmethyl, pyridin-2-yloxymethyl, pyridin-3-yl, pyridin-3-yl-ethynyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-4-yl-ethynyl, tetrahydrofuran-3-ylmethyl,tetrahydrofuran-3-ylcyanomethyl, tetra-hydropyrdin-4-yl, tetra-hydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethane-1-yl, tetra-hydropyran-4-ylcyanomethyl or tetra-hydropyran-4-yl formed one or two bonds to mesmore carbon substituents =O, 2,3-di-hydrobenzofuran-3,3-di-yl, 2,3-di-hydrofuro[2,3-b]pyridine Petition 870250111477, dated 12 / 04 / 2025, p. 66 / 545, 59 / 499 3,3-di-yl, tetra-hydropyran-3,3-di-yl, 6,7-di-hydro-5H-cyclopentane[c]pyridine-6,6-di-yl, or tetra-hydropyran-4,4-di-yl, or two substituents linked to carbon atoms, forming adjacent,2-forme-di-1 para-1m 3-cyanobenzene-1,2-di-yl, 5-methyl-5 cyanotetra-hydropyran-3,4-di-yl, 3-cyanocyclo-hexane-1,2-di-yl, 3-methoxybenzene 1,2-di-yl, benzene-1,2-di-yl, 3-oxocyclo-hexyl-1,2-di-yl, 3-cyanocyclopentane-1,2-di-yl or pyridine-3,4-di-yl.

[0102] In some embodiments, Q is selected from the group consisting of: rq2rQ3 NRQ3 N rNQ1 rNQ1 in which: Each of Vi, V2, V3, and V4 is independently CH, N, C(F), C(CH3), C(OH), C(OCH3), or C(CN); each of V5, V6 and V7 is, independently, C(R17a)(R17b) or C(=O), where each of R17ae R17bé is independently selected from hydrogen, halo, -C1-C3 alkyl, -C1-C3 haloalkyl, -O-C1-C3 alkyl, -O-C1 Petition 870250111477, dated 04 / 12 / 2025, page 67 / 545 60 / 499 C3 haloalkyl, and no more than two of V5, V6 and V7 are C(=O); RNQ1 is hydrogen, -S(O)2-RQ11 optionally substituted, -C(O)RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted; each RQ2 is independently hydrogen, CN, -S(O)2-RQ11 optionally substituted, -C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted; or RNQ1 and RQ2 join the atoms to which they are attached to form a 4- to 8-membered ring, optionally substituted, where the ring formed by taking RNQ1 and RQ2 together is optionally further fused to a 5- to 6-membered ring; Each RQ3 is independently hydrogen, CN, -S(O)2-RQ11 optionally substituted, -C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4-14 membered heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted, or two RQ3s bonded to the same atom join to form =CH, =O, =S or =NRV4; or two RQ3s bonded to the same atom join to the atom to which they are bonded to form an optionally substituted 4- to 8 membered ring, wherein the ring formed taken each RQ3 together is optionally further fused to a 5- to 6 membered ring; or RNQ1 and RQ3 combine with the atoms to which they are attached to form a 4- to 8-membered ring, optionally substituted, where the ring formed by taking RNQ1 and RQ3 together is optionally additionally Petition 870250111477, dated 04 / 12 / 2025, p. 68 / 545 61 / 499 cast to a 5 to 6 member ring; Each of RQ11 and RQ12 is independently a C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl or heteroaryl, wherein each of RQ11 and RQ12 is optionally substituted; or RQ11 and RQ12 join the atoms to which they are attached to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RQ11 and RQ12 together is optionally fused to another 5- to 6-membered ring; and “**” represents a portion of Q that is attached to the Z ring.

[0103] In some modalities, Q is or RQ1. In some some modalities, Q is modalities, Q In some modalities, Q is In rQ2 in some modalities, Q is In some modalities, Q is Petition 870250111477, dated 04 / 12 / 2025, p. 69 / 545 62 / 499 RQ2RQ3 nRQ3 n RNQ1 In some modalities, Q is In In some modalities, Q is... RQ2. In In some modalities, Q is In some modalities, Q is... In some modalities, Q is RNQ1. In some In some modalities, Q is modalities, Q rNQ1

[0104] In some modalities, Q is selected from the group that rNQ1 rQ2 Petition 870250111477, dated 04 / 12 / 2025, p. 70 / 545 63 / 499 rq2 In some In some modalities, Q is modalities, Q is rNQ1 In RQ2, Q is... In some modalities, Q In some modalities, Q is In some modalities, Q is

[0105] In some forms, the compound has the structure of the formula (Id): RQ2(Id), or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. Petition 870250111477, dated 04 / 12 / 2025, p. 71 / 545 64 / 499

[0106] In some embodiments, the compound has the structure of the formula (Ie): (i.e.), or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0107] In some forms, the compound has the structure of the formula (Ig): (Ig), or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where Qa is a saturated heterocyclyl of 4 to 9 members.

[0108] In some forms, the compound has the structure of formula (Ij): (Ij), or a pharmaceutically prepared salt Petition 870250111477, dated 04 / 12 / 2025, p. 72 / 545 65 / 499 acceptable, an enantiomer, a stereoisomer or a tautomer thereof.

[0109] In some embodiments, the compound has the structure of the formula (Ik): an enantiomer, a stereoisomer, or a tautomer of the same.

[0110] In some embodiments, the compound has the structure of an enantiomer, a stereoisomer, or a tautomer of the same.

[0111] In some modalities, Q is selected from the group consisting of: Petition 870250111477, dated 04 / 12 / 2025, p. 73 / 545 66 / 499 in which: “1” indicates a portion of Q linked to X; and Q is additionally optionally replaced. In some modalities, Q is 1. In In some modalities, Q is... In some modalities, Q is 1. In some In some modalities, Q is 1 In some modalities, Q is In some modalities, Q is In some In some modalities, Q is 1. In Petition 870250111477, dated 04 / 12 / 2025, p. 74 / 545 67 / 499 In some modalities, Q is 1. In some modalities, Q is . In the In some modalities, Q is 1. In some modalities, Q is In some modalities, Q is 1. In some In some modalities, Q is 1. In some modalities, Q is 1. In some modalities, Q is In some modalities, Q is 1.

[0112] In some modalities, Q is selected from the group consisting of: R24 Petition 870250111477, dated 04 / 12 / 2025, p. 75 / 545 68 / 499 where: R is -CH2CH3, -CH2CH-OCH3, -CH2CHF2, -CH2-CN, CH2(CH3)2-CN, -C(CH3)2-CH2CN, -CH2CH2-CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, 2-cyano-5methoxyphenyl, 2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6bromophenyl, 2-methoxyethan-1-yl, 2-cyanopropan-2-yl, 2-tetrahydropyran-4-yletan-1-yl, 3-cyanopentan-3-yl, 2-cyano-4-methoxybutan-2-yl or R is R23 is hydrogen or halogen, such as fluorine; R24 is hydrogênio, chlorine, -CN, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CN, -CH(CN)-CH3, -C(CH3)2-CN, -C(CH2CH3)2-CN, -CH2-CH2-CN, -C(CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -OCH3, -CH2-OCH3, -CeCH, -CeC-CH3, -S(O)2CH3, 1-(cyclopentyl)-1-cyanoethane-1-yl, 1-(tetrahidropyran-4-yl)-1-cyanoethane-1-yl, 1-(tetra-hidrofuran-3-yl)-1-cyanoethane-1-yl, 1,3dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1cyanocyclopropyl, 1-cyanocylopentyl, 1-methyl-1,2,3,6-tetra-hidropyridin-4-yl, 1methylpyrazol-3-yl, 1-methylpyrazol-4-ylcyanomethyl, 1-methylpiperidin-4-yl, 1-methylpyrazol5-yl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxietan-1yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetra-hidropyran-4-yloxy)phenyl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,3-dicyanopropan-2-yl, 2-chlorophenyl, 2-cyano-3-(tetrahydropyran-4-yl)propan-2-yl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl,2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-6-chlorophenyl, 2-cyano-6, Petition 870250111477, dated 04 / 12 / 2025, page 76 / 545 69 / 499 fluorophenyl, 2-cyano-6-(tetra-hydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxycarbonyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(1,1-dioxothiomorpholin-4-ylmethyl)phenyl, 3-(2methoxyethan-1 -yl)phenyl, 3,5-difluoro-4-(pyrrolidin-1 -ylcarbonyl)phenyl, 3-cyano-2methylpropan-2-yl, 3-cyano-2-methylpropan-2-yl, 3-cyano-2-yl, 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yn-1-yl, 3-methoxy-2-methylbutan-2-yl, 3methoxymethyl-5-methylisoxazol-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2methylbutan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyridin-2-ylmethyl, pyridin-3-yl,pyridine-3-ylmethyl, pyridine-4-ylmethyl, tetra-hydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetra-hydropyran-4-yl or tetra-hydropyran-4-ylcyanomethyl;, R27é hydrogen, -CH3, -CHF2, -CH2CH3, -CH2-O-CH3, -CH2CN, CN, -CH2-O-CH2-CN, -C(O)-N(CH3)2, -C(O)-NH-CH3, -2-CH2-CH-O-CH 3-methoxyphenyl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2-cyanophenyl, 3cyanophenyl, phenyl, 2-benzylmethyl ether, 2-(2-methoxyethyl)benzene, 2-(2difluoromethoxyethyl)methoxyethyl 2-(2-dimethylmethoxyethyl)benzene, pyridine-3-yl, pyridine-2yl, pyridine-3-ylmethyl or tetra-hydropyridine-4-yl or R24e R27 unites to form 4-cyanobenzene-1,2-di-yl, 3cyanobenzene-1,2-di-yl, 5-methyl-5-cyanotetra-hydropyran-3,4-di-yl, 3-cyanocyclohexane-1,2-di-yl, zedino-1,2,2methoxybene benzene-1,2-di-yl, 3-oxocyclo-hexyl1,2-di-yl, 3-cyanocyclopentane-1,2-di-yl or pyridine-3,4-di-yl; R28e hydrogen, −CH3 or −CH2−O−CH3; and R29 is hydrogen, acetyl, CN, -CH2-CN, -CH2-CH2-CN, -CH2-OCH3, -CH=CH-CN, -CH2-OC(O)-N(CH3)2, morpholin-4-ylmethyl, pyrazol-1-ylmethyl, pyridin-3-yl, pyridin-3-ylethynyl, pyridin-2-yloxymethyl or 2-cyanopropan-2-yl or Petition 870250111477, dated 04 / 12 / 2025, page 77 / 545 70 / 499 R28 and R29 combine to form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridin-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5Hcyclopenta[c]pyridin-6-yl, tetrahydropyran-4,4-diyl or 4-methoxycyclohexane. In some embodiments, Q is In some modalities, Q is In some sports, Q R24N is 1. In some modalities, Q is In some modalities, Q is In some sports, Q In some modalities, Q is In some modalities, Q is

[0113] In some embodiments, R3 is -CH3, -CH2CH3, -(CH2ECH3, -CH(CH3)2, -CH(CH3)CH2CH3, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl or tetrahydropyran-4-yl.

[0114] In one aspect, the invention provides a compound with the structure of Formula IIa or Formula IIb: Petition 870250111477, dated 04 / 12 / 2025, p. 78 / 545 71 / 499 Formula IIa Formula llb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is Petition 870250111477, dated 04 / 12 / 2025, page 79 / 545 72 / 499 linked to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently hydrogen or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y 5 is CRx, CH, CH2 or N; Y 6 is CRz, C(O), CH, CH2 or N; Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or Petition 870250111477, dated 04 / 12 / 2025, page 80 / 545 73 / 499 R13e and R2se combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group; R2 is absent, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7e and R8se combine with the carbon atom to which they are attached. Petition 870250111477, dated 04 / 12 / 2025, p. 81 / 545 74 / 499 linked to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, C1-C3 heteroalkyl Petition 870250111477, dated 04 / 12 / 2025, p. 82 / 545 75 / 499 optionally replaced or C1-C3 alkyl optionally replaced; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; R21 is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0115] In one aspect, the disclosure presents a composite of Structural formula IIa-1: Formula IIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, C1-C4 Petition 870250111477, dated 04 / 12 / 2025, page 83 / 545 76 / 499 optionally substituted heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y5 is CRx, CH, CH2 or N; Petition 870250111477, dated 04 / 12 / 2025, p. 84 / 545 77 / 499 Y6é CRz, C(O), CH, CH2 or N; Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Rzé hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13e and R2se combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group; R2 is absent, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; Petition 870250111477, dated 04 / 12 / 2025, page 85 / 545 78 / 499 R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. Petition 870250111477, dated 04 / 12 / 2025, p. 86 / 545 79 / 499 or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; and R21 is hydrogen or optionally substituted C1-C3 alkyl.

[0116] In some forms, the disclosure presents a compound with structural formula IIa-2: R2 < / xR5T Formula IIa-2 Petition 870250111477, dated 04 / 12 / 2025, p. 87 / 545 80 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is, independently, either hydrogen or C1-C4 alkyl. Petition 870250111477, dated 04 / 12 / 2025, p. 88 / 545 81 / 499 optionally replaced; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y 5 is CH, CH2, CF, CHF, CF2 or N; Y6 is C(O), CH, CH2, CF, CHF, CF2 or N; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13e and R2se combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group; R2 is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or Petition 870250111477, dated 04 / 12 / 2025, page 89 / 545 82 / 499 R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 90 / 545 83 / 499 R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; and R21 is hydrogen or optionally substituted C1-C3 alkyl.

[0117] In some embodiments, a compound with the structure of Formula IIa-3R7RlOaA is provided in this document. R11 Formula IIa-3 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines Petition 870250111477, dated 04 / 12 / 2025, p. 91 / 545 84 / 499 represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is -CH(R9)- or >C=CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone, a haloacetal or an alkynyl sulfone; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is, independently, H or C1-C4 alkyl optionally substituted; Petition 870250111477, dated 04 / 12 / 2025, p. 92 / 545 85 / 499 Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y5 is CH, CH2, CF, CHF, CF2 or N; Y6 is C(O), CH, CH2, CF, CHF, CF2 or N; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13e and R2se combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group; R2 is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached. Petition 870250111477, dated 04 / 12 / 2025, page 93 / 545 86 / 499 linked to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is C1-C6 optionally substituted alkyl, C1-C6 heteroalkyl Petition 870250111477, dated 04 / 12 / 2025, page 94 / 545 87 / 499 optionally substituted, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; and R11 is hydrogen or C1-C3 alkyl.

[0118] In some forms, the disclosure presents a compound with structural formula IIa-4: Formula IIa-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of Petition 870250111477, dated 04 / 12 / 2025, page 95 / 545 88 / 499 -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone, a haloacetal or an alkynyl sulfone; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y5 and Y6 are, independently, CH, CF, or N; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. Petition 870250111477, dated 04 / 12 / 2025, page 96 / 545 89 / 499 optionally replaced; R2 is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or Petition 870250111477, dated 04 / 12 / 2025, p. 97 / 545 90 / 499 optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0119] In some embodiments of compounds of the present invention, G is optionally substituted C1-C4 heteroalkylene.

[0120] In some embodiments, a compound with the structure of Formula IIa-5 is provided: Formula IIa-5 Petition 870250111477, dated 04 / 12 / 2025, p. 98 / 545 91 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; X2 is O or NH; X3 is N or CH; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are, independently, CH, CF, or N; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl Petition 870250111477, dated 04 / 12 / 2025, p. 99 / 545 92 / 499 substituted, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, Petition 870250111477, dated 04 / 12 / 2025, p. 100 / 545 93 / 499 C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0121] In some embodiments of compounds of the present invention, X2 is NH. In some embodiments, X3 is CH. In some embodiments, R11 is hydrogen. In some embodiments, R11 is C1-C3 alkyl. In some embodiments, R11 is methyl.

[0122] In some embodiments, a compound of the present invention has the structure of Formula IIa-6: Formula IIa-6 Petition 870250111477, dated 04 / 12 / 2025, p. 101 / 545 94 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are, independently, CH or N; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. Petition 870250111477, dated 04 / 12 / 2025, p. 102 / 545 95 / 499 optionally replaced; R2 is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or Petition 870250111477, dated 04 / 12 / 2025, p. 103 / 545 96 / 499 optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0123] In some embodiments of a compound of the present invention, X1 is optionally substituted C1-C2 alkylene. In some embodiments, X1 is methylene. In some embodiments, X1 is methylene substituted by a C1-C6 alkyl group or a halogen. In some embodiments, X1 is CH(Br)-. In some embodiments, X1 is -CH(CH3)-. In some embodiments, R5 is hydrogen. In some embodiments, R5 is optionally halogen-substituted C1-C4 alkyl. In some embodiments, R5 is methyl. In some embodiments, Y4 is C. In some embodiments, R4 is hydrogen. In some embodiments, Y5 is CH. In some embodiments, Y5 is CF. In some embodiments, Y6 is CH. In some embodiments, Y6 is CF. In some embodiments, Y1 is C. In some embodiments, Y2 is C. In some embodiments, Y3 is N. In some embodiments, R3 is absent. In some Petition 870250111477, dated 04 / 12 / 2025, p. 104 / 545 97 / 499 modalities, Y7 is C. In some modalities, Y4 is C and R15 is F.

[0124] In some embodiments, a compound of the present invention has the structure of Formula IIa-7: Formula IIa-7 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is -N(H or CH3)C(O)(CH2)- wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl Petition 870250111477, dated 04 / 12 / 2025, page 105 / 545 98 / 499 optionally substituted, 3- to 6-membered heterocycloalkyl optionally substituted, 6- to 10-membered aryl optionally substituted or 5- to 10-membered heteroaryl optionally substituted; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6e and R7se combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or Petition 870250111477, dated 04 / 12 / 2025, p. 106 / 545 99 / 499 optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0125] In some embodiments of a compound of the present invention, R6 is hydrogen. In some embodiments, R2 is hydrogen, cyano, optionally substituted C1C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is fluoroalkyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is -CHCΞCH. In some embodiments, R2 is CH2C^CCH3. In some embodiments, R7 is optionally substituted C1-C3 alkyl. In some embodiments, R7 is C1-C3 alkyl. In some embodiments, R8 is optionally substituted C1-C3 alkyl. In some embodiments, R8 is C1-C3 alkyl. Petition 870250111477, dated 04 / 12 / 2025, p. 107 / 545 100 / 499

[0126] In some embodiments, a compound of the present invention has the structure of Formula IIa-8: Formula IIa-8 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is -N(H or CH3)C(O)(CH2)- wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl Petition 870250111477, dated 04 / 12 / 2025, page 108 / 545 101 / 499 replaced, aril of 6 to 10 members optionally replaced or heteroaril of 5 to 10 members optionally replaced; R2 is a 3- to 6-membered C1-C6 alkyl or cycloalkyl group; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0127] In some embodiments of a compound of the present invention, R13 is optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 6-membered cycloalkenyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R13 is optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl.

[0128] In some embodiments of a compound of the present MeO MeO MeO MeO N N MeO invention, R13é MeO or In Petition 870250111477, dated 04 / 12 / 2025, p. 109 / 545 102 / 499 MeO In some embodiments of a compound of the present invention, R13 is or a stereoisomer (e.g., atropisomer) thereof. MeO (sb— embodiments of a compound of the present invention, R13é \= / . In In some forms, R13 is / or a stereoisomer thereof. In some modalities, R13 is / .

[0129] In some embodiments, a compound of the present invention has the structure of Formula IIa-9: Formula IIa-9 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is -N(H or CH3)C(O)(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, Petition 870250111477, dated 04 / 12 / 2025, p. 110 / 545 103 / 499 optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; R2 is a 3- to 6-membered C1-C6 alkyl, C1-C6 fluoroalkyl, or cycloalkyl compound; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. Xee Xfsion, independently, N, CH or CR17; and R12 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 6-membered heterocycloalkylene. R17 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0130] In some embodiments of a compound of the present Petition 870250111477, dated 04 / 12 / 2025, p. 111 / 545 104 / 499 invention, Xeé N and Xf is CH. In some embodiments, Xeé CH and Xf is N.

[0131] In some embodiments of compounds of the present invention, R12 is optionally substituted C1-C6 heteroalkyl. çh3,, . ç / χ,OMβ embodiments, R12 is aOMe,OMe, , * In some ch3 Y^ochf2ch2ch3 or In some embodiments of a compound of the present invention, R12 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R12 is OMe.

[0132] In some embodiments, a compound of the present invention has the structure of Formula IIa-10: Formula IIa-10 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is hydrogen, optionally substituted amino, C1-C4 alkoxy Petition 870250111477, dated 04 / 12 / 2025, page 112 / 545 105 / 499: 3 to 8 optionally substituted members; R2 is a 3- to 6-membered C1-C6 alkyl or cycloalkyl group; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Xeé CH or CR17; and R17 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0133] In some embodiments, a compound of the present invention has the structure of Formula IIa-11: Formula IIa-11 Petition 870250111477, dated 04 / 12 / 2025, p. 113 / 545 106 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R2 is a 3- to 6-membered C1-C6 alkyl or cycloalkyl group; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0134] In some embodiments, a compound of the present invention has the structure of Formula II-VI: Petition 870250111477, dated 04 / 12 / 2025, p. 114 / 545 107 / 499 Formula II-VI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; Petition 870250111477, dated 04 / 12 / 2025, p. 115 / 545 108 / 499 L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone, a haloacetal or an alkynyl sulfone; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y 5 is CH, CH2, CF, CHF, CF2 or N; Y6 is C(O), CH, CH2, CF, CHF, CF2 or N; R2 is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally replaced by Petition 870250111477, dated 04 / 12 / 2025, page 116 / 545 109 / 499 halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or Petition 870250111477, dated 04 / 12 / 2025, page 117 / 545 110 / 499 R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted H, F, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; R21 is hydrogen or C1-C3 alkyl (e.g., methyl); and Xee Xfsion, regardless of whether it's N or CH.

[0135] In some embodiments, a compound of the present invention has the structure of Formula II-VIa: R2J Formula II-VIa Petition 870250111477, dated 04 / 12 / 2025, p. 118 / 545 111 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; R2 is C1-C6 alkyl, C1-C6 fluoroalkyl or 3- to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Xee Xfsion, regardless of whether it's N or CH; Petition 870250111477, dated 04 / 12 / 2025, p. 119 / 545 112 / 499 R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0136] In some embodiments of a compound of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0137] In some embodiments, a compound of the present invention has the structure of Formula II-VIb: Formula II-VIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; L is absent or is a ligand; and Petition 870250111477, dated 04 / 12 / 2025, p. 120 / 545 113 / 499 W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone or an alkynyl sulfone; In some embodiments of a compound of the present invention, A is an optionally substituted 6-membered arylene.

[0138] In some embodiments, a compound of the present invention has the structure of Formula II-VIc: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bonded to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; Petition 870250111477, dated 04 / 12 / 2025, p. 121 / 545 114 / 499 G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R)7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R)7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is absent or is a ligand; W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, an inone, a haloacetal or an alkynyl sulfone; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently or optionally substituted H or C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y 5 is CH, CH2, CF, CHF, CF2 or N; Y6 is C(O), CH, CH2, CF, CHF, CF2 or N; R2 is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14 is absent or R2 and R14 combine with the atom to which they are attached. Petition 870250111477, dated 04 / 12 / 2025, page 122 / 545 115 / 499 linked to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally replaced by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7e R8se combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, C2-C6 Petition 870250111477, dated 04 / 12 / 2025, page 123 / 545 116 / 499 optionally substituted alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted 6 to 10 membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted H, F, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R9 and R9' combine with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0139] In some forms, Z is -C(O)-.

[0140] In some embodiments, A is optionally substituted C2-C4 alkylene. In some embodiments, A is optionally substituted C3 alkylene. In some embodiments, A is: V .

[0141] In some embodiments A is optionally substituted C2-C4 alkenylene. In some embodiments A is C3 alkenylene. Petition 870250111477, dated 04 / 12 / 2025, p. 124 / 545 117 / 499 optionally substituted. In some embodiments, A is optionally substituted C1-C4 heteroalkylene. In some embodiments, A is optionally substituted C2 heteroalkylene. In some embodiments, A is:

[0142] In some forms, A has the structure: R13a R13 where R13 is hydrogen, halogen, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; and R13a is hydrogen or halogen. In some embodiments, R13 is hydrogen. In some embodiments, R13 and R13a are each hydrogen. In some embodiments, R13 is hydroxyl, methyl, fluoromethyl or difluoromethyl.

[0143] In some embodiments, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is: hn-n

[0144] In some embodiments, A is optionally substituted 5- to 6-membered heteroarylene. In some modalities, A is: Petition 870250111477, dated 04 / 12 / 2025, p. 125 / 545 118 / 499 HN-N

[0145] In some embodiments, A is C1-C4 heteroalkylene ο optionally substituted. In some embodiments, A is:CH3. In some embodiments, A is optionally a 3- to 6-membered heterocycloalkylene. substituted. In some modalities, A is: the modalities, A is or In some

[0146] In some embodiments, R9 is optionally substituted H, F, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments, R9 is: ^CF3^CHF2^ΟΗ3 / ^CF3Ao'CH3 ch3CF3 / \Α^οη3h3co UCH3 HO Petition 870250111477, dated 04 / 12 / 2025, p. 126 / 545 119 / 499 In some sports, R9 is: In some embodiments, R9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0147] In some embodiments of a compound of the present invention, B is optionally substituted 6-membered arylene. In some embodiments, B is 6-membered arylene. In some embodiments, B is: λ / w

[0148] In some modalities, R13 is R17 In some disciplines, R13 is R17.

[0149] In some modalities, R13 is where Z1 is N or CH; m is 1 or 2; R18, R19, R20 and R25 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, Petition 870250111477, dated 04 / 12 / 2025, p. 127 / 545 120 / 499 optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R18 and R20 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl group or an optionally substituted 3- to 8-membered heterocycloalkyl group; or R20 and R25 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R19 and R20 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered cycloalkyl heterocycloalkyl.

[0150] In some modalities, R13 is R18 In some disciplines, R13 is R18.

[0151] In some embodiments, R18 is methyl.

[0152] In some modalities, R13 is or

[0153] In some embodiments of a compound of the present invention, R7 is methyl.

[0154] In some embodiments of a compound of the present Petition 870250111477, dated 04 / 12 / 2025, p. 128 / 545 121 / 499 invention, R8 is methyl.

[0155] In some forms, R21 is hydrogen.

[0156] In some embodiments of a compound of the present invention, B is -CHR9-. In some embodiments, R9 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, B is optionally substituted 6-membered arylene. In some embodiments, B is absent.

[0157] In some modalities, L has the structure of Formula Lo: Aχ12_Eλ Formula L0 wherein X12 is O, S, SO2, NH, CH2, C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene or optionally substituted C2-C4 alkynylene and is attached to ring A; and And it is a linkage, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C6 alkenylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 5- to 12-membered arylene, or optionally substituted 5- to 12-membered heteroarylene.

[0158] In some embodiments of a compound of the present invention, the ligand has the structure of Formula II-II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula II-II where A1 is a bond between the ligand and B; A2 is a bond between A and the ligand; B1, B2, B3 and B4, each independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, Petition 870250111477, dated 04 / 12 / 2025, p. 129 / 545 122 / 499 Optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical linkage linking A1-(B1)f-(C1)g-(B2)h-a-(B3)i-(C2)j-(B4)k-A2. In some embodiments, the linker is acyclic.In some forms, the binder has the structure of Formula II-IIa:. Formula II-IIa where Xa is absent or N; R14 is absent, hydrogen or C1-C6 alkyl is optionally substituted; and L2 is absent, -SO2-, optionally substituted C1-C4 alkylene or Optionally substituted C1-C4 heteroalkylene, in which at least one of Xa, R14, or L2 is present. In some embodiments, the ligand has the following structure: Petition 870250111477, dated 04 / 12 / 2025, p. 130 / 545 123 / 499 O or In some forms, the ligand has the following structure: nHICH3. In some forms, L is In some modalities, L is

[0159] In some embodiments, the ligand is or comprises a cyclic moiety. In some embodiments, the ligand has the structure of Formula IIIb: Formula II-IIb where o is 0 or 1; R15 is hydrogen or, optionally, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heterocycloalkylene; X4 is absent, optionally substituted C1-C4 alkylene, O, NCH3 or optionally substituted C1-C4 heteroalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0160] In some forms, the ligand has the structure of Petition 870250111477, dated 04 / 12 / 2025, p. 131 / 545 124 / 499 Formula II-IIb-1: Formula II-IIb-1 where o is 0 or 1; R15 is hydrogen or, optionally, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heterocycloalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0161] In some forms, the ligand has the following structure: Petition 870250111477, dated 04 / 12 / 2025, p. 132 / 545 125 / 499 Petition 870250111477, dated 04 / 12 / 2025, p. 133 / 545 126 / 499 or

[0162] In some forms, the ligand has the structure of Formula II-IIc: Formula II-IIc wherein R15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; and R15a, R15b, R15c, R15d, R15e, R15f, and R15g are, independently, hydrogen, halo, hydroxy, cyano, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R15b and R15d combine with the Petition 870250111477, dated 04 / 12 / 2025, p. 134 / 545 127 / 499 carbons to which they are attached to form an optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heterocycloalkylene.

[0163] In some forms, the ligand has the following structure: Petition 870250111477, dated 04 / 12 / 2025, p. 135 / 545 128 / 499 or

[0164] In some forms, the ligand has the following structure: Petition 870250111477, dated 04 / 12 / 2025, p. 136 / 545 129 / 499 Petition 870250111477, dated 04 / 12 / 2025, p. 137 / 545 130 / 499 Petition 870250111477, dated 04 / 12 / 2025, p. 138 / 545 131 / 499 or

[0165] In some forms, the ligand has the structure

[0166] In some forms, the ligand has the structure

[0167] In some modalities, a Formula II linker is selected from the group consisting of

[0168] In one aspect, the invention provides a compound with the structure of Formula IIIa or Formula IIIb: Formula IIIa Formula IIIb Petition 870250111477, dated 04 / 12 / 2025, p. 139 / 545 132 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O). , -NHC(O)NH- , -NHC(O)NCH3- , -NHC(O)O- -NHC(S). , -NHC(S)NH- , -NHS(O)2- or -NHS(O)2NH·. L is a ligand; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 140 / 545 133 / 499 R7 and R8 are each independently selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to form a 3-membered cycloalkyl group; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6, join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0169] In one aspect, the invention provides a compound with the structure of Formula IIIa-1: Formula IIIa-1 or pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 141 / 545 134 / 499 stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O). , -NHC(O)NH- , -NHC(O)NCH3- , -NHC(O)O- -NHC(S). , -NHC(S)NH- , -NHS(O)2- or -NHS(O)2NH·; L is a ligand; X4 and X5 are, each independently, CH2, CH(CH3) or NH; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy. Petition 870250111477, dated 04 / 12 / 2025, page 142 / 545 135 / 499 optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to form a 3-membered cycloalkyl group; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0170] In some forms, the disclosure presents a compound with structural formula IIIa-2: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Petition 870250111477, dated 04 / 12 / 2025, p. 143 / 545 136 / 499 γ8 θ -NHC(O)- , -NHC(O)NH- , -NHC(O)NCH3- , -NHC(O)O- -NHC(S)- , -NHC(S)NH- , -NHS(O)2-Qu-NHS(O)2NH-. L is a ligand; X4 and X5 are, each independently, CH2, CH(CH3) or NH; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R7 and R8 are each independently selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to form a 3-membered cycloalkyl group.

[0171] In some embodiments, the compound has the structure of Formula IIIa-3: Petition 870250111477, dated 04 / 12 / 2025, p. 144 / 545 137 / 499 Formula IIIa-3 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; Y8 is -NHC(O)-, -NHC(O)NH- -NHC(S)- -NHC(S)NH- -NHS(O)2or -NHS(O)2NH-; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl Petition 870250111477, dated 04 / 12 / 2025, page 145 / 545 138 / 499 members optionally replaced, 6-member aril optionally replaced, 5 or 6-member heteroaril optionally replaced; and R10 is hydrogen or optionally substituted C1-C6 heteroalkyl. In some embodiments, R10 is hydrogen.

[0172] In some embodiments, R13 is optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R13 is optionally substituted phenyl or optionally substituted pyridine.

[0173] In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, or phenyl. In some embodiments, A is not an optionally substituted phenyl or benzimidazole. In some embodiments, A is not hydroxyphenyl.

[0174] In some forms, Y8 is -NHC(O)- or -NHC(O)NH-.

[0175] In some embodiments, the compound has the structure of Formula IIIa-4: Formula IIIa-4, or a pharmaceutically acceptable salt, is an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. Petition 870250111477, dated 04 / 12 / 2025, p. 146 / 545 139 / 499

[0176] In some embodiments, the compound has the structure of Formula IIIa-5: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0177] In some embodiments, the compound has the structure of Formula IIIa-6: Petition 870250111477, dated 04 / 12 / 2025, p. 147 / 545 140 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0178] In some embodiments, the compound has the structure of Formula IIIa-7: Formula IIIa-7, or a pharmaceutically acceptable salt, is an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0179] In some embodiments, the compound has the structure of Formula IIIa-8: Formula IIIa-8 Petition 870250111477, dated 04 / 12 / 2025, p. 148 / 545 141 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0180] In some embodiments, the compound has the structure of Formula IIIa-9: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 149 / 545 142 / 499 or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is H. In some embodiments, X3 is N, m is 1, and R11 is H.

[0181] In some embodiments, the compound has the structure of Formula IIIa-10: Formula IIIa-10 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0182] In some embodiments, the compound has the structure of Formula IIIa-11: Formula IIIa-11 Petition 870250111477, dated 04 / 12 / 2025, p. 150 / 545 143 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0183] In some embodiments (for example, of either Formula IIIa-10 or IIIa-11), R6 is methyl.

[0184] In some embodiments, the compound has the structure of Formula IIIa-12 or Formula IIIa-13: Formula IIIa-12, Formula IIIa-13 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0185] In some embodiments, the compound has the structure of Formula IIIa-a: Formula IIIa-a, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein a is 0 or 1. Petition 870250111477, dated 04 / 12 / 2025, p. 151 / 545 144 / 499

[0186] In some embodiments, the compound has the structure of Formula IIIa-a1: N ΓNH' Formula IIIa-a1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0187] In some embodiments, the compound has the structure of Formula IIIa-a2: Formula IIIa-a2 Petition 870250111477, dated 04 / 12 / 2025, p. 152 / 545 145 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0188] In some embodiments, the compound has the structure of Formula IIIa-a3: Formula IIIa-a3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (for example, optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0189] In some embodiments, the compound has the structure of Formula IIIa-a4: Formula IIIa-a4 Petition 870250111477, dated 04 / 12 / 2025, p. 153 / 545 146 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0190] In some embodiments, the compound has the structure of Formula IIIa-a5: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 154 / 545 147 / 499 R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0191] In some embodiments, the compound has the structure of Formula IIIa-a6: N R6 Formula IIIa-a6 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0192] In some embodiments, the compound has the structure of Formula IIIa-a7: N R6 Formula IIIa-a7 or a pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 155 / 545 148 / 499 stereoisomer or a tautomer thereof.

[0193] In some embodiments (for example, of either Formula IIIa-a6 or IIIa-a7), R6 is methyl.

[0194] In some embodiments, the compound has the structure of Formula IIIa-a8 or Formula IIIa-a9: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0195] In some embodiments, the compound has the structure of Formula III-IVa: Formula III-IVa, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein a is 0 or 1.

[0196] In some embodiments, the compound has the structure of Formula III-IVa-1: Petition 870250111477, dated 04 / 12 / 2025, p. 156 / 545 149 / 499 Formula III-IVa-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0197] In some embodiments, the compound has the structure of Formula III-IVa-2: Petition 870250111477, dated 04 / 12 / 2025, p. 157 / 545 150 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0198] In some embodiments, the compound has the structure of Formula III-Iva-3: Formula III-IVa-3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (for example, optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0199] In some embodiments, the compound has the structure of Formula III-IVa-4: Formula III-IVa-4 Petition 870250111477, dated 04 / 12 / 2025, p. 158 / 545 151 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0200] In some embodiments, the compound has the structure of Formula III-IVa-5: Formula III-IVa-5, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 159 / 545 152 / 499 R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0201] In some embodiments, the compound has the structure of Formula III-IVa-6: Formula III-IVa-6 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0202] In some embodiments, the compound has the structure of Formula III-IVa-7: Formula III-IVa-7 Petition 870250111477, dated 04 / 12 / 2025, p. 160 / 545 153 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0203] In some embodiments (for example, of either Formula III-IVa-6 or III-IVa-7), R6 is methyl.

[0204] In some embodiments, the compound has the structure of Formula III-IVa-8 or Formula III-IVa-9: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0205] In some embodiments, Y8 is -NHS(O)2- or -NHS(O)2NH

[0206] In some embodiments, the compound has the structure of Formula III-Va: Formula III-Va, or pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 161 / 545 154 / 499 stereoisomer or a tautomer thereof, wherein a is 0 or 1.

[0207] In some embodiments, the compound has the structure of Formula III-Va-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0208] In some embodiments, the compound has the structure of Formula III-Va-2: Petition 870250111477, dated 04 / 12 / 2025, p. 162 / 545 155 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0209] In some embodiments, the compound has the structure of Formula III-Va-3: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (for example, optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0210] In some forms, the compound has the structure of Formula III-Va-4: Petition 870250111477, dated 04 / 12 / 2025, page 163 / 545 156 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0211] In some forms, the compound has the structure of Formula III-Va-5: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 164 / 545 157 / 499 R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0212] In some embodiments, the compound has the structure of Formula III-Via: Formula III-VIa, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein a is 0 or 1.

[0213] In some embodiments, the compound has the structure of Formula III-VIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted starch. Petition 870250111477, dated 04 / 12 / 2025, p. 165 / 545 158 / 499 substituted, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0214] In some embodiments, the compound has the structure of Formula III-VIa-2: (R3)n R2 Formula III-VIa-2 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0215] In some embodiments, the compound has the structure of Formula III-VIa-3: Formula III-Via-3, or pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 166 / 545 159 / 499 stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0216] In some embodiments, the compound has the structure of Formula III-Via-4: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0217] In some embodiments, the compound has the structure of Formula III-VIa-5: Petition 870250111477, dated 04 / 12 / 2025, p. 167 / 545 160 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0218] In some embodiments, the compound has the structure of Formula III-VIIa: Formula III-VIIa, or pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 168 / 545 161 / 499 stereoisomer or a tautomer thereof, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1.

[0219] In some embodiments, the compound has the structure of Formula III-VIIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0220] In some embodiments, the compound has the structure of Formula III-VIIa-2: Petition 870250111477, dated 04 / 12 / 2025, p. 169 / 545 162 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0221] In some embodiments, the compound has the structure of Formula III-VIIa-3: Formula III-VIIa-3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (for example, optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0222] In some embodiments, the compound has the structure of Formula III-VIIa-4: Formula III-VIIa-4 Petition 870250111477, dated 04 / 12 / 2025, p. 170 / 545 163 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0223] In some embodiments, the compound has the structure of Formula III-VIIa-5: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 171 / 545 164 / 499 R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0224] In some embodiments (for example, of any of Formulas VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4 or VIIa-5), R9 is methyl.

[0225] In some forms, Y is -NHS(O)- or -NHS(O)NH-.

[0226] In some embodiments, the compound has the structure of Formula III-VIIIa: Formula III-VIIIa, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein a is 0 or 1.

[0227] In some embodiments, the compound has the structure of Formula III-VIIIa-1: or a pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 172 / 545 165 / 499 stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0228] In some embodiments, the compound has the structure of Formula III-VIIIa-2: Formula III-VIIIa-2 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0229] In some embodiments, the compound has the structure of Formula III-VIIIa-3: or a pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 173 / 545 166 / 499 stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0230] In some embodiments, the compound has the structure of Formula III-VIIIa-4: Formula III-VIIIa-4 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0231] In some embodiments, the compound has the structure of Formula III-VIIIa-5: Formula III-VIIIa-5, Petition 870250111477, dated 04 / 12 / 2025, p. 174 / 545 167 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0232] In some embodiments, the compound has the structure of Formula III-IXa: Formula III-IXa, Petition 870250111477, dated 04 / 12 / 2025, p. 175 / 545 168 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein a is 0 or 1.

[0233] In some embodiments, the compound has the structure of Formula III-IXa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0234] In some embodiments, the compound has the structure of Formula III-IXa-2: Formula III-IXa-2 Petition 870250111477, dated 04 / 12 / 2025, p. 176 / 545 169 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0235] In some embodiments, the compound has the structure of Formula III-IXa-3: Formula III-IXa-3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (for example, optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0236] In some embodiments, the compound has the structure of Formula III-IXa-4: Formula III-IXa-4 Petition 870250111477, dated 04 / 12 / 2025, p. 177 / 545 170 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0237] In some embodiments, the compound has the structure of Formula III-IXa-5: Formula III-IXa-5, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 178 / 545 171 / 499 R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0238] In some embodiments, the compound has the structure of Formula III-Xa: Formula III-Xa, or a pharmaceutically acceptable salt, is an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1.

[0239] In some embodiments, the compound has the structure of Formula III-Xa-1: Formula III-Xa-1, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X2 is N or CH; Each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted starch. Petition 870250111477, dated 04 / 12 / 2025, p. 179 / 545 172 / 499 substituted, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; en is an integer from 1 to 4.

[0240] In some embodiments, the compound has the structure of Formula III-Xa-2: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0241] In some embodiments, the compound has the structure of Formula III-Xa-3: Petition 870250111477, dated 04 / 12 / 2025, p. 180 / 545 173 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4 and R5 are independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0242] In some embodiments, the compound has the structure of Formula III-Xa-4: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0243] In some embodiments, the compound has the structure of Formula III-Xa-5: Formula III-Xa-5, Petition 870250111477, dated 04 / 12 / 2025, p. 181 / 545 174 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R8 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl group. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0244] In some embodiments of any aspect described in this document, a is 0. In some embodiments of any of the aspects above, a is 0.

[0245] In some embodiments of any aspect described in this document, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is selected from -CH2CH3 or -CH2CF3.

[0246] In one aspect, the invention provides a compound with the Petition 870250111477, dated 04 / 12 / 2025, p. 182 / 545 175 / 499 Formula IVa or Formula IVb structure: R3 Formula IVa Formula IVb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 183 / 545 176 / 499 any two of RL1, RL2, RL3, RL4, RL5 and RL6 join with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0247] In some embodiments, the compound has the structure of Formula IVa-1 or Formula IVb-1 or R1 Formula IVa-1 Formula IVb-1 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; Petition 870250111477, dated 04 / 12 / 2025, page 184 / 545 177 / 499 R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0248] In some embodiments, the compound has the structure of Formula IVa-2: or a pharmaceutically acceptable salt thereof, where A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; Petition 870250111477, dated 04 / 12 / 2025, page 185 / 545 178 / 499 R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0249] In some forms, the disclosure presents a compound with structural formula IVa-3: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, C1-C6 Petition 870250111477, dated 04 / 12 / 2025, page 186 / 545 179 / 499 optionally substituted alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl.

[0250] In some embodiments, a compound with the structure of Formula IVa-4 is provided in this document: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0251] In some embodiments of compounds of the present invention, A is optionally substituted thiazole, optionally substituted oxazole, optionally substituted morpholino, optionally substituted pyrrolidinyl, optionally substituted pyridyl, optionally substituted azetidinyl, optionally substituted pyrazinyl, optionally substituted pyrimidine, optionally substituted piperidinyl, optionally substituted oxadiazole, optionally substituted thiadiazole, optionally substituted triazole, optionally substituted thiomorpholino or optionally substituted phenyl.

[0252] In some modalities, the disclosure presents a Petition 870250111477, dated 04 / 12 / 2025, page 187 / 545 180 / 499 compound of structural formula IVa5 Formula IVa5 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0253] In some embodiments, a compound with the structure of Formula IVa6 is provided: n-Vr3 Formula IVa6, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R4, R5 and R6 are independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; or R4 and R5 combine with the atoms to which they are bonded. Petition 870250111477, dated 04 / 12 / 2025, p. 188 / 545 181 / 499 to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R4 and R6 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl.

[0254] In some embodiments, a compound of the present invention has the structure of Formula IVa7: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0255] In some embodiments, a compound of the present invention has the structure of Formula IVa8: or a pharmaceutically acceptable salt, an enantiomer, a Petition 870250111477, dated 04 / 12 / 2025, p. 189 / 545 182 / 499 stereoisomer or a tautomer thereof.

[0256] In some embodiments, a compound of the present invention has the structure of Formula IVa9f: OK / rrR3 Formula IVa9 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0257] In some embodiments of a compound of the present invention, R2 is:

[0258] In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C6 alkyl. In some modalities, R3é: X .

[0259] In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C3 heteroalkyl. In some embodiments, R3 is: X .

[0260] In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is Petition 870250111477, dated 04 / 12 / 2025, p. 190 / 545 183 / 499 or

[0261] In some embodiments of a compound of the present invention, A is optionally substituted phenyl. In some embodiments, A is:

[0262] In some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from among the following, or a stereoisomer thereof:

[0263] In some embodiments of a compound of the present invention, the ligand has the structure of Formula IV-III: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula IV-III, wherein A1 is a linkage between the ligand and CH(R3); A2 is a linkage between A and the ligand; B1, B2, B3 and B4, each independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; each RN is independently, Petition 870250111477, dated 04 / 12 / 2025, p. 191 / 545 184 / 499 hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1;and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene or optionally substituted C1-C10 heteroalkylene or a chemical linkage connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k-A2;

[0264] In some embodiments of a compound of the present invention, the ligand is or comprises a cyclic moiety. In some embodiments, the ligand has the structure of Formula IV-IIIa: Formula IV-IIIa, where o is 0 or 1; R7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X1 is absent, optionally substituted C1-C4 alkylene, O, NCH3 or optionally substituted C1-C4 heteroalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene. Petition 870250111477, dated 04 / 12 / 2025, page 192 / 545 185 / 499 optionally substituted 3- to 12-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L2 is absent, -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted 3- to 6-membered heterocycloalkylene.

[0265] In some embodiments, the ligand is selected from, or a stereoisomer thereof: Petition 870250111477, dated 04 / 12 / 2025, p. 193 / 545 186 / 499 Petition 870250111477, dated 04 / 12 / 2025, p. 194 / 545 187 / 499

[0266] In some embodiments, the ligand is selected from, or a stereoisomer thereof: Petition 870250111477, dated 04 / 12 / 2025, p. 195 / 545 188 / 499 o or o

[0267] In some embodiments, a compound of the present invention has the structure of Formula IVa9: Formula IVa9, Petition 870250111477, dated 04 / 12 / 2025, p. 196 / 545 189 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein Cy1 is an optionally substituted 8- to 11-membered spirocyclic heterocycloalkylene or an optionally substituted 7- to 9-membered bicyclic heterocycloalkylene; and wherein W comprises a vinyl ketone or a vinyl sulfone.

[0268] In some embodiments, Cy1 is an optionally substituted 10- to 11-membered spirocyclic heterocycloalkylene.

[0269] In some embodiments, a compound of the present invention has the structure of Formula IVa10: Formula IVa10, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is O, C(R11)2, NR12, S or SO2; r is 1 or 2; each t is independently 0, 1 or 2; R11 and R12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and each R13 is independently -CH3.

[0270] In some embodiments, a compound of the present invention has the structure of Formula IVa11: Petition 870250111477, dated 04 / 12 / 2025, p. 197 / 545 190 / 499 Formula IVa11 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where X2 is O, C(R11)2, NR12, S or SO2; r is 1 or 2; each t is independently 0, 1 or 2; R11 and R12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and each R13 is independently -CH3, F, or two R13s bonded to the same atom combine with the atom to which they are bonded to form an optionally substituted C3C6 cycloalkyl, or two R13s bonded to the same atom combine with the atom to which they are bonded to form an optionally substituted 3- to 6-membered heterocycloalkyl.

[0271] In some embodiments, a compound of the present invention has the structure of Formula IVa12: Formula IVa12 Petition 870250111477, dated 04 / 12 / 2025, p. 198 / 545 191 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0272] In some embodiments, a compound of the present invention has the structure of Formula IVa13: Formula IVa13 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0273] In some embodiments, a compound of the present invention has the structure of Formula IVa14: Formula IVa14 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0274] In some modalities, r is 1. In some modalities, Petition 870250111477, dated 04 / 12 / 2025, p. 199 / 545 192 / 499 r is 2. In some modalities, X2 is O. In some modalities, X2 is S. In some modalities, X2 is SO2.

[0275] In some embodiments, X2 is NR12. In some embodiments, R12 is selected from, or a stereoisomer thereof: -CH3, , ^ ,v, b. or -H.

[0276] In some embodiments, X2 is C(R11)2. In some embodiments, each R11 is hydrogen.

[0277] In some embodiments, a compound of the present invention has the structure of Formula IVa15: o. / / Formula IVa15 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where Q1 is CH2, NR or O; Q2 is CO, NRN, or O; and Z is a 3- to 6-membered optionally substituted heterocycloalkylene or a 5- to 10-membered optionally substituted heteroarylene; or where Q1-Q2-Z is a 9- to 10-membered optionally substituted spirocyclic heterocycloalkylene.

[0278] In some embodiments, a compound of the present invention has the structure of Formula IVa16: Petition 870250111477, dated 04 / 12 / 2025, p. 200 / 545 193 / 499 Formula IVa16, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R14 is fluoro, hydrogen or C1-C3 alkyl; i is 0 or 1.

[0279] In some embodiments, R14 is fluoro and I is 1. In some embodiments, R14 is hydrogen and I is 0.

[0280] In some embodiments, a compound of the present invention has the structure of Formula IVa17: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0281] In some embodiments, a compound of the present invention has the structure of Formula IVa18: Petition 870250111477, dated 04 / 12 / 2025, p. 201 / 545 194 / 499 Formula IVa18 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0282] In one aspect, the disclosure presents a composite of Structural formula VIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; W is a crosslinking group comprising an aziridine, an Petition 870250111477, dated 04 / 12 / 2025, page 202 / 545 195 / 499 epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; and R2 is optionally substituted C1-C6 alkyl.

[0283] In one aspect, the invention provides a compound with the structure of Formula Va or Formula Vb: Formula Va, Formula Vb, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; Petition 870250111477, dated 04 / 12 / 2025, p. 203 / 545 196 / 499 R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0284] In some forms, the compound has the structure of Formula Va-1: Petition 870250111477, dated 04 / 12 / 2025, page 204 / 545 197 / 499 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0285] In some forms, the compound has the Va-2 formula structure: or a pharmaceutically acceptable salt thereof, wherein A is Petition 870250111477, dated 04 / 12 / 2025, page 205 / 545 198 / 499 optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, 3- to 10-membered heterocycloalkyl or optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl.

[0286] In some embodiments, a compound of the present invention has the structure of Formula V-Ia: Formula V-Ia or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0287] In some embodiments, a compound of the present invention has the structure of Formula V-II-1: Formula V-II-1 Petition 870250111477, dated 04 / 12 / 2025, p. 206 / 545 199 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof.

[0288] In some embodiments, a compound of the present invention has the structure of Formula V-II-2: O. / / Formula V-II-2, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein R6, R7 and R8 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; or R6e and R7se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R6e and R8se combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl group or an optionally substituted 3- to 8-membered heterocycloalkyl group.

[0289] In some embodiments, a compound of the present invention has the structure of Formula V-II-3: Petition 870250111477, dated 04 / 12 / 2025, p. 207 / 545 200 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.

[0290] In some embodiments, a compound of the present invention has the structure of Formula V-II-4: Formula V-II-4, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein X2 is CH2 or O; and o is 1 or 2.

[0291] In some embodiments, the compound has the structure of Petition 870250111477, dated 04 / 12 / 2025, p. 208 / 545 201 / 499 Formula VIa or Formula VIb; Formula VIa, Formula VIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; W is a crosslinking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Petition 870250111477, dated 04 / 12 / 2025, p. 209 / 545 202 / 499 each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0292] In some embodiments, the compound has the structure of Formula VIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; Petition 870250111477, dated 04 / 12 / 2025, page 210 / 545 203 / 499 W is a crosslinking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0293] In some embodiments, the compound has the structure of Formula VIa-2: Petition 870250111477, dated 04 / 12 / 2025, page 211 / 545 204 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; W is a crosslinking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; and R2 is optionally substituted C1-C6 alkyl.

[0294] In some embodiments of a compound of the present invention, X2 is CH2. In some embodiments, it is 1. In some embodiments, it is 2.

[0295] In some embodiments of a compound of the present invention, X6 is O. In some embodiments, it is 1. In some embodiments, it is 2.

[0296] In some embodiments of a compound of the present invention, R2e: or .

[0297] In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C6 alkyl. In some Petition 870250111477, dated 04 / 12 / 2025, p. 212 / 545 205 / 499 modalities, R3é:

[0298] In some embodiments of a compound of the present invention, R3 is optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3 is:

[0299] In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is: or

[0300] In some embodiments of a compound of the present invention, A is optionally substituted phenyl. In In some modalities, A is:

[0301] In some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some modes, A is selected from among the following, or one Its stereoisomer:

[0302] In some embodiments of a compound of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X1 is CH2. In some embodiments, X6 is O. In some embodiments, m is 1, n is 1 and X6 is CH2. In some embodiments, m is 1, n is 1 and X6 is O.

[0303] In some embodiments of a compound of the present invention, m is 2. In some embodiments, X6 is CH2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2, X6 is CH2 and n is 1. In some embodiments, m is 2 and X6 is 0. In some embodiments, m is 2, X6 is Petition 870250111477, dated 04 / 12 / 2025, p. 213 / 545 206 / 499 The value of en is 1. In some modalities, m is 2, X6 is 0.

[0304] In some embodiments of a compound of the present invention, W comprises an aziridine. In some embodiments, W comprises an optionally substituted cyclopropyl-aziridinyl moiety. In some embodiments, W is selected from the following, or a stereoisomer thereof: or

[0305] In some embodiments of a compound of the present invention, W comprises an epoxide. In some embodiments, W is selected from the following, or a stereoisomer thereof: or

[0306] In one aspect, the invention provides a compound having the structure of Formula VIIa or Formula VIIb: Formula VIIa Formula VIIb Petition 870250111477, dated 04 / 12 / 2025, p. 214 / 545 207 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; X6, X7 and X8 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form a C3-C8 Petition 870250111477, dated 04 / 12 / 2025, p. 215 / 545 208 / 499 optionally substituted cycloalkyl or a 3- to 8-membered heterocyclyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2, or 3.

[0307] In some forms, the compound has the structure of Formula VIIa-1: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; X6, X7 and X8 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or heterocycloalkyl of 3 to 10 Petition 870250111477, dated 04 / 12 / 2025, page 216 / 545 209 / 499 members optionally replaced; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2, or 3.

[0308] In some embodiments, the disclosure presents a compound with structural formula VIIa-2: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; X6, X7, and X8 are each independently selected from among Petition 870250111477, dated 04 / 12 / 2025, p. 217 / 545 210 / 499 CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0309] In some embodiments, a compound of the present invention has the structure of Formula VI-Ia, Formula VI-Ib, Formula VI-Ic: Oχ / / Formula VI Yes, Petition 870250111477, dated 04 / 12 / 2025, p. 218 / 545 211 / 499 Formula VI-Ib, Formula VI-Ic, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.

[0310] In some embodiments, a compound of the present invention has the structure of Formula VI-II: or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is C1-C6 optionally substituted alkyl, 3 to 6 cycloalkyl Petition 870250111477, dated 04 / 12 / 2025, p. 219 / 545 212 / 499 members optionally substituted or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0311] In some embodiments, a compound of the present invention has the structure of Formula VI-V: ox / / Formula VI-V or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0312] In some embodiments, a compound of the present invention has the structure of Formula VI-VI: Petition 870250111477, dated 04 / 12 / 2025, page 220 / 545 213 / 499 Formula VI-VI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0313] In some embodiments, a compound of the present invention has the structure of Formula VI-VII: Petition 870250111477, dated 04 / 12 / 2025, page 221 / 545 214 / 499 or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0314] In some embodiments, a compound of the present Va, the invention has the structure of Formula VI-Va, Formula VI-Vb, Formula VI-Vc: Formula VI Formula VIPetition 870250111477, dated 04 / 12 / 2025, page 222 / 545 215 / 499 Vb, Formula VI-Vc, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.

[0315] In some embodiments, a compound of the present invention has the structure of Formula VI-Vd, Formula VI-Ve, Formula VI-Vf: Petition 870250111477, dated 04 / 12 / 2025, page 223 / 545 216 / 499 Formula VI-Vf, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.

[0316] In one aspect, the invention provides a compound having the structure of Formula XI: Formula XI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, or optionally substituted C2-C4 alkenylene; Petition 870250111477, dated 04 / 12 / 2025, page 224 / 545 217 / 499 W is optionally substituted heterocycloalkyl with 3 to 10 members or optionally substituted cycloalkyl with 3 to 10 members; X4e CH2 or NH; R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or 5-membered heteroaryl the 10 optionally substituted members; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R3 is hydrogen; or R2e R3se combine with the atoms to which they are attached to form an optionally substituted 8- to 14-membered heterocycloalkyl; Each of R4, R5, R6, and R7 is hydrogen; or R4 and R6 are hydrogen and R5 and R7 combine with the atoms to which they are attached to form an optionally substituted four-membered cycloalkyl group; or R5 and R7 are hydrogen and R4 and R6 combine with the atoms to which they are attached to form an optionally substituted four-membered cycloalkyl group; R10 is -OR11 or -NR12R13; R11, R12 and R13 are each independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12 and R13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 225 / 545 218 / 499 each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; and is 0, 1, 2 or 3.

[0317] In some embodiments, A is optionally substituted thiazol-diyl, optionally substituted oxazol-diyl, optionally substituted morpholino-diyl, optionally substituted pyrrolidinyl-diyl, optionally substituted piperidinyl-diyl, or optionally substituted phenyl. In some embodiments, A is optionally substituted thiazol-diyl or optionally substituted morpholino-diyl. In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is: or In some modalities, A is

[0318] In some embodiments of a compound of the present invention, A is optionally substituted phenylene. In some embodiments, A F or F. In some modalities, A is

[0319] In some embodiments of a compound of the present invention, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is an optionally substituted 6-membered heterocycloalkylene. In some embodiments, A is selected from among Petition 870250111477, dated 04 / 12 / 2025, p. 226 / 545 219 / 499 below, or a stereoisomer thereof: In some embodiments, A is selected from among the following, or a stereoisomer thereof:

[0320] In some embodiments of a compound of the present invention, R1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments of a compound of the present invention, R1 is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments of a compound of the present invention, R1 is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments of a compound of the present invention, R1 is:

[0321] In some embodiments of a compound of the present d or where each D indicates a hydrogen atom having an isotopic enrichment factor for deuterium of at least 5.

[0322] In some embodiments of a compound of the present invention, R2 is:

[0323] In some embodiments of a compound of the present Petition 870250111477, dated 04 / 12 / 2025, p. 227 / 545 220 / 499 invention, R2é: D d DD d or , where each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.

[0324] In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments of a compound of the present invention, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is: or FF. In some modalities, R3 is: çd3 In some modalities, R3 is: , where each D indicates a hydrogen atom having an isotopic enrichment factor for deuterium of at least 5.

[0325] In some embodiments of a compound of the present invention, R3 is optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3 is: or . In some modalities, R3 is:

[0326] In some embodiments of a compound of the present invention, R2 is or CF3; R3 is or or

[0327] In some modes, R2 is or CF3; R3 is or or ns Petition 870250111477, dated 04 / 12 / 2025, p. 228 / 545 221 / 499

[0328] In some embodiments of a compound of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X1 is CH2. In some embodiments, X2 is CH2. In some embodiments, X3 is CH2. In some embodiments, m is 1, n is 1 and each of X1, X2 and X3 is CH2.

[0329] In one aspect, the invention provides a compound having the structure of Formula Ic: Formula Ic or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer or a tautomer thereof, where: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is attached to X, and a second ring in Q is attached to A; X is a connection; a linear chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)O-2; *-CH2-O-; *-CH2-S(O)O-2-; *-O-CH2-; or *-CH2-S(O)O-2-, where “*” represents a portion of X attached to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl )-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene. Petition 870250111477, dated 04 / 12 / 2025, page 229 / 545 222 / 499 optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; T is a second ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl or optionally substituted C1-C3 heteroalkyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8 is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 combine to form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 is a ring atom in Q, the carbon atom to which R7 is attached, and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3; Each R5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; Petition 870250111477, dated 04 / 12 / 2025, p. 230 / 545 223 / 499 X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6, join with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0330] In some embodiments of any of the compounds described in this document, T has the structure of Formula XV: Formula XV

[0331] In some Formula XV categories, z is 0.

[0332] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVa: Formula XV

[0333] In some forms, T has the structure of

[0334] In some forms, with formula XV, z is 1.

[0335] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVb: Petition 870250111477, dated 04 / 12 / 2025, p. 231 / 545 224 / 499 Formula XVb

[0336] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVc: Formula XVc

[0337] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVd: Formula XVd

[0338] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVe: Formula XV

[0339] In some Formula XV categories, z is 2.

[0340] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVf: Petition 870250111477, dated 04 / 12 / 2025, p. 232 / 545 225 / 499 Formula XVf

[0341] In some embodiments, where RL1 is hydrogen. In some embodiments, RL1 is optionally substituted C1-C6 alkyl. In some embodiments, RL1 is methyl, ethyl, or trifluoromethyl. In some embodiments, RL1 is optionally substituted C1-C6 heteroalkyl. In some embodiments, RL1 is methoxy or ethoxy. In some embodiments, RL1 is optionally substituted C2-C6 alkynyl. In some embodiments, RL1 is ethynyl.

[0342] In some embodiments, RL2 is hydrogen. In some embodiments, RL2 is halogen. In some embodiments, RL2 is fluorine.

[0343] In some embodiments, RL3 is hydrogen. In some embodiments, RL3 is optionally substituted C1-C6 alkyl. In some embodiments, RL3 is methyl.

[0344] In some embodiments, RL4 is hydrogen.

[0345] In some embodiments, RL1 and RL4 combine to form an optionally substituted C4 cycloalkyl.

[0346] In some embodiments, RL1 and RL3 combine to form an optionally substituted C4 cycloalkyl. In some embodiments, RL1 and RL3 combine to form an optionally substituted C5 cycloalkyl.

[0347] In some embodiments, two RL1s combine to form an optionally substituted C3-C6 cycloalkyl.

[0348] In some embodiments, RL1 and RL2 combine to form an optionally substituted C3-C6 cycloalkyl.

[0349] In some modalities, T is: Petition 870250111477, dated 04 / 12 / 2025, p. 233 / 545 226 / 499

[0350] In some modalities, T is:

[0351] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVI: rL5rls Formula XVI Petition 870250111477, dated 04 / 12 / 2025, p. 234 / 545 227 / 499

[0352] In some modes, X9 is -NRL6-.

[0353] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVIa: Formula XVIa

[0354] In some embodiments of any of the compounds described in this document, T has the structure of Formula XVIb: Formula XVIb

[0355] In some embodiments, RL6 is optionally substituted C1-C6 alkyl. In some embodiments, RL6 is methyl.

[0356] In some forms, X9 is -C(O)-. In some forms, X9 is -S(O)2-.

[0357] In some embodiments, RL5 is hydrogen. In some embodiments, RL5 is optionally substituted C1-C6 alkyl. In some embodiments, RL5 is optionally substituted C3-C8 cycloalkyl. In some embodiments, two RL5ses combine to form an optionally substituted C3-C8 cycloalkyl.

[0358] In some embodiments of any of the compounds described in this document, T is: Petition 870250111477, dated 04 / 12 / 2025, pp. 235 / 545 228 / 499 or

[0359] In some embodiments of any of the compounds described in this document, T is:

[0360] In some embodiments of any of the compounds described in this document, T does not have the structure of:

[0361] In some modalities, L has the structure of Formula XIII: A1-(Z1)f-(C1)g-(Z2)h-(D1)-(Z3)-(C2)b(Z4)k-A2 Formula XIII where A1 is a link between the ligand and the rest of the macrocycle; A2 is a linkage between A and the ligand; Z1, Z2, Z3 and Z4 are each independently optionally substituted C1-C3 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C1-C2 alkenylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 3- to 8-membered cycloalkylene, O, NRN or a crosslinking group comprising a vinyl ketone, an inone, a vinyl sulfone, Petition 870250111477, dated 04 / 12 / 2025, p. 236 / 545 229 / 499 an alkynyl sulfone, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an epoxide, an oxazolium or a glycal; RN is hydrogen, optionally substituted C1-C4 alkyl or optionally substituted 6-membered arylene; C1 and C2 are each independently carbonyl or O; f, g, h, i, j, k are each independently O or I;and D1 is optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 3- to 8-membered cycloalkylene or optionally substituted C1-C3 heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene or a chemical bond linking A1-(Z1)f-(C1)g-(Z2)h- to -(Z3)i-(C2)j-(Z4)k-A2.;

[0362] In some Formula XIII binder modalities, f is 0. In some modalities, f is 1. In some modalities, g is 0. In some modalities, g is 1. In some modalities, h is 0. In some modalities, h is 1. In some modalities, i is 0. In some modalities, j is 1. In some modalities, k is 0. In some modalities, k is 1.

[0363] In some embodiments of Formula XIII ligands, Z1 is NRN. In some embodiments, RN is optionally substituted C1-C4 alkyl. In some embodiments, RN is methyl.

[0364] In some Formula XIII ligand embodiments, C1 is carbonyl.

[0365] In some embodiments of Formula XIII ligands, D1 is a 3- to 8-membered cycloalkylene. In some embodiments, D1 is optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, C2-C6 Petition 870250111477, dated 04 / 12 / 2025, p. 237 / 545 230 / 499 optionally substituted alkynylene or optionally substituted C1-C3 heteroalkylene. In some embodiments, D1 is optionally substituted 3- to 8-membered heterocycloalkylene.

[0366] In some embodiments of Formula XIII ligands, Z4 is O. In some embodiments, Z4 is optionally substituted C1-C3 alkylene. In some embodiments, Z3 is optionally substituted C1-C3 alkylene.

[0367] In some forms, L has the structure of Formula VIII: Aχ5^Z^ Formula VIII where X5 is O or CH2 and is attached to ring A; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene.

[0368] In some Formula VIII binder types, X5 is O.

[0369] In some embodiments of Formula VIII ligands, Z is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, Z is optionally substituted 5-membered heterocycloalkylene. In some embodiments, Z is optionally substituted pyrolidine-diyl.

[0370] In some modalities, L has the structure of Formula VIIIa: R30 R31R30 Formula VIIIa where X9 is NR, O or CH2 and is attached to ring A; X10 is CH or N; X11 is NR'', O, C(O), C(O)N(R''')2 or CH2; Petition 870250111477, dated 04 / 12 / 2025, page 238 / 545 231 / 499 R'' is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R''', C(O)OR''', C(O)N(R''')2, S(O)R''', S(O)2R''' or S(O)2N(R''')2; each R''' is independently hydrogen, optionally substituted C1-C4 alkyl or optionally substituted 3- to 6-membered heterocycloalkylene; R30 and R32 are, independently, hydrogen, optionally substituted C6-C10 aryl, or optionally substituted C1-C6 alkylene; R31 is hydrogen, optionally substituted C6-C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene; eqer are independently 0, 1, 2, or 3.

[0371] In some modalities, L has the structure of Formula VIIIb: Z x11A Αχ9^Χ^ R31Formula VIIIb

[0372] In some classes, L has the structure of Formula VIIIc: H ^31 Formula VIIIc

[0373] In some modalities, L has the structure of Formula VIIId: R31 Formula VIIId Petition 870250111477, dated 04 / 12 / 2025, p. 239 / 545 232 / 499

[0374] In some modalities, L has the structure of Formula VIIIe: R31 Formula VIIIe

[0375] In some modalities, L has the structure of Formula VIIIf: Formula VIIIf

[0376] In some modalities, L has the structure of Formula VIIIg: or R31 Formula VIIIg

[0377] In some Formula VIIIa binder types, the The linker is:

[0378] In some forms, the ligand has the following structure: where R37 is hydrogen or C1-C4 substituted alkyl; R38 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7-membered heterocycloalkyl, C1-C6 heteroalkyl Petition 870250111477, dated 04 / 12 / 2025, pp. 240 / 545 233 / 499 optionally substituted, 3- to 6-membered cycloalkyl optionally substituted or 8- to 11-membered spirocyclic heterocycloalkylene optionally substituted; eq is 0, 1, 2 or 3.

[0379] In some forms, the ligand has the following structure: / ^o J> VrR”xo where R38 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 8- to 11-membered spirocyclic heterocycloalkylene; eyee are independently 1, 2 or 3.

[0380] In some forms, the binder has the structure of Formula XII: r36, Formula XII in which the left-hand O atom is bonded to ring A; R35 is NR36C(O)CH2N(R36)2 or optionally substituted 3- to 6-membered heterocycloalkylene; and each R36 is optionally substituted C1-C4 alkyl.

[0381] In some forms, the ligand has the structure of Formula XIV: Formula XIV Petition 870250111477, dated 04 / 12 / 2025, p. 241 / 545 234 / 499 in which X is O and is connected to ring A; Each X13 is independently either O or NR34; and each R34 is independently either hydrogen or optionally substituted C1-C6 alkyl.

[0382] In some classes, L has the structure of Formula IX: Formula IX in which B is an optionally substituted 3- to 6-membered heterocycloalkylene. R22 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, C6-C10 aryl, OO H-^H-^μ26μ27 R23, O, * or the optionally replaced; R23 and R24 are each independently hydrogen or optionally substituted C1-C6 alkyl; R25 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocyclyl; R26 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and Petition 870250111477, dated 04 / 12 / 2025, page 242 / 545 235 / 499 R27 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0383] In some forms, the Formula IX binder has the structure of Formula X: Formula X

[0384] In some Formula IX or X binder forms, j / 27 R22 is a . In some embodiments, R27 is optionally substituted C1-C6 alkyl. In some embodiments, R27 is optionally substituted C2-C6 alkenyl. In some embodiments, R27 is optionally substituted C2-C6 alkynyl. In some embodiments, R27 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R27 is optionally substituted C2-C6 heteroalkenyl. In some embodiments, R27 is optionally substituted C2-C6 heteroalkynyl. In some embodiments, R27 is optionally substituted C3-C10 cycloalkenyl. In some embodiments, R27 is hydrogen. In some embodiments, R27 is optionally substituted C3-C10 cycloalkyl. In some embodiments, R27 is optionally substituted 3- to 10-membered heterocyclyl.

[0385] In some Formula IX or X binder types, Petition 870250111477, dated 04 / 12 / 2025, p. 243 / 545 236 / 499 d26 p R22 is I. In some embodiments, R26 is a 5- to 10-membered heteroaryl group optionally replaced. In some embodiments, R26 is a 3- to 10-membered heterocyclic group optionally replaced.

[0386] In some embodiments of Formula IX or X linkers, R22 is an optionally substituted 3- to 6-membered heterocycle.

[0387] In some embodiments of compounds of Formula I, Formula II, Formula III, Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula V or Formula VI, A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is optionally substituted 6-membered arylene. In some embodiments, A is: or

[0388] In some modalities, A is:

[0389] In any embodiment in this document, a compound of the present invention may be modified with a substituent as found in any one or more of the following applications, incorporated herein by reference in their entirety: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO 2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO 2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684.

[0390] In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or Petition 870250111477, dated 04 / 12 / 2025, pp. 244 / 545 237 / 499 stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Certain Compounds of the Present Invention And N° Structure A1 0. A ,A y0 „ VQ ·' 2 xx £1A N—' £ A2 °vOv o. <í A8 °γΌγ° 0 / / WN ArA at / λ ο ς <r A9 °γθγ° o , ·' I ΑΆ χξ ΠΠ 0 )= / \J c ; r Petition 870250111477, dated 04 / 12 / 2025, p. 245 / 545 238 / 499 Ex N° Structure A10 0x ^0 'VN V1 0 I ·' ÍK jp o ^4 fy / TY Η V )= / f Ο ς N—' / A11 N 0 I ·' azV )= / N·^'^ O 5 7 A12 Μ^ X_ Zo° 1ΖZCZ „LJ<.iO P 7·Μ·_ \=' N-^Sjf^ O / A14 “γΟγ0 0 . zj ηΛαΧ ° V- 1 H L. Ο ς A15 2%^ ~y~ f Xi ί^ζθ o ; / A16 573⁄4 (CnrV7 Ύ1 O ; Ό 4 Petition 870250111477, dated 04 / 12 / 2025, p. 246 / 545 239 / 499 Ex Structure N° A17 -o LJHJ ppo 0 ς <í A18 °γ·0·γ° o , 1 JAX CA Ak o 0 0 / A19 - 00 li 0 0 ς / A20 J-yO \ O ZI ZI O '-- χ 1 x 7—JJH 0 / A22 O ZI zx caCL o *—)--( k 1 ''οΑγΑ» Petition 870250111477, dated 04 / 12 / 2025, p. 247 / 545 240 / 499 Ex N° Estrutura A23 τ} ί --s ° Ο ' ΙΖ ΙΖ ο 1 ^=ο U ° r A24 •VCC“ ο CMu'V.....UQ - Ν—7 / A25 ιΡγ? X ° Ο -Τ ζτ . fA ο *—V )—ί ''ο-^γΑτ - yQ A26 Τι I 1Lο vÁzví^ τζ jr χζ ο Jr CðZLc'Γ ν>'(λ A27 0-. ,sL. ,tL^OV Vs 0 ί J Χ\λ -ο L- 1 ΗχΝ^0 Ο Ν—' <ί A28 ΙΞ ΙΖ Ο —ΓΥ-ς χ° Petition 870250111477, de 04 / 12 / 2025, pág. 248 / 545 241 / 499 Ex N° Estrutura A29 ''ί— / o iz xz o \= / vo A30 0. A -0 VN γ 0 ί . 2 w [A fjl / w li '\ h _jy >=rn —v V c> N— / A31 „N. >0 YY Y o < / rsV o ' Φ Cl A32 ογΌγ° 0 , JH AaA -v A ΛΗ-γ Π AN—' 4 _ A33 °γθγ° 0 / 2 w AAa ο ς N— <í A34 Άγ 0 . Y hAaA Λ<Λ z / 1 ^=< Ν 'Ύ^ f \ Petition 870250111477, de 04 / 12 / 2025, pág. 249 / 545 242 / 499 Ex N° Estrutura A35 Ex Js. yN. .0 VN f 0 1 ° X XX Zr N—7 / A36 oAi X / C ó c Xp π J o ; X affijTiEtl A37 γθγ 0 J HI â x < / ,Y X / / \ / Ύ Y N \ / X II J H N ( O N—' 0 / A38 °yOy° o . °' Í XX Jxíxxjl X 3 < / A39 O'x ss'L XX .0 V X O i 2 xXk X Λ / / ^hXXi Y H Q A40 yQy 0 x XX \ Υξ íl N 0 >=* nY: G as N—* <f Petition 870250111477, de 04 / 12 / 2025, pág. 250 / 545 243 / 499 Ex N° Estrutura A41 o zi zi A°\ v^xZ / 1 ο X—?—í i Ύ ''ο-'Χ-ργί \ A42 Ύ η Ύ i °' d ΓΤ \ / —x JJH 1Γ A43 «γΓγ» o . ·' a zaV \=# O ó A44 WQ ·' J ZaAÊ ,ΤηιγΟί.Α' y=MAj 1 M ο ς < / A45 W* N N? 0 I 2 L W .à 0 JJ, ^-ΐ O Ç 7 A46 0^^kb,.N. ,0 „ W o I / 2 w V-r <7 r π o Nç[ JÊ^S;<XiJLN<--i Λλ ο ς <ϊ Petition 870250111477, de 04 / 12 / 2025, pág. 251 / 545 244 / 499 And N° Structure A47 Οχ yN. χθ VN f 0 1 • 2 xY OV iron 0 A48 'γΟγ o . JHI Ã.1 < X Aκ V XX ox ChxDaj / ) ^F3 4 A49 XX» o ' £ X'X υΧι·,' / OAN—fh F 0 A50 Ox ,,ίχ „N. xO VNY 0 A 1 HI x5 a XA1 O 1 A H □ 2 2 A xzAA”0 c> N—7 / A52 CY x xO 2 “AY / pl Xi A3 “ZXNz \ Ya 11 H Petition 870250111477, dated 04 / 12 / 2025, p. 252 / 545 245 / 499 Ex No. Structure A53 CL·  ^NX.OVN f 0 I , ? xsV \=* / —NP° A54 Ύ'Ρζι x Λ.Χ %V / — ι \ Γ fl To <i a55 cl· v n 0 ι 2 xyawx>= / / —N -JO^r N —' / A56 / oo ~i ~i Kt OO '—>=< A57 ss.L .0 VN >=* 0 I ·' Í X8V XXc / X^ of / A58 Ofe^'k V' N 0 i ·' XX"V \=* NX Ω 0 / Petition 870250111477, de 04 / 12 / 2025, pág. 253 / 545 246 / 499 Ex N° Estrutura A59 > ηΛΛΧ A / 7 A Η yMll η 02 K p yx A60 νθγ° ο 2 ηΧα,Λ - ν ,L - Λ Η Χ° >— 1 \ f Π Το 0 2 A61 Αν ν ΛΗ V AcAxv ο ς <Γ A62 VX Η Χο Q ς 7 A63 Γι cxP w CM / A64 Υ S Υ S 1 / 2 Αν XX ° / 1 Η 1 Υ— <\ κ ι1 0 (Axj- / Ο X Petition 870250111477, de 04 / 12 / 2025, pág. 254 / 545 247 / 499 Ex N° Estrutura A65 Cd e-.LA .0 VNV ò I 1 HIA1 ° X AK l \=* νΑΠ CQ / A66 7¾¼ --0\ AV <í A67 O ZT z— Q o '_\=Z ' XA A68 CU .X „N. ,0 VNA 0 I • 2 rA P / pCA s )=S hj^Aí^ N— A69 %Á^Y°o I - / xXó rV и^Ι j pí': A<!-- A70 °yO^° n , I »li Λ -0 L 1 HOAW A 4' A71 '^TAT । y=Z^ —u © oX O zz O AZ -->—ZO! T Petition 870250111477, de 04 / 12 / 2025, pág. 255 / 545 248 / 499 Ex Structural No. A72 or TH Γ II a A Ά / lAA-çA,' Q ; 4 A73 .0 V tE V o I . 2 Γ·Ν —or L^· ΑΝ-?0 / / y= / or ; A75 -4 % o | or zt o \ HX z=\ A°,l VA1 o >—)—( A76 γθγ 0 . ' £ AC o <í A77 I Ill ° A AH Ά° íALAy^A^An·' )= / 0 / γ\ P <3 A78 J> ° z— { EPAA '= o Z-= 1 A79 -0 L· A h Ay> 7 ~~C~^o •'"'szk N QaXJ opL O ; NJ 4 Petition 870250111477, dated 04 / 12 / 2025, p. 256 / 545 249 / 499 And N° Structure A80 Q. .. L .fl -o VN 0 —o .L·' U x N-7 A A81 yCy o ° L í HL \ yr ii jh λ=* NO ç / A82 °VOv° 0 1 / AZ!V \=* G ; N—' <ϊ A83 Ύν, Xu Τι \U~vT^ / \U° -r A84 23⁄41⁄4 cX ' <r A85 °yCu 0 . z uU —o L xL H a O <f A86 »yQy» „ J AaT -o L- 1 H ΐΑΤγ’γΤΖ-'χΤ,··- ΓΓ'^ U O Petition 870250111477, dated 04 / 12 / 2025, p. 257 / 545 250 / 499 Ex N° Structure A87 h T 8 i - / Λ8 V o - IN—* / A88 r Ύ°''· o zz' o / 'po A89 °γθγ o / 2 w <<ΎΖΥΎ - ck N —' <f A90 V rT V* o I H [ II < r M PP ίΊΐ f \=* Ν'' O ; N — <ϊ A91 ίΓ^Ξ τΎθ' tPU-c ÇyvO Ο 3ZZ O 1 / ^Q A92 »γθγ’ o . ·' i X!V (ίπΎθ'0-7 \=^ N'P^:- N—2 <f Petition 870250111477, dated 04 / 12 / 2025, p. 258 / 545 251 / 499 And N° Structure A93 YY1}= / \ oo ZCZ O wos A94 0^''^N^N'xií0 0 I x&p O ; N—' X A95 0. L .0 Y n V o . J Xu Ο ς °^Β N~' <í A96 VN f 0 I - / zA Αχ / 0 A97 Y ιΓ Τ . çypp xz xz O 1 ° 'r~ A98 n 0x ssA ,0 y xN'' y 0 ·- í V' ) p £1 \=< (Ά-ν \ Petition 870250111477, dated 04 / 12 / 2025, p. 259 / 545 252 / 499 And N° Structure A99 €Q / f \--1 --s O z \ \ QvP ΖΕΣΣ IZ O 'O __ A100 -7th I o zx o 7th IO o \—L·'' ''o'TpjA. A101 Á -0 VNS* 0 1 J ηΧαΛ -°.<v AH Ύ 7 A102 γθγ% > hAaA A- X XH -Ύ <í A103 7 T'" .o --xo Çk”P xZ xZ O w° ο Γ A104 ΧΧγ°χ XZ IZ o ô ° X Petition 870250111477, dated 04 / 12 / 2025, p. 260 / 545 253 / 499 Ex N° Estrutura A105 Ο ΞΙ zl . Λα ο / \ CX A106 0.  „N. ,0 VNV 0 I 2 XV o'' N— / A107 CL· X „hk .0 VN Vs 0 I 7 / W rf ( Ο N— / A108 Ο*. Á .0 VNT 0 1 °' 2 XV \ / AJH / CÇ ( Q / A109 τΧ'0'' XmüXa \ W ° Λλ CXXy χζ ιζ ο ο μ A110 1 „Ν,.Ο % ν r ο I °' Λ Γ·Υ ΛΧύΧα Q - ' Ν—7 / Petition 870250111477, de 04 / 12 / 2025, pág. 261 / 545 254 / 499 Ex N° Estrutura A111 • 2 XsV A >=* AxX O ; / A112 —{° ο=σ l O ZX ZX XÁ τ T ° ''o'y) A113 CK S.,.L^ „hL .0 VN f 0 I °' i X!V )=* C 0< N—7 / A114 0-. ,-LN ,0 VNX 0 IJH АхЛ -0 L í HJ, 0 ^| / и N7^0 O s 4 A115 o xnv O ZX o —Z '-- s=z A116 τΎ0'' \= / —\ o O °4 OryVp IZ iZ O ° A Petition 870250111477, de 04 / 12 / 2025, pág. 262 / 545 255 / 499 Ex N° Structure A117 yo J1 χΖ IZ O / ° A A118 O<1 -X o O ' (Λ- / Ο o ZZZ o νΦ· o A119 ΑΦ= o = = o >-o \ oo X—V- >=f ιζΧ* A120 V-hU 0. ζ·Φ \=* Ν'ΦΦ c ; N—' / A121 O^k As. / Petition 870250111477, dated 04 / 12 / 2025, p. 263 / 545 256 / 499 And No. Structure A123 C< X .0 VN f* 0 I p 2 XX <J V N—* F F / A124 Cu X X .-0 -°, X X H 0 XXM Ο Ά A C·7 FZ A125 tkl ,N. ,0 Ύ fl Ύ í I / r° ΛΛ·'^ 0 l- l H ,lk.5O nXíXXXXC <XX(J u / =* ,N H o N—' / A126 Xx., O I >x>P xZ IZ O IX ° Γ A127 0. XVN f 0 1 H Á AA oz í jXnX XX O ^XXfXA o ; N—' / A128 ΧΑγ°-χ y^-ZJ X>—-k XX X—\ ° M_v °X O-XX O XZ o \ Vo o f- Petition 870250111477, dated 04 / 12 / 2025, p. 264 / 545 257 / 499 Ex N° Estrutura A129 A xn. -o Ύ íl Ύ 3 I / Ar AAA / / >=* nA / n 4 o N— / A130 CL·  „hk .0 ύ ti r B . 0. r uò v AA ri / / AAUy^0^ >=* AA OXN—7 FF / A131 Ay ° i AA Aí / A 0 k A132 o. ,.sL -.nt N 0 7° HA Λ CÁ A k _AP £1 / / ΑΑτγ^Α \=ZN Ο ς / A133 °=< (1 o zx zx CA. L· O o 7—\ ^ο'Χ-γ'Ν Ca A134 A .0 VN 'T 0 I} AaA -o £ Á H .LAA Ο Λ7 / / yA'A ''° \=* νΆΑ N / Petition 870250111477, de 04 / 12 / 2025, pág. 265 / 545 258 / 499 Ex N° Estrutura A135 iz xz o A136 ,NX_ .0 VN 0 I - 8 Z! Y )=* 8 k A137 i Ik o ^=? \ O yYlZR' o tz o ° F~ A138 _γ v / y -Ύ\ O ZI j 0^0 O )---( TXJ A139 >0 - 8 Yv YxA^· c ; A140 .X „Y YN f 0 IJ AaA ~° Jr JL H 1 A / / \=* O s / Petition 870250111477, de 04 / 12 / 2025, pág. 266 / 545 259 / 499 Ex N° Estrutura A141 γΟγ ο , - X ΖΑ Q-cCr^0}=* N Ο ς d A142 X ,Ν. .0 7 ! Υ , ΑΡ A143 Οχ Ρ χΝ. -0 γ Ν f 0 IJ ηΛ\^ -ο X Ζ Η L >= / 'ο ο ς Ν—'ζ / A144 Οχ A xsO Υ Ν f Ο 1 ζ ηΛΑλ -ο XX Η L _ΑΡ £1 y=r N-^ss^ 'Ο ο ς / A145 Οχ 4χ χΝχ .0 γ- Ν f 0 1 , a - ζγ χ , / ξ [|!ν '° cf ν Ν—' / A146 Οχ Ρ χΝ^^Ο γ· Ν Υ 0 I ζ ηΛαλ -ο XX Η L _ΑΡ £1 / / ^pZyyXXo -¾ nAí? Ο k Ν—' / / Petition 870250111477, de 04 / 12 / 2025, pág. 267 / 545 260 / 499 Ex N° Estrutura A148 Οχ Jx .0 0 η Υ S i 0 H ,.N, ,0 N—' / A149 CA ,-L -0 VNV* 0 I °' x "X!Y ΧΡχχθ'Α cT' N— / A150 Çn ç zz 0 > \ Xo '*r~ A151 O Ox < L >0 '-'N' 0 . i XaA κί H ''''τ'2 (JO J uv= / nA^ n-· A152 Οχ <(Ιχ „fcL VN 0 I c) / A153 sX >0^0 N V5 0 IJ ZaX -0 γί H -Nv° y · Az CMAJ HV Petition 870250111477, de 04 / 12 / 2025, pág. 268 / 545 261 / 499 Ex N° Estrutura A154 o CA ,A .N ..0 Al V* 0 I c ηAlA —0 íç' H ,.N. cAljA; ( r° A155 n Ca AN v 0 I γ hAaA ° á ΛH w- / / / / A'Y| η 0 O \= / nYX A A156 A Α. °A^'<HX O ZI ) cAA Y'\ V \ A O '--iç J---{ Aj A157 ϊ A°'· \—f Aca ° O ' ^.O XZ 0 A> A158 r A0· \—f Aua. ° O ' xz o ιηΓμ. ~'r~ A. o ' A159 ί. ,.íA. s>^ —\ y=\ a—x ° O 1 R>P xz xz o ? A° Petition 870250111477, de 04 / 12 / 2025, pág. 269 / 545 262 / 499 Ex N° Estrutura A160 CkÁ XX X) N 0 ι TH II v / / Y xf fl / ° N -í Κ.-Α-.Ζ'-'Χ, -—j / / IXYV A161 ρχ .}-- / \·--- OO ' °x O IZ ox° A162 o. P XX x ; b xv nP~ \= / κι-XX A163 o< sL ,n...x V' V 'ηΧ ο ι J -XaX —0 J. H / í ' Γ 11 Os aT / / yXfT a A164 X w X ο ΞΙ Z-* A°vV v3 --Xs^zX' A165 n CL· A Λ. >0 ' 2 νΛ >X ώ X / / Vo 8=f ΝΥχ l A166 Οχ. -,-k υΥχ-1 ;! хх —а Λ- 1 H o \ _ X \ XN \ / / Xy^X^ \=* nA / ^ < Petition 870250111477, de 04 / 12 / 2025, pág. 270 / 545 263 / 499 And N° Structure A167 YO LZT Co >-η, <θ O —Jç )—( '—A.JZ·'''''' A168 YO zx o Xo IOO X-Αγ Υ= / A169 -JpO -XO O ZX o >o zi—0 . f_A1 o \_ ,κ, ίζ θ ο )—í A171 o 0\uA -NxxjO , / ΛΜ 0 Xx χί. H Α'Ύ' N>c riNjjr < / y-fí Ύ 3^^ < A172 n XJxx^O A* TJ A* 0 1 i H AA-À "° Λ Λ H Y° n-í •vxx 7 Yrp ' 0 X) \ Χ,ΝίΝ N- / 'e N--^' H A173 o_____L j< V N 0 J 'o r AY 0 J— xL — ΐΑΥχΧγ.γ jAA Petition 870250111477, dated 04 / 12 / 2025, p. 271 / 545 264 / 499 And No. Structure A174 0 HA \=< 'jXZ A175 L ,N. ^0 λ ;a xv 0 χΧ / XH ΥΎ nV*GjCi=V OVuT^ A176 ου9ύ°1 I c / / AV nVíVVi a \=t yA ( A177 °yQy°° J χ0 / vx. 8V \=Ύ A Η Vxío nÃCxXaVX (ηΎΤ Α= / νΑ4 <. A179 η o< A VnY ο 1 J hAxA —o ^ Í- J< H yxv ,V.-'Y Αγ,χ-χW=i V / / v A* o IIH Ii A -o H ^N^>0 N >r\Xi0IJ < vn j 0 \=?' Petition 870250111477, dated 04 / 12 / 2025, p. 272 / 545 265 / 499 And No. Structure A181 ο ? ϊΧλ / íΛ L1 T A182 A183 A184 A185 A186 A187 Petition 870250111477, dated 04 / 12 / 2025, page 273 / 545 266 / 499 Example No. Structure A188 A189 A190 A191 A192 A193 A194 Petition 870250111477, dated 04 / 12 / 2025, page 274 / 545 267 / 499 Example No. Structure A195 A196 A197 A198 A199 A200 ^4^4. A201 Petition 870250111477, dated 04 / 12 / 2025, page 275 / 545 268 / 499 Ex No. Structure A202 A203 A204 A205 A206 A207 A208 Petition 870250111477, dated 04 / 12 / 2025, page 276 / 545 269 / 499 Ex No. Structure A209 A210 A211 A212 cZ jpA A213 A214 A215 Petition 870250111477, dated 04 / 12 / 2025, page 277 / 545 270 / 499 Ex No. Structure A216 A217 A218 A219 A220 A221 A222 Petition 870250111477, dated 04 / 12 / 2025, page 278 / 545 271 / 499 Ex No. Structure A223 A224 A225 A226 A227 A228 / FA- A229 Petition 870250111477, dated 04 / 12 / 2025, page 279 / 545 272 / 499 Ex No. Structure A230 A231 A232 A233 A234 A235 A236 Petition 870250111477, dated 04 / 12 / 2025, pages 280 / 545 273 / 499 Ex Structure No. A237 A238 A239 Av. A240 A241 A242 A243 Petition 870250111477, dated 04 / 12 / 2025, page 281 / 545 274 / 499 Ex No. Structure A244 A245 A246 A247 A248 A249 A250 Petition 870250111477, dated 04 / 12 / 2025, page 282 / 545 275 / 499 Ex No. Structure A251 A252 A253 A254 A255 A256 A257 Petition 870250111477, dated 04 / 12 / 2025, page 283 / 545 276 / 499 Ex No. Structure A258 A259 A260 A261 A262 A263 A264 Petition 870250111477, dated 04 / 12 / 2025, page 284 / 545 277 / 499 Ex Structure No. A265 A266 A267 A268 A269 A270 A271 #9 Petition 870250111477, dated 04 / 12 / 2025, pages 285 / 545 278 / 499 Ex No. Structure A272 2¾¼ A273 A274 A275 2¾¼ 4 Γ A276 A277 Alt y r_ JPA A278 «JÍL% . , 2 ΗΛν Petition 870250111477, dated 04 / 12 / 2025, p. 286 / 545 279 / 499 Ex No. Structure A279 Gku A280 An / u jpz'·' P Γ A281 A282 A283 At 4-i< nj» A284 A285 yr; TÍ'^· Petition 870250111477, dated 04 / 12 / 2025, p. 287 / 545 280 / 499 Ex No. Structure A286 A287 A288 A289 A290 A291

[0391] A pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is also provided. Petition 870250111477, dated 04 / 12 / 2025, pp. 288 / 545 281 / 499 acceptable.

[0392] A conjugate, or salt thereof, of a compound of the present invention is also provided, wherein the compound of the present invention has a covalent warhead attached to a monovalent organic moiety.

[0393] In some embodiments o...

Claims

1. COMPOUND characterized by being selected from Formula Ia, Formula Ib, Formula IIa, Formula IIb, Formula IIa-1, Formula IIIa, Formula IIIb, Formula IIIa-1, Formula IVa, Formula IVb, Formula Va, Formula Vb, Formula VIa, Formula VIb, Formula VIIa, Formula VIIb or Formula XI, or a pharmaceutically acceptable salt thereof, wherein Formula Ia has the structure of: ,RL3 rL3 Formula Ia wherein: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is linked to X and a second ring in Q is linked to A; X is a connection; C1-C3 linear chain alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)o-2-; *-CH2-O-; *-CH2-S(O)o2-; *-O-CH2-;or *-CH2-S(O)o-2-, wherein “*” represents a portion of X bonded to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl; R7 is optionally substituted hydrogen, halogen, or C1-C3;R8 is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 together form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 and a ring atom at Q, the carbon atom to which R7 is attached, and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3; each R5 is independently halogen, optionally C1-C3 alkyl or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2 or 3; z is 0, 1 or 2; Petition 870250111477, dated 04 / 12 / 2025, page 509 / 545 3 / 37 X9 is -NRL6-, -C(O)- or -S(O)2-;and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl; where Formula Ib has the structure of: Formula Ib where: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, an optionally substituted 7- to 12-membered bicyclic heterocyclylene, in which a first ring in Q is linked to X and a second ring in Q is linked to A; X is a connection;C1-C3 linear chain alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl and -O-C1-C3 alkyl; -O-; -S(O)o-2-; *-CH2-O-; *-CH2-S(O)o2-; *-O-CH2-; or *-CH2-S(O)o-2-, wherein “*” represents a portion of X attached to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, C1-C4 Petition 870250111477, dated 04 / 12 / 2025, page. 510 / 545 4 / 37 optionally substituted heteroalkylene or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl or optionally substituted 3- to 7-membered heterocyclyl;R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl or optionally substituted C1-C3 heteroalkyl; R7 is hydrogen, halogen or optionally substituted C1-C3; R8 is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 7-membered heterocyclyl; or R7 and R8 together form =CH2, an optionally substituted C3-C6 cycloalkyl or a saturated 3- to 7-membered heterocyclyl; or R8 and a ring atom in Q, the carbon atom to which R7 is attached and X to form a saturated or unsaturated 4- to 9-membered heterocyclyl that is fused to Q; R6 is hydrogen or -CH3;each R5 is independently halogen, optionally substituted C1-C3 alkyl or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2 or 3; z is 0, 1 or 2; Petition 870250111477, dated 04 / 12 / 2025, p. 511 / 545 5 / 37 X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5 and RL6 join to the atoms to which they are attached and to any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIa has the structure of: Formula IIa or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds;A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; Petition 870250111477, dated 04 / 12 / 2025, page. 512 / 545 6 / 37 B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene;G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X3 is N or CH; q is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is independently hydrogen or optionally substituted C1-C4; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CRx, CH, CH2, or N; Y6 is CRz, C(O), CH, CH2, or N; Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl;Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl or R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen-substituted C1-C4 alkyl, cyano, hydroxy or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl;R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; Petition 870250111477, dated 04 / 12 / 2025, p. 514 / 545 8 / 37 R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl or R7 and R8 combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or Petition 870250111477, dated 04 / 12 / 2025, p. 515 / 545 9 / 37 R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9', combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; R21 is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-;and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIb has the structure of: Formula IIb Petition 870250111477, dated 04 / 12 / 2025, p. 516 / 545 10 / 37 or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, C(O)O-CH(R6)- where C is bonded to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X3 is N or CH; q is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is independently hydrogen or optionally substituted C1-C4; Y1 is C, CH, or N; Petition 870250111477, dated 04 / 12 / 2025, p. 517 / 545 11 / 37 Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CRx, CH, CH2, or N; Y6 is CRz, C(O), CH, CH2, or N;Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; Petition 870250111477, 04 / 12 / 2025, p. 518 / 545 12 / 37 R15 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl;R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl. Petition 870250111477, dated 04 / 12 / 2025, page. 519 / 545 13 / 37 optionally substituted or 6 to 10 membered aryl optionally substituted or R7' and R8' combine with the carbon atom to which they are attached to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl;R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9', combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; R21 is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)- or -S(O)2-;and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3 cycloalkyl or a 3- to 8-membered heterocyclyl; where Formula IIa-1 has the structure of: r21 Formula IIa-1 or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds;A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9' or >CR9R9' where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, Petition 870250111477, 04 / 12 / 2025, p. 521 / 545 15 / 37 C(O)O-CH(R6)- where C is bonded to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene or 3- to 8-membered heteroarylene; L is a ligand; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)q; X2 is O or NH; X3 is N or CH; q is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently hydrogen or optionally substituted C1-C4; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CRx, CH, CH2 or N; Y6 is CRz, C(O), CH, CH2 or N;Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl;R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R14 is absent or R2 and R14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 heteroalkyl, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted aryl or R7 and R8 combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl;R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl; or R7' and R8' combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. or R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9', combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or optionally substituted C1-C3 alkyl; and R21 is hydrogen or optionally substituted C1-C3 alkyl; wherein Formula IIIa has the structure of: Formula IIIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;Y8 is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHC(S). Petition 870250111477, dated 04 / 12 / 2025, page 525 / 545 19 / 37 -NHC(S)NH-, -NHS(O)2- or -NHS(O)2NH-; L is a ligand; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or 3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from F or CH3 or R7 and R8 combine with the atoms to which they are attached to produce a 3-membered cycloalkyl; each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-;and Petition 870250111477, dated 04 / 12 / 2025, p. 526 / 545 20 / 37 each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;wherein Formula IIIb has the structure of: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O)-, -NHC(O)MH-, -NHC(O)NCH-, -NHC(O)O-, -NHC(S)·-NHC(S)NH-, -NHS(O)2- or -NHS(O)2NH-; Petition 870250111477, dated 04 / 12 / 2025, p. 527 / 545 21 / 37 L is a linker; R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or 3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from F or CH3 or R7 and R8 combine with the atoms to which they are attached to produce a 3-membered cycloalkyl; Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; t is 0, 1, 2 or 3; z is 0, 1 or 2;X9 is -NRL6-, -C(O)- or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5 and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;wherein Formula IIIa-1 has the structure of: Formula IIIa-1 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y8 is -NHC(O)-, -NHC(O)NH0 11 xS. NN CH3 -NHC(O)NCH3- -NHC(O)O- -NHC(S)- -NHC(S)NH-, -NHS(O)2- or -NHS(O)2NH-; L is a ligand; X4 and X5 are each independently CH2, CH(CH3) or NH;Petition 870250111477, dated 04 / 12 / 2025, page 529 / 545 23 / 37 R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or 3- to 7-membered heterocycloalkyl;R7 and R8 are each independently selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to produce a 3-membered cycloalkyl; each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; wherein Formula IVa has the structure of: Petition 870250111477, dated 04 / 12 / 2025, p. 530 / 545 24 / 37 Formula IVa or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand;R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl;or any two of RL1, RL2, RL3, RL4, RL5 and RL6 join to the atoms to which they are attached and to any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl; each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; wherein Formula IVb has the structure of: Formula IVb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand;R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; Petition 870250111477, dated 04 / 12 / 2025, page 532 / 545 26 / 37 z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; Each of RL1, RL2, RL3, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and with any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl; each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2, or 3; wherein Formula Va has the structure of: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand;R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; wherein Formula Vb has the structure of: Petition 870250111477, dated 04 / 12 / 2025, page 534 / 545 28 / 37 Formula Vb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl; R2 is optionally substituted C1-C6 alkyl;R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 combine with the atoms to which they are attached and with any intervening atoms to form a C3 Petition 870250111477, dated 04 / 12 / 2025, page. 535 / 545 29 / 37 Cs optionally substituted cycloalkyl or a 3- to 8-membered heterocycloalkyl; each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3;wherein Formula VIa has the structure of: Formula VIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a crosslinking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1;R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand;W is a crosslinking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, a Netoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium or a glycal; X6 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; z is 0, 1, or 2; X9 is -NRL6-, -C(O)-, or -S(O)2-;Each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 combine with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl; each R33 is independently halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. and Petition 870250111477, dated 04 / 12 / 2025, page 538 / 545 32 / 37 t is 0, 1, 2 or 3;wherein Formula Vila has the structure of: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; X6, X7 and X8 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1C6 heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl;R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, Petition 870250111477, 04 / 12 / 2025, p. 539 / 545 33 / 37 isotopically enriched for deuterium; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 10-membered heteroarylene; L is a ligand; Petition 870250111477, dated 04 / 12 / 2025, pp. 540 / 545 34 / 37 X6, X7 and X8 are each independently selected from CH2, CHF, CF2, C=O or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1C6 heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl;R2 is optionally substituted C1-C6 alkyl; R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted heterocycloalkyl, wherein each hydrogen is independently, optionally, isotopically enriched for deuterium; z is 0, 1 or 2; X9 is -NRL6-, -C(O)- or -S(O)2-; each of RL1, RL2, RL3, RL4, RL5 and RL6 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL5, and RL6 combine with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3C8 cycloalkyl or a 3- to 8-membered heterocyclyl;Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2 or 3; and Petition 870250111477, dated 04 / 12 / 2025, page 541 / 545 35 / 37 wherein Formula XI has the structure of: or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene or optionally substituted C2-C4 alkenylene; W is optionally substituted 3- to 10-membered heterocycloalkyl or optionally substituted 3- to 10-membered cycloalkyl; X4 is CH2 or NH;R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl. Petition 870250111477, dated 04 / 12 / 2025, page. 542 / 545 36 / 37 optionally substituted, 6-membered aryl optionally substituted, 5- or 6-membered heteroaryl optionally substituted; and R3 is hydrogen;or R2 and R3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl; each of R4, R5, R6, and R7 is hydrogen; or R4 and R6 are hydrogen and R5 and R7 combine with the atoms to which they are attached to form an optionally substituted four-membered cycloalkyl; or R5 and R7 are hydrogen and R4 and R6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; R10 is -OR11 or -NR12R13; R11, R12, and R13 are each independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12 and R13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;Each R33 is independently a halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; et is 0, 1, 2, or 3.

2. COMPOUND, or a pharmaceutically acceptable salt thereof, characterized by being of Table 1.

3. PHARMACEUTICAL COMPOSITION characterized by comprising a compound, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

4. METHOD OF CANCER TREATMENT in a subject in need, Petition 870250111477, dated 04 / 12 / 2025, pp. 543 / 545 37 / 37, the method being characterized by comprising administering to the subject a therapeutically effective amount of a compound, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as defined in claim 3.

5. A METHOD FOR TREATING A RAS PROTEIN-RELATED DISORDER in a subject in need, the method being characterized by comprising administering to the subject a therapeutically effective amount of a compound, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as defined in claim 3.

6. METHOD FOR INHIBITING A RAS PROTEIN IN A CELL, the method being characterized by comprising bringing the cell into contact with an effective amount of a compound, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as defined in claim 3.