DEGRADAÇÃO VISADA DE VAV1

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades Proto-oncogene VAV 1 protein (VAV1). The chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having an inflammatory or autoimmune disorder.

Description

"TARGETED DEGRADATION OF VAV1" TECHNICAL AREA

[0001] The present invention discloses chemical entities (for example, a compound or a pharmaceutically acceptable salt thereof) that degrade the human Proto-oncogene VAV 1 (VAV1) protein. These chemical entities are useful, for example, for treating an individual (for example, a human individual) having a disorder or disease that can be treated by reducing the level of VAV1. This description also discloses compositions containing these chemical entities as well as methods of use and manufacture of these chemical entities. BACKGROUND

[0002] The ubiquitin-proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting targeted protein degradation using small molecule degraders is emerging as a novel modality in disease treatment. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues (also called molecular glue degraders; “MGDs”), to promote polyubiquitination and ultimately proteasomal degradation of novel protein substrates involved in disease development. Molecular glues bind to both the E3 ligase and the target protein.It is believed that the interaction between the molecular glue and the E3 ligase creates a surface that promotes the formation of a complex with the target protein, allowing for the subsequent degradation of the target protein. Examples of molecular glues for E3 ligase cereblon incleum: Thalidomide, Lenalidomide, and Pomalidomide, all of which are drugs. Petition 870260070484, dated 07 / 16 / 2026, p. 6 / 1215 2 / 573 imide immunomodulators (IMiDs) approved by the FDA for use in hematologic cancers.

[0003] VAV family proteins, including VAV1, VAV2 and VAV3 are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. VAV1 is a 95 kDa protein that is a positive regulator of T cell receptor and B cell receptor signaling. VAV1 expression is normally highly restricted to hematopoietic cells. VAV1 becomes rapidly phosphorylated to tyrosine in response to a variety of stimuli, including stimulation of the T cell receptor (TCR), B cell receptor (BCR), and various cytokine receptors. VAV1 regulates multiple cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T and B cells, natural killer cells, and osteoclasts) through the activation of certain GTPases. VAV1-mediated functions include gene transcription, development, and activation of immune cells (e.g., T and B cells).VAV1 is a positive regulator of TCR signaling, including the secretion of the cytokines T-activated nuclear factor (NFAT), interferon gamma (IFNy), and interleukin-2 (IL-2).

[0004] Knock-in mice having a mutated VAV1 with disrupted GEF activity but intact GEF-independent function show reduced T cell proliferation and activation in response to allogeneic stimulation and showed reduced T cell expansion in a systemic graft-versus-host model (Haubert et al. 2012 Transplantation Immunology 26: 212, 2012). VAV1-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) induced by MOG(5-55), a commonly used model of multiple sclerosis (Korn et al. 2003 Journal of Neuroimmunology 139:17). Finally, genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screenings Petition 870260070484, dated 07 / 16 / 2026, page 7 / 1215 3 / 573 in primary human T cells identified VAV1 as an important positive regulator of T cell function (Schmidt et al. 2022 Science 375: 6580). SUMMARY

[0005] This description presents chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade the proto-oncogene VAV 1 (VAV1) protein. These chemical entities are useful, for example, in treating an individual (e.g., a human individual) having a disorder or disease that can be treated by reducing the level of VAV1, thereby reducing VAV activity in cells. By reducing the level of VAV1, the chemical entities can reduce signaling in certain immune cell activation pathways. For example, the chemical entities can be used to reduce inflammation or autoimmune activity. They may be useful in treating, for example, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, chronic lymphocytic leukemia, ulcerative colitis, psoriasis, cutaneous lupus, axial spondyloarthritis, and graft-versus-host disease.This description also presents compositions containing the chemical entities as well as methods of use and manufacture thereof.

[0006] VAV1 is a dominant signal transduction protein in the adaptive immune system. It is a positive regulator of immune receptor signaling in both T cells and B cells. Thus, a reduction in VAV1 can reduce immune cell activation, immune cell proliferation, and the production of various cytokines. For at least these reasons, VAV1 degradation may be therapeutically beneficial in a variety of disease conditions.

[0007] In one aspect, this description presents compounds of Formula (I) or pharmaceutically acceptable salts thereof, Petition 870260070484, dated 07 / 16 / 2026, p. 8 / 1215 4 / 573 in which X, Y, R1, R2, R3, R4, R5, R6, L1 and n can be defined anywhere here.

[0008] In one aspect, this description presents compounds of Formula (II) or pharmaceutically acceptable salts thereof, Formula (II) in which X, Y, R1, R2, R3, R4, R5, R6, L1 and n can be defined anywhere here.

[0009] In one aspect, this description presents compounds of Formula (III) or pharmaceutically acceptable salts thereof, Formula (III) in which X, Y, R1, R2, R3, R4, R5, R6, L1 and n can be defined anywhere here.

[0010] In one aspect, this description presents compounds of Formula (IV) or pharmaceutically acceptable salts thereof, Petition 870260070484, dated 07 / 16 / 2026, p. 9 / 1215 5 / 573 Formula (IV) in which X, Y, R1, R2, R3, R4, R5, R6, L1 and n can be defined anywhere here. Definitions

[0011] The term “pharmaceutically acceptable salt” refers to those salts which, within the scope of good medical judgment, are suitable for use in contact with the tissues of humans and lower animals without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. The pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.Examples of pharmaceutically acceptable non-toxic acidic addition salts are salts of an amino group formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods employed in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, and heptanoate salts. Petition 870260070484, dated 07 / 16 / 2026, page 10 / 1215 6 / 573 hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Pharmaceutically acceptable salts derived from suitable bases include salts of alkali metals, alkaline earth metals, ammonium and N+(C1-4 alkyl)4. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0012] As used herein, “VAV1” refers to naturally occurring VAV1, also known as VAV or p95vav (e.g., mammalian VAV1, preferably human (Homo sapiens)) and encompasses naturally occurring variants, such as allelic variants and splice variants, that retain functional activity of VAV1.

[0013] An “individual” to whom administration is contemplated includes, but is not limited to, humans (i.e., a man or woman of any age range, for example, a pediatric individual (e.g., young, child, adolescent) or an adult individual (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, for example, a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, swine, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the individual is a human. In certain embodiments, the individual is a non-human animal. The terms “human”, “individual” and “patient” and “individual” are used interchangeably herein. Petition 870260070484, dated 07 / 16 / 2026, page 11 / 1215 7 / 573

[0014] Disease, disorder and condition are used interchangeably here.

[0015] As used herein, and unless otherwise specified, the terms “treat,” “treating,” and “treatment” encompass an action that occurs while an individual is suffering from the specified disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition or slows or delays the progression of the disease, disorder, or condition (“therapeutic treatment”).

[0016] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the present invention may vary depending on factors such as the desired biological outcome, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the individual.

[0017] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term “therapeutically effective amount” may encompass an amount that improves overall therapy, reduces or prevents symptoms or causes of disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0018] The compounds described here also include isotopically labeled compounds that are identical to those recited here, Petition 870260070484, dated 07 / 16 / 2026, page 12 / 1215 8 / 573 except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound of the description may have one or more H atoms replaced by deuterium.

[0019] The term “halo” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0020] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a linear or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 carbon atoms (inclusive) in it. Alkyl groups may be unsubstituted or substituted by one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0021] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by an independently selected halo.

[0022] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0023] The term “alkylene” refers to a divalent alkyl group (e.g., -CH2-).

[0024] The term “alkenyl” refers to an acyclic hydrocarbon chain that can be a linear chain or a chain Petition 870260070484, dated 07 / 16 / 2026, p. 13 / 1215 9 / 573 branched having one or more carbon-carbon double bonds. The alkenyl fraction contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 carbon atoms (inclusive) in it. Alkenyl groups may be unsubstituted or substituted by one or more substituents.

[0025] The term “alkynyl” refers to an acyclic hydrocarbon chain that can be a linear or branched chain having one or more carbon-carbon triple bonds. The alkynyl fraction contains the indicated number of carbon atoms. For example, C2-6 indicates that the group can have from 2 to 6 carbon atoms (inclusive) in it. Alkynyl groups may be unsubstituted or substituted by one or more substituents.

[0026] The term “aryl” refers to a mono-, bi-, tri-, or polycyclic group of 6-20 carbons in which at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic ring system); and where 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, and the like.

[0027] The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons and, more preferably, 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, Petition 870260070484, dated 07 / 16 / 2026, p. 14 / 1215 10 / 573 bicyclo[3.2.0]heptanil, bicyclo[3.1.1]heptanil, bicyclo[2.2.2]octanyl and bicyclo[4.1.0]heptanil, bicyclo[4.2.0]octanyl, similar. The cycloalkyl bicyclo[2.2.1]heptanil, bicyclo[3.2.1]octanyl also includes spirocyclic rings (for example, bicyclospirocyclic in which two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[3.6]decanyl, spiro[2.2]pentanyl, spiro[3.5]nonanyl, spiro[2.6]nonanyl, spiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0028] The term “cycloalkenyl” as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl groups may include multiple fused and / or bridging and / or spirocyclic rings.

[0029] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having from 5 to 20 ring atoms, alternatively 5, 6, 9, 10 or 14 ring atoms; and having 6, 10 or 14 shared pi electrons in a cyclic array; wherein at least one Petition 870260070484, dated 07 / 16 / 2026, p. 15 / 1215 11 / 573 rings in the system are aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but it need not be a ring containing a heteroatom, for example, tetrahydroquinolinyl). The heteroaryl groups may be unsubstituted or substituted by one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[ b ][1,4]dioxinila, benzo[ d][1,3]dioxolila, 2,3-dihydrobenzofuranila, tetra-hidroquinolinila, 2,3-di-hidrobenzo[ b ][1,4]oxati-inila, isoindolinila e outros.In some embodiments, the heteroaryl is selected from tienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0030] The term “heterocyclyl” refers to a saturated mono-, bi-, tri-, or polycyclic ring system with 3-16 carbon atoms (e.g., monocyclic ring system with 5-8 members, bicyclic with 8-12 members, or tricyclic with 11-14 members) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), in which 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups Petition 870260070484, dated 07 / 16 / 2026, page 16 / 1215 12 / 573 include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. The heterocyclyl group may include multiple fused and bridging rings. Non-limiting examples of fused / bridged heterocyclyl include: 2-azabicyclo[1.1.0]butanyl, 2azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl,3azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl,6azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl,2azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,2oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl,2oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl,5oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl,3oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl,6oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl,2oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1] Octanyl and similar Heterocyclyl groups also include spirocyclic rings (for example, bicyclic spirocyclic groups in which two rings are connected through only one atom). Non-limiting examples of spirocyclic heterocyclides include 2-azaespiro[2.2]pentanil, 4-azaespiro[2.5]octanil, 1-azaespiro[3.5]nonanil, 2-azaespiro[3.5]nonanil, 7-azaespiro[3.5]nonanil, 2-azaespiro[4.4]nonanil, 6-azaespiro[2.6]nonanil, 1,7-diazaespiro[4.5]decanil, 7-azaespiro[4.5]decanil, 2,5-diazaespiro[3.6]decanil, 3-azaespiro[5.5]undecanil, 2-oxaespiro[2.2]pentanil, 4-oxaespiro[2.5]octanil, 1-oxaspiro[3.5]nonanyl,2oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl,2oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane,1,7dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9. Petition 870260070484, dated 07 / 16 / 2026, page 17 / 1215 13 / 573 azaespiro[5.5]undecanyl and similar compounds. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0031] The term “heterocycloalkenyl” as used herein means a partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., a monocyclic ring system with 5-8 members, a bicyclic system with 8-12 members, or a tricyclic system with 11-14 members) having 13 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl.As partially unsaturated cyclic groups, heterocycloalkenyl groups can have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl groups can include multiple fused and / or bridging and / or spirocyclic rings.

[0032] Certain groups, such as θ', can be considered as: (i) a heterocycloalkenyl that is substituted by an oxo group; or (ii) a heteroaryl group.

[0033] As used herein, when a ring is described as being “aromatic,” it means that said ring has a continuous, delocalized π-electron system. Typically, the number of π-electrons outside the Petition 870260070484, dated 07 / 16 / 2026, p. 18 / 1215 14 / 573 plane corresponds to Hückel's rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole and the like.

[0034] As used herein, when a ring is described as being “partially unsaturated,” it means that said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; for example, one or more double or twin bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0035] For the avoidance of doubt, and unless otherwise specified, for cyclic rings and groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the melting points are located (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., )); (ii) on a single ring atom (spiro-fused ring systems) (e.g., ) or (iii) a contiguous array of ring atoms (ring-bridged systems having all bridge lengths > 0) (e.g., or ). Petition 870260070484, dated 07 / 16 / 2026, page 19 / 1215 15 / 573

[0036] Additionally, the atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.

[0037] Additionally, the compounds generically or specifically disclosed herein include all tautomeric forms, or “tautomers,” of said compounds. To give a non-limiting example, a description of a compound with the group ό is also a description of a compound with the group ό. As another non-limiting example, a description of a compound with the group oh is also a description of a compound with the group

[0038] The compounds generically or specifically disclosed herein include all stereoisomeric forms, including all diastereomeric and entantiomeric forms, unless specifically indicated or the context indicates otherwise. Compounds with chiral centers may occur as racemates, individual enantiomers (e.g., as the (R) enantiomer or (S) enantiomer) or diastereomers and mixtures thereof. All such stereoisomeric forms are included within the embodiments discussed herein, including mixtures thereof. Petition 870260070484, dated 07 / 16 / 2026, page 20 / 1215 16 / 573

[0039] Additionally, compounds of one enantiomeric form may epimerize into the other enantiomeric form. Thus, unless specifically indicated or the context indicates otherwise, the description of an enantiomer encompasses the isolated enantiomer and a mixture, such as a racemic mixture, of the (R) and (S) enantiomers if the enantiomers epimerize. For example, a description of isolated as well as a mixture of encompasses both including a racemic mixture of the two enantiomers. Similarly, a compound comprising a chiral center disclosed herein without its enantiomeric form indicated includes the isolated enantiomer and a mixture, such as a racemic mixture, of the (R) and (S) enantiomers if the enantiomers epimerize. For example, isolated as well as a mixture of encompasses both including a racemic mixture of the two enantiomers.

[0040] As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substituteable hydrogen atoms are substituted) Petition 870260070484, dated 07 / 16 / 2026, p. 21 / 1215 17 / 573 by one or more substituents other than hydrogen) as well as substituted structural fractions substituted by the indicated range of substituents other than hydrogen. For example, “optionally 1-4Ra substituted C1-C4 alkyl” is intended to encompass both unsubstituted C1-C4 alkyl and 1-4Ra substituted C1-C4 alkyl.

[0041] As used herein, the term “hydrogen bond acceptor” is intended to include any functional group containing a heteroatom, usually oxygen or nitrogen, having one or more lone pairs suitable for hydrogen bonding with a polarized hydrogen atom. A more detailed discussion of hydrogen bond acceptors and a list of accepted hydrogen bond acceptors is found in Laurence et al., J. Med. Chem., 2009, 52, 4073-4086 and Kenny et al., J. Med Chem. 2016, 59, 4278-4288, both of which are incorporated by reference in their entirety.

[0042] As used herein, the term “antibody” encompasses an immunoglobulin, whether naturally occurring or partially or wholly synthetically produced, and fragments thereof. The term also encompasses any protein having a binding domain that is homologous to an immunoglobulin binding domain. “Antibody” further includes a polypeptide comprising a structural region of an immunoglobulin gene or fragments thereof that specifically binds to and recognizes an antigen. The use of the term antibody is intended to include whole antibodies, polyclonal, monoclonal and recombinant antibodies, fragments thereof, and further includes single-chain antibodies, humanized antibodies, murine antibodies, mouse-human monoclonal antibodies, mouse-primate monoclonal antibodies, chimeric primate-human monoclonal antibodies, anti-idiotype antibodies, antibody fragments, such as, for example, scFv, (scFv)2, Fab, Fab' and F(ab')2, F(abl)2, Fv, dAb and Fd fragments, Petition 870260070484, dated 07 / 16 / 2026, page 22 / 1215 18 / 573 Antibody-related bodies and polypeptides. The antibody includes bispecific and multispecific antibodies as long as they exhibit the desired biological activity or function.

[0043] As used herein, an “antibody fragment” comprises a portion of an intact antibody, usually the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab',

[0044] F(ab')2 and Fv; diabodies; linear antibodies; fragments produced by a Fab expression library, antiidiotypic antibodies (anti-Id), CDR (complementarity-determining region) and epitope-binding fragments of any of the above that bind immunospecifically to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0045] As used herein, the term “antibody-drug conjugate” refers to an antibody or antibody fragment linked, for example, covalently, to a compound of the description.

[0046] Details of one or more embodiments of the invention are shown in the accompanying drawings and in the description below. Other features and advantages of the invention will be apparent from the description and drawings and from the claims. DESCRIPTION OF THE FIGURES

[0047] FIG. 1 is a schematic illustration of certain aspects of the relationship of VAV1 with certain proteins involved in the activation of T cell receptors. VAV1 is a positive regulator of T cell receptor signaling, including interferon gamma production and IL-2 secretion.

[0048] FIG. 2A shows the dose-dependent decrease in VAV1 levels in primary human T cells after 24 h of Petition 870260070484, dated 07 / 16 / 2026, p. 23 / 1215 19 / 573 treatment with a compound presented in Table 1 (“selected VAV1 MGD”) compared to DMSO control as assessed by flow cytometry (y-axis represents normalized VAV1 levels for DMSO control; x-axis illustrates doses of the selected VAV1 MGD).

[0049] FIG. 2B shows that VAV1 is significantly and selectively degraded by selected VAV1 MGD in Jurkat cells after 24 h of treatment as assessed by quantitative TMT proteomics (the y-axis represents the confidence p-value [-log™]; the x-axis represents the magnitude of protein change [logs] relative to DMSO control samples).

[0050] FIGS. 3A-3C show that VAV1 degradation results in the inhibition of several hallmarks of TCR-mediated activity after TCR stimulation of primary human T cells. Cells were treated with the selected VAV1 MGD for 24 h followed by TCR stimulation (anti-CD3 / anti-CD28 antibodies). CD69 surface expression (24 hr), IL-2 secretion (48 hr), and proliferation (96 hr) were assessed at various time points after TCR stimulation (the y-axis represents the percentage of CD69 activation, IL-2 secretion, or proliferation relative to the TCR-stimulated DMSO control; the x-axis illustrates the doses of the selected VAV1 MGD).

[0051] FIG. 4 shows the concentration of selected VAV1 MGD in plasma over time and the associated decrease in normalized VAV1 protein levels to β-actin relative to pretreatment after a single oral dose of selected VAV1 MGD at 10 mg / kg (y-axis represents hours post-single oral dose of selected VAV1 MGD [hour]; left y-axis represents the concentration of selected VAV1 MGD in ng / mL in plasma, hole-filled; right y-axis represents the percentage [%] of VAV1 protein levels normalized to β-actin protein levels). Petition 870260070484, dated 07 / 16 / 2026, p. 24 / 1215 20 / 573 actin and in relation to the pre-dose in blood cells (filled triangles).

[0052] FIG. 5 shows that oral administration of the selected VAV1 MGD in an experimental autoimmune encephalomyelitis (EAE) model induced by MOG35-55 led to inhibition of disease progression. Mice were immunized by subcutaneous injection on day 0 with an emulsified mixture consisting of the synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) and M. tuberculosis mixed with Freund's incomplete adjuvant. Additionally, mice were injected intraperitoneally with pertussis toxin at 0 and 48 hours. Mice were monitored for symptom development and scored for clinical signs of EAE disease (0 = no signs of disease; 1 = tail or hind limb weakness; 2 = tail and hind limb weakness; 3 = partial hind limb paralysis; 4 = complete hind limb paralysis; 5 = moribund), once daily (QD), dosing began on day 12 and ended on day 18.Dexamethasone administered orally every four days (QD) from day 12 to day 18 was used as a comparative treatment. 10 mg / kg of the selected VAV1 MGD prevented the progression of EAE disease, as observed for mice treated with Dexamethasone at 1 mg / kg (x-axis represents days post-immunization start [days]; y-axis represents clinical EAE score, [mean ± SEM]; empty circle: vehicle, PO, QD; inverted filled triangles, VAV1 MGD 10 mg / kg, PO, QD; filled square, Dexamethasone 1 mg / kg, PO, QD).

[0053] FIG. 6A shows that oral administration of VAV1 MGD in an experimental autoimmune encephalomyelitis (EAE) model induced by MOG35-55 led to inhibition of disease progression in a dose-dependent manner. Mice were immunized by subcutaneous injection on day -12 with an emulsified mixture. Petition 870260070484, dated 07 / 16 / 2026, page 25 / 1215 21 / 573 consisting of a synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) and M. tuberculosis mixed with Freund's incomplete adjuvant. Additionally, mice were injected intraperitoneally with pertussis toxin on days -12 and -10. Mice were monitored for symptom development and scored for clinical signs of EAE disease (0 = no signs of disease; 1 = tail or hind limb weakness; 2 = tail and hind limb weakness; 3 = partial hind limb paralysis; 4 = complete hind limb paralysis; 5 = moribund) every 3 days until day 0. Dosing began on day 0 and ended on day 13 with vehicle (PO, QD), dexamethasone (1 mg / kg, PO QD) and VAV1 MGD (1, 0, 1, 0.01 mg / kg, PO, QD).1 mg / kg of VAV1 MGD prevented the progression of EAE disease as observed for mice treated with Dexamethasone at 1 mg / kg (x-axis represents days post-immunization start [days]; y-axis represents clinical EAE score, [mean ± SEM]; closed circle: vehicle; solid triangle up, VAV1 MGD 1 mg / kg; closed triangle down, VAV1 MGD 0.1 mg / kg; open triangle, VAV1 MGD 0.01 mg / kg; open circle, Dexamethasone 1 mg / kg).

[0054] FIG. 6B shows that oral administration of VAV1 MGD degraded VAV1 in the spinal cord in a dose-dependent manner proportional to the reduction in clinical scores. On day 6, 4 mice per group were sacrificed, spinal cords were excised and homogenized, and Western blotting was then used to assess VAV1 levels normalized to β-actin and shown relative to vehicle-treated mice. Statistical analysis was performed using a one-way ANOVA with Dunnett's multiple comparisons. ns = not significant, ***p<0.001, ****p<0.0001.

[0055] FIG. 7 shows that oral administration of MGD of VAV1 Petition 870260070484, dated 07 / 16 / 2026, p. 26 / 1215 22 / 573 in a T-cell transfer-induced colitis model led to inhibition of disease progression. CD17-SCID mice were injected intraperitoneally with 0.5 x 10⁶ non-pathogenic low-activated CD45RB T cells (no disease control group) or naive pathogenic CD45RB high-activated cells (treatment groups). From the day of cell transfer (day 0), mice were monitored daily for disease activity index (DAI) comprising weight loss and stool consistency assessment. On day 0, two hours post-cell transfer, mice were orally (PO) treated daily (QD) with vehicle or MGD of VAV1 1 mg / kg for 42 days.1 mg / kg of VAV1 MGD prevented colitis progression (x-axis represents days post-disease induction and treatment initiation [days]; y-axis represents DAI score [mean ± SEM]; open circles, non-pathogenic control; closed black circles, vehicle; closed triangles, VAV1 MGD 1 mg / kg).

[0056] FIG. 8A shows that oral administration of VAV1 MGD in a collagen-induced arthritis model led to inhibition of disease progression. To induce collagen-induced arthritis (CIA), fifteen DBA / 1 mice were intravenously injected with an emulsified mixture consisting of 100 μg of chicken collagen II emulsified in incomplete Freund's adjuvant, then 18 days later subcutaneously injected with chicken collagen II emulsified in complete Freund's adjuvant. This immunization induces the activation and expansion of collagen-specific T and B cells that migrate to the paw joints. Once in the paw joints, the activated T cells induce the destruction of articular and bone tissue, leading to redness and swelling of the phalanges, and the B cells produce antibodies against collagen II. After the second immunization, the mice were monitored daily for signs Petition 870260070484, dated 07 / 16 / 2026, page 27 / 1215 23 / 573 clinical presentations of the disease were as follows: 0 = erythema and redness; 1 = Mild erythema or redness near the tarsal, ankle, or metatarsal, or one toe with erythema and redness; 2 = Ankles and metatarsals are slightly erythematous and swollen with two or more toes with erythema and redness; 3 = Moderate erythema and swelling of the ankle, wrists, and ankles; 4 = Ankles, wrists, metatarsals, and toes are severely red and swollen. Upon onset of the disease, mice were randomly assigned to treatment groups: vehicle (PO, QD), anti-TNF (10 mg / kg, IP, Q3D), or VAV1 MGD (1 mg / kg, PO, QD) and treated for 21 days. 1 mg / kg of VAV1 MGD prevented arthritis progression (x-axis represents days post-disease onset and treatment initiation [days]; y-axis represents clinical score [mean ± SEM]; circles, vehicle; triangles, VAV1 MGD 1 mg / kg).

[0057] FIG. 8B shows that oral administration of VAV1 MGD in a collagen-induced arthritis model led to decreased production of anti-collagen II IgG1 antibodies. At the end of the study, serum was collected and the amount of anti-collagen II IgG1 antibodies was measured by ELISA. Statistical analysis was performed using an unpaired two-tailed t-test. *p<0.05.

[0058] FIG. 9 illustrates VAV1 as a key downstream mediator of the B cell receptor (BCR). Markers of engagement with the BCR pathway include CD69 surface activation and IL6 and IgG secretion.

[0059] FIGS. 10A -10C show that degradation mediated by VAV1 MGD reduces BCR-mediated CD69 expression and IL-6 and IgG secretion from primary human B cells. Purified primary human B cells were treated with VAV1 MGD for 24 hours followed by stimulation with anti-IgM and recombinant human IL-4 for 24 hours (for CD69 expression and IL-6 secretion) or with Petition 870260070484, dated 07 / 16 / 2026, p. 28 / 1215 24 / 573 anti-IgM, BAFF, IL-21, and sCD40L for 5 days (for IgG secretion). FIG. 10A shows CD69 expression, which was then evaluated in CD19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change from DMSO-stimulated controls. The Y-axis shows the relative percentage of CD19+ B cells expressing CD69, and the X-axis shows the VAV1 MGD concentration. FIG. 10B shows IL-6 secretion, which was evaluated in the supernatant by alpha-lysa. IL-6 secretion is shown as a percentage (%) change from DMSO-stimulated controls. The Y-axis shows the relative percentage of IL-6 level, and the X-axis shows the VAV1 MGD concentration. FIG. 10C shows IgG secretion, which was evaluated in the supernatant by alpha-lysa. IgG secretion is shown as a percentage (%) change relative to DMSO-stimulated controls.The Y-axis shows the relative percentage of IgG level and the X-axis shows the MGD concentration of VAV1.

[0060] FIG. 11 shows that treatment with VAV1 MGD of selected B-cell lymphoma cell lines decreases growth with increasing concentration. REC-1, OCI-LY10, and SLVL cells were treated for 5 days with indicated concentrations of VAV1 MGD. At 5 days of treatment, cell growth was measured by cell titration brightness and normalized to T0 and DMSO.

[0061] FIG. 12 shows that treatment with MGD of VAV1 of Subcutaneously implanted REC-1 CDX decreases in vivo growth. CB17 SCID mice (10 per group) were subcutaneously inoculated in the right flank with 5x10⁶ REC-1 cells. After the mean tumor volume of all mice reached 100-150 mm³, the mice were treated with vehicle or VAV1 MGD at 10 mg / kg PO QD. On the indicated days post-treatment initiation, the tumor volume was measured. The mice were sacrificed when the Petition 870260070484, dated 07 / 16 / 2026, page 29 / 1215 25 / 573 tumor volume reached 2000 mm3.

[0062] FIG. 13 shows an X-ray powder diffraction (XRPD) pattern of the A crystal form of compound 185. DETAILED DESCRIPTION

[0063] This description presents chemical entities (e.g., a pharmaceutically acceptable compound or salt thereof) that degrade and / or otherwise inhibit the Proto-oncogene VAV 1 (VAV1) protein. These chemical entities are useful, for example, for treating an individual (e.g., a human individual) having a disorder or disease associated with VAV1 polymorphisms or dysregulated lymphocytes (e.g., T cells). This description also presents compositions containing them as well as methods of use and manufacture thereof. Compounds Compounds of Formulas (I), (II), (III) and (IV)

[0064] The description presents compounds of Formula (I) or pharmaceutically acceptable salts thereof, Formula (I) where: L1 is: • a connection; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(alkylene C0-C4)-, -(alkylene Ci-C4)-C(=O)-*, *-(alkylene Ci-C4)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; • -(C=O)-; or Petition 870260070484, dated 07 / 16 / 2026, p. 30 / 1215 26 / 573 • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; and each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; Each of R6 is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl that is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; n is selected from 0, 1, 2 and 3; R7 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each occurrence of Rae selected independently from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; Petition 870260070484, dated 07 / 16 / 2026, p. 31 / 1215 27 / 573 S(O)i-2NR'R''; -S(O)i-2(C1-4 alkyl); and cyano; each occurrence of Rbé independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 substituents Rcindependently selected; each occurrence of R is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl that is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(O)o-2(C1-4 alkyl); -NReRf; -OH; -S(O)1-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, deuterium, optionally C1-6 alkyl Petition 870260070484, dated 07 / 16 / 2026, p. 32 / 1215 28 / 573 replaced by 1-3 R independently selected; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxos or Ra; and • C6-10 aryl optionally replaced by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

[0065] This description also includes compounds of Formula (II) or pharmaceutically acceptable salts thereof, Petition 870260070484, dated 07 / 16 / 2026, p. 33 / 1215 29 / 573 Formula (II) where: L is: • a connection; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, (C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; • -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; and each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is independently selected from the group consisting Petition 870260070484, dated 07 / 16 / 2026, p. 34 / 1215 30 / 573 in: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by 1-6 R independently selected; C3-6 cycloalkyl that is optionally substituted by 1-4 R independently selected; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; n is selected from 0, 1, 2 and 3; each occurrence of Rae selected independently from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbé independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 substituents Petition 870260070484, dated 07 / 16 / 2026, p. 35 / 1215 31 / 573 Rcindependently selected; each occurrence of R is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl that is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(OM alkyl C1-4); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(alkyl C1-10); -C(=O)O(alkyl C1-4); -C(=O)OH; N(R')C(=O)(alkyl C1-4), -C(=O)NR'R'', Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted by 1-3 R independently selected; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; -S(O)1-2(C1-4 alkyl); OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, where 1-4 Petition 870260070484, dated 07 / 16 / 2026, p. 36 / 1215 32 / 573 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, where at least one ring in the system is aromatic and where the heteroaryl is optionally replaced by 1-4 oxos or Ra; and • C6-10 aryl optionally replaced by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl. This description also includes compounds of Formula (III) or pharmaceutically acceptable salts thereof, Formula (III) where: L1: • It's a connection; • is *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, (Ci-C4 alkylene)-C(=O)-*, *-(Ci-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; • is -(C=O)-; Each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; with the condition that -L1-R1 does not include OO, NO, NN, OS, SS, or NS bonds; with the additional condition that L1 must be a bond when R1 is CN, halo, or -NR'C(O)R''; and with the additional condition that Petition 870260070484, dated 07 / 16 / 2026, p. 37 / 1215 33 / 573 that L1 cannot be a bond when R1 is hydrogen; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; Each of R6 is independently selected from the group consisting of: deuterium; halo; cyano; C1-10 alkyl which is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl which is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2E-2 Rg; n is selected from 0, 1, 2 and 3; each occurrence of Rae selected independently from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbé independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl including 5-10 ring atoms, where 1-4 Petition 870260070484, dated 07 / 16 / 2026, p. 38 / 1215 34 / 573 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, where at least one ring in the system is aromatic and where the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 substituents Rcindependently selected; each occurrence of R is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl that is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, C1-6 alkyl optionally substituted by 1-3 R independently selected; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl groups including 3-7 ring atoms, where 1-3 of the ring atoms are heteroatoms, each Petition 870260070484, dated 07 / 16 / 2026, p. 39 / 1215 35 / 573 independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxos or Ra; and • C6-10 aryl optionally replaced by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl. This description also includes compounds of Formula (IV) or pharmaceutically acceptable salts thereof. Formula (IV) where: L1é: • a connection; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, (Ci-C4 alkylene)-C(=O)-*, *-(Ci-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; or • -(C=O)-; Each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, Rb, -ORb, -SRb, Petition 870260070484, dated 07 / 16 / 2026, page 40 / 1215 36 / 573 N(R')Rb, CN, halo and -NR'C(O)R''; with the condition that -L1-R1 does not include OO, NO, NN, OS, SS, or NS bonds; with the additional condition that L1 must be a bond when R1 is CN, halo, or -NR'C(O)R''; and with the additional condition that L1 cannot be a bond when R1 is hydrogen; R2 is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OMe, F and Cl; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is Rc independently selected; n is selected from 0, 1, 2 and 3; each occurrence of Rae independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbé independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl group including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heteroaryl group is optionally substituted by 1-4 substituents Petition 870260070484, dated 07 / 16 / 2026, p. 41 / 1215 37 / 573 Rc independently selected; and • aryl Ce-10 optionally replaced by 1-4 substituents Rcindependently selected; each occurrence of R is independently selected from the group consisting of: halo; cyano; C1-10 alkyl that is optionally substituted by 1-6 R independently selected; C2-ε alkenyl; C2-ε alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i2NR'R''; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R”, Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, C1-e alkyl optionally substituted by 1-3 R independently selected; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; -S(O)1-2(C1-4 alkyl); OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; C1-e alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently Petition 870260070484, dated 07 / 16 / 2026, p. 42 / 1215 38 / 573 selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and in which the heteroaryl is optionally replaced by 1-4 Ra; and • C6-10 aryl optionally replaced by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

[0066] In certain modalities, L1-R1 does not include OO, NO, NN, OS, SS or NS.

[0067] In certain modes, L1 has to be a link when R1é CN, halo ou -NR'C(O)R''.

[0068] In certain embodiments, L1 cannot be a bond when R1 is hydrogen.

[0069] In certain modalities, L1-R1 does not include OO, NO, NN, OS, SS or NS, L1 must be a bond when R1 is CN, halo or -NR'C(O)R''; and L1 cannot be a bond when R1 is hydrogen.

[0070] In certain embodiments: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted by 1-2 Rae where * indicates the attachment point of L1 to the ring; or when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; X and Y are both CH, or one of X and Y is N and the other is CH; R1 is Rb; R2 is hydrogen, chlorine, fluorine, or methyl; R3, R4 and R5 are hydrogen or halo; Petition 870260070484, dated 07 / 16 / 2026, p. 43 / 1215 39 / 573 R6 is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; and Rbé: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

[0071] In certain modalities: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring; or L1 when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; X and Y are both CH, or one of X and Y is N and the other is CH; R1 is Rb; R2 is hydrogen, chlorine, fluorine, or methyl; Petition 870260070484, dated 07 / 16 / 2026, p. 44 / 1215 40 / 573 R3, R4 and R5 are hydrogen or halo; R6 is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; and Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

[0072] In certain modalities: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted by 1-2 Rae where * indicates the attachment point of L1 to the ring; or when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; X and Y are both CH, or one of X and Y is N and the other is CH; R1 is Rb; R2 is hydrogen, chlorine, fluorine, or methyl; R3, R4 and R5 are hydrogen or halo; n is 0; and Rbé: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 Petition 870260070484, dated 07 / 16 / 2026, p. 45 / 1215 41 / 573 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, where at least one ring in the system is aromatic and where the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents. Rc Identity

[0073] In certain embodiments, Rce is selected independently from the group consisting of: halo; C1-10 alkyl which is optionally replaced by 1-6 Rg independently selected; C1-4 alkoxy; Rge -(CH2)i-2 Rg. L1 Identity

[0074] In certain embodiments, L1 is a linkage, -(C=O)-,*O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-,*NR'(C=O)(C0-C4 alkylene)- or *-(C1-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring.

[0075] In certain embodiments, L1 is a linkage, -(C=O)-,*O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-,*NR'(C=O)(C0-C4 alkylene)- or *-(C1-C4 alkylene)-C(=O)-.

[0076] In certain embodiments, L1 is a linkage, -(C=O)-,*O(C1-C4 alkylene), *-C1-C4 alkylene-, *-(C1-C4 alkylene)-C(=O)-, *NH'(C0-C4 alkylene)- or *-NH'(C=O)(C0-C4 alkylene)-, wherein the alkylene is optionally replaced by 1-2 Ra, and wherein * indicates the attachment point of L1 to the ring.

[0077] In certain embodiments, L1 is a linkage, -(C=O)-, *O(C1-C4 alkylene), *-C1-C4 alkylene- or *-(C1-C4 alkylene)-C(=O)-.

[0078] In certain embodiments, L1 is a linkage, *-OCH2-, *OCH2CH2, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2CH2-, -(C=O)- or *-(CH2)-C(=O)-.

[0079] In certain embodiments, L1 is a linkage or -CH2-. Petition 870260070484, dated 07 / 16 / 2026, p. 46 / 1215 42 / 573

[0080] In certain modes, L1 is a link.

[0081] In certain embodiments, L1 is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by R1 and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc. Identity of X and Y

[0082] In certain modalities, X and Y are both CH or one of X and Y is N and the other is CH.

[0083] In certain modalities, X and Y are both CH. R1 Identity

[0084] In certain modalities, R1 is Rb.

[0085] In certain embodiments, Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

[0086] In certain embodiments, Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and the hydrogen bond acceptor being selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group, and an oxygen-containing aliphatic or cycloaliphatic group.

[0087] In certain embodiments, Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and wherein the hydrogen bond acceptor is selected from an amide, lactam, carbamate, pyridone, pyrimidinone, piperazinone, pyridazinone, urea, sulfonamide, sulfone, pyrimidine, pyrazine, pyridazine, pyridine, oxazole, isoxazole, oxadiazole group, Petition 870260070484, dated 07 / 16 / 2026, page 47 / 1215 43 / 573 thiazole, thiadiazole, imidazole, pyrazole, oxazole, isoxazole, oxadiazole, oxetane, tetrahydrofuran, tetrahydropyran or methoxyalkyl.

[0088] In certain modalities, Rbé: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

[0089] In certain modalities, Rbé: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

[0090] In certain modalities, Rbé: • heterocyclyl or heterocycloalkenyl including 5-10 atoms Petition 870260070484, dated 07 / 16 / 2026, p. 48 / 1215 44 / 573 annular, wherein 1-3 annular atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one heteroatom is N or N(Rd), and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 annular atoms, wherein 1-4 annular atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one heteroatom is N or N(Rd), wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

[0091] In certain embodiments, Rc is selected independently of halo, C1-4 alkyl which is optionally replaced by 1-3 halo atoms independently selected and C1-4 alkoxy.

[0092] In certain embodiments, Rb is selected from the group consisting of: Petition 870260070484, dated 07 / 16 / 2026, p. 49 / 1215 45 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 50 / 1215 46 / 573 o IS Vo and X, each of which is optionally replaced by 1-4 independently selected R substituents.

[0093] In certain embodiments, Rbé heteroaryl includes 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected Rcin.

[0094] In certain embodiments, Rbé heteroaryl includes 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o—2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected Rcin.

[0095] In certain embodiments, Rbé is a heteroaryl group including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-2 independently selected Rcin.

[0096] In certain embodiments, Rbé heteroaryl includes 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2.

[0097] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 51 / 1215 47 / 573 consistent in / Χ,^N e> , en , each of which is optionally replaced by 1-2 Rc independently selected.

[0098] In certain modalities, Rbé selected from the group consisting of Rdé CH3. optionally in which

[0099] In certain modalities, Rbé selected from the group consisting of , optionally in which Rdé CH3. >=n

[0100] In certain modalities, Rbé selected from and

[0101] In certain modalities Rbé

[0102] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 52 / 1215 48 / 573 consistent in

[0103] In certain modalities, Rbé selected from the group consisting of

[0104] In certain embodiments, R is selected from the group consisting of C1-10 alkyl which is optionally replaced by 1-6 Rae -NReRf independently selected, optionally wherein R is methyl or -NH2.

[0105] In certain modalities, Rbé selected from the group consisting of

[0106]

[0107] In certain sports, Rbé In certain modalities, RbéRC

[0108] In certain embodiments, Rce is a C1-10 alkyl group that is optionally replaced by independently selected 1-6 Rae -NReRfin, optionally wherein Rce is methyl.

[0109] In certain modalities, Rbé / .

[0110] In certain embodiments, Rbé is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected R substituents.

[0111] In certain embodiments, Rbé heteroaryl including 6 atoms Petition 870260070484, dated 07 / 16 / 2026, p. 53 / 1215 49 / 573 annular, where 1-4 of the annular atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2.

[0112] In certain modalities, Rbé selected from the group consisting of

[0113]

[0114] In certain sports, Rbé In certain embodiments, Rbé is a heteroaryl group including 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 independently selected oxo or R groups.

[0115] In certain embodiments, Rbé heteroaryl includes 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxos or Rcin independently selected.

[0116] In certain embodiments, Rbé heteroaryl includes 9 ring atoms, wherein at least one ring in the system is aromatic, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxos and Rc.

[0117] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 54 / 1215 50 / 573 consisting of which is optionally replaced by 1-4 Rc independently selected.

[0118] In certain modalities, Rbé selected from the group consisting of and

[0119] In certain embodiments, Rbé heteroaryl includes 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), Petition 870260070484, dated 07 / 16 / 2026, p. 55 / 1215 51 / 573 N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxo or R groups independently selected.

[0120] In certain modalities, Rbé selected from the group consisting of , each of which is optionally selected independently.

[0121] In certain modalities, Rb is replaced by 1-4 Rce selected from the group I and consisting of

[0122] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0123] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 4-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0124] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl including 5-6 ring atoms, where 1-3 Petition 870260070484, dated 07 / 16 / 2026, p. 56 / 1215 52 / 573 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0125] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl including 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0126] In certain embodiments, Rbé is a heterocycloalkenyl group including ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0127] In certain modalities, Rbé

[0128] In certain modalities, Rdé CH3.

[0129] In certain modalities, Rb optionally replaced by 1-2 independently selected R-type substitutes.

[0130] Ϊ J-Rc In certain sports, Rbé Petition 870260070484, dated 07 / 16 / 2026, p. 57 / 1215 53 / 573

[0131] In certain modalities, Rbé o·

[0132] In certain embodiments, Rcou each occurrence of Rcé selected from the group consisting of C1-10 alkyl optionally substituted by 1-6 Ra, C1-4 alkoxy, halo and -NReRfin independently selected.

[0133] In certain embodiments, Rce is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluorine, chlorine and NH2.

[0134] In certain modalities, R1 is selected from the group consisting of f

[0135] In certain embodiments, Rbé is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0136] In certain modalities, Rbé selected from the group consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 58 / 1215 54 / 573 o each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0137] In certain embodiments, Rcé methyl, halo, methoxy or CF3.

[0138] In certain modalities, Rbé selected from the group consisting of

[0139] In certain modalities, Rbé selected from the group consisting of or the (for example, Petition 870260070484, dated 07 / 16 / 2026, p. 59 / 1215 55 / 573 o o F

[0140] In certain modalities, Rdé CH3.

[0141] In certain sports, Rbé

[0142] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0143] In certain embodiments, Rbé heterocyclyla includes 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0144] In certain modalities, Rbé selected from the group consisting of each of which is optionally replaced by 1-4 Rc.

[0145] In certain embodiments, Rcé halo or C1-6 alkyl.

[0146] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 60 / 1215 56 / 573 consistent in (for example, (for example,

[0147] . oH ). In certain sports, Rbé is selected from the group consisting of

[0148]

[0149] In certain sports, Rbé In certain embodiments, Rbé is a heterocycloalkenyl group including ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. Rd

[0150] In certain modalities, Rbé0, optionally where n'n· Rbé 0'

[0151] In certain modalities, Rbé selected from the group consisting of

[0152] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 7-10 ring atoms, where 1-3 Petition 870260070484, dated 07 / 16 / 2026, p. 61 / 1215 57 / 573 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0153] In certain embodiments, Rbé heterocyclyl includes 7-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0154] In certain embodiments, Rbé heterocyclyl including 7 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl is optionally substituted by 1-4 independently selected R substituents.

[0155] In certain modalities, Rbé selected from the group consisting of each of which is optionally replaced by 1-4 independently selected R-c substitutes.

[0156] In certain modalities, Rbé selected from the group consisting of & Petition 870260070484, dated 07 / 16 / 2026, p. 62 / 1215 58 / 573

[0157] In certain embodiments, Rbé heterocyclyl includes 8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl is optionally replaced by selected. 1-4 substituents Regardless of the modalities, Rbé selected from group o consisting of

[0158] In certain (for example, or replaced by ), each of 1-4 substitutes which is optionally Rcindependently selected. modalities, Rbé selected from group o the

[0159] In certain (for example, consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 63 / 1215 59 / 573

[0160] In certain embodiments, Rbé is a heterocyclyl group including 9 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0161] In certain modalities, Rbé selected from the group consisting of Rd the Vo, each of which is optionally replaced by 1-4 independently selected R-substitutes.

[0162] In certain modalities, Rdé CH3.

[0163] In certain modalities, Rbé selected from the group / / °0 <X°Λν0ο o consistindo em \ , cr^ ,k, o—, e

[0164] In certain embodiments, Rbé is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc;

[0165] In certain modalities, Rbé, optionally replaced by an Rc. R2 Identity Petition 870260070484, dated 07 / 16 / 2026, page 64 / 1215 60 / 573

[0166] In certain embodiments, R2 is hydrogen, chlorine, fluorine, or methyl.

[0167] In certain forms, R2 is chlorine. Identity of R2, R3, R4 and R5 and value of n

[0168] In certain embodiments, R3, R4 and R5 are hydrogen or halo.

[0169] In certain embodiments, R3 is halo or hydrogen and R4 and R5 are hydrogen.

[0170] In certain embodiments, R3, R4 and R5 are hydrogen.

[0171] In certain embodiments, R2 is chlorine, and R3, R4 and R5 are hydrogen.

[0172] In certain modes, n is 0.

[0173] In certain embodiments, n is 0 and R3, R4 and R5 are hydrogen; and / or L1 is a linkage, -(C=O)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *NR'(C=O)(C0-C4 alkylene)- or *-(C1-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring.

[0174] In certain modalities, n is 1 or 2. R6 Identity

[0175] In certain embodiments, R6 is selected from the group consisting of deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 R independently selected; C1-4 alkoxy, C1-4 haloalkoxy; and -NReRf; optionally wherein R6 is selected from the group consisting of deuterium, cyano, chlorine, fluorine, methyl, ethyl, -CHF2, methoxy, -OCHF2 and -NH2.

[0176] In certain embodiments, R6 is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl.

[0177] In certain embodiments, R6 is selected from the group consisting of deuterium, fluorine and methyl.

[0178] In certain modalities, R6 is deuterium, optionally in Petition 870260070484, dated 07 / 16 / 2026, p. 65 / 1215 61 / 573 which is n is 4. Formulas I-1, I-2, I-3 and I-4

[0179] In certain embodiments, the compound is a compound of formula (I-1) H Q-.N.___,___. L1 YY f YrRb Formula (I-1).

[0180] In certain embodiments, the compound is a compound of the formula (I-2) H jLRZIh Formula (I-2), where X is -NH- or -O-.

[0181] In certain modalities, X is -O-.

[0182] In certain embodiments, the compound is a compound of the formula (I-3) °^N^O . ___ ιΓ jl T rir*b Formula (I-3).

[0183] In certain embodiments, the compound is a compound of formula (I-4) Formula (I-4).

[0184] In certain forms, R2 is chlorine.

[0185] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and in Petition 870260070484, dated 07 / 16 / 2026, p. 66 / 1215 62 / 573 wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

[0186] In certain embodiments, Rbé is a heterocycloalkenyl group including ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0187] In certain modalities, Rbé , each of which is optionally replaced by of 1-2 independently selected R-substituents.

[0188] In certain modalities, Rbé which is optionally replaced by 1-2 Rc independently selected.

[0189] In certain sports, Rbé

[0190] In certain embodiments, Rcou each occurrence of Rcé selected from the group consisting of C1-10 alkyl optionally substituted by 1-6Ra, C1-4 alkoxy, halo and -NReRfindependently Petition 870260070484, dated 07 / 16 / 2026, p. 67 / 1215 63 / 573 selected.

[0191] In certain embodiments, Rce is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluorine, chlorine and NH2.

[0192] In certain modalities, Rbé selected from the group

[0193] In certain modalities, Rbé θ'

[0194] In certain embodiments, Rbé is a heteroaryl group including 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected R substituents.

[0195] In certain modalities, Rbé selected from the group consisting of u, eN, each of which is optionally replaced by 1-2 Rc independently selected. Petition 870260070484, dated 07 / 16 / 2026, p. 68 / 1215 64 / 573

[0196] In certain modalities, Rbé selected from the group consisting of Rdé CH3. AM.N v n, optionally where

[0197] In certain modalities Rbé , optionally where Rdé CH3.

[0198] In certain modalities, Rbé

[0199] In certain embodiments, Rbé is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0200] In certain modalities, Rbé selected from the group consisting of the Petition 870260070484, dated 07 / 16 / 2026, p. 69 / 1215 65 / 573

[0201] In certain modalities, Rbé selected from the group consisting of or (for example, faith

[0202]

[0203]

[0204] In certain modalities, Rdé CH3. In certain sports, Rbé In certain embodiments, Rbé is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rcin.

[0205] In certain embodiments, Rbé heteroaryl includes 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2.

[0206] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 70 / 1215 66 / 573 consisting of

[0207] In certain modalities, Rbé

[0208] In certain embodiments, Rbé is a heteroaryl group including 9 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0209] In certain modalities, Rbé selected from the group the N—Rdo N—Rd , each of which is optionally replaced by 1-4 independently selected Rc values.

[0210] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 71 / 1215 67 / 573 consisting of and the

[0211] In certain embodiments, Rbé heteroaryl includes 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxos and Rcin independently selected.

[0212] In certain modalities, Rbé selected from the group consisting of , each of which is optionally replaced by 1-4 independently selected Rs.

[0213] In certain modalities, Rbé selected from the group consisting of

[0214] In certain embodiments, Rbé heterocyclyla includes 7-10 ring atoms, where 1-3 ring atoms are heteroatoms, Petition 870260070484, dated 07 / 16 / 2026, p. 72 / 1215 68 / 573 each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0215] In certain embodiments, Rbé is a heterocyclyl group including 7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl group is optionally replaced by 1-4 independently selected R substituents.

[0216] In certain modalities, Rbé selected from the group consisting of each of which is optionally replaced by 1-4 independently selected R-c substitutes.

[0217] In certain sports, Rbé is selected from the group. consisting of θ'

[0218] In certain embodiments, Rbé is a heterocyclyl group including 8 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl group is optionally Petition 870260070484, dated 07 / 16 / 2026, p. 73 / 1215 69 / 573 replaced by selected. 1-4 substituents R independently is selected from group o oo consisting of

[0219] In certain modalities, Rb (for example, or replaced by ), each of 1-4 substitutes which is optionally Rcindependently selected. modalities, Rbé selected from group o oo consisting of

[0220] In certain (for example, ). In certain embodiments, Rbé heterocyclyl including 9 atoms or

[0221] ring-shaped, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0222] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 74 / 1215 70 / 573 consisting of the each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0223] In certain modalities, Rdé CH3.

[0224] In certain modalities, Rbé selected from the group consisting of and

[0225] In certain forms, R2 is chlorine. Formulas (Ia) and (Ib)

[0226] In certain embodiments, the compound is a compound of Formula (Ia).

[0227] In certain embodiments, the compound is a compound of formula (Ib) Formula (Ib). Petition 870260070484, dated 07 / 16 / 2026, p. 75 / 1215 71 / 573 Particular compounds of Formulas (I), (II), (III), (IV) and (V)

[0228] In certain embodiments, the compound is selected from the group consisting of the compounds in Table 1 or from a pharmaceutically acceptable salt thereof. H 1 ] CK.N. XXXxO

[0229] In certain embodiments, the compound is either a pharmaceutically acceptable salt thereof. Hi | O^,N. ,0 „J TTχ / Χ

[0230] In certain embodiments, the compound is Mou a pharmaceutically acceptable salt thereof. C^O IH XXXXT

[0231] In certain embodiments, the compound is a pharmaceutically acceptable salt thereof. C^o IH CK.N,,O XXX Xj

[0232] In certain embodiments, the compound is either a pharmaceutically acceptable salt thereof.

[0233] In certain embodiments, the compound exists in a racemic mixture. In certain embodiments, the compound in a mixture H IJ racemic is either a pharmaceutically acceptable salt thereof.

[0234] In certain embodiments, this description presents a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0235] In certain forms, the compound is not Petition 870260070484, dated 07 / 16 / 2026, p. 76 / 1215 72 / 573 ΤΧΧ n / ^áa XX n^jüvjTX ο^^FCT'N-'A) -ν' Y^O'^-^'CI ono AaAA 0^ν% Η , \AΗ, \ΑΗou ^ιΧΧΗN'NA.oy^ α°γΝγ° kAAAJ N.

[0236] In some forms, the compound has a Dmax of 20% or higher.

[0237] In some embodiments, the present invention provides a compound of Formula (V): R4 Formula (V) or a pharmaceutically acceptable salt thereof, where: L1é: • a connection; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, (C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; • -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group Petition 870260070484, dated 07 / 16 / 2026, page 77 / 1215 73 / 573 consisting of oxo and Rc; and each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; Each of R6 is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl that is optionally substituted by independently selected 1-6 R-alkyl; C3-6 cycloalkyl that is optionally substituted by independently selected 1-4 R-alkyl; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; n is selected from 0, 1, 2 and 3; R7 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, Ome, F, Cl and Br; each occurrence of Rae selected independently from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb comprises a hydrogen bond acceptor; each occurrence of R is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally replaced by 1-6 R independently selected; C3-6 cycloalkyl which is optionally replaced by Petition 870260070484, dated 07 / 16 / 2026, p. 78 / 1215 74 / 573 of 1-4 Selected Raindependents; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(OMalkyl C1-4); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted by 1-3 R independently selected; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)1-2NR'R''; -S(O)1-2(C1-4 alkyl); OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 oxos or Ra; and • C6-10 aryl optionally replaced by 1-4 Ra; Petition 870260070484, dated 07 / 16 / 2026, p. 79 / 1215 75 / 573 each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

[0238] In some embodiments where Rb comprises a hydrogen bond acceptor, Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y. In some embodiments, Rb comprises a hydrogen bond acceptor within six atoms of the carbon atom between X and Y. In some embodiments, Rb comprises a hydrogen bond acceptor within five atoms of the carbon atom between X and Y. In some embodiments, Rb comprises a hydrogen bond acceptor within four atoms of the carbon atom between X and Y. In some embodiments, Rb comprises a hydrogen bond acceptor within three atoms of the carbon atom between X and Y. Hydrogen bond acceptor groups

[0239] In some embodiments where Rb comprises a hydrogen bond acceptor, the hydrogen bond acceptor is selected from a carbonyl, sulfonyl group, nitrogen-containing heteroaromatic group, oxygen-containing heteroaromatic group, and an oxygen-containing aliphatic or cycloaliphatic group.

[0240] In some embodiments where Rb comprises a hydrogen bond acceptor, the hydrogen bond acceptor is selected from an amide, lactam, carbamate, pyridone, pyrimidinone, piperazinone, pyridazinone, urea, sulfonamide, sulfone, pyrimidine, pyrazine, pyridazine, pyridine, oxazole, isoxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, oxazole, isoxazole, oxadiazole, oxethane, tetrahydrofuran, tetrahydropyran or methoxyalkyl group.

[0241] In some embodiments where Rb comprises a hydrogen bond acceptor, the hydrogen bond acceptor is selected from: Petition 870260070484, dated 07 / 16 / 2026, p. 80 / 1215 76 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 81 / 1215 77 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 82 / 1215 78 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 83 / 1215 79 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 84 / 1215 80 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 85 / 1215 81 / 573 Compounds of Formula IV

[0242] In one aspect, this description presents compounds of Petition 870260070484, dated 07 / 16 / 2026, p. 86 / 1215 82 / 573 Formula (IV) or pharmaceutically acceptable salts thereof, Formula (IV) or a pharmaceutically acceptable salt thereof, where: L1é: • a connection; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1 alkylene- C4- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, (C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, where the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the ring comprising X and Y; or • -(C=O)-; Each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, Rb, -ORb, -SRb, N(R')Rb, CN, halo and -NR'C(O)R''; with the condition that -L1-R1 does not include OO, NO, NN, OS, SS, or NS bonds; with the additional condition that L1 must be a bond when R1 is CN, halo, or -NR'C(O)R''; and with the additional condition that L1 cannot be a bond when R1 is hydrogen; R2 is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OMe, F and Cl; Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is Rc independently selected; n is selected from 0, 1, 2 and 3; each occurrence of Rae independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; Petition 870260070484, dated 07 / 16 / 2026, page 87 / 1215 83 / 573 C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyan; each occurrence of Rbé independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heteroaryl is optionally substituted by 1-4 independently selected R-substituents; and • C6-10 aryl optionally substituted by 1-4 substituents Rcindependently selected; each occurrence of R is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally replaced by 1-6 R independently selected; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)o-2(C1-4 alkyl); -NReRf; -OH; -S(O)i2NR'R''; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rge -(CH2K2 Rg; each occurrence of Rdé independently selected from the group consisting of: hydrogen, C1-6 alkyl optionally substituted by 1-3 R independently selected; -C(O)(C1-4 alkyl); C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); Petition 870260070484, dated 16 / 07 / 2026, p. 88 / 1215 84 / 573 OH; and C1-4 alkoxy; each occurrence of Ree Rfé independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rgé independently selected from the group consisting of: C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 Ra; and C6-10 aryl optionally replaced by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl. Variable L1

[0243] In some embodiments, L1*-O(alkylene C0-C4), *S(alkylene C0-C4)-, *-alkylene C1-C4- or *-NR'(alkylene C0-C4)-, wherein the alkylene is optionally replaced by 1-2 Rae where * indicates the attachment point of L1 to the phenyl ring.

[0244] In some embodiments, L1 is *-O(C0-C4 alkylene)-, wherein the alkylene portion is optionally replaced by 1-2Ra. In some embodiments, L1 is *-O(C1-C4 alkylene)-, wherein the portion Petition 870260070484, dated 07 / 16 / 2026, p. 89 / 1215 85 / 573 of alkylene is optionally replaced by 1-2 Ra. In some embodiments, L1 is *-O(C1-C4 alkylene)- unsubstituted. For example, L1 can be *-OCH2- or *-OCH2CH2.

[0245] In certain forms, L1 is *-OCH2- .

[0246] In certain embodiments, L1 is an optionally substituted C1-C4 *-alkylene by 1-2 Ra. In certain embodiments, L1 is an unsubstituted C1-C4 *-alkylene. In certain embodiments, L1 is selected from the group consisting of -CH2-, -CH(CH3)-, -C(CH3)2- and -CH2CH2CH2-. For example, L1 may be -CH2-.

[0247] In certain embodiments, L1 is *-NR'(C0-C4 alkylene)-, wherein the alkylene portion is optionally replaced by 1-2Ra. In certain embodiments, L1 is *-NR'(C1-C4 alkylene)-, wherein the alkylene portion is optionally replaced by 1-2Ra. In certain embodiments, L1 is *-NR'(C1-C4 alkylene)-, wherein the alkylene portion is not replaced. In certain embodiments, -R'- is H. For example, L1 may be . For yet another example, L1 may be -NH-.

[0248] In certain modalities, L1 is -(C=O)-. Variables X and Y

[0249] In certain modalities, X and Y are both CH.

[0250] In certain modalities, one of X and Y is N, and the other of X and Y is CH.

[0251] In certain modalities, X is N, and Y is CH.

[0252] In certain forms, Y is N, and X is CH. Variable R1

[0253] In some embodiments, R1 is hydrogen.

[0254] In some modalities, R1 is Rb.

[0255] In some modalities, R1 is selected from the group consisting of -ORbe -N(R')Rb.

[0256] In some embodiments, Rbé heteroaryl includes 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, Petition 870260070484, dated 07 / 16 / 2026, p. 90 / 1215 86 / 573 each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected R. In some embodiments, R is a heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected R.

[0257] In certain embodiments, Rbé is a heteroaryl group including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heteroaryl group is optionally replaced by 1-2 independently selected Rcin.

[0258] In certain embodiments, Rbé is heteroaryl including 5 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2. In certain embodiments, Rbé is selected from the group consisting of v> N, each of which is optionally replaced by 1-2 independently selected Rs.

[0259] In certain modalities, Rbé selected from the group consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 91 / 1215 87 / 573 Am-n O N, optionally where Rdé CH3.

[0260] In certain embodiments, Rbé is selected from the group consisting of eN<; / N-Rd, optionally where Rdé CH3. In certain sports, Rbé selected from

[0261]

[0262] For example, Rb can be

[0263] In certain modalities, Rbé selected from the group consisting of In certain sports, Rbé is selected from the group consisting of In certain embodiments, R is selected from the group consisting of C1-10 alkyl groups that are optionally replaced by 1-6 Rae -NReRf groups independently selected, optionally wherein R is methyl or -NH2. In certain embodiments, R is selected from the group consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 92 / 1215 88 / 573

[0264] In certain modalities Rbé In certain embodiments, Rbé Rc. In certain embodiments, Rcé is a C10 alkyl group that is optionally replaced by 1-6 Rae-NReRf. Selected independently, optionally in which Rcé methyl. In certain sports, Rbé

[0265] In some embodiments, Rbé is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected R-substituents. In certain embodiments, Rbé is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2. In certain embodiments, Rbé is selected from the group consisting of For example, Rb can be

[0266] In some embodiments, Rbé is a heteroaryl group including 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rcin. In Petition 870260070484, dated 07 / 16 / 2026, p. 93 / 1215 89 / 573 some embodiments, Rbé heteroaryl including 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected Rcin.

[0267] In some embodiments, Rbé is a heteroaryl group including 9 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl group is optionally replaced by 1-4 substituents independently selected from the list consisting of oxo and Rc. In certain embodiments, Rbé is selected from the group consisting of each of which is optionally replaced by 1-4 Rc independently selected.

[0268] In certain modalities, Rbé selected from the group the consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 94 / 1215 90 / 573

[0269] In some embodiments, Rbé is a heteroaryl group including 10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rc. In certain embodiments, Rbé is selected from the group consisting of Rd, Rde Rd, each of which is optionally replaced by 1-4 independently selected Rc. In certain embodiments, Rbé is selected from the group consisting of

[0270] In some embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0271] In some embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 4-6 ring atoms, where 1-3 ring atoms are heteroatoms, each independently Petition 870260070484, dated 07 / 16 / 2026, p. 95 / 1215 91 / 573 selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0272] In some embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0273] In certain embodiments, Rbé heterocyclyl or heterocycloalkenyl including 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0274] In certain embodiments, Rbé is a heterocycloalkenyl group including ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, .oxRd. In certain embodiments, Rdé CH3.

[0275] For example, Rb can be modalities, Rbéo / sou Petition 870260070484, dated 07 / 16 / 2026, p. 96 / 1215 92 / 573

[0276] As another example, Rbé οΛ, which is replaced by 1-2 independently selected R substituents. Ϊ -j-Rc

[0277] In certain embodiments. Rbé °Έ . In certain such embodiments, each occurrence of Rcé selected from the group consisting of C1-10 alkyl optionally substituted by 1-6 Ra, C1-4 alkoxy, halo and -NReRf independently selected. In certain embodiments, Rcé selected from the group consisting of methyl, ethyl, CHF2, -CF3, methoxy, fluorine, chlorine and NH2. In certain embodiments, Rbé selected from the group consisting of f

[0278] In some embodiments, Rbé is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbé is selected from the group consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 97 / 1215 93 / 573 o and is optionally replaced by , each of which consists of 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these forms, Rcé methyl, halo, methoxy or CF3.

[0279] In certain modalities, Rbé selected from the group consisting of O OOO

[0280] In certain modalities, Rbé selected from the group consisting of or the (for example, Petition 870260070484, dated 07 / 16 / 2026, p. 98 / 1215 94 / 573 faith In certain of these modalities, Rdé CH3.

[0281] For example, Rb can be

[0282] In some embodiments, Rbé heterocyclyl or heterocycloalkenyl including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0283] In some embodiments, Rbé is a heterocyclyl group including 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. In some embodiments, Rbé is selected from the group consisting of each of which is optionally replaced by 1-4 Rc. In certain of these embodiments, Rc is halo or C1-6 alkyl.

[0284] In certain modalities, Rbé selected from the group Petition 870260070484, dated 07 / 16 / 2026, p. 99 / 1215 95 / 573 (for example, consisting of and (for example, or ).

[0285] In some modalities, Rbé selected from the group consisting of

[0286] For example, Rb can be

[0287] In some embodiments, Rbé is a heterocycloalkenyl group including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. . Rd

[0288] In certain modalities, Rbéo, optionally where Rbé

[0289] In some modalities, Rbé selected from the group consisting of

[0290] In some embodiments, Rbé heterocyclyl or heterocycloalkenyl includes 7-10 ring atoms, where 1-3 ring atoms are heteroatoms, each independently Petition 870260070484, dated 07 / 16 / 2026, pp. 100 / 1215 96 / 573 selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0291] In some embodiments, Rbé heterocyclyl includes 7-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0292] In some embodiments, Rbé is a heterocyclyl group including 7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl group is optionally replaced by 1-4 independently selected R-substituents. In certain embodiments, Rbé is selected from the group consisting of °', each of which is optionally replaced by 1-4 independently selected R-substituents. In certain embodiments, Rbé is selected from the group consisting of °'

[0293] In some embodiments, Rbé is a heterocyclyl group including 8 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl group is optionally Petition 870260070484, dated 07 / 16 / 2026, pp. 101 / 1215 97 / 573 replaced by 1-4 independently selected substitutes Rc. In certain modalities, Rb is selected from the group 0 0 ), each of which is optionally replaced by 1-4 independently selected Rc substituents. In certain embodiments, R is selected from the group consisting of the (for example, or the ).

[0294] In some embodiments, Rbé is a heterocyclyl group including 9 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbé is selected from the group consisting the each of which is optionally replaced by 1-4 substitutes independently Petition 870260070484, dated 07 / 16 / 2026, p. 102 / 1215 98 / 573 selected from the group consisting of oxo and Rc. In certain of these modalities, Rdé CH3. In certain modalities, Rbé selected from the group consisting of

[0295] In some embodiments, Rb is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; In certain embodiments, Rb may be optionally replaced by an Rc. Variables R2, R3, R4 and R5

[0296] In some embodiments, R2 is hydrogen.

[0297] In some embodiments, R2 is chlorine or fluorine. In certain embodiments, R2 is chlorine.

[0298] In some embodiments, R3, R4 and R5 are hydrogen.

[0299] In some embodiments, R2 is chlorine, and R3, R4 and R5 are hydrogen. Variable ne R6

[0300]

[0301]

[0302] In some modes, n is 0. In some modes, n is 1 or 2. In some modes, R6 is selected from the group. consisting of halo; cyano; C1-10 alkyl which is optionally replaced by independently selected 1-6 R-Alkoxy; C1-4 alkoxy, C1-4 haloalkoxy; and -NReRf; optionally wherein R6 is selected from the group consisting of cyano, chlorine, fluorine, methyl, ethyl, -CHF2, methoxy, OCHF2 and -NH2. Petition 870260070484, dated 07 / 16 / 2026, p. 103 / 1215 99 / 573 Non-limiting combinations Formula (I-1)

[0303] In some embodiments, a compound of formula (IV) is a compound of formula (I-1) H YY 2 jTTXRb Formula (I-1). Formula (I-2)

[0304] In some embodiments, a compound of formula (IV) is a compound of formula (I-2) H θγγr2í^VX\ / Rb Formula (I-2), where X is -NH- or -O-.

[0305] In certain Formula (I-2) configurations, X is -NH-.

[0306] In certain Formula (I-2) configurations, X is -O-.

[0307] In certain forms of Formula (I-2), R2 is chlorine.

[0308] In certain embodiments of Formula (I-2), Rbé is a heteroaryl group including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 of the independently selected R groups.

[0309] In certain Formula (I-2) categories, Rbé selected of the group consisting of Petition 870260070484, dated 07 / 16 / 2026, p. 104 / 1215 100 / 573 each of which is optionally replaced by 1-2 independently selected Rc substitutes. In certain Formula (I-2) configurations, Rb is selected from the group consisting optionally in which Rdé CH3. In certain Formula (I2) configurations, Rbé selected from the group consisting optionally in which Rdé CH3. N-Rd

[0310] In certain Formula (I-2) categories, Rbé selected from the group consisting of

[0311] In certain Formula (I-2) categories, Rbé N— Formula (I-3)

[0312] In some embodiments, a compound of formula (IV) is a compound of formula (I-3) Formula (I-3).

[0313] In certain forms of Formula (I-3), R2 is chlorine.

[0314] In certain embodiments of Formula (I-2), Rbé is a heterocycloalkenyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the Petition 870260070484, dated 07 / 16 / 2026, p. 105 / 1215 101 / 573 heterocycloalkenyl is optionally replaced by 1-4 independently selected substituents from the group consisting of oxo and Rc.

[0315] In certain Formula (I-3) modalities, Rbé o'^^ or each of which is optionally replaced by of 1-2 independently selected R-substitutes. In certain Formula (I-3) modalities, Rbé o', which is optionally replaced by 1-2 independently selected R-substitutes.

[0316] For example, Rb can be θ'

[0317] I -jRc In certain Formula (I-3) categories, Rbé In certain embodiments, each occurrence of R is selected from the group consisting of C1-10 alkyl optionally substituted by 1-6 Ra, C1-4 alkoxy, halo and -NReRf independently selected. The compound of any of claims 121 or 122, wherein R is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluorine, chlorine and NH2. In certain embodiments, Rbé selected from the group consisting of f Petition 870260070484, dated 07 / 16 / 2026, page 106 / 1215 102 / 573

[0318] In certain embodiments of Formula (I-3), Rbé is a heteroaryl group including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rc substituents. In certain embodiments of Formula (I-3), Rbé selected from the group consisting of , each of which is optionally replaced by 1-2 Rc independently selected.

[0319] In certain of these modalities, Rbé selected from the group consisting of optionally in which Rdé CH3.

[0320] For example, Rb may be Rdé CH3. N—Rd, optionally in Petition 870260070484, dated 07 / 16 / 2026, p. 107 / 1215 103 / 573

[0321]

[0322] For yet another example, Rb can be In certain embodiments of Formula (I-3), Rbé is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain such embodiments, Rbé is selected from the group consisting of

[0323] In certain of these modalities, Rbé selected from the group consisting (for example, or the in Petition 870260070484, dated 07 / 16 / 2026, pp. 108 / 1215 104 / 573 ugly In certain of these modalities, Rdé CH3.

[0324] For example, Rb can be

[0325] In certain embodiments of Formula (I-3), Rbé is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heteroaryl group is optionally replaced by 1-4 of the independently selected Rcin.

[0326] In certain embodiments of Formula (I-3), Rbé heteroaryl includes 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2.

[0327] In certain Formula (I-3) modalities, Rbé selected from the group consisting of N. For example, Rb can be

[0328] In certain forms of Formula (I-3), R2 is chlorine. Formula (I-4)

[0329] In some embodiments, a compound of formula (IV) is a compound of formula (I-4) Petition 870260070484, dated 07 / 16 / 2026, p. 109 / 1215 105 / 573 Formula (I-4).

[0330] In some forms of Formula (I-4), R2 is chlorine.

[0331] In some embodiments of Formula (I-4), Rbé is a heterocycloalkenyl group including 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0332] In some Formula (I-4) modes, Rbé 0^^-^, which is optionally replaced by 1-4 Rcin independently selected. For example, Rbé ^.

[0333] In certain embodiments of Formula (I-4), Rbé is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0334] In certain modalities, Rbé selected from the group consisting of Petition 870260070484, dated 07 / 16 / 2026, pp. 110 / 1215 106 / 573 o and

[0335] In certain modalities, Rbé selected from the group consisting or the in (for example, faith

[0336] In certain of these modalities, Rdé CH3.

[0337] For example, Rb could be the Formula (I-5)

[0338] In some embodiments, a compound of formula (IV) is a compound of formula (I-5) Formula (I-5). Petition 870260070484, dated 07 / 16 / 2026, pp. 111 / 1215 107 / 573

[0339]

[0340] including In some Formula (I-5) configurations, R2 is chlorine. In some embodiments of Formula (I-5), Rbé heterocyclyl 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)o-2, and wherein the heterocyclyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these HN modalities, Rb is selected from the group consisting of the O' . In certain of these modalities, Rbé selected from the group consisting of the the F (for example, the (for example, The or the LJ0Λ For example, Rb can be L

[0341] In some embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heteroaryl group including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0342] In some Formula (I-1), (I-2), (I-3), (I-4) categories the N or (I-5), Rbé selected from the group consisting of 0 Petition 870260070484, dated 07 / 16 / 2026, pp. 112 / 1215 108 / 573 O. o o o I-H×Òí ν , , e χ^χ..^, each of which is optionally replaced by 1-4 independently selected Rc. In certain of these embodiments, Rb is selected from the group consisting of

[0343] In some embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heteroaryl group including 10 ring atoms, wherein 1-4 of these ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rcin. In certain of these embodiments, Rbé is selected from the group consisting of 1IReR, each of which is optionally replaced by 1-4 independently selected Rc. In certain Petition 870260070484, dated 07 / 16 / 2026, pp. 113 / 1215 109 / 573 of these modalities, Rbé selected from the group consisting of

[0344] In some embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heterocyclyl group including 7-10 ring atoms, wherein 13 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0345] In certain embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heterocyclyl group including 7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl group is optionally replaced by 1-4 independently selected Rc substituents. In certain of these embodiments, Rbé is selected from the group consisting of the each of which is optionally replaced by 1-4 independently selected substituents Rc. In certain of these embodiments, Rb is selected from the group consisting of THE Petition 870260070484, dated 07 / 16 / 2026, pp. 114 / 1215 110 / 573

[0346] In certain embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heterocyclyl group including 8 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 independently selected R substituents. In certain of these Rbé selected from the group consisting of modalities (for example, or ), each of which is optionally replaced by 1-4 independently selected substituents Rc. In certain of these embodiments, Rb is selected from the group consisting the (for example, or

[0347] In some embodiments of Formula (I-1), (I-2), (I-3), (I-4) or (I-5), Rbé is a heterocyclyl group including 9 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. In some embodiments of Formula (I-1), (I-2), (I-3), (I-4) or Petition 870260070484, dated 07 / 16 / 2026, pp. 115 / 1215 111 / 573 (I-5), Rbé selected from the group consisting of 'Rd and the o, each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these modalities, Rdé CH3. In certain of these modalities, Rbé selected from the group consisting of .0 N Formulas (Ia) and (Ib)

[0348] In some embodiments, a compound of formula (IV) is a compound of formula (Ia) Formula (Ia).

[0349] In some embodiments, a compound of formula (IV) is a compound of formula (Ib) Formula (Ib). Pharmaceutical Compositions

[0350] In another aspect, the present invention provides a Petition 870260070484, dated 07 / 16 / 2026, pp. 116 / 1215 112 / 573 pharmaceutical composition that includes any of the compounds described herein, or a pharmaceutically acceptable salt thereof (for example, a therapeutically effective amount of the compound or salt), and a pharmaceutically acceptable excipient.

[0351] The pharmaceutical compositions provided herein may be administered by a variety of routes including, but not limited to, oral (enteric) administration, parenteral (injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration and intranasal administration.

[0352] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate precise dosing. The term “unit dosage forms” refers to physically distinct units suitable as unit dosages for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampoules, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minimal component with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0353] Suitable liquid dosage forms for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and distribution agents, colorants, flavors and the like. Solid dosage forms may include, for example, any Petition 870260070484, dated 07 / 16 / 2026, pp. 117 / 1215 113 / 573 of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a slider such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavor.

[0354] Injectable compositions are typically based on sterile injectable saline solution or phosphate-buffered saline solution or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minimal component with the remainder being the injectable excipient and the like.

[0355] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will typically be combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance dermal penetration and stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope of the description provided herein.

[0356] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be achieved using a reservoir patch or a porous membrane type or a variety of solid matrix. Petition 870260070484, dated 07 / 16 / 2026, pages 118 / 1215 114 / 573

[0357] The components described above for orally, injectable or topically administered compositions are merely representative. Other materials as well as processing techniques and the like are presented in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. Methods of use

[0358] In one aspect, this description presents methods of degrading VAV1 in an individual, which include administering to the individual an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing the degradation of the VAV1 protein. In some embodiments, VAV1 is a regulator of T cells. In one embodiment, the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon.

[0359] In another aspect, this description presents methods for degrading VAV1, which include: (i) contacting a compound described herein or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

[0360] In some embodiments, the compounds described herein can bind to a specific amino acid sequence of VAV1, thereby causing VAV1 degradation. In other embodiments, such VAV1 degradation is mediated by the compound interacting with both the specific amino acid sequence of VAV1 and an E3 ligase. In other embodiments, the E3 ligase comprises cereblon.

[0361] In an additional aspect, this description presents methods of treatment for a variety of dysfunctions that include administering Petition 870260070484, dated 07 / 16 / 2026, pp. 119 / 1215 115 / 573 the pharmaceutical compounds and compositions described herein. Such disorders include, without limitation, autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis) and disease in a transplant setting (e.g., graft-versus-host disease). Other disorders include those caused by or associated with dysregulated lymphocyte development or activation.

[0362] In one aspect, this description presents methods of treating a disorder caused by or associated with the development or activation of dysregulated lymphocytes in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is an autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis). In some embodiments, the disorder is a disease in a transplant setting (e.g., graft-versus-host disease). In some embodiments, the disorder is a malignancy (e.g., T-cell or B-cell malignancy). In some embodiments, the lymphocyte is a T cell.

[0363] In one aspect, this description presents methods of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, T-cell receptor signaling is enhanced CD69, IFNγ, or IL-2 surface expression.

[0364] In one aspect, this description presents methods for treating a disorder caused by or associated with VAV1 polymorphisms in an individual in need of treatment. Petition 870260070484, dated 07 / 16 / 2026, pp. 120 / 1215 116 / 573 comprising administering to the individual a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0365] In one aspect, this description presents methods of treating a disorder caused by or associated with immunopathologies in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is an autoimmune disorder. In some modalities, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and associated dysfunctions, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease,Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated dysfunctions, inflammatory eye disease, keratoconjunctivitis, myocarditis, or hepatitis. In some modalities, the disorder is a cancer, tumor, or other malignancy, optionally where the disorder is a T-cell or B-cell malignancy. In some modalities, the disorder is selected from the group consisting of: leukemia, lymphoma, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, Petition 870260070484, dated 07 / 16 / 2026, pages 121 / 1215 117 / 573 hairy cell leukemia, nasal and nasal-type NK / T cell lymphoma, mycosis fungoides and Sézary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous lymphoproliferative disorders of CD-30 positive T cells, cutaneous T-cell lymphoma, panniculitis-type cutaneous T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma and non-Hodgkin lymphomas (e.g., non-Hodgkin B-cell lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma).Diseases in the transplant setting include graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary artery disease.

[0366] In one aspect, the description presents methods of treatment of a disorder caused by or associated with VAV1 polymorphisms in an individual in need thereof or caused by or associated with immunopathologies in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0367] In some modalities, the disorder is mediated by cells T. In some modalities, the disorder is selected from the group consisting of Type I or II Diabetes, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer's disease, Acute Graft-Related Disease. Petition 870260070484, dated 07 / 16 / 2026, pages 122 / 1215 118 / 573 against the Host or T-cell mediated kidney disease.

[0368] In some forms, the disorder is mediated by cells T / B. In some modalities, the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, an allergic disorder (e.g., asthma, allergic contact dermatitis, rhinitis, or contact dermatitis), an autoimmune liver disease (e.g., biliary sclerosis or sclerosing cholangitis), chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft-versus-Host Disease, lupus nephritis, pulmonary arterial hypertension, or vasculitis.

[0369] In some embodiments, the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis. In preferred embodiments, the disorder is ulcerative colitis.

[0370] In some embodiments, the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia. In preferred embodiments, the disorder is chronic lymphocytic leukemia.

[0371] In one aspect, the description relates to a method of treating ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondyloarthritis, the method comprising administering to the individual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In preferred forms, the disorder is ulcerative colitis. Petition 870260070484, dated 07 / 16 / 2026, pages 123 / 1215 119 / 573

[0372] In one aspect, the description relates to a method of treating B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia, the method comprising administering to the individual an amount H 1 ] CK.N. .N. J XJÇvO therapeutically effective compound or a pharmaceutically acceptable salt thereof. In preferred embodiments, the method is a treatment method for chronic lymphocytic leukemia.

[0373] In some modalities, the description relates to a method of treating patients exhibiting CD226 overexpression.

[0374] In some modalities, the description relates to a method of treating patients having a risk variant of CD226.

[0375] In some modalities, the description relates to a method of treating patients having a CD226 polymorphism.

[0376] In some embodiments, the description relates to a method of treating patients having a Gly307Ser (G307S) amino acid substitution in CD226 (rs763361T allele).

[0377] In one aspect, the description relates to a method of treating a disorder caused by or associated with dysregulation of lymphocyte development or activation in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0378] In some forms, the lymphocyte is a T cell.

[0379] In some forms, the lymphocyte is a B cell. Petition 870260070484, dated 07 / 16 / 2026, pp. 124 / 1215 120 / 573

[0380] In one aspect, the description relates to a method of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0381] In one aspect, the description relates to a method of treating a disorder caused by or associated with VAV1 polymorphisms in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0382] In one aspect, the description relates to a method of treating a disorder caused by or associated with immunopathologies in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0383] In some forms, the disorder is an autoimmune disorder.

[0384] In some modalities, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and associated dysfunctions, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn's disease or colitis). Petition 870260070484, dated 07 / 16 / 2026, pages 125 / 1215 121 / 573 ulcerative, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated dysfunctions, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0385] In one aspect, the description provides a pharmaceutically acceptable compound or salt for use in any of the treatment methods described above. In some embodiments, the pharmaceutically acceptable compound or salt thereof is a pharmaceutically acceptable compound or salt thereof as described herein. In a further aspect, the description provides the use of a pharmaceutically acceptable compound or salt for the manufacture of a medicament for any of the treatment methods described above. In some embodiments, the pharmaceutically acceptable compound or salt thereof is a pharmaceutically acceptable compound or salt thereof as described herein. Process for manufacturing compound 185 and intermediates thereof

[0386] In one aspect, this description provides a process for manufacturing an intermediate of compound 185, the process comprising: / ^Cl (i) couple a compound of the formula and a compound from the formula ^NH to form a compound Xj (ii) borylar to (Intermediate I). ^^ci Γ T ; followed by XjX° to form Petition 870260070484, dated 07 / 16 / 2026, pp. 126 / 1215 122 / 573

[0387] In some embodiments, step (i) comprises performing an Ullmann coupling. In some embodiments, step (i) comprises catalyzing the reaction using copper(I) iodide. In some embodiments, step (i) comprises adding a ligand that is N1,N2-bis(furan-2-ylmethyl)oxalamide (BFMO). In some embodiments, step (i) comprises adding BFMO and copper(I) iodide.

[0388] In some embodiments, step (i) comprises dissolving the compound of formula and a compound of formula ^NH in a suitable solvent, followed by the addition of BFMO and then catalyzing the reaction with copper(I) iodide.

[0389] In some forms, step (ii) involves performing a Miyaura Borilation.

[0390] This process provides improved selectivity compared to other processes for manufacturing compound 185. In particular, the use of the starting material provides improved selectivity of the borylation step compared to the use of other substituted benzene rings, such as

[0391] In one aspect, this description provides a process for manufacturing an intermediate of compound 185, the process comprising: (i) react a compound with a compound to form a compound ; followed by Petition 870260070484, dated 07 / 16 / 2026, pp. 127 / 1215 123 / 573 (ii) Cl CN Br O. perform a deprotection of the compound ^Br to Y Cl form a compound ™; followed by Cl CN Br (ii) react the compound to form a compound (iv) with a compound Cl CN Br THE. ; followed by Cl CN Br perform a cyclization of the compound the. to provide (Intermediate II).

[0392] In some modalities, stage (i) comprises a Hurtley arilation. take to

[0393] In some forms, step (iii) involves performing a Michael addition.

[0394] Previously, Intermediate II was prepared starting to From Br Cl and reacting with N-bromosuccinimide and hydrogen peroxide Benzoyl Br for preparing Cl CN Br Cl, then add TMSCN to the formula. The present process is advantageous over the previous process because Intermediate II can be synthesized without the need for benzoyl peroxide, which can be explosive and is therefore not a safe reagent for large-scale use. Additionally, the Petition 870260070484, dated 07 / 16 / 2026, pp. 128 / 1215 Intermediate II, 124 / 573, can be synthesized without the need for TMSCN, which is toxic and therefore not suitable for large-scale syntheses.

[0395] In one aspect, this description provides a process for manufacturing compound 185, the process comprising: / ^Cl (i) couple a compound of the formula and a compound of the formula to form a compound ; followed by (ii) borylation of the compound to form (Intermediate I); Br Cl CN (ii) react a compound f with a compound It's to form a compound ; followed by (iv) performing a deprotection of the compound to form a compound followed by (v) react the compound with a compound to form a compound ; followed by Petition 870260070484, dated 07 / 16 / 2026, pp. 129 / 1215 125 / 573 Cl CN (vi) perform a cyclization of compound0 H ci°YNY° to provide (Intermediate II); and (vii) couple Intermediate I and Intermediate II to provide compound 185.

[0396] This process takes advantage of the improved selectivity in the reaction to produce Intermediate I, as well as the improved safety and reduced toxicity of the reaction to produce Intermediate II.

[0397] In a modality, stage (i) comprises at least one of the following stages: ^_CI (1) dissolve the compound of the formula and the compound of C.oNHem in a suitable solvent, for example a volume of N,N-dimethylacetamide (DMAc) three times the volume of the compound of formula ^^.Cl ; (2) add N1,N2-bis(furan-2-ylmethyl)oxalamide (BFMO, 6 mol%) and tripotassium phosphate (K3PO4, 2 eq.) to the mixture obtained in (1); (3) Add copper(I) iodide (CuI, 4 mol%) to the mixture obtained in (2) and stir the resulting mixture at a temperature of 115 °C for 20 hours; (4) extinguish the mixture obtained in (3) with a suitable solvent, for example by adding a volume of aqueous ammonium hydroxide ci (NH4OH) six times the volume of the compound of formula Br used in step (1) and stir the resulting mixture at a temperature of 50 °C for 1 hour; Petition 870260070484, dated 07 / 16 / 2026, pp. 130 / 1215 126 / 573 (5) filter the mixture obtained in (4) and wash the resulting solid twice with a suitable solvent, for example a volume of NH4OH twice the volume of the compound of the formula used in step (1); (6) Wash the solid obtained in (5) twice with a suitable solvent, for example a volume of water twice the volume of the compound of the formula used in step (1); (7) dissolve the solid obtained in (6) in a suitable solvent, for example a volume of dichloromethane (DCM) five times the volume of the compound of formula Br^^^ used in step (1); (8) add silica to the mixture obtained in (7) and stir the resulting mixture for 2 hours; (9) filter the mixture obtained in (8) and wash the resulting solid with a suitable solvent, for example a volume of DCM seven times the volume of the compound of formula Br^^^ used in step (1).

[0398] In one embodiment, step (ii) comprises at least one of the following steps: (1) Dissolve [Pd cinnamyl Cl]2 (0.2 mol%) and XPhos (0.8 mol%) in a suitable solvent, for example 0.4 volumes of iPrOH, to produce a pre-formed [Pd] solution, stirring the mixture for 30 to 60 minutes at a temperature of 30 °C; (2) dissolve the compound of the formula in a suitable solvent, for example 9 volumes of iProH; (3) Add potassium acetate (KOAc, 2.5 eq) to the resulting mixture. Petition 870260070484, dated 07 / 16 / 2026, page 131 / 1215 127 / 573 in (2); (4) add a compound of the formula / 0 0\ (B2Pin2, 1.5 eq) to the mixture obtained in (3) and degas the resulting mixture; (5) add the pre-formed [Pd] solution obtained in (1) to the mixture obtained in (4) and rinse the resulting mixture with a suitable solvent, for example i PrOH (2 times 0.4 volumes); (6) heat the mixture obtained in (5) to 80 °C for 2 hours; (7) Cool the mixture obtained in (6) to 25 °C, stirring for two hours; (8) filter the mixture obtained in (7) and rinse the solid with a suitable solvent, for example i PrOH (2.4 volumes); (9) distill the combined filtrate and washes obtained in (8) to remove 10 volumes of solvent, for example iPrOH; (10) precipitate the mixture obtained in (9) by adding a suitable solvent, for example heptane (4 volumes); (11) cool the mixture obtained in (10) to 5 °C, stirring for an hour; (12) filter the mixture obtained in (11) to obtain a solid comprising the compound of formula ; (13) wash the solid obtained in (12) with a suitable solvent, for example cold heptane (2 times 2 volumes); (14) Dissolve the solid obtained in (13) in a suitable solvent, for example iPrOH (13 volumes), and add a suitable sequestrant (0.13% by weight), stirring for 2 hours at a temperature of 20°C; (15) filter the sequestrant and wash the resulting mixture with a suitable solvent, for example i PrOH (2 volumes); Petition 870260070484, dated 07 / 16 / 2026, p. 132 / 1215 128 / 573 (16) concentrate the mixture obtained in (15) until dryness at 45 °C under reduced pressure.

[0399] In a modality, stage (iii) comprises at least one of the following stages: Br áCI (i) uíssoivei o composta ua ivimuia F em um solvent capacitado, por exemplo DMAc (5 volumes, a 20°C); (2) add K3PO4 (5 eq) to the mixture obtained in (1); CN (3) add the compound of formula l·^ (0.6 eq) to the mixture obtained in (2) at 20°C; (4) Stir the mixture obtained in (3) for 2 hours at 120°C; CN (5) add the compound of formula (0.6 eq) to the mixture obtained in (4) at 120°C; (6) Stir the mixture obtained in (5) for 16 hours at 120°C; (7) Add H2O (5 volumes) to the mixture obtained in (6) at 20°C and allow phase separation to obtain an organic phase; (8) wash the organic phase obtained in (7) with H2O (1 volume) and Add 25% NaCl (1 volume) to a 20°C aqueous solution and allow phase separation to obtain an aqueous phase; (9) wash the aqueous phase obtained in (8) with 8% aq. NaHCO3 (6 volumes) and PrOAc (5 volumes) at 20°C and allow phase separation to obtain an organic phase; (10) Wash the organic phase obtained in (9) with 25% (6 volumes) aqueous NH4Cl at 20°C and allow phase separation to obtain an organic phase; (11) distill the organic phase obtained in (10) to remove Petition 870260070484, dated 07 / 16 / 2026, page 133 / 1215 129 / 573 solvent; (12) filter the mixture obtained in (11) over a polishing filter Cl CN Br to obtain a compound of the formula

[0400] In one embodiment, step (iv) comprises at least one of the following steps: Cl CNβγύ¥τΥ (1) dissolve the compound of the formula in a suitable solvent, for example toluene (3 volumes) at 20°C; (2) add PTSA (p-toluenesulfonic acid, 0.17 eq) to the mixture obtained in (1) at 20°C; (3) Heat the mixture obtained in (2) to 110°C and stir for hours; (4) Wash the mixture obtained in (3) with 8% (2 volumes) aqueous NaHCO3 at 20°C and allow phase separation to obtain an organic phase; (5) wash the organic phase obtained in (4) with 25% aqueous NaCl (3 volumes); (6) Distill the mixture obtained in (5) to remove solvent; (7) filter the mixture obtained in (6) over a polishing filter ^^.Br η^Όΐ to obtain a compound of the formula <CN.

[0401] In an embodiment, step (v) comprises at least one of the following steps: Cl CN (1) dissolve the compound of the formula in a suitable solvent, for example THF (8 volumes, at 20°C); (2) add NaOMe (0.05 eq) to the mixture obtained in (1); (3) cool the mixture obtained in (2) to 0°C; Petition 870260070484, dated 07 / 16 / 2026, page 134 / 1215 130 / 573 (4) add the compound of formula ο I (1.00 eq dissolved in a suitable solvent, for example 2 volumes of THF) to the mixture obtained in (3); (5) add NaHCO3 (8% aq., 1 volume) to the mixture obtained in (4); (6) filter the mixture obtained in (5) to obtain a filtrate; (7) distill the filtrate obtained in (6) under reduced pressure to remove solvent, for example 6 volumes of THF; (8) dilution of the mixture obtained in (7) with suitable solvents, for example 4 volumes of toluene and 2 volumes of NaCl (aq. at 25%), allowing rapid separation of the layer; (9) wash the organic phase obtained in (8) with a suitable solvent, for example 1 volume of NaCl (aq. at 25%); (10) distill the mixture obtained in (9) under reduced pressure to remove 4 volumes of solvent; (11) dilute the mixture obtained in (10) with 2 volumes of toluene; (12) distill the mixture obtained in (11) under reduced pressure to remove 2 volumes of solvent; (13) filter by polishing the mixture obtained in (12) to obtain the Cl CN compound of formula 0.

[0402] In one embodiment, step (vi) comprises at least one of the following steps: (1) Dissolve p-toluenesulfonic acid (PTSA) in a suitable solvent, for example toluene, at a temperature of 110°C; ci IΒΓγ^|CN(2) add the compound of formula M (dissolved in a suitable solvent, for example toluene) to the mixture obtained in (1) to Petition 870260070484, dated 07 / 16 / 2026, page 135 / 1215 131 / 573 over a prolonged period of time, for example 1.5 hours; (3) dilute the mixture obtained in (2) by adding a suitable solvent, for example NaHCO3 (aq. at 8%, volume 1) at a temperature of 75°C and allow phase separation of the resulting mixture; (4) sow the organic phase obtained in (3), then cool the resulting mixture to 20°C over 2 hours and maintain a temperature of 20°C for an extended period of time, for example, 14 hours; (5) filter the mixture obtained in (4) and wash the solid of the formula (1 volume); resulting with a suitable solvent, for example EtOH (6) dry the solid obtained in (5) at 40-50°C under reduced pressure.

[0403] In a modality, stage (vii) comprises at least one of the following stages: (1) dissolve the compound of the formula , the compound of the formula and Pd(dtbpf)Cl2 in a suitable solvent, for example THF (10 volumes); (2) add Na2CO3 (5.5 volumes aq., i.e., 2.5 eq of base) to the mixture obtained in (1) and stir for an extended period of time, for example 17 hours, at a temperature of 30°C; (3) extinguish the reaction mixture obtained in (2) with a suitable solvent, for example 13 volumes of NH4Cl; (4) filter the mixture obtained in (3) to produce a solid of Petition 870260070484, dated 07 / 16 / 2026, p. 136 / 1215 132 / 573 HI ]f' I formula ; (5) Wash the solid obtained in (4) with suitable solvents, for example wash the solid with THF:H2O in a ratio of 8:2, followed by washing with EtOH and finally washing with heptane. Polymorphic form of compound 185

[0404] In one respect, this description provides a way Hi | CK.N.~ .N. tjOlxx crystalline A of the free base of compound 185:, wherein Form A exhibits an XRPD pattern comprising peaks at approximately 16.5 ± 0.5, 17 ± 0.5, and 17.8 ± 0.5 degrees two-theta using copper K-alpha radiation. In some embodiments, Form A exhibits a pattern of XRPD comprising peaks at approximately 14 ± 0.5, 16.5 ± 0.5, 17 ± 0.5, 17.8 ± 0.5, and 19.5 ± 0.5 degrees two-theta using K-alpha copper radiation. In some embodiments, Form A exhibits an XRPD pattern comprising peaks at approximately 14 ± 0.5, 16.5 ± 0.5, 17 ± 0.5, 17.8 ± 0.5, and 19.5 ± 0.5 degrees two-theta using K-alpha copper radiation, as well as peaks between 21.5-23, 25.5-27, 27-28, and 29.5-31 degrees two-theta using K-alpha copper radiation.

[0405] In some modalities, the margin of error is ±0.4; ±0.3; ±0.2; ±0.1; or ±0.05.

[0406] In some embodiments, the crystal form A exhibits an XRPD pattern comprising the peaks shown in Table 1 below. Table 1 °2 Theta Appearance 14 Single 16.5 Single Petition 870260070484, dated 07 / 16 / 2026, page 137 / 1215 133 / 573 17 Single 17.8 Single 19.5 Single 21.5-23 Multiple 25.5-27 Multiple 27-28 Multiple 29.5-31 Multiple Table 1: XRPD table of the A crystal form of compound 185

[0407] In some embodiments, the A crystal form of the compound Figure 185 displays an XRPD pattern that is substantially similar to Figure 13. Degrading Conjugates

[0408] In one aspect there is a conjugate comprising a compound capable of degrading VAV1. For example, in one aspect there is an antibody-degrading conjugate or a pharmaceutically acceptable salt thereof comprising a compound capable of degrading VAV1. The conjugate includes a compound capable of degrading VAV1 or a pharmaceutically acceptable salt thereof that is conjugated to an antibody via a structural linking moiety. In some aspects, the compound is a compound of any of Formulas (I), (II), (III), (IV), (V), (I-1), (I-2), (I-3), (I-4), (Ia) and (Ib) or a pharmaceutically acceptable salt thereof.

[0409] In some forms, the conjugate has a structure according to Formula (A) below: Bm — (— M— I)a Formula (A) wherein I is a compound capable of degrading VAV1, for example, a compound of Formula (I), (II), (III), (IV), (V), (I-1), (I-2), (I-3), (I-4), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof as defined herein, M is a linking moiety and Bm is a linking moiety capable of Petition 870260070484, dated 07 / 16 / 2026, p. 138 / 1215 134 / 573 to bind specifically to an antigen. The binding fraction can be an antibody, antibody fragment, or antibody-binding fragment.

[0410] In some forms, M is a binder as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker may be a cleavable linker or a non-cleavable linker. In certain aspects, the linker may contain a heterobifunctional group. In the present invention, the term “heterobifunctional group” refers to a chemical moiety that connects the linker of which it is a part to the linking moiety. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to Bm may be achieved through chemical or enzymatic conjugation or a combination of both. Chemical conjugation involves the controlled reaction of accessible amino acid residues on the surface of the linking moiety with a reaction loop in the heterobifunctional group.Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine-mediated coupling, and coupling via an unnatural amino acid incorporated by genetic manipulation, where unnatural amino acid residues with a desired reaction loop are installed in Bm. In enzymatic conjugation, an enzyme mediates the coupling of the linker with an accessible amino residue in the linking moiety. Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and manipulation of N-glycans. Chemical conjugation and enzymatic conjugation can also be used sequentially. For example, enzymatic conjugation can also be used to install unique reaction loops in Bm to be used in subsequent chemical conjugation.

[0411] In some forms, M is a linker as defined in Petition 870260070484, dated 07 / 16 / 2026, page 139 / 1215 135 / 573 WO 2023 / 037268, which is incorporated by reference in its entirety. In some modalities, M is selected from the group consisting of CK,NH where: q is from 2 to 10; Z1, Z2, Z3, Z4, and Z5 are each independently absent or are a naturally occurring amino acid residue in the L or D configuration, provided that at least two of Z1, Z2, Z3, Z4, and Z5 are amino acid residues; ^éo point of attachment to the original (degrading) molecular fraction; e?é o point of attachment to the binding fraction.

[0412] In some embodiments, Z1, Z2, Z3, Z4, and Z5 are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L-glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L-asparagine, D-asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z1, Z2, Z3, Z4, and Z5 are amino acid residues.

[0413] The term “binding fraction” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding fraction may be an antibody, antibody fragment, or antigen-binding fragment. An antibody is a protein generated by the immune system that is capable Petition 870260070484, dated 07 / 16 / 2026, p. 140 / 1215 136 / 573 to recognize and bind to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, an antigen may have more than one corresponding antibody. The term “antibody” here is used in the broadest sense and specifically encompasses monoclonal antibodies, single-domain antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen of interest may be prepared using any technique known in the art that provides for the production of antibody molecules by continuous cell lines in culture.These include, but are not limited to, hybridoma technique, human B-cell hybridoma technique, and EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs for use in this description may be cultured in vitro or in vivo.

[0414] The expert would understand how to provide an appropriate binding fraction for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641-661 (2023), which is incorporated by reference in its entirety. In particular, an antibody, antibody fragment, or antibody-binding fragment used as a binding fraction must be able to target a particular cell surface marker or receptor associated with the disorder to be treated. For example, the antibody trastuzumab may be employed if the desired target is HER2. Petition 870260070484, dated 07 / 16 / 2026, p. 141 / 1215 137 / 573

[0415] In some embodiments, the binding fraction is capable of binding to a selected antigen of α4β7, CD3, CD4, CD20, OX40, CD28, ICOS PD-1, BCMA / TACL, CD52, CD30, CD19, CCR8, CD79b, CD22, CD4, CD7 and CD38 or combinations thereof.

[0416] In some embodiments, the binding moiety comprises an antibody selected from Vedolizumab, Etrolizumab, Teplizumab, Zanolimumab, Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab, Rocatinlimab, Nivolumab, Pembrolizumab, Alemtuzumab, Brentuximab vedotin, Tafasitamab, Loncastuximab, Mogamulizumab, Polatuzumab, Inotuzumab, Epratuzumab, Isatuximab and Daratumumab.

[0417] In some embodiments, the description provides a method of treatment for ulcerative colitis (UC), Crohn's disease (CD), human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), immune-mediated colitis (open PhI), type 1 diabetes (T1D), pouchitis, graft-versus-host disease (GvHD), celiac disease, rheumatoid arthritis (RA), psoriasis (PsO), late-onset rejection, pemphigus vulgaris, cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), Graves' disease, relapsing-remitting / primary progressive multiple sclerosis (RR / PPMS), lupus nephritis,Systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura, nephrotic syndrome; idiopathic thrombocytopenic purpura, microscopic polyangiitis, atopic dermatitis (AD), transplant rejection, juvenile idiopathic arthritis, multiple sclerosis (MS), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia, precursor cell lymphoblastic leukemia, anaplastic large cell lymphoma; Hodgkin's disease; Mycosis fungoides; peripheral T-cell lymphoma; primary anaplastic large cell lymphoma; T-cell lymphoma, adult T-cell leukemia-lymphoma; diffuse scleroderma; germ cell cancer; malignant mesothelioma; mastocytosis; non-Hodgkin's lymphoma; Sézary syndrome; Solid tumors, HIV infections. Petition 870260070484, dated 07 / 16 / 2026, page 142 / 1215. 138 / 573 1. Chronic lymphocytic leukemia; Follicular lymphoma; Granulomatosis with polyangiitis; Idiopathic thrombocytopenic purpura; Lymphoproliferative disorders; Microscopic polyangiitis; Marginal zone B-cell lymphoma; Relapsed-refractory diffuse large B-cell lymphoma (R / R DLBCL); B-cell lymphoma; Precursor B-cell lymphoblastic leukemia-lymphoma; Precursor lymphoblastic leukemia-lymphoma; Mantle cell lymphoma; Waldenstrom's macroglobulinemia; Cutaneous T-cell lymphoma; Richter's syndrome, relapsing / refractory acute lymphoblastic leukemia (R / R-ALL), precursor lymphoblastic leukemia-lymphoma, precursor B-cell lymphoblastic leukemia-lymphoma, chronic myelogenous leukemia (CML), cutaneous and peripheral T-cell lymphoma, acute biphenotypic leukemia; Burkitt's lymphoma, T-cell acute lymphoblastic leukemia (T-ALL), relapsing / refractory multiple myeloma (R / R MM), melanoma, acute myeloid leukemia; chronic lymphocytic leukemia;Myelodysplastic syndromes; plasmablastic lymphoma; precursor T-cell lymphoblastic leukemia-lymphoma; amyloid light chain amyloidosis, multiple myeloma (MM), and solid tumors in an individual in need thereof, wherein the method comprises administering the antibody-drug conjugate to the individual.

[0418] Exemplary combinations of antibodies, target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises an antibody listed in the table below and targets an antigen listed in the table below. In some respects, the description provides a method of treating a disorder listed in the table below, the method comprising administering to an individual in need thereof an antibody-drug conjugate comprising an antibody listed in Table 2 below. Table 2 Target Commercial Indication Petition 870260070484, dated 07 / 16 / 2026, p. 143 / 1215 139 / 573 α4β7 Ulcerative colitis (UC), Crohn's disease (CD), human immunodeficiency virus / acquired immunodeficiency syndrome (HIV / AIDS), immune-mediated colitis (open PhI), type 1 diabetes (T1D), pouchitis, graft-versus-host disease (GVHD), celiac disease Vedolizumab, Etrolizumab CD3 Type-1 diabetes (T1D) Teplizumab CD4 Rheumatoid arthritis (RA), psoriasis (PsO), late-onset transplant rejection Zanolimumab CD20 Pemphigus vulgaris, cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), Graves' disease, relapsing-remitting / primary progressive multiple sclerosis (RR / PPMS), lupus nephritis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), thrombocytopenic purpura Thrombotic, nephrotic syndrome; idiopathic thrombocytopenic purpura, microscopic polyangiitis Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab OX40 Atopic dermatitis (AD) Rocatinellimab CD28 Transplant rejection, rheumatoid arthritis (RA), idiopathic arthritis Petition 870260070484, dated 07 / 16 / 2026, page 144 / 1215 140 / 573 Juvenile PD-1 Autoimmune / inflammatory disorders Nivolumab, Pembrolizumab ICOS Autoimmune / inflammatory disorders BCMA / TACI Autoimmune / inflammatory disorders CD52 Multiple sclerosis (MS), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia, precursor cell lymphoblastic leukemia-lymphoma Alemtuzumab CD30 Anaplastic large cell lymphoma; Hodgkin's disease; mycosis fungoides; peripheral T-cell lymphoma; primary cutaneous anaplastic large cell lymphoma; T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), adult T-cell leukemia-lymphoma; diffuse scleroderma; germ cell cancer; malignant mesothelioma; Mastocytosis; non-Hodgkin's lymphoma; Sézary syndrome; Solid tumors, HIV-1 infections Brentuximab vedotin CD20 Chronic lymphocytic leukemia; diffuse large cell lymphoma Rituximab, Ublituximab, Petition 870260070484, dated 07 / 16 / 2026, p. 145 / 1215 141 / 573 B; follicular lymphoma; granulomatosis with polyangiitis; thrombocytopenic purpura; idiopathic; lymphoproliferative disorders; microscopic polyangiitis; non-Hodgkin lymphoma, marginal zone B-cell lymphoma Ofatumumab, Ocrelizumab, Inebilizumab CD19 Relapsed-refractory diffuse large B-cell lymphoma (R / R DLBCL), follicular lymphoma (FL), marginal zone B-cell lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), precursor B-cell lymphoblastic leukemia-lymphoma, precursor lymphoblastic leukemia-lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia Tafasitamab, Loncastuximab CCR8 Adult T-cell leukemia-lymphoma; Cutaneous T-cell lymphoma; Mycosis fungoides; peripheral T-cell lymphoma; Sézary syndrome; Mogamulizumab CD79b; Diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), follicular lymphoma, chronic lymphocytic leukemia (CLL), lymphoma; Polatuzumab Petition 870260070484, dated 07 / 16 / 2026, page 146 / 1215 142 / 573 Non-Hodgkin's lymphoma (NHL), Richter's syndrome CD22 Relapsed / refractory acute lymphoblastic leukemia (R / R-ALL), precursor lymphoblastic leukemia-lymphoma, precursor B-cell lymphoblastic leukemia-lymphoma, chronic myelogenous leukemia (CML), non-Hodgkin's lymphoma (NHL) Inotuzumab, Epratuzumab CD4 Cutaneous and peripheral T-cell lymphoma, acute biphenotypic leukemia; Burkitt's lymphoma CD7 T-cell acute lymphoblastic leukemia (T-ALL) CD38 Relapsed / refractory multiple myeloma (R / R MM), melanoma, acute myeloid leukemia; chronic lymphocytic leukemia; diffuse large B-cell lymphoma (DLBCL); follicular lymphoma; mantle cell lymphoma; myelodysplastic syndromes; plasmablastic lymphoma; precursor B-cell lymphoblastic leukemia-lymphoma; precursor T-cell lymphoblastic leukemia-lymphoma; T-cell lymphoma; Macroglobulinemia of Isatuximab, Daratumumab Petition 870260070484, dated 07 / 16 / 2026, p. 147 / 1215 143 / 573 Waldenstrom, amyloid light chain amyloidosis, multiple myeloma (MM), solid tumors

[0419] In some forms, I is one of the Compounds 101-510.

[0420] In some embodiments, the description provides a pharmaceutically acceptable antibody-drug conjugate or salt thereof in accordance with Formula (A1): Formula (A1) where X, Y, R1, R2, R3, R4, R5, R6, R7, L1 and n can be defined anywhere here, M is a binding fraction and Bm is a binding fraction that is capable of specifically binding to a protein, as defined above. In some embodiments, X, Y, R1, R2, R3, R4, R5, R6, R7, L1 and n are defined to provide a compound selected from any of Compounds 101-510.

[0421] In some embodiments, the description provides a pharmaceutically acceptable antibody-drug conjugate or salt thereof according to Formula (A2) or (A3). Formula (A2) Petition 870260070484, dated 07 / 16 / 2026, p. 148 / 1215 144 / 573 Formula (A3)

[0422] In some embodiments, the description provides a pharmaceutically acceptable antibody-drug conjugate or salt thereof in accordance with Formula (A4): where X, Y, R1, R2, R3, R4, R5, R6, R7, L1 and n can be defined anywhere here, M is a binding fraction and Bm is a binding fraction that is capable of specifically binding to a protein, as defined above. In some embodiments, X, Y, R1, R2, R3, R4, R5, R6, R7, L1 and n are defined to provide a compound selected from any of Compounds 101-510.

[0423] In some embodiments, the description provides a pharmaceutically acceptable antibody-drug conjugate or salt thereof according to Formula (A5) or (A6). Petition 870260070484, dated 07 / 16 / 2026, page 149 / 1215 145 / 573

[0424] The antibody-drug conjugate may be administered as part of a pharmaceutical composition. The pharmaceutical composition may include excipients such as those listed herein. Non-Limiting Exemplary Compounds

[0425] In some embodiments, the compound is selected from the group consisting of the compounds outlined in Table 3 or from a pharmaceutically acceptable salt thereof.

[0426] Unless otherwise indicated, the symbol * in a chiral center denotes that this chiral center has been resolved (i.e., it is a unique epimer) and the absolute stereochemistry at that center has not been determined. Table 3 No. de Composto Estrutura 101 HH,N. 102 z \ z / KJ _____ / \ - \=ZP \ ZI o 103 h II O^N^O .0. XJXjíXjr Petition 870260070484, de 16 / 07 / 2026, pág. 150 / 1215 146 / 573 104 \ o \ / —$ P \ ZI o 105 H yy XYY c,x^x^y^x 106 O Λ ZA õ-K o )==^ XZ 2 0' 107 О~Ί 0==^..>\ 0>___N___.0 N Cl r H II 1 i 1 Γ 108 \ \ y— oon / =\ \ / —— '=\ / ° \ ZI O 109 o \ ZI / ^\ '° Vt fí~ “ od 110 o XZ 2 o 2=\ δ-Ο zr z N z 111 o Iz / o >=\ õ— z—° 133 s. o> S] Cl ' H s^N' >° H2N 134 H . θ> Xjl HN, >° 135 cr H Ci\ ***^1 1 X / NX 136 NJ Cl θ'' H 137 F. 1 °^y H -N 'PF χ II 1 IJ 138 ci„ °> S] Cl HN« P H2N' L 139 X o> S| Cl x H Sz'1^' P Petition 870260070484, de 16 / 07 / 2026, pág. 154 / 1215 150 / 573 140 The ci ||the XxXx^x-Xx 141 the Gc CK ^N. x,O x-. .0. x < / XJojQt 142 Η 0^. -Ν. Λ) ΧΧαΧΧ 143 αχ / ία Η 144 ν JLJ ci X xL __Μ' << θ Ο^Ν^Ο Ν\ J Η 145 __Μ' << Η 146 Γ^Ί^01 ν JLJ ci X xL __' << Ο^Ν^Ο Ν\ 1 Η 147 αίοΐχ Η Petition 870260070484, de 16 / 07 / 2026, pág. 155 / 1215 151 / 573 Petition 870260070484, de 16 / 07 / 2026, pág. 156 / 1215 152 / 573 156 Η 'CÇyCCO 157 —-Nl hn—' Cl γ II N 158 \ / —P \ ZI O 159 HO>. ^N. ..O Ύ YX jYYY ji N 160 1 z zp O \ I- \=< .o \ ZZ O 161 H 1 1 XXajC^ 162 o H 1) XXXjQt 163 H ^7 XjÇlX^T Petition 870260070484, dated 07 / 16 / 2026, p. 157 / 1215 153 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 158 / 1215 154 / 573 172 xL·. Cl IL Jx ______ ct n^o γ\ H r ZN— 173 _Nl h NY|] Cl 1 1 174 1 H xíX X*\ (K .N. .,0 r^N |^|1 Cl p 0 175 H 176 H- O ϸ.\ xxi ^NOO0LíYJf 177 -~Nl H n^x^ Y^Y ci YY 178 ccjo^x H 179 χ^·Ν -^X Cl \ Jx x\ H IL / N— Petition 870260070484, dated 07 / 16 / 2026, p. 159 / 1215 155 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 160 / 1215 156 / 573 188 Η XCO^· 189 Η XCO^· 190 Η X) Cl — 191 Ο H ΧλτΎΎ0 192 —N ZL ON XXaX> 193 N==l —N 1 HH XXjyCj 194 H —-z.l O^^N^^z.0 Cl i 195 Η Γ^7 CU Petition 870260070484, dated 07 / 16 / 2026, p. 161 / 1215 157 / 573 Petition 870260070484, de 16 / 07 / 2026, pág. 162 / 1215 158 / 573 . Petition 870260070484, de 16 / 07 / 2026, pág. 163 / 1215 159 / 573 212 Vo H 1 \ O- ^5.0 XJoljQt 213 ο Õ—4 A Ο ΖΖ 2 ο 214 Vt / ° / —ζ -—\ / ο \= / ζζ / ο 215 ο \ ΖΙ / =\ '° ζζ ο 216 ζν __ / ο '=\ / ° \ ΖΙ Ο 217 ζν __ / ο '=\ / ° \ ΖΙ Ο 218 π ζ— \ / —— -Ο \ ΖΙ Ο 219 Η Ο^. .-Ο / χ ci ί| 0^° Petition 870260070484, de 16 / 07 / 2026, pág. 164 / 1215 160 / 573 220 O ζ-ωχ __ / iro / =\ ο \ ζ-Ρ \ ΖΙ Ο 221 O 'ÓQjX / cx'- 222 O 223 ο ΧΖ 2 Ο λ õ—y ° \ Ο 224 ο ΧΖ 2 °Ζ Λ-λ õ—C y ° \ ζχ 225 \ ζ— ο= / / \ / —- '=\ / ° \ ζζ O 226 Π Π \ / —- / ° \ ζζ ο 227 Ο ΧΖ 2 Ο Λ ό—C y ΧΖ Petition 870260070484, de 16 / 07 / 2026, pág. 165 / 1215 161 / 573 228 Λ '° / / 1 Η Η ΥΥ ΙΥ ι1 Υ Υ 0 229 o'! Η Ν ίΓ Υί CI γ γ 230 / ==ι Ο 231 R \ ζ- \=Ζ ο \ ΖΙ Ο 232 Ο= / Ζ ζ—Ζ \ Ζ-^=( .Ο \ ΖΙ ο 233 Γ0 θ-\ ζ ° / =^ ζζ / θ' 234 ο \ ΖΙ / =< ο 4 λ— Τ' 235 Õ—4 Λ ° V— χζ / Ο Petition 870260070484, de 16 / 07 / 2026, pág. 166 / 1215 162 / 573 236 ο \ ZI / =< ο \ / ° ζ—\ V— -η π τι 237 UU V— Uζ Ο λ Õ—Ç / ο )= / ΖΖ 2 ο' 238 ο \ ζζ Ζ=Ζ Ο Ζ θ Ζ. λ LL 5——ί U. ζ—Ζ 239 ΛΧ°ΟύΟ Η 240 Ο \ ΖΙ / =\ '° % 241 ο \ ΖΙ / =\ '° Ζ ο ο ο / Ç ο 242 ο \ ζζ / =< Ο Ζ —Õ \ “ Ζ—Ζ Petition 870260070484, de 16 / 07 / 2026, pág. 167 / 1215 163 / 573 243 Η Tçyxo 244 ο \ ZI / =< O ά λ LL U- 5—U- Z—( O= / / 245 °'^zZ%Yz'F H 1 1 XXxXX 246 Οχ / ^ H 1 ] 247 j—z \ '—z θ-\ / ° jT^ ZZ 2 o 248 Η Η Γ \ 0-s.^N^ / O .N. YY Ϊ1 ΓΥ Y 249 o ZZ 2 o / =\ Õ— o ^z 1 251 P o M: \ Z-^=( .O \ zz o Petition 870260070484, de 16 / 07 / 2026, pág. 168 / 1215 164 / 573 252 0 253 A. α—\ / O / = / zz / ο 254 Q Ο z—ç O—X / o / =' zz / o' 255 ar 1 256 P —z 2—\ o o-fA o / =^ zz \ ​​257 H , O. _N. _,O χχ XX χχ / in r ii N r−0 258 FxJ H >X. x~xx\ O. .N. ΛΛ FN |Ί Cl and O.. x <L. kx. JL Jx jx J ° Petition 870260070484, dated 07 / 16 / 2026, p. 169 / 1215 165 / 573 259 ο ξ HN—¥ N—i °=( / / ° ci / — Νν_θ_θ 260 H OÇyXX» 261 o 262 YH ^k xís^ χθ í ιΎΊct f YY o. .^ík X J x!kO f YY o. ·>—CT N^O II HO 264 ?Ύ ^υ\ύί k ^N JJ Cl xk Ύ ·>—ct n ^o II H o 265 o II H xA, x-\ O- .N_ UJ Ç N ]^ |] Cl Y 266 O οΥοο. Petition 870260070484, dated 07 / 16 / 2026, p. 170 / 1215 166 / 573 267 jáLoUu, Η 268 Η , in r ιι Ν γL Ux Us. U*sU Ux J 269 H 270 The son 271 the son0 272 the TOXPHOL) 273 the H II .N. ^5.0 JU _ νΧχΧΛΧ k / N^N 274 o Η II Ο- .N. Xi N in ii n ysA Petition 870260070484, dated 07 / 16 / 2026, p. 171 / 1215 167 / 573 275 \ TT \ 1 í|x> xk x^S. then .N. A / H II 0 276 H OCyXX» 277 H C N f || Cl X χ χΝ. xL ^xK^xskx^LxJ ^Xji^ 278 HP 279 HP 280 0 °C / \ N—\ \=< Cl Where \ / ° \— NH θ' 281 H OÇyxn<> Petition 870260070484, of 16 / 07 / 2026, p. 172 / 1215 168 / 573 282 0 Cl Z ff\ / ° NH oz 283 o 284 H , OÇyXCf 285 H 286 H ΧΟψϊ 287 o Axupy 288 H 289 Petition 870260070484, of 16 / 07 / 2026, p. 173 / 1215 169 / 573 290 291 0 HN \ / ~\ / cr / =\ 0 292 00¾. o 293 294 O 295 o ÔCO1£pÒ'° 296 XÇyOY 297 δχιΓύ* Petition 870260070484, of 16 / 07 / 2026, p. 174 / 1215 170 / 573 Petition 870260070484, of 16 / 07 / 2026, p. 175 / 1215 171 / 573 305 ο F r*FF Cl xk O^N^ H Ό 'N' 306 F'. FT FO' ^N. 5.0 jLíÇl H -'Nx«^0 307 O-, H ,N, ^.O Jl Cl 308 Jl f^ll g cr 'Ν' H ^0 Cl ,Ν^, 309 Jl ιΊι u cr 'N' H ^0 Cl z 310 fi 0 ° N- N- H- H- H Η / H 311 cr 'N' H Jl ^o Cl ^S^S'N'Z^ ZO Petition 870260070484, dated 07 / 16 / 2026, p. 176 / 1215 172 / 573 312 CK H Cl 0 313 0 V Cl x; tf 'NZ O' ^'Ν'^Ο n' Π H 'n- / 314 ¢-° H 'Nx^° jL Cl 315 cr 'rr ^0 Cl 0 H Γ N 316 CK, HN,, 0 Clx N ) ) _^o nC N / 317 cr Jl Cl H cr 318 0 í ci « 'N^ ct n H zAsO' Petition 870260070484, dated 07 / 16 / 2026, p. 177 / 1215 173 / 573 319 0 V— NH \ '---Ç Cl 0 320 U° \ y z--' \ / —θ p \ zx O 321 η 1 1 y 0%. _N. z.0 YY Ϊ1 ΓΥ 322 Uu.^1 O= / / Z--' \ / —θ p \ zx O 323 n / Z--f \ / —— P \ zx O 324 / —o \ / —- ^=( p \ zx O 325 u ÍYijY zA. zA^ Cl zíA zA. < N O-^N^O 1 1 H °x / \ Petition 870260070484, dated 07 / 16 / 2026, p. 178 / 1215 174 / 573 Petition 870260070484, dated 07 / 16 / 2026, p. 179 / 1215 175 / 573 332 Tl Η k CK -Ν. .ο xxjcxt 333 ο ( ζι ο \W 334 ο 0 νΡ“ 335 Η Ο^Ν^Ο αΝτ° Ν Ν 1 336 Η 1 1 xjCoc^ Petition 870260070484, dated 07 / 16 / 2026, p. 180 / 1215 176 / 573 337 Voi L / NH 0 338 OH XXjÇlJf 339 \ H yó^o° 340 h ro TT i nC^ ii Y~Y\Y^Y\Y |TJ 341 _kY^Í ' H VN^l CI°YNY° U* 342 o xz / (0 \=xn yj / ^z < Yo z 343 ç>° zp - x” / o TZ \ o7 Petition 870260070484, de 16 / 07 / 2026, pág. 181 / 1215 177 / 573 344 η Δ Τ Τ ι ίΥΥ Γ γγ 345 Ο χζ / Ο7 \=\ õ -yj 346 γγ0 η ΥΥΥ ? γ γ Ν\ΔνΔΔΥ XJ 347 ο \ ζτ / = / ο 4 / 7 - A Π Π 348 LL 1 Õ y ο χζ \ Ο 349 ΓΥθ Η ΥΌγγΤ 350 Ç <Y ΟιΜγ° ο 351 (\ Ζ A / / \ / - \ Ζ=Ε Ο Petition 870260070484, de 16 / 07 / 2026, pág. 182 / 1215 178 / 573 352 o \ zx o 353 o \ zx / = / _o A / / θ (\ ZA / / Z—Z / 354 QO o \ zx o 355 i~0 Λ1 h X Yil ? Ύ Y Xj 356 Z—v> A / / o \ zx o 357 o xz / O_ õ—(( \ <o>O 358 H u ? Υ T XX Petition 870260070484, de 16 / 07 / 2026, pág. 183 / 1215 179 / 573 359 η 360 Η 361 Η ι 1 O^N. χθ „ / xAJ TYaJY F 362 tX^cr 363 Η Υ^Ν'Ν^ T^yX>° 364 365 Petition 870260070484, de 16 / 07 / 2026, pág. 184 / 1215 180 / 573 366 H φ 71 Ι T T 0 ΑχΑχ / ^\Α\Α XJ 367 Οχ / \ κ° >τΝΗ 0 368 Γα^ Α^χι FAA l^nh ο 369 >=\ ο (\ ζ A / / \ / \= / Ο \ ΗΙ Ο 370 Η Ο^χ-χ / Ν 0^ Ν < Η [I 1 ill \^ν Λ^Α Αχ Αχ > F^AyA^ 371 1—ΝΖ / 1 Η rriyy Petition 870260070484, de 16 / 07 / 2026, pág. 185 / 1215 181 / 573 372 373 H Çj XXXXJT 374 H OnQfxT 375 H / n O^N^O χ^χ^-χ^Ν P kXXxU lYV XJ 376 H Nz / vx Cl V । J 11 i 1 JN 377 H S_x^x^ Ο^Μχ,Ο ύω ΙΧΙΧΤ 378 H ΙΝΟ^ΙΧ° 379 H CK χΟ XXajQ Xx^Qp^ Petition 870260070484, de 16 / 07 / 2026, pág. 186 / 1215 182 / 573 380 IZ z / ) \\ / / õ—\ O IZ 2 oz 381 H 382 Z—\ o=( / -nz—' 4 z / / o \ ZT o 383 o IZ / oz \=\ õ -γ )> Z 7 Z^. o=( / -Z.—' 384 z^ / / / Ά \ / - \ ZI O 385 HP । ° <xx N < H || | ill VN 386 / —o \ ZT o 387 z^ z—' Ω \=Z O \ ZI O Petição 870260070484, de 16 / 07 / 2026, pág. 187 / 1215 183 / 573 388 V'-A ci°vV° TXXXJ 389 o iz / O \=\ õ — / zy / —H \ <f>õ \ ZI ο 393 / / 7 H / \i=7 O^ / N^O N vOLCXY0 394 0 Ί / / Z \ 'λ \= / O \ ZI O Petition 870260070484, de 16 / 07 / 2026, pág. 188 / 1215 184 / 573 395 χγ O^N^O N'N ХХиХХЛ0 396 NX / / 7 °^N^° r, ^ .,-N N TXXXX? 397 HA / Nx CXN^O TXXXX? XX 398 % õ—ç yo IZ / a 399 o \ ZI niuô---X / = / o \\ / 7—" a 400 H ✓Νχ_ / \ΖΝ< O^ / N^O Γ YYf 7 í YY XJ 401 / =zx z / > \\ / / õ—YX ° / xz \ o Petition 870260070484, de 16 / 07 / 2026, pág. 189 / 1215 185 / 573 402 Ya Cl% HA° 0 Cr 403 Π H Cl% HA 0 Cr 404 Va XX 0 c'o' ^N' HX) 405 y μ o ci°V Cj H Νχ^ί >0 406 H Ο.,Ν,Χ) γΟΙ 0 JL °->° kJAN" 407 L / N\XAx π Η Ί Cl% H / N\ XD ° AAx Petition 870260070484, de 16 / 07 / 2026, pág. 190 / 1215 186 / 573 408 H / γΑγΑ ci°VN^° —N 7 T H ill \^N XJ 409 Nγ'Ά αΥΫ 0 ΥΥχΥχΥΥ [fjj 410 1 I H ,Ν\ Λ Ο^ / Ν^Ο ΥιΠ ι Τ Τ 411 Υ|Π ι Τ Τ 0 'ΑΥυ / Ά 412 Ά Υ° b—ζ (\ ζ A / / \ / -- \ Z:c Ο 413 / \ Η V / N^ Λ CK / Ν^Ο / Τ Υ|1 ? γ τ 0 ΥΥχΥΥ-Υ XX 414 Υ^Ι Η νΝχζΧ Λ CE / N-^D υ γγ ? γ τ 0 ΥΥχΥχΥΥΥΥ XX Petition 870260070484, de 16 / 07 / 2026, pág. 191 / 1215 187 / 573 415 H AAiI ci0YNf° XT 416 ου7 ZH— O \ zx O 417 H L / F ΟγΝ oc| XT 418 ο ιζ \ Ο_ Õ —7 2 °νζ 419 rNY° η ^Νγγ οι°γΝγ° FAA^yM 420 H Υ Υ Υ ? ΓΑΑ ι ιχ 421 H CA / N'.O Λ1 / 0. Τ Υ ι1 ΡΓΑ γ Petition 870260070484, de 16 / 07 / 2026, pág. 192 / 1215 188 / 573 422 H Υ Y ? YYV Ί] ΑΧ 0 423 ο \ ζ^-Ζ ο \ / -- CX / σκ ο° 424 υ H οι°γΝγ° 425 0 H -νΛν^^, οι°γΝγ° 426 H ria^rr 427 λΡ >=\ ο (\ ζ Ά / / \ / \ ζτ ο 428 i TT 0 ΑΑΑxΑxΑ Petition 870260070484, de 16 / 07 / 2026, pág. 193 / 1215 189 / 573 429 f OHC|O?:;:.N 0 XX 430 HP N. n. N < T II I ill XJ 431 H rn ci Y y O^O 432 o xz / oz \=\ õ -P )> oz γ z—, O=( / Z.—* 433 8 y / / \=Z o \ Z:L o 434 H n°^NX^° KN Ti X Cl L^UJjXJ 435 z^. o=( / z—' (\ z V / / \ / \=Z o \ ZI o 436 z—< o=( / TI Z—' \ / ~^=\ O \ ZI o Petition 870260070484, de 16 / 07 / 2026, pág. 194 / 1215 190 / 573 437 H Υ Y ? CTV V 438 H °Λ ZNV O^Ν^Ο Υ Τ ? ίΥ'° 439 ο izb δ ° ΗοΥ 440 ο \ ΖΙ / = / ο 4 / 7 οζ 441 ο \ ζχ / = / _ο ζ^~ °^( / ο 442 H °χΝχ° CI III \\ Τ Τ 0 Ν= / 443 UYp η Tf Petition 870260070484, de 16 / 07 / 2026, pág. 195 / 1215 191 / 573 444 C / ° '—z O IZ \ o 445 h F \ / N. / x Λ Οχ,Ν^Ο XXjxXY 446 F\ / -x xx xO h XXaÍXJ 447 o IZ \ O_ \=\ õ—X 8 448 H xN. >X / -tx Λ Ο^χΝ^χΟ ^ιΠ i TT 0 \^ΥΥΥϊΥχΥΥχΧΥ 449 fJi 8^8 η 450 / =( ° X / Ζ Υ= / ο \ ζ=ι· ο Petition 870260070484, de 16 / 07 / 2026, pág. 196 / 1215 192 / 573 451 The tz \ õ —ά ζΖ y ο Ο / 452 < The ο ο \ ζτ ο 453 Ζ=\ ζ / ) \\ / / Õ— / 2 ο )=7 ΙΖ \ ο 454 The °γΝγοα fY'Y°ro 455 the \ ΖΞΕ / = / ο 4 / 7 ~ The οζ 456 0 θ' / —\ 0 \ / ΗΝγ 0 457 Γ~ η Υ Υη ? Υ Τ XX Petition 870260070484, de 16 / 07 / 2026, pág. 197 / 1215 193 / 573 458 RFFYH 0 459 0 H t >0 r»c 460 Cl· jl JJ] ^0 / > N 0' H 'O 461 x / N' ,0 Cl°^ H í>° FH 462 ,0 DD Cl 0<: HDD ij 463 0 FF Clo^ O5 H '0 Petition 870260070484, de 16 / 07 / 2026, pág. 198 / 1215 194 / 573 464 H 1 Γ ΧΧΧΧΧ 465 0 / ==x / =x UCN VAY4 Cl / —\ 0 \ / hna 0 466 0 hnA o=( ) 0 Cl 2—' 467 H 11 <Α / Ν,χΟ Λ N. / 0 XXTjOt 468 o °É 469 F Γ'Αέ h Petition 870260070484, de 16 / 07 / 2026, pág. 199 / 1215 195 / 573 470 A ° / =\ o IZ / o 471 o \ Z=E o 472 H °ΔΝΔ° oi / AAX / N i T i \\ T ' / > 473 HQ^N^Q OI / ΥΥΝ 1 Τ ? \\ Ί u ΥΑχΑγΑΥ No 474 \ 1 HA / IY Λ OxX / Nx / O τ t π ΐ XJ 475 Η 1 °YNY° ci PfN / V XJ 476 Xf Π FH TXxOlT Petition 870260070484, de 16 / 07 / 2026, pág. 200 / 1215 196 / 573 477 p ° \ ζ \ / -- \ Z=L ο 478 ° ^00 \ ΖΙ ο 479 ζ r ο 0 ο \ ζτ ο 480 ΧΧι / XXX ( X / ° η ° 481 ΥΧ. Ο 482 Ο \ ΖΙ 7Ζ= / Ο XX— ο ρ ΖΙ 483 ο τζ / Ο \=ξ - Χ\ # X ζι Petition 870260070484, de 16 / 07 / 2026, pág. 201 / 1215 197 / 573 484 jfX HXXX XX? CTN^OH 485 XXXjQ> iTj 486 þþhod 487 XX & XX CT N^ON H H 488 H / °XyX> 489 H Yn'N^ T^yoo 490 H μ TÇyCO 491 H h T:ÇyOõ Petition 870260070484, de 16 / 07 / 2026, pág. 202 / 1215 198 / 573 492 H H xyoy 493 H n 494 χΧτο H H 495 TÇyÕO 496 H O^Νχ^Ο η ZVN XJOLÁXy0 ΧΧΧθχΧΧ-· 497 H n °YNr°ci χν,κ 498 H <νΝ- °VNV° ΓΙ χ^χ^Ν Ν ΤΧαΧΧ? χτ 499 η Γ^Ν'Ν^ T^yOO Petition 870260070484, de 16 / 07 / 2026, pág. 203 / 1215 199 / 573 Petition 870260070484, de 16 / 07 / 2026, pág. 204 / 1215 200 / 573 507 fX XX α XX ° η ° γγ 508 Η At π / μ 509 η / X TÇyCü 510 Λ X ίι UXN Ο-^Ν^Ο Η νγ Ν Petition 870260070484, de 16 / 07 / 2026, pág. 205 / 1215 201 / 573

[0427] A general synthetic strategy that can be used to prepare compounds of Formula I is illustrated in General Scheme 1. An aryl halide AA where Zi is any suitable halogen (e.g., Br or I) can be coupled with an aryl boronate AB using any suitable metal-catalyzed coupling conditions. The specific groups X, Y, L1, R1, R2, R3, R4, R5, R6, and R7 are selected based on the desired groups in the compound of Formula I. The desired compound can be prepared using a Suzuki coupling reaction with a palladium catalyst complex such as Pd(dtbpf)Cl2 (DBTF = 1,1'-Bis(di-tert-butylphosphino)ferrocene) or Pd(dppf)Cl2 (dppf = 1,1'-Bis(diphenylphosphino)ferrocene) in the presence of a base such as potassium phosphate. A suitable solvent such as DMF (dimethylformamide) or dioxane may be used, or a suitable solvent mixture such as dioxane and water may be used.

[0428] Alternatively, compounds of formula I can be prepared from the reaction of an aryl boronate of formula AC and an aryl halide of formula AD using Suzuki cross-coupling conditions. Z2 is any halide (Br, I, Cl) or triflate group that can be used in a metal-catalyzed coupling reaction from AD to boronate AC. The desired compound can be prepared using a Suzuki coupling reaction with a palladium catalyst complex such as APhos Pd G3, Brettphos Pd G3, Pd(dppf)Cl2 or Pd(dppf)Cb <H2Cl2 na presença de uma base adequada tal como K3PO4. Um solvente adequado tal como DMF (dimetilformamida) ou dioxano pode ser usado, ou uma mistura de solventes adequada tal como dioxano e água pode ser usada.

[0429] Aryl boronate AC can be prepared from aryl halides AA using Bis(pinacolato)diboron, a catalyst such as [PdcinnamylCl]2 and a ligand such as Xphos. A weak base such as sodium acetate, in a solvent such as iPrOH, can be used. The reaction Petition 870260070484, dated 07 / 16 / 2026, page 206 / 1215 202 / 573 can be performed at a high temperature, for example 60 degrees Celsius, 80 degrees Celsius or 100 degrees Celsius. General Scheme 2

[0430] General Scheme 2 provides an exemplary synthetic procedure for the preparation of the starting material AA used in General Scheme 1. The compound AE, where Zi is a suitable halogen atom (e.g., Br or I), can be converted into a benzyl halide of formula AF using conditions for benzyl halogenation. For example, N-bromosuccinimide and benzoyl peroxide in a solvent such as carbon tetrachloride at elevated temperatures (e.g., 80 degrees Celsius or 90 degrees Celsius) yield AF.

[0431] A benzyl nitrile intermediate such as AG can be prepared from benzyl halide AF by treatment with a cyanating reagent such as trimethylsilyl cyanide, in the presence of a desilylation reagent such as tert-butylsilyl fluoride or tetra-n-butylammonium fluoride (TBAF) and a solvent such as dichloromethane at a temperature such as 0-25 degrees Celsius.

[0432] The Michael addition of a compound of formula AG with an acrylate such as compound AH can be performed using a base Petition 870260070484, dated 07 / 16 / 2026, p. 207 / 1215 203 / 573 such as sodium methoxide in a solvent such as tetrahydrofuran at room temperature. Rs1 is any suitable alkyl group that is labile to acid treatment. For example, Rs1 may be tert-butyl at a temperature such as 0-25 degrees Celsius.

[0433] Compound AI can be converted into intermediate AA by treatment with a strong acid such as sulfuric acid, in a solvent such as acetic acid, at elevated temperatures (e.g., 90 degrees Celsius). General Scheme 3

[0434] General Scheme 3 provides an alternative exemplary synthetic procedure for the preparation of the starting material AA used in General Scheme 1. The compound AJ, where Z2 is a suitable labile halide group (e.g., fluorine), can be subjected to a nucleophilic aromatic substitution (Hurtley arylation) with a reagent such as tert-butyl cyanoacetate AK. A solvent such as dimethylacetamide in the presence of a base such as potassium phosphate can be used to originate AL.

[0435] Benzyl nitriles of formula AG can be prepared by hydrolysis and decarboxylation of AL by treatment with an acid such as p-toluenesulfonic acid, in a solvent such as Petition 870260070484, dated 07 / 16 / 2026, page 208 / 1215 204 / 573 toluene at 120 degrees Celsius.

[0436] Benzyl nitrile AG can be converted to AI by a Michael addition reaction to an acrylate reagent such as AH, where Rs1 is an alkyl group that forms an ester. The ester formed by Rs1 must be labile to hydrolysis by acid treatment. The Michael addition reaction can be carried out by treatment with a base such as sodium methoxide in a solvent such as toluene at zero degrees Celsius.

[0437] Compound AA can be prepared from AI by treatment with an acid such as p-toluenesulfonic acid in a solvent such as toluene at elevated temperatures (e.g., 110 degrees Celsius). General Scheme 4

[0438] General Scheme 4 provides a specific exemplary synthetic strategy for the preparation of a compound of formula AN where the aryl halide AM can be used as starting material AD in General Scheme 1. W1 is any suitable substituent that gives a compound of formula I.

[0439] The compound AN can be prepared by coupling AC and AM under metal-catalyzed conditions. For example, treatment with [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium phosphate in a solvent such as dioxane. The reaction can be carried out at temperatures such as 80 degrees Celsius. Petition 870260070484, dated 07 / 16 / 2026, p. 209 / 1215 205 / 573 General Scheme 5

[0440] General Scheme 5 provides a specific exemplary synthetic strategy for the preparation of a compound of formula AN where aryl boronate AO can be used as starting material AD in General Scheme 1. Wi is any suitable substituent that gives a compound of formula I.

[0441] The compound AN can be prepared by coupling AA and AO under metal-catalyzed conditions. For example, treatment with [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) and a base such as potassium phosphate in a solvent such as dioxane. The reaction can be carried out at an elevated temperature such as 80 degrees Celsius. General Scheme 6 AP AM AO

[0442] General Scheme 6 provides a specific exemplary synthetic strategy for the preparation of aryl halides of formula AM (where Z4 is any suitable halide such as chlorine, bromine or iodine) and aryl boronates AO. Compounds AM and AO can be used as starting materials AD and AB, respectively, in General Scheme 1. Wi is any suitable substituent that gives a compound of formula I. Petition 870260070484, dated 07 / 16 / 2026, p. 210 / 1215 206 / 573

[0443] A substituted pyridone of formula AQ can be coupled to a di-haloaryl compound AP using copper-catalyzed conditions. One synthetic strategy involves treatment with copper iodide and a base such as potassium phosphate in a solvent such as dimethylacetamide. The reaction can be carried out at 115 degrees Celsius for 20 hours. Alternative conditions involve a copper iodide catalyst in the presence of a ligand. For example, N1,N2-Bis(furan-2-ylmethyl)oxalamide (BFMO) or 4,7-dimethoxy-1,10-phenanthroline ligand.

[0444] An aryl borate of formula AO can be prepared from AM and a suitable borylation agent (such as Bis(pinacolate)diboron) using any metal-catalyzed conditions for borylation. For example, cinnamyl dimer and palladium chloride in the presence of 0.4 mol% Xphos ligand or Pd(dppf)Cl2 can be used. The reaction can be carried out in a suitable solvent such as isopropanol or dioxane at 80 degrees Celsius. General Scheme 7

[0445] General Scheme 7 provides exemplary synthetic strategies for the preparation of various aryl halides of Petition 870260070484, dated 07 / 16 / 2026, page 211 / 1215 207 / 573 formulas AT, AV and AX, which can be used as starting materials AD in General Scheme 1. In some cases, X and Y can be carbon, or X, Y or both can be nitrogen depending on the desired substituents of formula I. Z5 and Z6 are any suitable halogens. W2, W3 and W4 are any suitable substituents that provide a compound of formula I. Ti = C, O or N-alkyl.

[0446] A synthetic approach to a lactam, carbamate, or pyrimidinone compound of formula AT involves a copper-catalyzed coupling of lactams or pyrimidinone AS with aryl halides AR. Copper iodide and a ligand such as N,N'-Dimethylethylenediamine (DMEDA). The reaction can be carried out in the presence of a base such as potassium phosphate or potassium carbonate and a solvent such as toluene, DMSO, dioxane, DMF, or NMP. Elevated temperatures such as 90 degrees Celsius or 110 degrees Celsius may be required.

[0447] In some examples (where X and Y = N or X = N and Y = C and Z6 = Cl), an ether of formula AV can be prepared by treating halide AR with alcohols of formula AU under basic conditions. In some examples, pretreating AU with a base such as sodium hydride in a solvent such as THF followed by the addition of AR at 0 degrees Celsius.

[0448] In some examples (where X = N and Y = C and Z6 = Cl), compounds of the formula AX can be prepared from the reaction of AW with AR using any suitable nucleophilic substitution conditions. A base such as cesium carbonate in a solvent such as dimethyl sulfoxide (DMSO) at 100 degrees Celsius can be used. General Scheme 8 Petition 870260070484, dated 07 / 16 / 2026, p. 212 / 1215 208 / 573 AY νιΟ BR·! ν,ο BA BB BC

[0449] General Scheme 8 provides a representative synthetic strategy for intermediates of formula BA from a benzyl halide of formula AY and pyridone AZ. Z7 is a suitable halide such as bromine, chlorine or iodine. W5 is any suitable substituent that results in a compound of formula I. The N-alkylation of pyridones AZ can be carried out using a base such as potassium carbonate in the presence of cetyltrimethylammonium bromide (CTAB) phase transfer catalyst in a solvent such as water. The reaction can be carried out at temperatures such as 50 degrees Celsius. A compound of formula BN can be similarly prepared from a compound of formula AS and AY.

[0450] A compound of the formula BC can be prepared from AY is an aryl boronate or boronic acid of formula BB. Vi can be hydrogen or any suitable alkyl group that forms a BB boronate. General Scheme 9 Petition 870260070484, dated 07 / 16 / 2026, page 213 / 1215 209 / 573 BF BD

[0451] General Scheme 9 provides a representative synthetic strategy for intermediates of formula BF that can be used as starting material AD in General Scheme 1. Boronic acid or a boronic ester of formula BD can undergo coupling with an amide or pyridone BE to give BF. Some representative conditions for this reaction include copper acetate (Cu(OAc)2) in the presence of pyridine and 4A molecular sieves. The reaction can be carried out in a solvent such as dichloromethane at room temperature (approx. 25 degrees Celsius). General Scheme 10 W8 BI BG BJ

[0452] General Scheme 10 provides a general synthetic strategy for intermediates of formula BJ that can be used as a starting material AD in General Scheme 1. Zs is any suitable halide. Ws and W9 are any suitable substituents that provide a compound of formula I. A compound of formula BI can be prepared by reacting BG and BH in the presence of a catalyst such as [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a base such as potassium carbonate in a Petition 870260070484, dated 07 / 16 / 2026, pp. 214 / 1215 210 / 573 mixture of dioxane and water solvents. The reaction can be carried out at a temperature of 100 degrees Celsius. A triflate of formula BJ can be prepared by treating alcohol BI with trifluoromethanesulfonic anhydride and pyridine in dichloromethane at zero degrees Celsius. General Scheme 11rw10z' BK BM

[0453] General Scheme 11 provides a general synthetic strategy for intermediates of formula BM that can be used as a starting material AD in General Scheme 1. Z9 and Z10 are any suitable halides. A1 is any suitable atom or group suitable to provide a compound of formula I, for example, oxygen, NH or N-methyl. W10 is heteroaryl or any suitable substituents that provide a compound of formula I. A compound of formula BM can be prepared by N-alkylation of BK with any aryl halide BL. The reaction can occur in the presence of a base, such as cesium carbonate, in a polar solvent such as dimethylformamide at temperatures such as 80 degrees Celsius. The compound of formula BM can undergo cross-coupling reactions with compounds of formula AD using a catalyst such as BrettPhos Pd3 complex in the presence of a base such as potassium phosphate. The reaction can be carried out in a solvent such as dioxane at 100 degrees Celsius. General Scheme 12 Petition 870260070484, dated 07 / 16 / 2026, p. 215 / 1215 211 / 573 BO AY Zhw10 BP

[0454] Scheme 12 provides a general synthetic approach for the preparation of compounds of formula BP that can be used as starting material AD in Scheme 1. W10 is any suitable aryl or heteroaryl group that provides a compound of formula I. An organometallic zinc reagent can be prepared by treating compound AY with a Zn-Cu metal in the presence of a solvent such as a mixture of toluene and dimethylacetamide at elevated temperatures (e.g., 80 degrees Celsius). The addition of an aryl or heteroaryl halide such as BO and a palladium catalyst such as Pd(PPh3)4 in a solvent such as toluene, at room temperature, can be used to generate compounds of formula BP. EXAMPLES

[0455] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that, where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reagents, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reagents or solvent used, but such conditions can be determined by a person skilled in the art by routine optimization.

[0456] Abbreviations: DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; ESI: electrospray ionization; h: hours; Petition 870260070484, dated 07 / 16 / 2026, pages 216 / 1215 212 / 573 HATU: 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC: high-performance liquid chromatography; MeCN: acetonitrile; MS: mass spectrometry; NCS: N-chlorosuccinimide; NMR: nuclear magnetic resonance; TEA: triethylamine; and THF: tetrahydrofuran. Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A)

[0457] To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, 146 mmol, 1.00 eq) in tetrachloromethane (240 mL) were added / V-bromosuccinimide (28.7 g, 161 mmol, 1.11 eq) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.05 eq). The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and the filter cake was washed with ethyl acetate (2 χ 75 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 200 g Silica Flash Column, Ethyl Acetate 0~3% / Petroleum Ether gradient eluent @ 150 mL / min) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.8 g, 73.1 mmol, 50% yield) obtained as a colorless liquid. 1H NMR (400 MHz, CDCh) δ= 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (dd, J= 8.0, 1.6 Hz, 1H), 7.15-7.11 (m, 1H), 4.62 (s, 2H).

[0458] To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.0 g, 70.3 mmol, 1.00 eq) and trimethylsilane (10.5 g, 105 mmol, 1.76 mL, 1.50 eq) in dichloromethane (200 mL) was added fluoride Petition 870260070484, dated 07 / 16 / 2026, page 217 / 1215 213 / 573 tetrabutylammonium (1.0 M in THF, 105 mL, 1.50 eq) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 1.5 h. The reaction mixture was washed with water (3 χ 150 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, Ethyl Acetate 0-60% / Petroleum Ether Gradient Eluent @ 60 mL / min) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, CDCb) δ = 7.65 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 0.8 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 3.89 (s, 2H). the

[0459] To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 1.00 eq) in tetrahydrofuran (130 mL) were added sodium methylate (620 mg, 11.5 mmol, 0.200 eq) and tert-butyl acrylate (7.34 g, 57.3 mmol, 8.31 mL, 1.00 eq) dropwise at 0°C. The mixture was then stirred at 20°C for 2 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 χ 50 mL). The combined organic layers were washed with brine (3 χ 80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase column (C18, 330 g, flow: 100 mL / min; gradient: from 10-65% water (0.1% formic acid) in acetonitrile over 40 min) to give tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (7.50 g, 19.0 mmol, 33% yield) obtained as a colorless liquid. 1H NMR (400 MHz, CDCb) δ = 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.49 (dd, J = 8.8, 5.6 Hz, Petition 870260070484, dated 07 / 16 / 2026, pp. 218 / 1215 214 / 573 Η), 2.54 - 2.38 (m, 2Η), 2.29 - 2.09 (m, 2H), 1.46 (s, 9H) Intermediate AA-1

[0460] To a solution of ferc-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (4.70 g, 11.9 mmol, 1.00 eq) in acetic acid (30 mL) was added sulfuric acid (5.52 g, 56.3 mmol, 3.00 mL, 4.72 eq). The mixture was stirred at 90°C for 3 h. Cooled to room temperature, the reaction mixture was poured into ice-cold water (120 mL) and the filter cake was washed with water (2 x 50 mL). The filter cake was dried under reduced pressure to yield 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (2.89 g, 9.46 mmol, 79% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 10.93 (s, 1H), 7.72 (dd, J = 8.0, 0.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 - 7.26 (m, 1H), 4.32 (dd, J = 12.0, 4.8 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.53 -2.53 (m, 1H), 2.30 - 2.34 (m, 1H), 2.03-1.97 (m, 1H). MS (ESI) m / z 303.9[M+H]+ Intermediate A

[0461] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (5.00 g, 16.5 mmol, 1.00 eq) in dioxane (80 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (5.04 g, 19.8 mmol, 1.20 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.21 g, 1.65 mmol, 0.10 eq) and potassium acetate (4.87 g, 49.6 mmol, 3.00 eq) in a portion Petition 870260070484, dated 07 / 16 / 2026, p. 219 / 1215 215 / 573 at 20 °C under a nitrogen atmosphere. The mixture was stirred at 85 °C for 3 h. The mixture was filtered and the filter cake was washed with ethyl acetate (2 χ 30 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0-50% ethyl acetate / petroleum ether gradient eluent @ 60 mL / min) to give 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (3.80 g, 8.70 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 7.52 (dd, J = 2.0, 7.2 Hz, 1H), 7.41 (dd, J = 2.0, 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 4.26 (dd, J = 5.2, 12.4 Hz, 1H), 2.81 - 2.70 (m, 1H), 2.59 - 2.53 (m, 1H), 2.33 2.23 (m, 1H), 1.99 - 1.93 (m, 1H), 1.31 (s, 12H). MS (ESI) m / z 350.2 / 352.2 [M+H]+ Synthesis of 3-(4'-(bromomethyl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Intermediate B)

[0462] To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, To carbon tetrachloride (146 mmol, 1 eq) N-bromosuccinimide (28.8 g, 162 mmol, 1.11 eq) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.0500 eq) were added. The mixture was stirred at 90°C for 16 h. The reaction mixture was filtered and the filter cake was washed with ethyl acetate (2 x 75 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (25.1 g, crude) and 1-bromo-3-(bromomethyl)-2-chlorobenzene (7.90 g, 26.3 mmol, 18% yield) as both colorless liquids. Petition 870260070484, dated 07 / 16 / 2026, pages 220 / 1215 216 / 5731H NMR (400 MHz, DMSO-c / 6) δ =7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.65 (dd, J= 0.8, 7.6 Hz, 1H), 7.29 (t, J= 8.0 Hz, 1H), 4.80 (s, 2H).

[0463] To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (33.0 g, 116 mmol, 1.00 eq) and trimethylsilylformonitrile (17.3 g, 174 mmol, 21.8 mL, 1.50 eq) in dichloromethane (330 mL) was added tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (1 M, 174 mL, 1.50 eq) (1.0 M in tetrahydrofuran, 105 mL, 1.50 eq) dropwise at 0°C. The mixture was stirred at 20°C for 1.5 h. The reaction mixture was washed with water (3 χ 150 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (5.80 g, 25.2 mmol, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 7.80 (dd, J= 1.0, 8.0 Hz, 1H), 7.57 (dd, J= 0.8, 7.6 Hz, 1H), 7.35 (t, J= 8.0 Hz, 1H), 4.18 (s, 2H). the

[0464] A mixture of 2-(3-bromo-2-chlorophenyl)acetonitrile (13.3 g, 57.7 mmol, 1.00 eq), ferc-butyl acrylate (7.40 g, 57.7 mL, 8.38 mL, 1.00 eq) and sodium methoxide (623 mg, 11.5 mmol, 0.200 eq) in tetrahydrofuran (130 mmol) was added at 0°C. The reaction was stirred at 20°C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 χ² 50 mL). The combined organic layers were washed with brine (3 χ² 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified. Petition 870260070484, dated 07 / 16 / 2026, pp. 221 / 1215 217 / 573 by silica-gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give ferc-butyl 4-(3-bromo-2-chloro-phenyl)-4-cyano-butanoate (25.0 g, crude) as yellow oil. 1H NMR (400 MHz, DMSO-c / 6) δ = 7.82 (dd, J= 1.4, 8.0 Hz, 1H), 7.60 (dd, J= 1.6, 8.0 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H), 4.62 (dd, J= 6.8, 8.0 Hz, 1H), 2.45 - 2.30 (m, 2H), 2.20 - 2.08 (m, 2H), 1.38 (s, 9H) Pd(PPh3)4, K2CO3. DME / water, 90°C, 3h

[0465] A mixture of ferc-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (10.0 g, 27.9 mmol, 1.00 eq), (4(hydroxymethyl)phenyl)boronic acid (4.66 g, 30.7 mmol, 1.10 eq) and potassium carbonate (7.71 g, 55.7 mmol, 2.00 eq), palladium; triphenylphosphane (3.22 g, 2.79 mmol, 0.100 eq) in 1,2-dimethoxyethane (9.00 mL) and water (3.00 mL) was stirred at 90°C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature and poured into water (30 mL), the two layers were separated. The aqueous phase was extracted with ethyl acetate (3 χ 30 mL), the organic layer was washed with brine (30 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give ferc-butyl 4-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-4-cyanobutanoate (6.07 g, 15.7 mmol, 56% yield) as yellow oil. 1H NMR (400 MHz, DMSO-c / 6) δ = 7.60 (dd, J= 1.6, 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.45 - 7.34 (m, 5H), 5.25 (t, J = 6.0 Hz, 1H), 4.63 (dd, J= 6.8, 8.0 Hz, 1H), 4.56 (d, J= 6.0 Hz, 2H), 2.46 - 2.37 (m, 2H), 2.23 2.14 (m, 2H), 1.39 (s, 9H) Petition 870260070484, dated 07 / 16 / 2026, p. 222 / 1215 218 / 573

[0466] A mixture of ferc-butyl 4-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-cyanobutanoate (6.00 g, 15.6 mmol, 1.00 eq) and sulfuric acid (5.52 g, 56.3 mmol, 3.00 mL, 3.62 eq) in acetic acid (30.0 mL) was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was poured into water (120 mL) and the filter cake was washed with saturated sodium bicarbonate (3 × 20 mL). The filter cake was dried under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / (ethyl acetate / methanol / dichloromethane = 2 / 2 / 1) = 1 / 0 to 0 / 1), trituration with 2-methoxy-2-methylpropane (20 mL) at 25°C for 15 min and filtered. The filter cake was dried to give 3(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (2.78 g, 7.08 mmol, 45% yield, 84% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.92 (s, 1H), 7.48 - 7.34 (m, 6H), 7.31 (dd, J = 2.0, 7.2 Hz, 1H), 5.13 (s, 2H), 4.34 (dd, J = 4.8, 12.0 Hz, 1H), 2.87 - 2.71 (m, 1H), 2.60 - 2.51 (m, 1H), 2.40 - 2.27 (m, 1H), 2.08 2.00 (m, 1H) MS (ESI) m / z 312.0 [M-17]+ Intermediate B

[0467] A mixture of 3-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione (1.40 g, 4.25 mmol, 1.00 eq) in dichloromethane Petition 870260070484, dated 07 / 16 / 2026, page 223 / 1215 219 / 573 (5.00 mL) was added to hydrogen bromide (2.98 g, 12.2 mmol, 2.00 mL, 33% purity in acetic acid, 2.86 eq) at 0°C. The reaction was heated to 25°C and stirred for 3 h. The mixture was poured into a saturated sodium bicarbonate solution (30.0 mmol) and filtered. The filter cake was dried under reduced pressure to give the crude product. The crude product was triturated with ethyl acetate (10 mL) at 20°C for 10 min and filtered. The filter cake was dried under reduced pressure to yield 3-(4'-(bromomethyl)-2-chloro-[1,1'-biphenyl]-3yl)piperidine-2,6-dione (1.33 g, 2.85 mmol, 67% yield, 84% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 7.57 - 7.51 (m, 2H), 7.43 - 7.35 (m, 4H), 7.34 - 7.30 (m, 1H), 4.77 (s, 2H), 4.40 - 4.30 (m, 1H), 2.85 - 2.74 (m, 1H), 2.54 - 2.51 (m, 1H), 2.40 - 2.27 (m, 1H), 2.09 - 2.02 (m, 1H) MS (ESI) m / z 392.2 [M+H]+ Characterization of other fundamental intermediates in the preparation of compounds of formula I

[0468] The characterization for Intermediates of general formula AA was used to prepare the compound of formula I. Intermediates AA-2 to AA-9 were prepared according to general scheme 2 or 3 and analogously to 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione as described in the preparation of Intermediate A. Table 4 Name NMR 3-(3-bromo-2-fluorophenyl)-piperidine-2,6-dione AA-2 1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.66 - 7.62 (m, 1H), 7.35 - 7.33 (m, 1H), 7.17 - 7.13 (m, 1H), 4.15 - 4.11 (m, 1H), 2.80 - 2.71 (m, 1H), 2.58 - 2.56 (m, 1H), 2.28 2.18 (m, 1H), 2.05 - 1.98 (m, 1H). MS Petition 870260070484, dated 07 / 16 / 2026, page 224 / 1215 220 / 573 (ESI) m / z 285,9 [M+H]+ 3-(3-bromo-2,6- diclorofenil)piperidina-2,6diona AA-3 1H RMN (400 MHz, DMSO-d6) δ = 11,02 (d, J = 3,6 Hz, 1H), 7,78 (dd, J = 4,0, 8,8 Hz, 1H), 7,54 - 7,40 (m, 1H), 4,87 - 4,60 (m, 1H), 2,93 - 2,80 (m, 1H), 2,59 - 2,53 (m, 1H), 2,41 2,31 (m, 1H), 2,01 - 1,88 (m, 1H) 3-(3-bromo-2-cloro-6- fluorofenil)piperidina-2,6-diona AA-4 1H RMN (400 MHz, DMSO-d6) δ = 11,02 (s, 1H), 7,82 (dd, J = 5,8, 9,2 Hz, 1H), 7,28 (t, J = 9,2 Hz, 1H), 4,55 - 4,46 (m, 1H), 2,90 - 2,78 (m, 1H), 2,58 - 2,54 (m, 1H), 2,22 - 1,89 (m, 2H). MS (ESI) m / z 322,0 [M+2H]+ 3-(3-bromo-2,6- difluorofenil)piperidina-2,6diona AA-5 1H RMN (400 MHz, DMSO-d6) δ = 11,04 (s, 1H), 7,75 (dt, J = 6,0, 8,8 Hz, 1H), 7,18 (dt, J = 1,6, 9,2 Hz, 1H), 4,34 (dd, J = 5,2, 12,8 Hz, 1H), 2,91 - 2,75 (m, 1H), 2,63 - 2,54 (m, 1H), 2,23 - 2,10 (m, 1H), 2,09 - 2,01 (m, 1H).MS (ESI) m / z 304.0 [M+H]+ 3-(3-bromo-6-chloro-2- fluorophenyl)piperidine-2,6-dione AA-6 1H NMR (400 MHz, DMSO-d6) δ = 11.03 (s, 1H), 7.72 (dd, J = 8.4, 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.45 (dd, J = 12.4, 5.2 Hz, 1H), 2.892.80 (m, 1H), 2.58–2.55 (m, 1H), 2.19–2.07 (m, 1H), 2.02–1.98 (m, 1H). 1H). MS (ESI) m / z 322.0 [M+H]+ 3-(3-bromo-2-(trifluoromethyl)phenyl)piperidine- 1H NMR (400 MHz, CDCl3) δ = 8.27 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.36. Petition 870260070484, 7 / 16 / 2026, p. 225 / 1 221 / 5 2,6-dione AA-7 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 4.40 - 4.03 (m, 1H), 2.89 2.81 (m, 1H), 2.78 - 2.66 (m, 1H), 2.35 - 2.16 (m, 2H). MS (ESI) m / z 335.9 [M+H]+ 3-(3-bromo-2-methyl-phenyl)piperidine-2,6-dione AA-8 1H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.20 - 7.14 (m, 1H) 1H), 2.05 - 1.94 (m, 1H) MS (ESI) m / z 282.1 [M+H]+ 3-(5-bromo-2-chlorophenyl)piperidine-2,6-dione AA-9 1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.45 - 7.41 (m, 1H), 4.23 (dd, J = 5.0, 12.8 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.58 - 2.53 (m, 1H), 2.41 - 2.31 (m, 1H), 2.01 1.95 (m, 1H). General synthetic procedure for the preparation of compounds of formula I from aryl bromide intermediate AA and commercially available or synthetically accessible boronic acids or esters.

[0469] 3-(3-Bromo-2-chlorophenyl)piperidine-2,6-dione (1 eq.), appropriate boronic acid or pinacolalate (approx. 1.5-2 eq.), were mixed in DMF-water 20:1 (approx. 0.7 mL) and then cataCXium A PD G3 (0.05 eq.), Petition 870260070484, dated 07 / 16 / 2026, page 226 / 1215 222 / 573 RuPhos Pd G4 (0.05 eq.) and sodium bicarbonate (NaHCO3) were added in a portion under an inert atmosphere. The reaction mixture was sealed and heated for 15 hours at 90°C. Then, the mixture was cooled to room temperature and trifluoroacetic acid (TFA) was added dropwise until neutral pH. The mixture was evaporated under reduced pressure and the residue was dissolved in DMSO (approx. 0.7 mL). The DMSO solution was treated with the sequestering agent SiliaMetS DMT, filtered, analyzed by LCMS, and transferred for purification by HPLC. Example 1. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 154) Pd(dppf)CI2;K3PO4DMF, 100 *0, 16 h

[0470] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6dione (250 mg, 826 pmol, 1.00 eq, two batches), 1-methyl-3-((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1 / - / -pyrazole (286 mmol, 909 pmol, 1.10 eq) in dimethylformamide (8 mL) were added [1,1bis(diphenylphosphino)ferrocene]dichloropalladium (II) (60.5 mg, 82.6 pmol, 0.10 eq) and potassium phosphate (526 mg, 2.48 mmol, 3.00 eq). The mixture was degassed and purged with nitrogen three times, then stirred at 100°C for 16 h. The reaction mixture was cooled to 25°C and then filtered with a Celite pad, washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g silica flash column, ethyl acetate gradient eluent). Petition 870260070484, dated 07 / 16 / 2026, page 227 / 1215 223 / 573 0-80% / Petroleum ether @ 60 mL / min). The desired fraction was collected and concentrated under reduced pressure, then the residue was ground with dimethylformamide (4 mL) at 25°C for 10 minutes, filtered, washed with n-hexane (5 mL), dried under reduced pressure to yield 3-(2-chloro-4'((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (278.9 mg, 673.64 pmol, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 10.91 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.41 - 7.26 (m, 5H), 7.17 - 7.05 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 4.33 (dd, J= 5.2, 12.0 Hz, 1H), 3.84 (s, 3H), 2.79 (m, 1H), 2.56 (m, 1H), 2.32 (m, 1H), 2.11 - 1.99 (m, 1H); MS (ESI) m / z 410.0 [M+H]+. Example 2. Synthesis of 3-(2-chloro-4,-((2-oxopyridin-1(2H)-yl)methyl)[1,1'-biphenyl]-3-yl)pyperidin-2,6-dione (compound 156) Pd(dppf)Ci2, K3PO4 DMF, 100 °C, 16 h

[0471] A mixture of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (450 mg, 1.34 mmol, 90% purity, 1.00 eq), 1-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one (502 mg, 1.34 mmol, 83% purity, 1.00 eq), potassium phosphate (852 mg, 4.01 mmol, 3.00 eq) and [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (196 mg, 268 pmol, 0.20 eq) in A / , / V-dimethylformamide (23 mL) was degassed and purged with nitrogen 3 times. The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 40 g Silica Flash Column, Ethyl Acetate 100-100% / Petroleum Ether gradient eluent). Petition 870260070484, dated 07 / 16 / 2026, page 228 / 1215 224 / 573 @ 40 mL / min) followed by Prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm χ 10 μm; mobile phase: [water (formic acid) - acetonitrile]; % B: 24%-54%, 10 min) and lyophilized to yield 3-(2-chloro-4'-((2oxopiridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (327 mg, 788 μmol, 59% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.86 (dd, J = 2.0, 6.8 Hz, 1H), 7.45 (ddd, J = 2.0, 6.8, 9.2 Hz, 1H), 7.41 - 7.31 (m, 6H), 7.28 (dd, J = 2.0, 7.2 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 6.27 (dt, J = 1.2, 6.8 Hz, 1H), 5.16 (s, 2H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 2.85 - 2.70 (m, 1H), 2.58 - 2.51 (m, 1H), 2.32 (dq, J = 4.0, 12.8 Hz, 1H), 2.09 - 1.98 (m, 1H); MS (ESI) m / z 407.0 [M+H]+ Example 3. Synthesis of 3-(2-chloro-3'-(((tetrahydrofuran-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 190)

[0472] 3-(2-chloro-3'-(((tetrahydrofuran-3-yl)oxy)methyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione and 4,4,5,5-tetramethyl-2-(3-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)-1,3,2-dioxaborolan according to General Scheme 1. 1H NMR (400 MHz, DMSO-d6) δ = 11.01 - 10.87 (m, 1H), 7.50 - 7.28 (m, 7H), 4.59 - 4.44 (m, 2H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 4.27 - 4.17 (m, 1H), 3.78 - 3.64 (m, 4H), 2.84 - 2.74 (m, 1H), 2.58 - 2.55 (m, 1H), 2.40 2.27 (m, 1H), 2.11 - 1.92 (m, 3H); MS (ESI) m / z 398.1 [MH]- Example 4. Synthesis of 3-(2-chloro-3'-methyl-4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 155) Petition 870260070484, dated 07 / 16 / 2026, p. 229 / 1215 225 / 573 ο Pdídppf)CI2lK3PO4 DMF, 100 °C, 18 h compound 155

[0473] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (141 mg, 0.466 mmol, 1.00 eq), 4-(2-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (178 mmol, 0.512 mmol, 1.10 eq) in dimethylformamide (5 mL) were added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (34.1 mg, 46.6 µmol, 0.10 eq) and tripotassium phosphate (296 mg, 1.40 mmol, 3.00 eq). The mixture was degassed and purged with nitrogen three times, then stirred to 100°C for 16 h. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate 0-80% / Petroleum Ether gradient eluent @ 50 mL / min).The desired fraction was collected and concentrated under reduced pressure, then purified by Prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 pm; mobile phase: [water (formic acid) - acetonitrile]; % B: 8%-38%, 10 min) and lyophilized to yield 3-(2-chloro-3'-methyl-4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione (82.6 mg, 185 pmol, 40% yield) as a white solid. 1H NMR (400 MHz, CDCb) δ = 8.11 (s, 1H), 7.33 - 7.26 (m, 2H), 7.22 7.18 (m, 2H), 7.17-7.14 (m, 1H), 6.86 (d, J = 9.0 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.80 - 3.72 (m, 4H), 2.91 (t, J = 5.6 Hz, 2H), Petition 870260070484, dated 07 / 16 / 2026, page 230 / 1215 226 / 573 2.84 - 2.76 (m, 1H), 2.75 - 2.71 (m, 1H), 2.70 - 2.64 (m, 4H), 2.37 - 2.29 (m, 2H), 2.26 (s, 3H); MS (ESI) m / z 443.1 [M+H]+ Example 5. Synthesis of 3-(2-fluoro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 150)

[0474] (3-bromo-2-fluorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2-fluoro-3-methylbenzene according to General Scheme 2.

[0475] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenol (2.53 g, 11.5 mmol, 1.50 eq) in acetic acid (20 mL) were added potassium carbonate (2.12 g, 15.3 mmol, 2.00 eq) and 3-(chloromethyl)-1-methyl-1H-pyrazole (1.00 g, 7.66 mmol, 1.00 eq). The mixture was stirred at 65°C for 16 h. The reaction mixture was filtered with a Celite pad, and the filter cake was washed with acetonitrile (100 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate 0~50% / Petroleum Ether Gradient Eluent @ 40 mL / min) to give 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)methyl)-1H-pyrazole (2.32 g, 7.09 mmol, 93% yield) as yellow oil.

[0476] 3-(2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1-methyl-3-((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole and 3-(3-bromo-2-fluorophenyl)piperidine-2,6-dione according to General Scheme 1. MS (ESI) m / z 394.3 [M+H]+ Example 6. Synthesis of 3-(2,4-dichloro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 146) Petition 870260070484, dated 07 / 16 / 2026, page 231 / 1215 227 / 573

[0477] 3-(3-bromo-2,6-dichlorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2,4-dichloro-3-methylbenzene according to General Scheme 2.

[0478] 3-(2,4-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,Γbiphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2,6dichlorophenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole according to General Scheme 1. MS (ESI) m / z 444.1 [M+H]+ Example 7. Synthesis of 3-(2-chloro-4-fluoro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 144)

[0479] 3-(3-bromo-2-chloro-6-fluorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2-chloro-4-fluoro-3-methylbenzene according to General Scheme 2. THE Compound 144

[0480] 3-(2-chloro-4-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2chloro-6-fluorophenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.99 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.09 (d, J = 8.8 Hz, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 4.50 (dd, J= 5.2, 12.0 Hz, 1H), 3.84 (s, 3H), 2.91 - 2.79 (m, 1H), 2.56 (s, 1H), 2.16-2.08 (m, 1H), 2.07 (s, 1H), 2.07- 1.96 (m, 1H); MS (ESI) m / z 428.1 [M+H]+ Petition 870260070484, dated 07 / 16 / 2026, page 232 / 1215 228 / 573 Example 8. Synthesis of 3-(4-chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 145)

[0481] 3-(3-bromo-6-chloro-2-fluorophenyl)piperidine-2,6-dione was prepared from 1-bromo-4-chloro-3-(chloromethyl)-2-fluorobenzene according to General Scheme 2. DMF, 100 °C, 16 h BPin Pd(dppf)CI2, K3PO4

[0482] 3-(4-chloro-2-fluoro-4'-((1 -methyl-1 H-pyrazol-3-yl)methoxy)-[1,1 biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-6chloro-2-peridiophenyl-2,6-piperidine) 1-methyl-3-((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1 / - / -pyrazole in accordance with 0 General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.99 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.49-7.39 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H, 2H), 1H), 5.04 (s, 2H), 4.48-4.41 (m, 1H), 3.83 (s, 3H), 2.90-2.81 (m, 1H), 2.58-2.55 (m, 1H), 2.20-2.13 (m, 1H, 1H), 2.0-2.1 (m, 1H); MS (ESI) m / z 428.1 [M+H]+Example 9. Synthesis of 3-(2',4-dichloro-4'-((1-methyl-1 H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione compound (13) / Cl K2CO3 MeCN, 25–65 °C, 16 h

[0483] To a solution of 4-bromo-3-chlorophenol (715 mg, 3.45 mmol, 1.50 eq) in acetonitrile (150 mL) was added potassium carbonate (635 mg, 4.6 mmol, 2.00 eq). The mixture was stirred at 25°C for 0.5 Petition 870260070484, dated 07 / 16 / 2026, page 233 / 1215 229 / 573 h. Then, 1-3-(chloromethyl)-1-methyl-1H-pyrazole (300 mg, 2.30 mmol, 1.00 eq) was added, the reaction mixture was stirred at 65°C for 15.5 h. The reaction mixture was cooled to 25°C and filtered through a Celite pad and washed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate 0~50% / Petroleum Ether gradient eluent @ 40 mL / min) to give 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (678 mg, 2.11 mmol, 92% yield) as a white solid.

[0484] A solution of 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (200 mg, 663 pmol, 1.00 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (185 mg, 730 pmol, 1.10 eq), potassium acetate (195 mg, 1.99 mmol, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (48.5 mg, 66.3 µmol, 0.10 eq) in dioxane (8 mL). The mixture was degassed and purged with nitrogen three times, then stirred at 100°C for 3 h. The mixture was cooled to 20°C, filtered with a Celite pad, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate 0~50% / Petroleum Ether gradient eluent @ 40 mL / min) and then purified by reversed-phase column chromatography (formic acid condition at 0.1%) to give 3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)methyl)-1-methyl-1H-pyrazole (62 mg, 128 pmol, 19% yield) as a white solid. Petition 870260070484, dated 07 / 16 / 2026, page 234 / 1215 230 / 573 Pd(dppf)CI2, K3PO4 DMF, 100 °C, 3 h

[0485] 3-(2',4-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1' biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(5-bromo-2chlorophenyl)piperidine-2,6-dione and 3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy)methyl)-1-methyl-1H-pyrazole according to General Scheme 1. MS (ESI) m / z 444.1 [M+H]+ Example 10. Synthesis of 3-(4-chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 152) MeCN, 65 °C, 16 ή / Cl K2CO3 B2P1ΓΊ2 Pd(dppf)CI2 KOAc dioxane, 90 °C, 5 h 1-methyl-3-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy)methyl)-1H-pyrazole was prepared from 4-bromo-3-methylphenol analogously to Example 9.1H NMR (400 MHz, DMSO-cfe) δ = 7.65 (d, J = 2.0 Hz, 1H); MS (ESI) m / z 329.0 [M+H]+ the Compound 152 Petition 870260070484, dated 07 / 16 / 2026, p. 235 / 1215 231 / 573

[0486] 3-(4-cloro-2-fluoro-4'-((1 -metil-1 / - / -pirazol-3-il)metóxi)-[1,1 bifenil]-3-il)piperidina-2,6-diona foi preparada a partir de 3-(5-bromo-2clorofenil)piperidina-2,6-diona e 1 -metil-3-((3-metil-4-(4,4,5,5-tetrametil1,3,2-dioxaborolan-2-il)fenóxi)metil)-1 / - / -pirazol de acordo com o Esquema Geral 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.89 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.12 (d, J = 8.4 Hz,1H), 6.95 (d, J = 2.4 Hz, 1H), 6.93 - 6.87 (m, 1H), 6.30 (d, J = 2.0 Hz,1H), 5.01 (s, 2H), 4.25 (dd, J= 5.2, 12.0 Hz, 1H), 3.83 (s, 3H), 2.84 - 2.71 (m, 1H), 2.56 - 2.53 (m, 1H), 2.38 - 2.32 (m, 1H), 2.21 (s, 3H), 2.07 -1.96 (m, 1H). MS (ESI) m / z 424.1 [M+H]+ Example 11. Synthesis of 3-(4'-amino-2-chloro-[1,T-biphenyl]-3yl)piperidine-2,6-diona (compound 130)

[0487] 3-(4'-amino-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.89 (s, 1 H), 7.28 - 7.35 (m, 1 H), 7.19 - 7.27 (m, 2 H), 7.07 (d, J = 8.4 Hz, 2 H), 6.61 (d, J = 8.4 Hz, 2 H), 5.24 (s, 2 H), 4.31 (dd, J = 12.0, 4.8 Hz, 1 H), 2.71 - 2.83 (m, 1 H), 2.57 - 2.63 (m, 1 H), 2.30 (d, J = 2.8 Hz, 1 H), 1.98 - 2.08 (m, 1 H); MS (ESI) m / z 314.9 [M+H]+ Example 12. Synthesis of 3-(2-chloro-4'-(methylamino)-[1,T-biphenyl]-3yl)piperidine-2,6-dione (compound 134) Petition 870260070484, dated 07 / 16 / 2026, p. 236 / 1215 232 / 573 compound 134

[0488] 3-(2-chloro-4'-(methylamino)-[1,1'-biphenyl]-3-i I) piperidine-2,6diona was prepared from 3-(3-bromo-2-chlorophenyl)piperidine-2,6diona and A / -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline according to General Esquema 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.9 (s, 1H), 7.38-7.29 (m, 1H), 7.28 - 7.19 (m, 2H), 7.15 (d, J= 8.8 Hz, 2H), 6.59 (d, J= 8.8 Hz, 2H), 5.83 (d, J = 4.4 Hz, 1H), 4.31 (dd, J = 5.2, 12.0 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.73 - 2.67 (m, 3H), 2.55 (d, J= 3.6 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.08 - 1.98 (m, 1H). MS (ESI) m / z 329.0 [M+H]+ Example 13. Synthesis of 3-(2-chloro-4'-( / sopropylamino)-[1,T-biphenyl]3-yl)piperidine-2,6-diona (compound 129)

[0489] 3-(2-chloro-4'-( / sopropylamino)-[1,1 '-biph en il]-3-i I) pi perid ina-2,6diona was prepared from A / - / sopropyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-diona de acordo com o Esquema Geral 1. MS (ESI) m / z 357.2, 359.2 [M+H]+ Example 14. Synthesis of 3-(2-chloro-6-iodo-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 179) Petition 870260070484, dated 07 / 16 / 2026, page 237 / 1215 233 / 573 Zn(CN)2. dppf, Pd2(dba)3 DMF, 110 *C. 16 1Ί compound 179

[0490] To a solution of 3-(2-chloro-6-iodo-4'-((1-methyl-1 / - / -pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (70.0 mg, 130 pmol, 1.00 eq) in dimethylformamide (2 mL) were added zinc cyanide (170 mg, 1.45 mmol, 11.1 eq), tris(dibenzylideneacetone)dipalladium (23.9 mg, 26.1 pmol, 0.200 eq) and 1,1-Bis(diphenylphosphino)ferrocene (14.5 mg, 26.1 pmol, 0.200 eq). The mixture was stirred at 110°C for 16 h under a nitrogen atmosphere. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl acetate gradient eluent 0-50% / petroleum ether @ 20 mL / min).The residue was then purified by Prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 µm; mobile phase: [water (formic acid) acetonitrile]; % B: 25%-58%, 9 min) to yield 3-(2-chloro-6-iodo4'-((1-methyl-1 / - / -pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-I)piperidina-2,6-dione (26.5 mg, 60.3 pmol, 46% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 10.99 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.68 (d, J= 2.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.33 (t, J= 8.0 Hz, 2H), 7.15 (d, J= 8.8 Hz, 2H), 6.35 (d, J= 2.0 Hz, 1H), 5.07 (s, 2H), 4.44 (dd, J= 5.2, 12.4 Hz, 1H), 3.85 (s, 3H), 2.85 - 2.75 (m, 1H), 2.60 - 2.56 (m, 1H), 2.39 - 2.32 (m, 1H), 2.08 - 2.00 (m, 1H). MS (ESI) m / z 435.1 [M+H]+Example 15. Synthesis of 3-(2-chloro-6-ethynyl-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 172) Petition 870260070484, dated 07 / 16 / 2026, p. 238 / 1215 234 / 573

[0491] 3-(2-chloro-6-iodo-4'-((1-methyl-1 / - / -pyrazol-3-yl)methoxy)-[1,1-biphenyl]-3-yl)piperidine-2,6-dione was prepared analogously to Example 14. To a solution of 3-(2-chloro-6-iodo-4'-((1-methyl-1 / - / -pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (200 mg, 373 pmol, 1.00 eq) and ethinyltrimethylsilane (110 mg, 1.12 mmol, 155 pmol, 3.00 eq) in tetrahydrofuran (5 mL) were added bis(triphenylphosphine)palladium(II) chloride (52.4 mg, 74.7 pmol, 0.200 eq), copper iodide (35.6 mg, 187 pmol, 0.500 eq) and triethylamine (151 mg, 1.49 mmol, 208 pL, 4.00 eq). The mixture was stirred at 25°C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl acetate gradient eluent 0~50% / petroleum ether @ 18 mL / min) to give 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (100 mg, 170 pmol, 46% yield) as brown gum.

[0492] To a solution of 3-(2-chloro-4'-((1-methyl-1 / - / -pyrazol-3 Petition 870260070484, dated 07 / 16 / 2026, page 239 / 1215 235 / 573 yl)methoxy)-6-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (100 mg, 170 μmol, 1.00 eq) in acetonitrile (4 mL) was added to cesium fluoride (150 mg, 988 μmol, 5.00 eq). The mixture was stirred at 25°C for 5 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [Hexane - ethanol]; % B: 5%-45%, 15 min) to yield 3-(2-chloro-6-ethynyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (51.5 mg, 117 μmol, 59% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 2.0 Hz, 1H), 5.03 (s, 2H), 4.32 (dd, J = 5.2, 12.0 Hz, 1H), 4.07 (s, 1H), 3.85 (s, 3H), 2.85 - 2.71 (m, 1H), 2.61 - 2.52 (m, 1H), 2.40 - 2.23 (m, 1H), 2.10 - 1.95 (m, 1H) MS (ESI) m / z 434.1 [M+H]+ Example 16. Synthesis of 3-(4'-((1H-imidazol-4-yl)methoxy)-2-chloro[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 167)

[0493] A solution of tert-butyl 4-(hydroxymethyl)-1H-imidazol-1-carboxylate (500 mg, 2.52 mmol, 1.00 eq), 4-iodophenol (666 mg, 3.03 mmol, 1.20 eq) and triphenylphosphine (992 mg, 3.78 mmol, 1.50 eq) in tetrahydrofuran (15 mL) and (E)-2,2'-(diazeno-1,2-di-ylbis(methylene))bis(2-methylmalonic acid) (765 mg, 3.78 mmol, 736 μL, 1.50 eq) at 0°C. The mixture was then stirred at 20°C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 25 g Silica Flash Column, Ethyl Acetate gradient eluent). Petition 870260070484, dated 07 / 16 / 2026, p. 240 / 1215 236 / 573 0-20% / Petroleum ether @ 80 mL / min) to yield ferc-butyl 4-[(4-iodophenoxy)methyl]imidazole-1-carboxylate (434 mg, 1.07 mmol, 43% yield) obtained as a white solid.

[0494] A solution of 4-[(4-iodophenoxy)methyl]-1H-imidazol-1-carboxylate ferc-butyl (150 mg, 0.375 mmol, 1.00 eq), 3-(2-chloro-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (172 mg, 0.412 mmol, 84% purity, 1.10 eq), [1,Tbis(diphenylphosphino)ferrocene]dichloropalladium (II) (27.4 mg, 0.0375 mmol, 0.100 eq) and potassium phosphate (239 mg, 1.12 mmol, 3.00 eq) in 1,4-dioxane (5 mL). The mixture was then degassed and purged with nitrogen three times and stirred at 80°C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product (170 mg, 0.343 mmol) was obtained as a green solid and used in the next step without further purification.

[0495] To a solution of ferc-butyl 4-[[4-[2-chloro-3-(2,6-dioxo-3-piperidyl)phenyl]phenoxy]methyl]imidazole-1-carboxylate (170 mg, 0.343 mmol, crude, 1.00 eq) in ethyl acetate (2 mL) was added Petition 870260070484, dated 07 / 16 / 2026, p. 241 / 1215 237 / 573 hydrochloric acid / ethyl acetate (4 M, 2 mL, 23.3 eq) was added dropwise at 0°C. The mixture was stirred at 25°C for 16 h. The reaction mixture was quenched by adding 5 mL of water at 25°C and then neutralized with saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate gradient eluent 0~100% / Petroleum Ether @ 30 mL / min), followed by Prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 µm; mobile phase: [water (formic acid) - acetonitrile]; % B: 10% - 30%, 9 min) to yield 3-(4'-((1H-imidazol-4-yl)methoxy)-2chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (10.4 mg, 0.0261 mmol, 8% yield, 99% purity) obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.39 - 7.27 (m, 5H), 7.20 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H), 4.33 (dd, J = 5.2, 12.0 Hz, 1H), 2.79 (s, 1H), 2.52 - 2.51 (m, 1H), 2.33 - 2.26 (m, 1H), 2.06 (s, 1H); MS (ESI) m / z 396.1[M+H]+ Example 17. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-imidazol-4yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 183)

[0496] 4-((4-iodophenoxy)methyl)-1-methyl-1H-imidazole was prepared from 4-iodophenol and (1-methyl-1H-imidazol-4-yl)methanol analogously to Example 16.

[0497] 3-(2-fluoro-3-(indolin-5-yl)phenyl)piperidine-2,6-dione was prepared from 4-((4-iodophenoxy)methyl)-1-methyl-1H-imidazole and 3-(2chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6 Petition 870260070484, dated 07 / 16 / 2026, page 242 / 1215 238 / 573 dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 7.60 (s, 1H), 7.38 - 7.27 (m, 5H), 7.25 (s, 1H), 7.12 - 7.05 (m, 2H), 4.96 (s, 2H), 4.33 (dd, J = 5.2, 12.0 Hz, 1H), 3.65 (s, 3H), 2.79 (ddd, J = 5.2, 12.4, 17.6 Hz, 1H), 2.55 (dl, J = 3.6 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.10 - 2.00 (m, 1H); MS (ESI) m / z 410.0 [M+H]+ Example 18. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-imidazol-5yl)metóxi)-[1,1'-biphenyl]-3-yl)piperidine-2,6-diona (compound 186)

[0498] 5-((4-iodofenóxi)methyl)-1-methyl-1 H-imidazol foi prepared from 4-iodophenol and (1-methyl-1 H-imidazol-5-yl)methanol similarly to Example 16.

[0499] 3-(2-chloro-4'-((1-methyl-1 H-imidazol-5-yl)methoxy)-[1,1'-biphenyl]3-yl)piperidine-2,6-diona was prepared from 5-[(4-iodofenoxy)methyl]1-methyl-imidazol and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)piperidine-2,6-diona according to Example 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 7.40 to 7.32 (m, 4H), 7.32 to 7.28 (m, 1H), 7.15, (7.15), (7.1H), 7.06 (s, 1H), 5.15 (s, 2H), 4.33 (dd, J = 4.8, 12.0 Hz, 1H), 3.66 (s, 3H), 2.83 2.73 (m, 1H), 2.56 (d, J = 3.6 Hz, 1H), 1H), 2.09 - 2.00 (m, 1H); MS (ESI) m / z 410.0 [M+H]+ Example 19. Synthesis of 3-(2-chloro-4'-(1-(1-methyl-1H-pyrazol-3yl)ethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 173)

[0500] 3-(2-chloro-4'-(1'-methyl-(1-1') H-pyrazole-3-yl)ethoxy)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 3-(1-(4-iodophenoxy)ethyl)-1methyl-1 H-pyrazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)piperidine-2,6-dione according to Scheme 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.38 to 7.24 (m, 5H), 7.06 to 7.00 (m, 2Hz), 6, 5 (2Hz, 2.2Hz), J 5.51 (q, J = 6.4 Hz, 1H), 4.32 (dd, J = 5.2, 12.0 Hz, 1H), 3.81 (s, 3H), 2.85 2.71 (m, 1H), 2.58 - 2.53 (m, 1H), - 1.99 (m, Petition 870260070484, of 16 / 07 / 2026, p. 243 / 1215 239 / 573 Η), 1.59 (d, J = 6.4 Hz, 3H); MS (ESI) m / z 424.1 [M+H]+ Example 20. Synthesis of 3-(2-chloro-4'-((3-methyl-2-oxopyridin-1(2H)yl)methyl)-[1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 187)

[0501] 1-(4-bromobenzyl)-3-methylpyridin-2(1 / - / )-one was prepared from 3-methylpyridin-2(1 H)-one and 1-bromo-4-(bromomethyl)benzene in accordance with General Scheme 8. ο APhos Pd G3, K3PO4 dioxane, 80 °C, 16 h compound 187

[0502] 3-(2-chloro-4'-((3-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4bromobenzyl)-3-methylpyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.92 (s, 1H), 7.76 - 7.69 (m, 1H), 7.43-7.32 (m, 7H), 7.31 -7.25 (m, 1H), 6.20 (t, J=6.8Hz, 1H), 5.17 (s, 2H), 4.38 - 4.27 (m, 1H), 2.86 - 2.72 (m, 1H), 2.56 (t, J = 3.2 Hz, 1H), 2.34 - 2.25 (m, 1H), 2.11 - 1.95 (m, 4H); MS (ESI) m / z 421.2 [M+H]+Example 21. Synthesis of 3-(2-chloro-4,-((6-methyl-2-oxopiridin-1(2H)yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 184)

[0503] 1-(4-bromobenzyl)-6-methylpyridin-2(1 / - / )-one was prepared from 1-bromo-4-(bromomethyl)benzene according to General Scheme 8. Petition 870260070484, dated 07 / 16 / 2026, page 244 / 1215 240 / 573 Pd(dppf)CI2, K3PO4dioxane, 100 °C, 12 h

[0504] 3-(2-chloro-4'-((6-methyl-2-oxopyridin-1 (2H)-yl)methyl)-[1,1 biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4bromobenzyl)-6-methylpyridine-2 / 1 / -one 1-(4-bromobenzyl)-6methylpyridin-2(1 H)-one according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.91 (s, 1H), 7.43 - 7.32 (m, 5H), 7.29 (dd, J= 2.0, 7.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 27, J Hz, 1H), 6.18 (d, J=6.8 Hz, 1H), 5.34 (s, 2H), 4.33 (dd, J=5.2, 12.0 Hz, 1H), 2.79 (ddd, J= 5.2, 12.0, 17.6 Hz, 15.6 Hz, J 1H), 2.38 - 2.32 (m, 1H), 2.31 (s, 3H), 2.08 - 1.99 (m, 1H); MS (ESI) m / z 421.0 [M+H]+ Example 22. Synthesis of 3-(2-chloro-4'-((5-methyl-2-oxopyridine-1(2H)yl)methyl)-[ 1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 188) XX / . / Br °XJJ Cetyltrimethylammonium bromide, K2CO3 ON J[ T H2O, 25-50 'C, 3 h 15 min ΑΧ

[0505] 1-(4-bromobenzyl)-5-methylpyridin-2(1 / - / )-one was prepared from 5-methylpyridin-2(1H)-one and 1-bromo-4-(bromomethyl)benzene according to General Scheme 8. dioxane, 100 °C, 16 h APhos Pd <33, K3POk Petition 870260070484, dated 07 / 16 / 2026, page 245 / 1215 241 / 573

[0506] 3-(2-chloro-4'-((5-methyl l-2-oxopyrid in-1 (2 H)-1 I) methyl l)-[ 1,1 biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-bromobenzyl)-5-methylpyridin-2(1 H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.91 (s I, 1H), 7.65 (s, 1H), 7.42 7.26 (m, 8H), 6.39 (d, J = 9.2 Hz, 1H), 5.10 (s, 2H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 2.85-2.71 (m, 1H), 2.55 (d, J =3.6 Hz, 1H), 2.32 (dq, J = 4.4, 12.8 Hz, 1H), 2.10-1.95 (m, 4H); MS (ESI) m / z 421,1 / 423,1 [M+H]+Exemplo 23. Synthesis of 3-(2-chloro-4,-((4-methyl-2-oxopyridin-1(2H)yl)methyl)-[1,1 '-biphenyl]-3-yl)piperidine-2,6-diona (compound 189) Cetyltrimethylaithionium brometho, K2CO3 H2O, 50 °C, 2 h

[0507] 1-(4-bromobenzyl)-4-methylpyridin-2(1 / - / )-one was prepared from 4-methylpyridin-2(1 H)-one and 1-bromo-4-(bromomethyl)benzene according to General Esquema 8. dioxane, 100 °C, 16h compost© 188

[0508] 3-(2-chloro-4'-((4-methyl-2-oxopyridin-1 (2H)-yl)meth l)-[ 1,1 'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4bromobenzyl)-4-methylpyridin-2(1) and H-one 3-(2-chloro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to 0 General Scheme 1. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.91 (s I, 1H), 7.72 (d, J = 6.8 Hz, Petition 870260070484, of 16 / 07 / 2026, p. 246 / 1215 242 / 573 1H), 7.38 to 7.27 (m, 7H), 6.25 (s, 1H), 6.13 (d, J = 6.4 Hz, 1H), 5.11 (s, 2H), 4.35 to 4.31 (m, 1H), 2.82 to 2.76 (m, 1H), J = 6.53, Hz, 1H), 2.33 - 2.31 (m, 1H), 2.14 (s, 3H), 2.07 - 2.02 (m, 1H); MS (ESI) m / z 421.1 / 423.0 [M+H, M+2+H]+ Example 24. Synthesis of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 185)

[0509] A solution of 1,4-di-iodobenzene (1.00 g, 3.03 mmol, To dimethyl sulfoxide (20 mL) and pyridin-2(1H)-one (28.26 mg, 3.03 mmol, 1.00 eq) and copper(I) iodide (578 mg, 3.03 mmol, 1.00 eq) and potassium carbonate (2.01 g, 14.6 mmol, 4.80 eq) were added under nitrogen. The mixture was stirred at 120°C for 3 hours under nitrogen. The reaction mixture was divided between ethyl acetate (30 mL) and water (30 mL). The organic phase was separated, washed with 60 mL (2 × 30 mL) of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl Acetate 0~10% / Petroleum Ether gradient eluent @ 20 mL / min) to give 1-(4-iodophenyl)pyridin2(1H)-one (800 mg, 2.42 mmol, 79.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.91 - 7.80 (m, 2H), 7.69 - 7.60 (m, 1H), 7.51 (ddd, J = 2.0, 6.8, 9.2 Hz, 1H), 7.27 - 7.17 (m, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.32 (dt, J = 1.2, 6.8 Hz, 1H) MS (ESI) m / z 298.0 [M+H]+ Petition 870260070484, dated 07 / 16 / 2026, p. 247 / 1215 243 / 573 O

[0510] To a solution of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (142 mg, 404 pmol, 1.20 eq) and 1-(4-iodophenyl)pyridin-2(1H)-one (100 mg, 337 pmol, 1.00 eq) in dioxane (5 mL) were added potassium phosphate (215 mg, 1.01 mmol, 3.00 eq) and [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 34.0 pmol, 0.100 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate (30 mL). The filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 µm; mobile phase: [water (formic acid) - acetonitrile]; % B: 36%-56%, 2 min).The residue was then purified by Prep-HPLC (column: YMC Triart C18 150*25 mm*5 pm; mobile phase: [water (hydrochloric acid) - acetonitrile]; % B: 30%-60%, 10 min) to give 3-(2-chloro4'-(2-oxopiridin-1(2H)-yl)-[1,1'-biphenyl]-3-I)piperidina-2,6-d ion a (18.6 mg, 46.40 pmol, yield 13.79%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 10.94 (s, 1H), 7.76 - 7.71 (m, 1H), 7.58 - 7.49 (m, 5H), 7.46 - 7.35 (m, 3H), 6.51 (d, J= 9.2 Hz, 1H), 6.34 m / z 393.0 [M+H]+.

[0511] An alternative synthesis for Compound 185 is provided below: Petition 870260070484, dated 07 / 16 / 2026, p. 248 / 1215 244 / 573

[0512] A mixture of (4-bromophenyl)boronic acid (3.00 g, 14.9 mmol, 1.00 eq), pyridin-2(1H)-one (1.70 g, 17.9 mmol, 1.20 eq), copper acetate (2.71 g, 14.9 mmol, 1.00 eq) and triethylamine (4.53 g, 44.8 mmol, 6.24 mL, 3.00 eq) in dichloroethane (5 mL) was degassed and purged with oxygen 3 times and then stirred at 25°C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g Silica Flash Column, Ethyl Acetate gradient eluent 0~80% / Petroleum Ether @ 40 mL / min) to give 1-(4-bromophenyl)pyridin-2(1H)-one (1.6 g, 6.33 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.75 - 7.67 (m, 2H), 7.67 - 7.60 (m, 1H) 7.51 (ddd, J = 9.2, 6.8, 2.0 Hz, 1H), 7.44 - 7.34 (m, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.32 (dt, J = 6.8, 1.2 Hz, 1H). MS (ESI) m / z 251.6 [M+H]+

[0513] A mixture of 1-(4-bromophenyl)pyridin-2(1H)-one (500 mg, 2.00 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (558 mg, 2.20 mmol, 1.10 eq), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 199 µmol, 0.100 eq) and potassium acetate (588 mg, 6.00 mmol, 3.00 eq) in dioxane (5 mL) was degassed and purged with nitrogen 3 times. The mixture was then stirred at 80°C for 3 hours under a nitrogen atmosphere.The reaction mixture was cooled to 25°C and concentrated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 25 g Silica Flash Column, Ethyl Acetate gradient eluent 0-100% / Petroleum Ether @ 60 mL / min) to yield 1-(4-(4,4,5,5. Petition 870260070484, dated 07 / 16 / 2026, p. 249 / 1215 245 / 573 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (500 mg, 1.53 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.79 (d, J = 7.6 Hz, 2H), 7.64 - 7.60 (m, 1H), 7.54 - 7.47 (m, 1H), 7.42 (d, J = 7.6 Hz, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.32 (t, J = 6.8 Hz, 1H), 1.31 (s, 12H). MS (ESI) m / z 298.0 [M+H]+ DMF, 100 °C, 16 h

[0514] A mixture of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (2.78 g, 9.20 mmol, 1.00 eq), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (3.00 g, 10.1 mmol, 1.10 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (672 mg, 918 μmol, 0.10 eq) and potassium phosphate (5.84 g, 27.5 mmol, 3.00 eq) in dimethylformamide (60 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 330 g Silica Flash Column, Ethyl acetate and dichloromethane gradient eluent at 100-100% / Petroleum ether @ 80 mL / min) followed by Prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 10 μm); mobile phase: [water (formic acid) - acetonitrile]; % B: 20% - 50%, 20 min) and lyophilized to yield 3-(2-chloro-4'-(2-oxopiridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (926 mg, 2.33 mmol, 25% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.73 (dd, J = 1.6, 6.8 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.47 - 7.35 (m, 3H), 6.51 (d, J = 8.8 Hz, 1H), 6.34 (dt, J = 1.6, 6.8 Hz, 1H), 4.43 - 4.33 (m, 1H), 2.87 - 2.74 (m, Petition 870260070484, dated 07 / 16 / 2026, p. 250 / 1215 246 / 573 1H), 2.60 - 2.54 (m, 1H), 2.42 - 2.29 (m, 1H), 2.12 - 2.02 (m, 1H); MS (ESI) m / z 392.9 [M+H]+ Example 25. Synthesis of 3-(2,4-difluoro-4'-((2-oxopyridin-1(2H)yl)methyl)-[ 1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 147)

[0515] To a solution of A / , / V, / \ / -trimethyl-hexadecan-1-ammonium bromide (450 mg, 1.23 mmol, 0.08 eq) in water (20 mL) was added pyridin-2(1 / 7)-one (1.50 g, 15.8 mmol, 1.00 eq) followed by potassium carbonate (3.27 g, 23.7 mmol, 1.50 eq). The mixture was stirred at 25°C for 15 min. Then, 1-bromo-4-(bromomethyl)benzene (4.34 g, 17.4 mmol, 1.10 eq) was added, and the mixture was stirred at 50°C for 4 h. The reaction mixture was cooled to 20°C. The reaction mixture was diluted with water (50 mL). The mixture was extracted with ethyl acetate (2 χ 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether / ethyl acetate = 10 / 1 (66 mL) at 25°C for 60 min.The mixture was filtered and the filter cake was dried under reduced pressure to yield 1-(4-bromobenzyl)pyridin-2(1 / 7)-one (3.30 g, 12.4 mmol, 78% yield) as a whitish solid.

[0516] A solution of 1-(4-bromobenzyl)pyridin-2(1 / 7)-one (3.30 g, 12.5 mmol, 1.00 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.48 g, 13.7 mmol, 1.10 eq) in dioxane (60 mL) were Petition 870260070484, dated 07 / 16 / 2026, p. 251 / 1215 247 / 573 added potassium acetate (3.68 g, 37.5 mmol, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (911 mg, 1.25 mmol, 0.10 eq). The mixture was stirred at 100°C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to 20°C, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 120 g Silica Flash Column, Ethyl Acetate gradient eluent 40-60% / Petroleum Ether @ 80 mL / min) to give 1-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1 / - / )-one (3.03 g, 8.08 mmol, 65% yield, 83% purity) as a yellow solid. Pd(dppf)CI2, K3PO4dioxane, 100 °C, 16 h

[0517] To a solution of 3-(3-bromo-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 329 pmol, 1.00 eq) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1 / - / )-one (113 mg, 301 pmol, 83% purity, 0.90 eq) in dioxane (3 mL) were added potassium phosphate (210 mg, 989 pmol, 3.01 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 34.2 pmol, 0.10 eq). The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl acetate gradient eluent 78-90% / Petroleum ether @ 15 mL / min) followed by Prep-HPLC (column: Phenomenex luna C18 150 χ 25 mm χ 10 pm; mobile phase: [water (formic acid) - acetonitrile]; % B: 18%-38%, 10 min) and lyophilized to yield 3-(2,4-difluoro-4'-((2-oxopiridin Petition 870260070484, dated 07 / 16 / 2026, p. 252 / 1215 248 / 573 (2 / - / )-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (49.2 mg, 119 pmol, 36% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.99 (s, 1H), 7.83 (dd, J = 2.0, 6.8 Hz, 1H), 7.54 - 7.41 (m, 4H), 7.38 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 9.2 Hz, 1H), 6.43 (d, J= 9.2 Hz, 1H), 6.26 (dt, J= 1.2, 6.8 Hz, 1H), 5.15 (s, 2H), 4.32 (dd, J =5.2, 12.4 Hz, 1H), 2.90 - 2.77 (m, 1H), 2.59 - 2.52 (m, 1H), 2.19 (dq, J= 3.6, 13.2 Hz, 1H), 2.12 - 2.02 (m, 1H); MS (ESI) m / z 409.0 [M+H]+ Example 26. Synthesis of 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-3yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 180)

[0518] 3-(2-chloro-4'-(((1 -methyl-1 H-pyrazol-3-yl)methyl)amino)-[1,1 biphenyl]-3-yl)piperidine-2,6-diona foi preparada a partir de 4-iodo- / V-((1metil-1 / - / -pyrazol-3-yl)metil)anilina e 3-(2-chloro-3-(4,4,5,5-tetrametil-1,3,2dioxaborolan-2-yl)fenyl)piperidine-2,6-diona de acordo com o Eschema Geral 1. MS (ESI) m / z 409.1 [M+H]+ Example 27. Synthesis of 3-(2-chloro-4'-(pyrrolidine-1-carbonyl)-[1,Tbifen yl]-3-yl)pi perid i na-2,6-diona (compound 181) Pd(dppf)CI2, K3PO4 dioxane - 100 °C, 16 h

[0519] A mixture of (4-bromophenyl)(pyrrolidin-1-yl)methanone (100 mg, 394 pmol, 1.00 eq), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)piperidine-2,6-diona (172 mg, 394 pmol, 80% pure, 1.00 eq), potassium phosphate (251 mg, 1.18 mmol, 3.00 eq) and [1,1-Bis(diphenylphosfino)ferroceno]dichloropaládio (II) (29.0 mg, 39.6 pmol, 0.10 eg) in dioxane (3 mL) after degassing and purgada com nitrogenic Petition 870260070484, dated 07 / 16 / 2026, p. 253 / 1215 249 / 573 times, then the mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate gradient eluent 85-95% / Petroleum Ether @ 40 mL / min) followed by Prep-HPLC (column: Phenomenex luna C18 150 χ 25 mm χ 10 pm; mobile phase: [water (formic acid) - acetonitrile]; % B: 26%-56%, 10 min) and lyophilized to yield 3-(2-chloro-4'-(pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (57.8 mg, 141 pmol, 36% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ = 10.93 (s I, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.43 - 7.37 (m, 2H), -7.37 (m, 2H), -7.31 (m, 2H), 4.36 (dd, J = 4.8, 12.8 Hz, 1H), 3.47 (td, J = 6.4, 18.0 Hz, 4H), 2.88 - 2.73 (m, 1H), 2.56 (d, J=3.2 Hz, 1H), d 1H), 2.12 -1.99 (m, 1H), 1.96 - 1.76 (m, 4H); MS (ESI) m / z 397.0 [M+H]+ Example 28. Synthesis of 3-(2-chloro-4-fluoro-4'-((2-oxopyridin-1(2H)yl)methyl)-[ 1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 143) Pd(dppf)CI2lK3PO4 dioxane,100ÚC,16 h

[0520] 3-(2-chloro-4-fluoro-4'-((2-oxopyridin-1 (2H)-yl)methi l)-[ 1,1 'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2chloro-6-fluorophenyl-2,6-piperidine-2) 1-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzyl)pyridin-2(1 / - / )-one according to 0 General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.98 (d, J = 6.4 Hz, 1H), 7.86 (dd, J = 2.0, 6.8 Hz, 1H), 7.45 (ddd, J= 2.0, 6.8, 9.2 Hz, 1H), 7.39 (s, 1H), 7.38 - 7.35 (m, 4H), 7.32 (s, 1H), 6.44 (d, J = 9.2 Hz, 1H), 6.30 - 6.25 (m, 1H), Petition 870260070484, dated 07 / 16 / 2026, p. 254 / 1215 250 / 573 5.16 (s, 2H), 4.50 (dd, J = 5.2, 12.4 Hz, 1H), 2.92 - 2.77 (m, 1H), 2.56 (d, J = 3.2 Hz, 1H), 2.21 - 2.07 (m, 1H), 2.06 - 1.95 (m, 1H); MS (ESI) m / z 425.0 [M+H]+ Example 29. Synthesis of 3-(4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-2(trifluoromethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 191)

[0521] 3-(3-bromo-2-(trifluoromethyl)phenyl)piperidine-2,6-dione was prepared from 1-bromo-3-methyl-2-(trifluoromethyl)benzene according to General Scheme 2. The 1-methyl-3-((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1 / - / -pyrazole according to General Scheme 1. MS (ESI) m / z 444.3 [M+H]+ Example 30. Synthesis of 3-(2-methyl-4'-((1-methyl-1H-pyrazol-3yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 192) Br

[0523] To a solution of 1,3-dibromo-2-methylbenzene (477 mg, 1.91 mmol, 3.00 eg), 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1 / - / -pyrazole (200 mg, 0.636 mmol, 1.00 eg) in dioxane (4 mL) and water (1 mL) were added [1,1Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (46.6 mg, 63.7 pmol, 0.100 eg) and potassium carbonate (202 mg, 1.91 mmol, 3.00 eg). The reaction mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. Petition 870260070484, dated 07 / 16 / 2026, p. 255 / 1215 251 / 573 The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate gradient eluent at 0-30% / petroleum ether @ 25 mL / min) to yield 3-(((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-methyl-1H-pyrazole (190 mg, 0.457 mmol, 72% yield) as gum yellow. 1H NMR (400 MHz, DMSO-d6) δ = 7.67 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 2.4, 6.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.21 - 7.14 (m, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.03 (s, 2H), 3.84 (s, 3H), 2.26 (s, 3H); MS (ESI) m / z 357.0 [M+H]+

[0524] To a solution of (2,6-bis(benzyloxy)pyridin-3yl)boronic acid (214 mg, 0.638 mmol, 1.20 eq), 3-(((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-methyl-1H-pyrazole (190 mg, 0.532 mmol, 1.00 eq) in dimethylformamide (4 mL) were added [1,1Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (38.9 mg, 53.2 pmol, 0.100 eq) and sodium carbonate (339 mg, 1.60 mmol, 3.00 eq). The reaction mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Petition 870260070484, dated 07 / 16 / 2026, page 256 / 1215 252 / 573 flash emoxy-gel chromatography (gradient eluent of ethyl acetate at 0~30% / petroleum ether @ 30 mL / min) to originate 2,6bis(benzyloxy)-3-(2-methyl-4'-((1 -methyl-1 / - / -pyrazol-3-yl)metoxy)-[ 1,1'-biphen i I]3-yl)pyridine (160 mg, 0.259 mmol, 49% yield) as a solid pack. 1H NMR (400 MHz, DMSO-cfe) δ = 7.67 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.37 (m, 2H), 7.36 - 7.28 (m, 6H), 7.26 - 7.18 (m, 3H), 7.16 - 7.05 (m, 4H), 6.54 (d, J = 8.0 Hz, 1H), 6.33 (d, J= 2.0 Hz, 1H), 5.37 (s, 4H), 5.03 (s, 2H), 3.84 (s, 3H), 1.92 (s, 3H); MS (ESI) m / z 568.3 [M+H]+

[0525] To a solution of 2,6-bis(benzyloxy)-3-(2-methyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)pyridine (80.0 mg, 0.141 mmol, 1.00 eq) in dioxane (2 mL) palladium on carbon (150 mg, 10% purity) was added, then the mixture was degassed with nitrogen three times and degassed with hydrogen three times, the resulting mixture was stirred at 40°C under hydrogen (15 psi) for 16 h. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl alcohol (50 mL), the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 µm; mobile phase: [water (formic acid) acetonitrile]; % B: 31%-64%, 9 min) and lyophilized to yield 3-(2-methyl-4'-((1-methyl-1 / - / -pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (47.1 mg, 0.119 mmol, 85% yield, 99% purity) as a white solid. Petition 870260070484, dated 07 / 16 / 2026, page 257 / 1215 253 / 5731H NMR (400 MHz, DMSO-cf) δ = 10.85 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.24- 7.16 (m, 3H), 7.12 - 7.05 (m, 4H), 6.33 (d, J = 2.0 Hz, 1H), 5.03 (s, 2H), 4.14 (dd, J = 4.8, 11.6 Hz, 1H), 3.84 (s, 3H), 2.82 - 2.70 (m, 1H), 2.54 (d, J = 4.0 Hz, 1H), 2.27-2.17(m, 1H), 2.14 (s, 3H), 2.09–1.99 (m, 1H); MS (ESI) m / z 390.1 [M+H]+ Example 31. Synthesis of 3-(2,2'-dichloro-4'-((1 -methyl-1 H-pyrazol-3yl)methoxy)-[ 1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 177) . Cl

[0526] A solution of 4-bromo-3-chlorophenol (715 mg, 3.45 mmol, 1.50 eq) and potassium carbonate (635 mg, 4.60 mmol, 2.00 eq) in acetonitrile (5.00 mL) was stirred at 25°C for 20 min, then 3(chloromethyl)-1-methyl-1H-pyrazole (300 mg, 2.30 mmol, 1.00 eq) was added at 65°C. The mixture was stirred at 65°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to yield 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (708 mg, 90% purity) as a white solid.

[0527] 3-(2,2'-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-((4-bromo-3chlorophenoxy)methyl)-1-methyl-1H-pyrazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS (ESI) m / z 444.0 [M+H]+ Example 32. Synthesis of 3-(4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 151) Petition 870260070484, dated 07 / 16 / 2026, page 258 / 1215 254 / 573

[0528] 3-(4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1,3-dibromobenzene, 1methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1 / - / pyrazole and (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid analogously to Example 30. MS (ESI) m / z 376.1 [M+H]+ Example 33. Synthesis of 3-(2-chloro-4'-(2-(2-oxopyridin-1(2H)-yl)ethyl)[1,r-biphenyl]-3-yl)piperidine-2,6-dione (compound 182)

[0529] 3-(2-chloro-4'-(2-(2-oxopiridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1-(4-bromophenethyl)pyridin2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS (ESI) m / z 421.1 [M+H]+ Example 34. Synthesis of 3-(2-chloro-4'-(3-(2-oxopyridin-1(2H)yl)propyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 178) Br

[0530] To a solution of A / , / V, / \ / -trimethyl-hexadecan-1-ammonium bromide (24.0 mg, 65.9 mmol, 0.09 eq) in water (4 mL) were added potassium carbonate (152 mg, 1.10 mmol, 1.53 eq) and pyridin-2(1H)-one (72.0 mg, 757 pmol, 1.05 eq). The mixture was stirred to Petition 870260070484, dated 07 / 16 / 2026, page 259 / 1215 255 / 573 The mixture was heated to 25°C for 15 min. Then, 1-bromo-4-(3-bromopropyl)benzene (200 mg, 720 μmol, 1.00 eq) was added. The mixture was stirred at 50°C for 6 h. The reaction mixture was cooled to 25°C and diluted with water (20 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl Acetate gradient eluent 80-100% / Petroleum Ether @ 30 mL / min) to give 1-(3-(4-bromophenyl)propyl)pyridin-2(1H)-one (90.0 mg, 260 μmol, 40% yield) as a yellow solid.

[0531] 3-(2-chloro-4'-(3-(2-oxopyridin-1(2 H)-yl)propyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1-(3-(4bromophenyl)propyridine-2(1H)-one 3-(2-chloro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione in accordance with the General Scheme 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 7.69 (dd, J = 2.0, 6.4 Hz, 1H), 7.43 to 7.25 (m, 8H), 6.37 (d, J = 9.2 Hz, 1H, 1H), J 1.2, 6.8 Hz, 1H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.95 (t, J = 7.6 Hz, 2H), 2.85 - 2.72 (m, 1H), 2.69 - 2.62 (m, 2.5 Hz), 2.40 - 2.25 (m, 1H), 2.09 - 1.93 (m, 3H); MS (ESI) m / z 435.1 [M+H]+ Example 35. Synthesis of 3-(4'-((1H-imidazol-1-yl)methyl)-2-chloro-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 140)

[0532] 3-(4'-((1 H-imidazol-1-yl)methyl)-2-chloro-[1,1 '-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1-(4-bromobenzyl)-1 Himidazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.92 (dl, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.46 - 7.23 (m, 8H), 6.94 (s, 1H), 5.27 (s, 2H), 3.4, J 12.4 Hz, 1H), 2.85 - 2.73 (m, 1H), 2.56 (dl, J = 3.2 Hz, 1H), 2.34 - 2.27 Petition 870260070484, of 16 / 07 / 2026, p. 260 / 1215 256 / 573 (m, 1 Η), 2.09 - 1.98 (m, 1H); MS (ESI) m / z 380.0 [M+H]+ Example 36. Synthesis of 3-(2-chloro-4'-((1-methyl-1 H-pyrazol-3-yl)methyl)[1,1'-biphenyl]3-yl)piperidine-2,6-dione (compound 176)

[0533] 3-(4-bromobenzyl)-1-methyl-1 H-pyrazole was prepared from 1-bromo-4-(bromomethyl)benzene and 1-methyl-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to Esqueral 8 . Pd(dppf)CI2, K3PO4dioxane, 100 °C, 16 tl "Pin

[0534] 3-(2-dichloro-4'-((1 -methyl-1 / - / -pyrazol-3-yl)methyl)-[1,1 '-biphenyl]-3yl)piperidine-2,6-dione was prepared from 3-(4-bromobenzyl)-1methyl-1 / - / -pyrazole and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.91 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.37 - 7.26 (m, 7H), 6.07 (d, J = 2.0 Hz, 14 Hz), J, 4, 2,5 12.0 Hz, 1H), 3.91 (s, 2H), 3.79 (s, 3H), 2.79 (m, 1H), 2.56 (d, J = 3.6 Hz, 1H), 2.33 (dd, J = 4.0, 12.8 Hz, 1H, 1H), -1, 19 (H); MS (ESI) m / z 394.0 [M+H]+ Example 37. Synthesis of 3-(2-chloro-4'-(4-((2-oxopyridin-1(2H)yl)methyl)piperidin-1-yl)-[ 1,1 '-biphenyl]-3-yl)piperidin-2,6-dione (compound 166) Petition 870260070484, of 16 / 07 / 2026, p. 261 / 1215 257 / 573

[0535] 3-(2-chloro-4'-(4-((2-oxopyridin-1(2 H)-yl)methyl)piperidin-1-yl)[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-((1-(4bromophenyl)-pyrimeth-2(1)-pyridine-2) H)-one and 3-(2-chloro-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H RMN (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 7.66 (dd, J = 1.6, 6.8 Hz, 1H), 7.41 (ddd, J = 2.0, 6.8, 8.8 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.30 - 3,73 (m, 4H), 2.84 - 2.72 (m, 1H), 2.72 - 2.63 (m, 2H), 2.57 - 2.52 (m, 1H), 2.39 - 2.26 (m, 1H), 2.10 - 1.91 (m, 2H), 1.58 (d, J = 11.2 Hz, 2H), 1.35 (dq, J = 3.2, 12.4 Hz, 2H); MS (ESI) m / z 490,1 [M+H]+ Exemplo 38. Síntese de 3-(2-chloro-4'-(1-(2-oxopiridin-1(2H)-il)etil)[1,1'-bifenil]-3-il)piperidina-2,6-diona (composto 174)

[0536] A sum of 1-bromo-4-(1-bromoetil)benzene (500 mg, 1.89 mmol, 1.00 eq) in dimethylformamide (6 mL) were added to cesium carbonate (1.23 g, 3.79 mmol, 2.00 eq) and pyridin-2(1H)-one (216 mg, 2.27 mmol, 1.20 eq). The mixture was then stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 4 g Silica Flash Column, Ethyl Acetate 0-50% / Petroleum Ether Gradient Eluent @ 20 mL / min). The compound 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one (310 mg, 1.10 mmol, 58% yield) was obtained as a white solid.

[0537] 3-(2-chloro-4'-(1-(2-oxopiridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2 Petition 870260070484, dated 07 / 16 / 2026, page 262 / 1215 258 / 573 dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS (ESI) m / z 421.1 [M+H]+ Example 39. Synthesis of 3-(2-chloro-4'-(1-(pyridin-2-yloxy)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 165)

[0538] To a solution of 1-bromo-4-(1-bromoethyl)benzene (500 mg, 1.89 mmol, 1.00 eq) in dimethylformamide (6 mL) were added to cesium carbonate (1.23 g, 3.79 mmol, 2.00 eq) and pyridin-2(1H)-one (216 mg, 2.27 mmol, 1.20 eq). The mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® Silica Flash Column 4 g, Ethyl Acetate gradient eluent 0-50% / Petroleum Ether @ 20 mL / min). 2-[1-(4-bromophenyl)ethoxy]pyridine (160 mg, 546 µmol, 28.8% yield) was obtained as a colorless oil.

[0539] 3-(2-chloro-4'-(1-(pyridin-2-yloxy)ethyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 2-(1-(4-bromophenyl)ethoxy)pyridine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1; MS (ESI) m / z 443.1 [M+Na]+ Example 40. Synthesis of 3-(2-chloro-4'-((2-oxopiperidin-1-yl)methyl)[1,r-biphenyl]-3-yl)piperidine-2,6-dione (compound 168) Petition 870260070484, dated 07 / 16 / 2026, page 263 / 1215 259 / 573 Br

[0540] To a solution of piperidin-2-one (1.00 g, 10.0 mmol, 1.00 eq) and sodium hydride (806 mg, 20.1 mmol, 60% purity, 2.00 eq) in tetrahydrofuran (10.0 mL) was added 1-bromo-4-(bromomethyl)benzene (2.52 g, 10.0 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) at 0°C, the mixture was stirred at 25°C for 16 h. The mixture was quenched with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (3 χ 30.0 mL). The combined organic layer was washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 1-(4-bromobenzyl)piperidin-2-one (1.54 g, 5.74 mmol, 56% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-cfe) δ = 7.57 - 7.43 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 4.46 (s, 2H), 3.14 (s, 2H), 2.37 - 2.21 (m, 2H), 1.68 (td, J= 3.2, 6.4Hz, 4H). MS (ESI) m / z 270.0 [M+3H]+

[0541] To a solution of 1-(4-bromobenzyl)piperidin-2-one (100 mg, 372 µmol, 1.00 eq), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (179 mg, 410 µmol, 80% purity, 1.10 eq) and methanesulfonate ([4-( / V, / \ / -dimethylamino)phenyl]d / -f-butylphosphine)(2Petition 870260070484, dated 16 / 07 / 2026, page 264 / 1215 260 / 573 amino-1,1-biphenyl-2-yl)palladium (II) (47.3 mg, 74.5 µmol, 0.200 eq) in dioxane (4.00 mL) was added to tripotassium phosphate (237 mg, 1.12 mmol, 3.00 eq) in a portion under a nitrogen atmosphere. The mixture was stirred at 100°C for 12 h. The mixture was diluted with saturated ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (3 χ 10.0 mL). The combined organic layer was concentrated to give crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give a crude product, which was purified by Prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 µm; mobile phase: [water (formic acid) - acetonitrile]; % B: 30%-60%, 10 min) and lyophilized to give 3-(2-chloro-4'-((2-oxopiperidin-1-yl)methyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione (16.09 mg, 38.9 µmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-ds) δ = 10.92 (s, 1H), 7.43 - 7.33 (m, 4H), 7.32 - 7.26 (m, 3H), 4.55 (s, 2H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.28 3.22 (m, 2H), 2.86 - 2.72 (m, 1H), 2.64 - 2.64 (m, 1H), 2.56 (tl, J = 3.6 Hz, 1H), 2.40 - 2.26 (m, 3H), 2.08 - 2.01 (m, 1H), 1.75 (tl, J = 3.2Hz, 4H). MS (ESI) m / z 411.1 [M+H]+ Example 41. Synthesis of 3-(2-chloro-4'-(pyridin-2-ylmethyl)-[1,1'-biphenyl]3-yl)piperidine-2,6-dione (compound 169)

[0542] 1-bromo-4-(bromomethyl)benzene (791 mg, 3.16 mmol, 1.00 eq) was added dropwise to a suspension of activated zinc (2.07 g, 31.7 mmol, 10.0 eq) in tetrahydrofuran (50.0 mL) under nitrogen. After the temperature reached 25°C, 2-bromopyridine was added to the mixture. Petition 870260070484, dated 07 / 16 / 2026, page 265 / 1215 261 / 573 (500 mg, 3.16 mmol, 301 µL, 1.00 eq) and tetrakis[triphenylphosphine]palladium (0) (731 mg, 633 µmol, 0.200 eq) in portions under nitrogen. The mixture was stirred at 25°C for 12 h. The mixture was filtered. The filtrate was dissolved in water (30 mL) and extracted with ethyl acetate (3 χ 30 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by reverse phase (C18, 120 g; condition: water / acetonitrile = 100:0 to 0:100, formic acid at 0.1%) to give 2-(4-bromobenzyl)pyridine (120 mg, 484 µmol, 15% yield) as colorless oil. dioxane, 100 ftC, 12 h Pd(dppf)CI2jK3PO4

[0543] 3-(2-chloro-4'-(pyridine in-2-i Methyl)-[ 1,1 '-biphen yl]-3-i I) pi perid ina-2,6diona was prepared from 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)piperidine-2,6-diona and 2-(4-bromobenzyl)pyridine de accord com 0 Esquema Geral 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.92 (s I, 1H), 8.52 (d, J = 4.0 Hz, 1H), 7.74 (dt, J= 1.6, 7.6 Hz, 1H), 7.41 - 7.32 (m, 7H), 7.31 - 7.27 (m, 1H), 7.26 - 7.21 (m, 1H), 4.34 (dd, J = 5.2, 12.0 Hz, 1H), 4.14 (s, 2H), 2.86 - 2.74 (m, 1H), 2.59 - 2.55 (m, 1H), 2.39 - 2.26 (m, 1H), 2.11 - 1.97 (m, 1H). MS (ESI) m / z 391.1 [M+H]+ Exemplo 42. Synthesis of 3-(2-cloro-4'-(pirazin-2-ylmetil)-[1,1 '-bifenil]3-yl)piperidina-2,6-diona (compound 159) Petition 870260070484, 16 / 07 / 2026, pág. 266 / 1215 262 / 573

[0544] To a solution of 4-bromobenzaldehyde (2.00 g, 10.8 mmol, 1.00 eq) and 2,2-dimethoxyethanamine (1.25 g, 11.9 mmol, 1.30 mL, 1.10 eq) in methanol (20.0 mL) was added acetic acid (64.9 mg, 1.08 mmol, 61.8 µL, 0.100 eq). The mixture was stirred at 20°C for 0.5 h. The mixture was concentrated under reduced pressure to yield (E)-L / -(4-bromobenzylidene)-2,2-dimethoxyethanamine (2.94 g, crude) as a colorless oil.

[0545] A solution of (E)- / V-(4-bromobenzylidene)-2,2-dimethoxyethanolamine (2.94 g, 10.8 mmol, 1.00 eq) in 2,2,2-trifluoroacetic acid (4.00 mL) was stirred at 75°C for 20 min under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. Saturated sodium bicarbonate solution was added to the residue until pH = 7 and then extracted with dichloromethane (3 χ 80 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (90 mL) and water (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give brown oil. The brown oil was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-(4-bromobenzyl)pyrazine (334 mg, 1.34 mmol, 12% yield) as a brown solid. Petition 870260070484, dated 07 / 16 / 2026, page 267 / 1215 263 / 573 Q composed 159

[0546] 3-(2-Chloro-4'-(pyrazin-2-ylmethyl)-[1,1'-biphenyl]-3-yl) piperidine2,6-dione was prepared from 2-(4-bromobenzyl)pyrazine and 3-(2chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ= 10.88 (s I, 1H), 8.68 (d, J= 1.2 Hz, 1H), 8.59 - 8.52 (m, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.40 - 7.20 (m, 7H), 4.30 (dd, J = 4.8, 12.0 Hz, 1H), 4.18 (s, 2H), 2.82 - 2.69 (m, 1H), 2.59 2.51 (m, 1H), 2.32 - 2.25 (m, 1H), 2.06 - 1.95 (m, 1H); MS (ESI) m / z 392.1 [M+H]+ Example 43. Synthesis of 3-(2-chloro-4'-((4-fluoro-2-oxopyridin-1(2H)yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 170) Br

[0547] 1-(4-bromobenzyl)-4-fluoropyridin-2(1 / - / )-one was prepared from 4-fluoropyridin-2(1 / - / )-one and 1-bromo-4-(bromomethyl)benzene according to General Scheme 8. Petition 870260070484, dated 07 / 16 / 2026, p. 268 / 1215 264 / 573 Ο APhos Pd G3, K3PO4DMF, 100 °C, 16 h

[0548] 3-(2-chloro-4'-((4-fluoro-2-oxopyridin-1 (2H)-yl)methyl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4bromobenzyl)-4-fluoropyridine-2 / 1 / 2-(e)-one 3-(2-chloro-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.91 (s I, 1H), 8.06 (t, J = 8.0 Hz, 1H), 7.40 - 7.33 (m, 6H), 7.29 (d, J = 7.2 Hz, 1.41 Hz), - 6.35 (m, 1H), 6.26 (dd, J= 2.4, 11.6 Hz, 1H), 5.16 (s, 2H), 4.33 (dd, J = 4.8, 12.4 Hz, 1H), 2.80 - 2.75 (m, 1H), 2.68 - 2.55 (m, 13H), 1H), 2.06 2.02 (m, 1H); MS (ESI) m / z 425.1 [M+H]+ Example 44. Synthesis of 3-[2-chloro-3-[4-[(4-methoxy-2-oxo-1pyridyl)methyl]phenyl]phenyl]piperidine-2,6-dione (compound 175) OMe CTAB, K2CO3H2O, 50 °C, 4 h

[0549] 1-[(4-bromophenyl)methyl]-4-methoxy-pyridin-2-one was prepared from 4-methoxy-1 / - / -pyridin-2-one and 1-bromo-4-(bromomethyl)benzene according to General Scheme 8. Petition 870260070484, dated 07 / 16 / 2026, p. 269 / 1215 265 / 573

[0550] 3-[2-chloro-3-[4-[(4-methoxy-2-oxo-1-pyridyl)methyl]phenyl]phenyl]piperidine-2,6-dione was prepared from 1-[(4-bromophenyl)methyl]-4-methoxy-pyridin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-cfe) δ = 10.91 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.41 - 7.33 (m, 4H), 7.33 - 7.26 (m, 3H), 6.01 (dd, J = 2.8, 7.6 Hz, 1H), 5.85 (d, J = 2.8 Hz, 1H), 5.09 (s, 2H), 4.40 - 4.28 (m, 1H), 3.74 (s, 3H), 2.86 - 2.70 (m, 1H), 2.58 - 2.52 (m, 1H), 2.36 - 2.29 (m, 1H), 2.10-1.98 (m, 1H); MS (ESI) m / z 437.2[M+H]+ Example 45. Synthesis of 3-(2-chloro-4'-((2-oxo-4(trifluoromethyl)pyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6dione (compound 171) The 3-(2-chloro-3-(4,4,5,5 Petition 870260070484, dated 07 / 16 / 2026, page 270 / 1215 266 / 573 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. 1H NMR (400 MHz, DMSO-c / 6) δ= 10.92 (s, 1H), 8.18 (d, J= 7.2 Hz, 1H), 7.42 - 7.34 (m, 6H), 7.31 - 7.25 (m, 1H), 6.85 (s, 1H), 6.56 (dd, J = 1.6, 7.2 Hz, 1H), 5.22 (s, 2H), 4.37 - 4.29 (m, 1H), 2.79 - 2.63 (m, 1H), 2.67 - 2.55 (m, 1H), 2.35 - 2.31 (m, 1H), 2.08 - 1.98 (m, 1H) MS (ESI) m / z 475.1 [M+H]+ Example 46. Synthesis of 3-(2-chloro-4'-(((1-methyl-1 H-pyrazol-3yl)oxy)methyl)-[1,1 '-biphenyl]-3-yl)piperidine-2,6-dione (compound 160) /

[0552] To a solution of 1-bromo-4-(bromomethyl)benzene (3.06 g, 12.2 mmol, 1.20 eq) in A / , / V-dimethylformamide (15.0 mL) were added 1-methyl-1 / - / -pyrazol-3-ol (1.00 g, 10.2 mmol, 1.00 eq) and potassium carbonate (1.70 g, 12.3 mmol, 1.21 eq) at 0°C. The mixture was stirred at 25°C for 1.5 h. Then, the mixture was stirred at 55°C for 4 h. The reaction mixture was divided between ethyl acetate (100 mL) and water (100 mL), and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase (C18, 80 g; condition: water / acetonitrile = 100:0 to 0:100, formic acid at 0.1%) and lyophilized to yield 3-((4-bromobenzyl)oxy)-1-methyl-1 / - / -pyrazole (160 mg, 497 µmol, 5% yield, 83% purity) as a white solid and 2-(4-bromobenzyl)-1-methyl-1,2-dihydro-3 / - / -pyrazol-3-one (350 mg, 1.30 mmol, 13% yield, 99% purity) as a white solid.

[0553] 3-(2'-chloro-4'-(((1 -methyl-1 H-pyrazol-3-yl)oxy)methyl)-[1,1 'biphenyl]-3-yl)piperidin-2,6-dione was prepared from 3-((4bromobenzyl H -pyramethyl)-1 3-(2-chloro-4′-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-iI)piperidine-2,6-dione of accord Petition 870260070484, dated 07 / 16 / 2026, p. 271 / 1215 267 / 573 with the Geral 1 Scheme. MS (ESI) m / z 410.1 [M+H]+ Example 47. Synthesis of 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 161) compound 161

[0554] To a solution of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (139 mg, 399 µmol, 1.20 eq) in dimethylformamide (4.00 mL) were added 1-(4-iodophenyl)piperidin-2-one (100 mg, 332 µmol, 1.00 eq), potassium phosphate (211 mg, 996 µmol, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.3 mg, 33.2 µmol, 0.100 eq). The reaction mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) and concentrated under reduced pressure to give a crude product.The crude product was purified by Prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 µm; mobile phase: [water (formic acid) acetonitrile]; % B: 28% - 58%, min) and lyophilized to yield 3-(2chloro-4'-(2-oxopiperidin-1-yl)-[1,1'-biphenyl]-3-1I)piperidine-2,6-dione (9.92 mg, 24.5 µmol, 7% yield, 98% purity) as a whitish solid. 1H NMR (400 MHz, DMSO-c / 6) δ = 10.92 (s I, 1H), 7.45 - 7.30 (m, 7H), 4.35 (dd, J = 4.8, 12.4 Hz, 1H), 3.66 (t, J= 5.6 Hz, 2H), 2.80 (ddd, J = 5.2, 12.4, 17.2 Hz, 1H), 2.59-2.53 (m, 1H), 2.42 (t, J=6.4 Hz, 2H), 2.37 Petition 870260070484, dated 07 / 16 / 2026, p. 272 / 1215 268 / 573 - 2.27 (m, 1H), 2.10 - 2.01 (m, 1H), 1.94 - 1.81 (m, 4H); MS (ESI) m / z 397.1 [M+H]+ Example 48. Synthesis of 3-(2-chloro-4'-(2-oxopyrrolidin-1-yl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 162) Pd(dppf)CI2, K3PO4 DMF, 100 C, 2 h

[0555] 3-(2-chloro-4'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine2,6-dione was prepared from 1-(4-bromophenyl)pyrrolidin-2-one and 3(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine2,6-dione according to 0 General Scheme 1. 1H NMR (400 MHz, MeOD) δ = 7.69 (d, J= 8.8 Hz, 2H), 7.45 - 7.41 (m, 2H), 7.40-7.35 (m, 1H), 7.34-7.29 (m, 2H), 4.34-7.29 (m, 2H), 4.3 (J, 9.2 Hz, 2.5 Hz 1H), 3.98 (t, J = 7.2 Hz, 2H), 2.87 - 2.76 (m, 1H), 2.74 - 2.66 (m, 1H), 2.63 (t, J= 8.0 Hz, 2H), 2.42 (dq, J= 4.4, 1.2 Hz, 2.27 Hz), 2.16 (m, 3H); MS (ESI) m / z 383.1 [M+H]+ Example 49. Synthesis of 3-(2-chloro-4'-(2-oxoazetidin-1-yl)-[1,1'biphenyl]-3-yl)piperidine-2,6-dione (compound 163)

[0556] 3-(2-chloro-4'-(2-oxoazetidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine2,6-dione was prepared from 1-(4-iodophenyl)azetidin-2-one and 3-[2chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6dione according to 0 General Scheme 1. MS (ESI) m / z =369.0[M+H]+ Example 50. Synthesis of 3-(2-οΙοΐΌ-4'-(1-ηΐθΙΙΙ-1Η-ρΐΓ3ζοΙ-3-ΙΙ)-[1,Γbifen il]-3-yl)pi compound perid idione- 4,6

[0557] 3-(2-chloro-4'-(1 -methyl-1 H-pyrazol-3-yl)-[ 1,1'-biphen il]-3yl)piperidine-2,6-dione was prepared from 3-(4-bromophenyl)-1-methyl Petition 870260070484, dated 07 / 16 / 2026, p. 273 / 1215 269 / 573 H -pyrazole and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2ylphenyl]piperidine-2,6-dione according to Geral Scheme 1 . MS (ESI) m / z 380.1 [M+H]+ Example 51. Synthesis of 3-(2-chloro-4'-((2-methyl-5-oxo-2,5-di-hydro1 / 7-pyrazol-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 158) Compound 158

[0558] 3-(2-chloro-4'-((2-methyl-5-oxo-2,5-di-hydro-1 / - / -pyrazole-1yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-2,6dione and 2-(4-bromobenzyl)-1-methyl-1,2-di-hydro-3H-pyrazole-3-one according to General Scheme 1 . 1H NMR (400 MHz, DMSO-c / 6) 5=10.9 (s I, 1H), 7.68 (d, J = 3.6 Hz, 1H), 7.41 - 7.33 (m, 4H), 7.31 - 7.27 (m, 1 H)„ 7.24 (s, 2.2H), (s 1H), 5.28 (d, J= 3.2 Hz, 1H), 5.03 (s, 2H), 4.33 (dd, J= 5.2, 12.0 Hz, 1H), 3.32 (s, 3H), 2.85 - 2.72 (m, 1H), 2.26 (m, 1H), 2.09 1.99 (m, 1H) MS (ESI) m / z 410.1 [M+H]+; Example 52. Synthesis of 3-(2-fluoro-4,-((2-oxopyridin-1(2H)-yl)methyl)[1,1 '-biphen yl]-3-yl)pi perid and na-2,6-dione (Compound 149)

[0559] 3-(2-fluoro-4'-((2-oxopiridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2-fluorophenyl)piperidine-2,6-dione and 1-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one according to General Scheme 1. Petition 870260070484, dated 07 / 16 / 2026, page 274 / 1215 270 / 573 MS (ESI) m / z 391.1 [M+H]+ Example 53. Synthesis of 3-(2-chloro-4'-(2-(2-oxopiperidin-1-yl)propan2-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 197)

[0560] To a solution of 2-(4-bromophenyl)propan-2-amine (500 mg, 2.34 mmol, 1.00 eq) and triethylamine (473 mg, 4.67 mmol, 650 µL, 2.00 eq) in dichloromethane (6 mL) was added to 5-bromopentanoyl chloride (559 mg, 2.80 mmol, 375 µL, 1.20 eq) at 0°C. The mixture was then stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, Ethyl Acetate 0~100% / Petroleum Ether gradient eluent @ 60 mL / min) to give the compound 5-bromo-N-[1-(4-bromophenyl)-1-methylethyl]pentanamide (1.71 g, 4.49 mmol, 96% yield) obtained as a white solid.

[0561] To a solution of sodium hydride (127 mg, 3.18 mmol, 60% purity, 1.20 eq) in tetrahydrofuran (5 mL) was added 5-bromo-N-(2-(4-bromophenyl)propan-2-yl)pentanamide (1.00 g, 2.65 mmol, 1.00 eq) at 0°C. The mixture was then stirred at 70°C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and quenched with a saturated ammonium chloride solution (15 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to remove the tetrahydrofuran and extracted with ethyl acetate (3 × 20 mL). The Petition 870260070484, dated 07 / 16 / 2026, page...

Claims

CLAIMS 1. Compound, characterized by having Formula (I): or a pharmaceutically acceptable salt thereof, wherein: L1 is: • a linkage; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene- or *-NR'(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted by 1-2Ra and wherein * indicates the point of attachment of L1 to the ring comprising X and Y; • -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc;and each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; Petition 870260031725, dated 06 / 04 / 2026, page 579 / 1278 2 / 59 each of R3, R4 and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 Ra independently selected; C3-6 cycloalkyl which is optionally replaced by independently selected 1-4 Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rg and -(CH2)i-2 Rg; n is selected from 0, 1, 2 and 3;R7 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; each occurrence of Ra is independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C14 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)1-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 independently selected Rc substituents; each occurrence of Rc is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted by 1-4 independently selected Ra; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH;N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rg and -(CH2)i-2 Rg; each occurrence of Rd is independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted by 1-3 Ra independently selected; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; deuterium; C1-6 alkyl; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rg is independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra;• heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 ring atoms are heteroatoms, Petition 870260031725, dated 06 / 04 / 2026, p. 581 / 1278 4 / 59 each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 oxos or Ra; and • C1-10 aryl optionally substituted by 1-4 Ra; each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

2. Compound, characterized by having Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof, wherein: L is: • a linkage; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C1-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2 Ra and wherein * indicates the point of attachment of L1 to the ring comprising X and Y; • -(C=O)-;or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system Petition 870260031725, dated 06 / 04 / 2026, page 582 / 1278 5 / 59 includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; and each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo and -NR'C(O)R''; R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc;Each of R6 is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by independently selected 1-6 Ra; C3-6 cycloalkyl which is optionally substituted by independently selected 1-4 Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rg and -(CH2)i-2 Rg; n is selected from 0, 1, 2 and 3; each occurrence of Ra being independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C14 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano;each occurrence of Rb being independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 independently selected Rc substituents; each occurrence of Rc is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted by 1-4 independently selected Ra; C2-6 alkenyl; C26 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rg and -(CH2)i-2 Rg;Each occurrence of Rd is independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted by 1-3 Ra independently selected; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; deuterium; C1-β alkyl; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rg is independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra;• heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 oxos or Ra; and • C6-10 aryl optionally substituted by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

3. Compound, characterized by having Formula (III): Formula (III) or a pharmaceutically acceptable salt thereof, wherein: Petition 870260031725, dated 06 / 04 / 2026, page 585 / 1278 8 / 59 L1: • is a connection; • is *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2 Ra and where * indicates the point of attachment of L1 to the ring comprising X and Y; • is -(C=O)-; Each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R')Rb, CN, halo, and -NR'C(O)R''; with the condition that -L1-R1 does not include OO, NO, NN, OS, SS, or NS bonds; with the additional condition that L1 must be a bond when R1 is CN, halo, or -NR'C(O)R''; and with the additional condition that L1 cannot be a bond when R1 is hydrogen;R2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each of R3, R4 and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is independently selected from the group consisting of: deuterium; halo; cyano; C1-10 alkyl which is optionally substituted by independently selected 1-6 Ra; C3-6 cycloalkyl which is optionally substituted by independently selected 1-4 Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; -C(=O)(C1-10 alkyl); C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R')C(=O)(C1-4 alkyl), C(=O)NR'R'', Rg and -(CH2)i-2 Rg; n is selected from 0, 1, 2 and 3; Petition 870260031725, dated 06 / 04 / 2026, p. 586 / 1278 9 / 59 each occurrence of Ra is independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R'';-S(O)i-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents; and • C6-10 aryl optionally substituted by 1-4 independently selected Rc substituents; each occurrence of Rc is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted by 1-4 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)1-2NR'R''; -NO2; C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH;Petition 870260031725, dated 06 / 04 / 2026, p. 587 / 1278 10 / 59 N(R')C(=O)(C1-4 alkyl), -C(=O)NR'R'', Rg and -(CH2)i-2 Rg; each occurrence of Rd is independently selected from the group consisting of: hydrogen, C1-6 alkyl optionally substituted by 1-3 Ra independently selected; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(C14 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C14 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rg is independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra;• heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 oxos or Ra; and • C6-10 aryl optionally substituted by 1-4 Ra; Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl. Petition 870260031725, dated 06 / 04 / 2026, p. 588 / 1278 11 / 59; 4. Compound, characterized by having Formula (IV): Formula (IV) or a pharmaceutically acceptable salt thereof, wherein: L1 is: • a linkage; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene- or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2Ra and wherein * indicates the point of attachment of L1 to the ring comprising X and Y; or • -(C=O)-; each of X and Y is independently selected from the group consisting of N and CH; R1 is selected from the group consisting of hydrogen, Rb, ORb, -SRb, -N(R')Rb, CN, halo, and -NR'C(O)R''; provided that -L1-R1 does not include OO, NO, NN, OS, SS, or NS bonds; with the additional condition that L1 must be a bond when R1 is CN, halo, or -NR'C(O)R''; and with the additional condition that L1 cannot be a bond when R1 is hydrogen; R2 is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OMe, F, and Cl;Each of R3, R4, and R5 is independently selected from the group consisting of hydrogen and Rc; each of R6 is independently selected from Rc; n is selected from 0, 1, 2, and 3; Petition 870260031725, dated 06 / 04 / 2026, page 589 / 1278 12 / 59 each occurrence of Ra is independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR'R''; S(O)i-2NR'R''; -S(O)1-2(C1-4 alkyl); and cyano; Each occurrence of Rb is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally substituted by 1-4 independently selected Rc substituents; and • C6-10 aryl optionally substituted by 1-4 independently selected Rc substituents; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted by independently selected 1-6 Ra; C2-6 alkenyl; C2-6 alkynyl;C1-4 alkoxy; -S(O)O-2(C1-4 alkyl); -NReRf; -OH; -S(O)i-2NR'R''; -NO2; -C(=O)(C1-10 alkyl); C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R')C(=O)(C1-4 alkyl), C(=O)NR'R'', Rg and -(CH2)i-2 Rg; each occurrence of Rd is independently selected Petition 870260031725, dated 06 / 04 / 2026, p. 590 / 1278 13 / 59 from the group consisting of: hydrogen, C1-6 alkyl optionally substituted by independently selected 1-3 Ra; C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(C14 alkyl); -C(O)O(C1-4 alkyl); -CONR'R''; -S(O)i-2NR'R''; -S(O)1-2(C14 alkyl); -OH; and C1-4 alkoxy;and each occurrence of Rg is independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 Ra; and • C6-10 aryl optionally replaced by 1-4 Ra;Each occurrence of R' and R'' is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

5. Compound, according to any one of claims 1 to 4, characterized in that: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, * Petition 870260031725, dated 06 / 04 / 2026, p. 591 / 1278 14 / 59 C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene) or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2Ra and wherein * indicates the attachment point of L1 to the ring; or be taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; where X and Y are both CH or one of X and Y is N and the other is CH; where R1 is Rb;where R2 is hydrogen, chlorine, fluorine or methyl; where R3, R4 and R5 are hydrogen or halo; wherein R6 is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; wherein Rb is: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic Petition 870260031725, dated 06 / 04 / 2026, p. 592 / 1278 15 / 59 and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxo and Rc substituents;6. Compound, according to any one of claims 1 to 5, characterized in that: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, *C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene) or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2Ra and wherein * indicates the attachment point of L1 to the ring; or L1 is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by R1 and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; where X and Y are both CH or one of X and Y is N and the other is CH; where R1 is Rb; where R2 is hydrogen, chlorine, fluorine or methyl;wherein R3, R4, and R5 are hydrogen or halo; wherein R6 is selected from the group consisting of deuterium, halo, and unsubstituted C1-10 alkyl; wherein Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

7. Compound, according to any one of claims 1 to 5, characterized in that: L1 is a linkage, -(C=O)-, *-O(C0-C4 alkylene)-, *C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene) Petition 870260031725, dated 06 / 04 / 2026, p. 593 / 1278 16 / 59 or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2Ra and wherein * indicates the point of attachment of L1 to the ring; or L1 is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted by Ri and is optionally further substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; where X and Y are both CH or one of X and Y is N and the other is CH; where R1 is Rb;where R2 is hydrogen, chlorine, fluorine or methyl; where R3, R4 and R5 are hydrogen or halo; where n is 0; in which Rb is: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted by 1-4 independently selected oxo and Rc substituents. Petition 870260031725, dated 06 / 04 / 2026, p. 594 / 1278 17 / 59; 8. Compound, according to any one of claims 1 to 7, characterized in that Rc is independently selected from the group consisting of: halo; C1-10 alkyl which is optionally substituted by independently selected 1-6 Ra; C1-4 alkoxy; Rg and -(CH2)i-2 Rg.

9. Compound, according to any one of claims 1 to 8, characterized in that L1 is a linkage, -(C=O)-, *O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally replaced by 1-2Ra and where * indicates the attachment point of L1 to the ring.

10. Compound, according to any one of claims 1 to 9, characterized in that L1 is a linkage, -(C=O)-, *O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1-C4 alkylene)-C(=O)-.

11. Compound, according to any one of claims 1 to 10, characterized in that L1 is a linkage, -(C=O)-, *O(C1-C4 alkylene), *-C1-C4 alkylene-, *-(C1-C4 alkylene)-C(=O)-, *NH'(C0-C4 alkylene)- or *-NH'(C=O)(C0-C4 alkylene)-, wherein the alkylene is optionally replaced by 1-2Ra, and where * indicates the attachment point of L1 to the ring.

12. Compound according to any one of claims 1 to 11, characterized in that L1 is a linkage, -(C=O)-, *O(C1-C4 alkylene), *-C1-C4 alkylene or *-(C1-C4 alkylene)-C(=O)-.

13. Compound according to any one of claims 1 to 12, characterized in that L1 is a bond, *-OCH2-, *OCH2CH2, -CH2-, -CH(CHs)-, -C(CH3)2-, -CH2CH2CH2-, -(C=O)- or *-(CH2)-C(=O)-.

14. Compound, according to any one of claims 1 to 13, characterized in that L1 is a linkage or -CH2-. Petition 870260031725, dated 06 / 04 / 2026, p. 595 / 1278 18 / 59 15. Compound according to any one of claims 1 to 14, characterized in that L1 is a linkage.

16. Compound, according to any one of claims 1 to 14, characterized in that X and Y are both CH or one of X and Y is N and the other is CH.

17. Compound according to any one of claims 1 to 16, characterized in that X and Y are both CH.

18. Compound, according to any one of claims 1 to 17, characterized in that R1 is Rb.

19. Compound, according to any one of claims 1 to 5 and 8 to 18, characterized in that Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

20. Compound, according to any one of claims 6 or 8 to 19, characterized in that Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and the hydrogen bond acceptor being selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group and an oxygen-containing aliphatic or cycloaliphatic group.

21. Compound, according to any one of claims 6 or 8 to 20, characterized in that Rb comprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and wherein the hydrogen bond acceptor is selected from an amide, lactam, carbamate, pyridone, pyrimidinone, piperazinone, pyridazinone, urea, sulfonamide, sulfone, pyrimidine, pyrazine, pyridazine, pyridine, oxazole, isoxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, oxazole, isoxazole, oxadiazole, oxethane, tetrahydrofuran, tetrahydropyran or methoxyalkyl group. Petition 870260031725, dated 06 / 04 / 2026, p. 596 / 1278 19 / 59 22. A compound according to any one of claims 1 to 21, characterized in that Rb is: • a heterocyclyl or heterocycloalkenyl group including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • a heteroaryl group including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)O-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

23. A compound according to any one of claims 1 to 22, characterized in that Rb is: • a heterocyclyl or heterocycloalkenyl group including 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • a heteroaryl group including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 substituents independently selected from oxo and Rc.

24. Compound according to any one of claims 1 to 23, characterized in that Rb is: Petition 870260031725, dated 06 / 04 / 2026, p. 597 / 1278 20 / 59 • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one heteroatom is N or N(Rd), and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one heteroatom is N or N(Rd), wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxo and Rc substituents.

25. Compound, according to any one of claims 1 to 24, characterized in that each Rc is independently selected from halo, C1-4 alkyl which is optionally substituted by 1-3 independently selected halo atoms and C1-4 alkoxy.

26. Compound, according to any one of claims 1 to 25, characterized in that Rb is selected from the group consisting of: Petition 870260031725, dated 06 / 04 / 2026, p. 598 / 1278 21 / 59 Petition 870260031725, dated 06 / 04 / 2026, p. 599 / 1278 22 / 59 which is optionally replaced by 1-4 independently selected substitutes Rc.

27. Compound, according to any one of claims 1 to 26, characterized in that Rb is heteroaryl including 510 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 of the independently selected Rc.

28. Compound, according to any one of claims 1 to 27, characterized in that Rb is heteroaryl including 5-6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected Rc.

29. Compound according to any one of claims 1 to 28, characterized in that Rb is heteroaryl including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, Petition 870260031725, dated 06 / 04 / 2026, p. 600 / 1278 23 / 59 each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-2 of the independently selected Rc.

30. Compound according to any one of claims 1 to 29, characterized in that Rb is heteroaryl including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2.

31. A compound, according to any one of claims 1 to 30, characterized in that Rb is selected from the group consisting of , each of which is optionally replaced by 1-2 independently selected Rc.

32. Compound, according to any one of claims 1 to 31, characterized in that Rb is selected from the group consisting of , and N , optionally where Rd is CH3.

33. Compound, according to any of the Petition 870260031725, dated 06 / 04 / 2026, p. 601 / 1278 24 / 59 claims 1 to 32, characterized by Rb being selected from the group consisting of , optionally where Rd is CH3.

34. Compound, according to any one of claims 1 to 33, characterized in that Rb is selected from 35. Compound, according to any one of claims 1 to 34, characterized in that Rb is 36. Compound, according to any one of claims 1 to 31, characterized in that Rb is selected from the group consisting of 37. Compound, according to any one of claims 1 to 31 and 36, characterized in that Rb is selected from the group consisting of 38. Compound, according to any one of claims 36 and 37, characterized in that Rc is selected from the group consisting of C1-10 alkyl which is optionally substituted by 1-6 Ra and -NReRf independently selected, optionally wherein Rc is methyl or -NH2.

39. Compound, according to any one of claims 1 to 31, characterized in that Rb is selected from the group Petition 870260031725, dated 06 / 04 / 2026, p. 602 / 1278 25 / 59 consisting of 40. Compound, according to any one of claims 1 to 31, characterized in that Rb is 41. Compound, according to any one of claims 1 to 31 and 40, characterized in that Rb is RC 42. Compound according to claim 40 or 41, characterized in that Rc is a C1-10 alkyl group that is optionally replaced by independently selected 1-6 Ra and -NReRf groups, optionally wherein Rc is methyl.

43. Compound, according to any one of claims 1 to 31 and 40 to 42, characterized in that Rb is 44. A compound according to any one of claims 1 to 28, characterized in that Rb is a heteroaryl group including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rc substituents.

45. Compound according to any one of claims 1 to 28 and 44, characterized in that Rb is heteroaryl including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2.

46. ​​Compound, according to any one of claims 1 to 28 and 44 and 45, characterized by Rb being selected Petition 870260031725, dated 06 / 04 / 2026, p. 603 / 1278 26 / 59 from the group consisting of 47. Compound, according to any one of claims 1 to 27 and 43 to 45, characterized in that Rb is 48. Compound, according to any one of claims 1 to 27, characterized in that Rb is heteroaryl including 710 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 14 independently selected oxos or Rc.

49. A compound according to any one of claims 1 to 27 and 48, characterized in that Rb is heteroaryl including 9-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxos or Rc.

50. A compound according to any one of claims 1 to 27 and 48 and 49, characterized in that Rb is heteroaryl including 9 ring atoms, wherein at least one ring in the system is aromatic, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 oxos and Rc independently selected.

51. Compound, according to any of the Petition 870260031725, dated 06 / 04 / 2026, p. 604 / 1278 27 / 59 claims 1 to 27 and 48 and 50, characterized in that Rb is selected from the group consisting of each of which is optionally replaced by 1-4 Rc selected independently.

52. Compound, according to any one of claims 1 to 27 and 48 to 51, characterized in that Rb is selected from the group consisting of oo with any one of claims 1 to 27 and 48 and 49, characterized in that Rb is a heteroaryl group including 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 oxo groups or Rc groups independently selected.

54. A compound, according to any one of claims 1 to 27, 48 and 49 or 53, characterized in that Rb is selected from the group consisting of IJIJ Rd and Rd, each of which is optionally replaced by 1-4 Rc selected independently.

55. Compound, according to any one of claims 1 to 27, 48 and 49 and 53 and 54, characterized in that Rb is selected from the group consisting of 56. Compound according to any one of claims 1 to 22, 25 and 26, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

57. Compound, according to any one of claims 1 to 22, 25, 26 or 56, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 4-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

58. Compound, according to any one of claims 1 to 26 and 56 and 57, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

59. Compound, according to any one of claims 1 to 26 and 56 to 58, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

60. Compound, according to any one of claims 1 to 26 and 56 to 59, characterized in that Rb is a heterocycloalkenyl group including 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

61. Compound, according to any one of claims 1 to 26 and 56 to 60, characterized in that Rb is θ' 62. Compound according to claim 61, characterized in that Rd is CH3.

63. Compound, according to any one of claims 1 to 26 and 56 to 61, characterized in that Rb is the ^*^, optionally replaced by 1-2 independently selected Rc substituents.

64. Compound, according to any one of claims 1 to 26, 56 to 61 or 63, characterized in that Rb is cr'^ .

65. Compound according to any one of claims 1 to 26, 56 to 61 or 62 and 63, characterized in that Rb is 66. Compound according to any one of claims 63 and 64, characterized in that Rc or each occurrence of Rc is selected from the group consisting of C1-10 alkyl optionally substituted by 1-6 Ra, C1-4 alkoxy, halo and -NReRf independently selected. Petition 870260031725, dated 06 / 04 / 2026, p. 608 / 1278 31 / 59 67. Compound according to any one of claims 63 to 65, characterized in that Rc is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluorine, chlorine and NH2.

68. Compound, according to any one of claims 1 to 26, 52 to 61, 63 and 64 and 66 and 67, characterized in that R1 is selected from the group consisting of OMe 69. Compound, according to any one of claims 1 to 26 and 56 to 59, characterized in that Rb is a heterocyclyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

70. Compound, of claims 1 to 26, 56 according to either 59 or 69, characterized in that Rb is selected from the group consisting of f NI os uo N i 1 Λ d Rd N γ Rd Ί ' 7 N'Rd o Petition 870260031725, dated 06 / 04 / 2026, p. 609 / 1278 32 / 59 which is optionally replaced, each of by 1-4 substituents independently selected from the group consisting of oxo and Rc.

71. Compound according to claim 70, characterized in that Rc is methyl, halo, methoxy or CF3.

72. Compound according to any one of claims 1 to 26, 56 to 59 or 69 to 71, characterized in that Rb is 73. Compound, according to any of claims 1 to 26, 56 to 59 and 69 to 72, characterized by Rb being Petition 870260031725, dated 06 / 04 / 2026, p. 610 / 1278 33 / 59 74. Compound, according to any one of claims 70 or 72 and 73, characterized in that Rb is CH3.

75. Compound, according to any one of claims 1 to 26, 56 to 59 and 69 to 73, characterized in that Rb is the Λό.

76. Compound, according to any one of claims 1 to 26 and 56 to 58, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

77. Compound according to any one of claims 1 to 26, 56 to 58 or 76, characterized in that Rb is a heterocycline including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycline is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

78. Compound, according to any one of claims 1 to 26, 56 to 58 and 76 and 77, characterized in that Rb is selected from the group consisting of and replaced by 1-4 Rc.

79. Compound according to claim 78, characterized in that Rc is a C1-6 halo or alkyl group.

80. Compound, according to any one of claims 1 to 26, 56 to 58 and 76 to 78, characterized in that Rb is selected from the group consisting of (for example, 81. Compound according to any one of claims 1 to 26, 56 to 58 or 76 to 78, characterized in that Rb is selected from the group consisting of 82. Compound, according to any of the Petition 870260031725, dated 06 / 04 / 2026, p. 612 / 1278 35 / 59 claims 1 to 26, 56 to 58 or 76 to 78 or 81, characterized by Rb being k. / .

83. Compound, according to any one of claims 1 to 26, 56 to 58 or 76, characterized in that Rb is a heterocycloalkenyl group including 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

84. Compound, according to any one of claims 1 to 26, 56 to 58, 76 or 83, characterized in that Rb is Rd NÁ N0, optionally where Rb is 0.

85. Compound, according to any one of claims 1 to 22, 25 or 26, characterized in that Rb is selected from the group consisting of 86. Compound, according to any one of claims 1 to 26 or 56, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 7-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, and wherein heterocyclyl or heterocycloalkenyl is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

87. Compound, according to any one of claims 1 to 26, 56 or 86, characterized in that Rb is a heterocyclyl (Petition 870260031725, dated 06 / 04 / 2026, p. 613 / 1278 36 / 59) including 7-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

88. Compound according to any one of claims 1 to 26, 56 or 86 and 87, characterized in that Rb is a heterocyclyl group including 7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 independently selected Rc substituents.

89. Compound, according to any one of claims 1 to 26, 56 or 86 to 88, characterized in that Rb is selected from the group consisting of oe, each of which is optionally replaced by 1-4 independently selected Rc substituents.

90. Compound, according to claim 89, characterized in that Rb is selected from the group consisting of Petition 870260031725, dated 06 / 04 / 2026, page 614 / 1278 37 / 59 91. Compound according to any one of claims 1 to 26, 56 or 86 and 87, characterized in that Rb is heterocyclyl including 8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl is optionally substituted by 1-4 independently selected Rc substituents.

92. Compound according to claim 91, characterized in that Rb is selected from the group consisting of one of which is optionally replaced by 1-4 independently selected Rc substituents.

93. Compound, according to any of claims 91 or 92, characterized by Rb being selected from Petition 870260031725, dated 06 / 04 / 2026, p. 615 / 1278 38 / 59 (by 94. Compound according to any one of claims 1 to 26, 56 and 86 and 87, characterized in that Rb is a heterocyclyl group including 9 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

95. Compound according to claim 94, characterized in that Rb is selected from the group consisting of and o, each of which is optionally replaced by 1-4 independently selected Rc substituents.

96. Compound according to the claim characterized by Rd ​​being CH3.

97. Compound according to claim 95 or characterized by Rb being selected from the group consisting of 95, 96, in 98. Compound, according to any one of claims 1 to 22, characterized in that Rb is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally replaced by 1-4 substituents independently selected from the group consisting of oxo and Rc.

99. Compound according to claim 98, characterized in that Rb is optionally replaced by an Rc.

100. Compound, according to any one of claims 1 to 99, characterized in that R2 is hydrogen, chlorine, fluorine or methyl.

101. Compound, according to any one of claims 1 to 100, characterized in that R2 is chlorine.

102. Compound, according to any one of claims 1 to 101, characterized in that R3, R4 and R5 are hydrogen or halo.

103. Compound according to any one of claims 1 to 102, characterized in that R3 is halo or hydrogen and R4 and R5 are hydrogen.

104. Compound according to any one of claims 1 to 103, characterized in that R3, R4 and R5 are hydrogen.

105. Compound according to any one of claims 1 to 104, characterized in that R2 is chlorine, and R3, R4 and R5 are hydrogen.

106. Compound according to any one of claims 1 to 105, characterized in that n is 0.

107. Compound according to any one of claims 1 to 106, characterized in that n is O and R3, R4 and R5 are hydrogen; and / or L1 is a linkage, -(C=O)-, *-C1-C4 alkylene-, *NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)- or *-(C1C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted by 1-2Ra and where * indicates the attachment point of L1 to the ring. Petition 870260031725, dated 06 / 04 / 2026, p. 617 / 1278 40 / 59 108. Compound according to any one of claims 1 to 107, characterized in that n is 1 or 2.

109. Compound, according to any one of claims 1 to 108, characterized in that R6 is selected from the group consisting of deuterium, halo; cyano; C1-10 alkyl which is optionally substituted by 1-6 Ra independently selected; C1-4 alkoxy, C1-4 haloalkoxy; and -NReRf; optionally in which R6 is selected from the group consisting of deuterium, cyano, chlorine, fluorine, methyl, ethyl, -CHF2, methoxy, -OCHF2 and -NH2.

110. Compound, according to any one of claims 1 to 109, characterized in that R6 is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl.

111. Compound, according to any one of claims 1 to 110, characterized in that R6 is selected from the group consisting of deuterium, fluorine and methyl.

112. Compound, according to any one of claims 1 to 111, characterized in that R6 is deuterium, optionally where n is 4.

113. Compound according to any one of claims 1 to 107, characterized in that the compound is a compound of formula (I-1) H .O , ____ L1 YY f 7I Rb Formula (I-1).

114. Compound, according to any one of claims 1 to 107 or 113, characterized in that the compound is a compound of formula (I-2) H Formula (I-2), Petition 870260031725, dated 06 / 04 / 2026, p. 618 / 1278 41 / 59 where X is -NH- or -O-.

115. Compound according to claim 114, characterized in that X is -O-.

116. Compound according to any one of claims 1 to 107 or 113, characterized in that the compound is a compound of formula (I-3) H iT Jl T \ iix^Rb kY Formula (I-3).

117. Compound, according to any one of claims 1 to 107 or 113, characterized in that the compound is a compound of formula (I-4) Formula (I-4).

118. Compound, according to any one of claims 113 to 117, characterized in that R2 is chlorine.

119. Compound, according to any one of claims 113 to 118, characterized in that Rb is a heterocyclyl or heterocycloalkenyl group including 3-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl or heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc; or heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxo and Rc substituents. Petition 870260031725, dated 06 / 04 / 2026, p. 619 / 1278 42 / 59 120. Compound, according to any one of claims 113 to 119, characterized in that Rb is a heterocycloalkenyl group including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycloalkenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

121. Compound, according to any one of claims 113 to 120, characterized in that Rb is θ' or Rd, each of which is optionally replaced by 1-2 independently selected Rc substituents.

122. Compound, according to any one of claims 113 to 121, characterized in that Rb is θ^, which is optionally replaced by 1-2 Rc selected independently.

123. Compound, according to any one of claims Ϊ J-Rc 113 to 122, characterized in that Rb is cr^ .

124. Compound, according to any one of claims 113 to 123, characterized in that Rb is 125. Compound according to claim 122 or 123, characterized in that Rc or each occurrence of Rc is selected from the group Petition 870260031725, dated 06 / 04 / 2026, page 620 / 1278 43 / 59 consisting of C1-10 alkyl optionally substituted by 1-6 Ra, C1-4 alkoxy, halo and -NReRf independently selected.

126. Compound according to claim 122, 123 or 125, characterized in that Rc is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluorine, chlorine and NH2.

127. Compound, according to any one of claims 113 to 120, characterized in that Rb is selected from the group 128. Compound, according to any one of claims 113 to 119, characterized in that Rb is a heteroaryl group including 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl group is optionally replaced by 1-4 independently selected Rc substituents.

129. Compound, according to any one of claims 113 to 119 or 128, characterized by Rb being selected, , -Rd, NCs / , Petition 870260031725, dated 06 / 04 / 2026, p. 621 / 1278 44 / 59 each of which is optionally replaced by 1-2 Rc selected independently.

130. Compound, according to any one of claims 113 to 119 and 128 and 129, characterized in that Rb is selected from the group consisting of N-Rd, N-Rd NN, optionally where Rd is CH3.

131. Compound, according to any one of claims 113 to 119 and 128 to 130, characterized in that Rb is optionally CH3 where Rd is CH3.

132. Compound, according to any one of claims 113 to 119 and 128 to 131, characterized in that Rb is 133. Compound according to any one of claims 113 to 118, characterized in that Rb is a heterocycline including 6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycline is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc. Petition 870260031725, dated 06 / 04 / 2026, p. 622 / 1278 45 / 59 134. Compound, according to any one of claims 113 to 118 or 133, characterized in that Rb is selected from the group consisting of 135. Compound, according to any of claims 113 to 118 and 133 to 134, characterized by Rb being (by selected from the group consisting of Petition 870260031725, dated 06 / 04 / 2026, page 623 / 1278 46 / 59 F 136. Compound according to claim 134 or 135, characterized in that Rd is CH3.

137. Compound according to claim 134 or 135, characterized in that Rb is 138. Compound, according to any one of claims 113 to 119, characterized in that Rb is heteroaryl including 6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heteroaryl is optionally replaced by 1-4 independently selected Rc.

139. Compound according to any one of claims 113 to 119 or 138, characterized in that Rb is heteroaryl including 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)0-2.

140. Compound, according to any one of claims 113 to 119 and 138 and 139, characterized in that Rb is selected from the group consisting of 141. Compound, according to any one of claims 113 to 119 and 138 to 140, characterized in that Rb is 142. Compound, according to any of the Petition 870260031725, dated 06 / 04 / 2026, p. 624 / 1278 47 / 59 claims 113 to 119, characterized in that Rb is a heteroaryl group including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl group is optionally replaced by 1-4 independently selected oxo and Rc substituents.

143. A compound according to any one of claims 113 to 119 or 142, characterized in that Rb is selected from the group consisting of each of which is optionally replaced by 1-4 Rc selected independently.

144. Compound, according to any one of claims 113 to 119 and 142 or 143, characterized in that Rb is selected from the group consisting of Petition 870260031725, dated 06 / 04 / 2026, p. 625 / 1278 48 / 59, and 145. Compound, according to any one of claims 113 to 119, characterized in that Rb is heteroaryl including 10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally replaced by 1-4 independently selected oxos and Rc.

146. Compound, according to any one of claims 113 to 119 and 145, characterized in that Rb is selected from the group consisting of IJI Rd Rd and IR , each of which is optionally replaced by 1 4 Rc selected independently.

147. Compound, according to any one of claims 113 to 119 and 145 and 146, characterized in that Rb is selected from the group consisting of Petition 870260031725, dated 06 / 04 / 2026, p. 626 / 1278 49 / 59 148. Compound, according to any one of claims 113 to 119, characterized in that Rb is a heterocycline including 7-10 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocycline is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

149. A compound according to any one of claims 113 to 119 or 148, characterized in that Rb is a heterocyclyl group including 7 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally replaced by 1-4 independently selected Rc substituents.

150. Compound, according to any one of claims 113 to 119 or 148 and 149, characterized in that Rb is optionally replaced by 1-4 independently selected Rc substituents.

151. Compound, according to any one of claims 113 to 119 or 148 to 150, characterized by Rb being selected from the group consisting of θ' 152. Compound, according to any one of claims 113 to 119 or 148, characterized in that Rb is heterocyclyl including 8 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl is optionally substituted by 1-4 independently selected Rc substituents.

153. Compound according to any one of claims 113 to 119, 148 or 152, characterized in that Rb is selected from the group consisting of (for example, or ), each of which is optionally replaced by 1-4 independently selected Rc substituents.

154. Compound, according to any of claims 113 to 119, 148 or 152 and 153, characterized by Rb being Petition 870260031725, dated 06 / 04 / 2026, p. 628 / 1278 51 / 59 selected from the group consisting of 155. Compound, according to any one of claims 113 to 119 or 148, characterized in that Rb is a heterocyclyl group including 9 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O and S(O)o-2, and wherein the heterocyclyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of oxo and Rc.

156. Compound, according to any one of claims 113 to 119, 148 or selected from the group consisting of is optionally substituted 155, characterized in that Rb is A in Rd, Rd or Vo, each of which by 1-4 substituents independently selected from the group consisting of oxo and Rc.

157. Compound according to claim 156, characterized in that Rd is CH3.

158. Compound, according to any one of claims 113 to 119, 148 or 155 to 157, characterized by Rb being Petition 870260031725, dated 06 / 04 / 2026, p. 629 / 1278 52 / 59 selected from the group consisting of 159. Compound, according to any one of claims 113 to 158, characterized in that R2 is chlorine.

160. Compound according to any one of claims 1 to 159, characterized in that the compound is a compound of formula (Ia) 161. Compound according to any one of claims 1 to 159, characterized in that the compound is a compound of formula (Ib) 162. Compound according to claim 1, characterized in that the compound is selected from the group consisting of the compounds in Table C1 or from a pharmaceutically acceptable salt thereof.

163. Compound according to claim 1, characterized in that the compound is: Petition 870260031725, dated 06 / 04 / 2026, p. 630 / 1278 53 / 59 or a pharmaceutically acceptable salt thereof.

164. Compound according to claim 1 or 163, characterized in that the compound is: / O or a pharmaceutically acceptable salt thereof.

165. Compound according to claim 1 or 163, characterized in that the compound is: ^\ / „O or a pharmaceutically acceptable salt thereof.

166. Compound according to any one of claims 163 to 165, characterized in that the compound exists in a racemic mixture.

167. Compound according to claim 1, characterized in that the compound is: or a pharmaceutically acceptable salt thereof.

168. Pharmaceutical composition, characterized by comprising the compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof, Petition 870260031725, dated 06 / 04 / 2026, pp. 631 / 1278 54 / 59 and a pharmaceutically acceptable excipient.

169. A method for degrading the Proto-oncogene vav 1 (VAV1) protein in an individual, characterized by comprising administering to the individual an effective amount of the compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof.

170. Method according to claim 169, characterized in that the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing the degradation of the VAV1 protein.

171. Method according to claim 169 or 170, characterized in that VAV1 is a regulator of a lymphocyte.

172. Method according to claim 171, characterized in that the lymphocyte is a T cell.

173. Method according to claim 171, characterized in that the lymphocyte is a B cell.

174. Method according to claim 169 or 170, characterized in that the compound interacts with E3 ligase before VAV1 interacts with E3 ligase.

175. Method, according to any one of claims 170 to 174, characterized in that the E3 ligase comprises cereblon.

176. A method for degrading the Proto-oncogene vav 1 (VAV1) protein, characterized by comprising: (i) contacting the compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof, with an E3 ligase; and (ii) the contacted E3 ligase interacting with VAV1, thereby degrading VAV1.

177. Method of treating a disorder caused by or associated with dysregulation of lymphocyte development or activation in an individual in need thereof, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof.

178. Method according to claim 177, characterized in that the lymphocyte is a T cell.

179. Method according to claim 177, characterized in that the lymphocyte is a C cell.

180. A method for treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in an individual in need thereof, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof.

181. Method according to claim 180, characterized in that the T cell receptor signaling is IFNγ, CD69 and / or IL-2.

182. A method for treating a disorder caused by or associated with VAV1 polymorphisms in an individual in need thereof, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof.

183. A method for treating a disorder caused by or associated with immunopathologies in an individual in need thereof, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in Petition 870260031725, dated 06 / 04 / 2026, pp. 633 / 1278 56 / 59, or any of claims 1 to 167, or a pharmaceutically acceptable salt thereof.

184. Method, according to claim 182 or 183, characterized in that the disorder is an autoimmune disorder.

185. Method according to claim 184, characterized in that the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and associated dysfunctions, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated dysfunctions,Inflammatory eye disease, keratoconjunctivitis, myocarditis, or hepatitis.

186. Method according to claim 182 or 183, characterized in that the disorder is a cancer, tumor or other malignancy, optionally in that the disorder is a hematologic malignancy (e.g., T-cell and B-cell malignancy).

187. Method, according to claim 186, characterized in that the disorder is selected from the group consisting of: leukemia, lymphoma, acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal and nasal-type NK / T-cell lymphoma, mycosis fungoides and Petition 870260031725, dated 06 / 04 / 2026, page.634 / 1278 57 / 59 Sézary, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous T-cell lymphoproliferative disorders positive for CD-30, cutaneous T-cell lymphoma, panniculitis-type cutaneous T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma and non-Hodgkin lymphomas (e.g., non-Hodgkin B-cell lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma).

188. Method according to claim 182 or 183, characterized in that the disorder is selected from the group consisting of Type I or II diabetes, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer's disease, Acute Graft-versus-Host Disease or T-cell mediated kidney disease.

189. Method, according to claim 182 or 183, characterized in that the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, an allergic disorder, an autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft-versus-Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

190. Method, according to claim 182, 183 or 189, characterized in that the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, syndrome of Petition 870260031725, dated 06 / 04 / 2026, page. 635 / 1278 58 / 59 Sjogren's disease, Graves' disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, biliary sclerosis, sclerosing cholangitis, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft-versus-Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

191. Method, according to claim 182 or 183, characterized in that the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondyloarthritis.

192. Method according to claim 182 or 183, characterized in that the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia.

193. Method according to claim 182 or 183, characterized in that the disorder is ulcerative colitis.

194. Method according to claim 182 or 183, characterized in that the disorder is chronic lymphocytic leukemia.

195. A method for treating a disease in a transplant setting in an individual in need of a transplant, characterized by comprising administering to the individual a therapeutically effective amount of the compound, as defined in claim 1, or a pharmaceutically acceptable salt thereof.

196. Method according to claim 193, characterized in that the disease in the transplant setting is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary artery disease. Petition 870260031725, dated 06 / 04 / 2026, pp. 636 / 1278 59 / 59 197. A method for degrading the vavl proto-oncogene protein (VAV1) in an individual suffering from an autoimmune disease or a disease in a transplant setting, characterized by comprising administering to the individual an effective amount of the compound, as defined in claim 1, or a pharmaceutically acceptable salt thereof.

198. Method according to claim 195, characterized in that the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and associated dysfunctions, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated dysfunctions,Inflammatory eye disease, keratoconjunctivitis, myocarditis, or hepatitis.

199. Method, according to claim 196, characterized in that the disease in the transplant setting is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary artery disease.

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