Compositions and methods of thiazole and 2-substituted benzothiazole as DUX4 inhibitors.

Description

1 / 108 “COMPOSITIONS AND METHODS OF 2-SUBSTITUTED THIAZOLE AND BENZOTHIAZOLE” CROSS-REFERENCE

[001] This application claims the benefit of Provisional Patent Applications Nos. US 63 / 436,362 (filed December 30, 2022) and 63 / 616,498 (filed December 29, 2023), which are incorporated herein by reference in their entirety. FIELD

[002] This document provides 2-substituted thiazole and benzothiazole compounds, methods and pharmaceutical compositions for use in the treatment of diseases (e.g., neuromuscular disorders, inflammatory disorders, facioscapulohumeral muscular dystrophy, acute lymphoblastic leukemia, B-cell leukemia, sarcomas (e.g., small round cell sarcoma), prostate cancer, multiple myeloma, lung cancer, colon cancer, solid cancers, rheumatoid arthritis, axial spondyloarthritis, viral infections, mononucleosis, encephalitis and varicella). In certain embodiments, 2-aryl thiazole or benzothiazole compounds are provided for the treatment of, for example, diseases characterized by incorrect expression of the double homeobox 4 (DUX4) in a human being, such as cancer. BACKGROUND OF THE INVENTION

[003] The double homeobox 4 (DUX4) gene is a gene of unknown function, whose dysregulation is responsible, for example, for facioscapulohumeral muscular dystrophy. Lemmers, Richard JLF et al., Science 2010, 329(5999):1650-3; doi: 10.1126 / science.1189044. No current pharmaceutical method is known to effectively control facioscapulohumeral muscular dystrophy.

[004] Therefore, there is a continuing need for compositions aimed at the effective treatment of diseases characterized by the incorrect expression of DUX4 and Petition 870260049430, dated 05 / 25 / 2026, page 8 / 223 2 / 108 other diseases and conditions. SUMMARY OF THE INVENTION

[005] Useful compounds are provided in this document, for example, for the treatment of diseases characterized by the misexpression of DUX4 (e.g., facioscapulohumeral muscular dystrophy; sarcoma; B-cell leukemia). In certain embodiments, 2-aryl thiazole or benzothiazole compounds exhibit remarkable efficacy or bioavailability, or both, in humans.

[006] In certain forms, the following are provided in this document: Formula I compounds: Cy-[_2(R2>n r4-R5 , Cy-L2 (R2)n r4.r5(I) or a pharmaceutically acceptable salt thereof, wherein: Each R1 is independently selected from the group that includes H and R2; m is an integer from 0 to 4; A wavy linkage indicates a single-linkage attachment of L to a free site of a thiazole or benzothiazole ring. L1 is selected from the group that includes a single bond, C1-6 alkyl and -(C=O)-; L2 is selected from the group that includes -(C=O)(NR3)-, -(C=O)-alkyl-, and -(NR3)(C=O)-; Cy is selected from the group that includes C3-9 cycloalkyl, C3-9 heterocyclyl, Petition 870260049430, dated 05 / 25 / 2026, p. 9 / 223 3 / 108 C3-C9heteroaryl and C6-ioaryl; Each R2 is independently selected from the group that includes halo, Ci-3alkoxy, C1-3 alkyl, cyano and R5; n is an integer from 0 to 2; Each R3 is selected independently from the group that includes H and C13 alkyl; R4 is a C1-6 alkylene, in which R4 is substituted by 0 to 4 R7 groups; R5 is selected from the group consisting of -O(CO)R6, -N(R3)(CO)R3, -N(R3)(CO)R6, -OR6, -(CO)R6, -(CO)N(R3)R3, -(CO)N(R3)R6, C3-7cycloalkyl, C3-9heterocyclyl, C6-10aryl and C3-C9heteroaryl; or, alternatively, R4 and R5 join to form a 5- to 8-membered cycloalkyl, aryl, heterocyclic or heteroaryl ring that is optionally substituted by 0 to 4 R7 groups; Each R6 is selected independently from the group that includes C16 alkyl. C3-7cycloalkyl, C3-9heterocyclyl, C6-10aryl and C3-C9heteroaryl; where R6 is substituted by 0 to 4 R7 groups; and each R7 is selected independently from the group that includes halo, C1-3alkoxy, and C1-3 alkyl.

[007] In certain embodiments, Formula II compounds are provided in this document: or (II) Petition 870260049430, dated 05 / 25 / 2026, p. 10 / 223 4 / 108 or a pharmaceutically acceptable salt thereof, where: Y is selected from the group that includes CH, CR2, -N=CH-, -N=CR2-, O, S, and N; where Y and Z1 are not both N; and Z1 is selected from the group that includes CH, CR2, -N=CH-, -N=CR2-, and N; where Y and Z1 are not both N.

[008] In certain embodiments, compounds are provided in this document, wherein the compounds are of Formula III: (III) or a pharmaceutically acceptable salt thereof, where: Z1 and Z2 are each selected from the group that includes CH, CR2, and N; where Z1 and Z2 are not both N.

[009] In certain embodiments, compounds of Formula IV are provided in this document: or a pharmaceutically acceptable salt thereof, where: R1 is selected from the group that includes -H, halo and C1-3 alkyl; Each R2 is selected independently of the group that includes halo. Petition 870260049430, dated 05 / 25 / 2026, p. 11 / 223 5 / 108 Ci-3alkoxy, and C1-3 alkyl; R4e Ci-6alkylene; R5 is selected from the group that includes -O(CO)R6, -NH(CO)R6, -OR6, (CO)R6, C3-7Cycloalkyl and C3-9heterocyclyl; and R6 is selected from the group that includes C1-6 alkyl, C3-7 cycloalkyl, C39 heterocyclyl and C3-9 heteroaryl.

[010] In certain modalities, Z1 and Z2 are each selected from the group that includes CH, CR2, and N. In certain modalities, Z1 and Z2 are each selected from the group that includes CH and N.

[011] In certain embodiments, R1 is H or methyl.

[012] In certain modes, n is 0.

[013] In certain modalities, R4 is replaced by 0 R2 groups.

[014] In certain embodiments, R5 is selected from the group that includes NH(CO)CH3, -O(CO)CH3, -(CO)CH3, and -OCH2CH3.

[015] In certain embodiments, the compound is selected from the group that includes the compounds in Table 6-1.

[016] In certain embodiments, the compound inhibits MBD3L2 RNA production at 11 mM (for example, as per the procedure in Example 7).

[017] In certain embodiments, the compound has an EC50 for DUX4 <10 mM. In certain embodiments, the compound has an EC50 for DUX4 <1 mM.

[018] In certain embodiments, pharmaceutical compositions comprising the following are provided in this document: the compound as disclosed herein, and a pharmaceutically acceptable excipient, carrier or diluent.

[019] In certain modalities, the composition is an oral formulation. Petition 870260049430, dated 05 / 25 / 2026, page 12 / 223 6 / 108

[020] In certain embodiments, methods for treating a patient are provided herein, comprising administering an effective amount of a compound or composition, as disclosed herein. In some embodiments, the patient is a human being. DETAILED DESCRIPTION DESCRIPTION OF EXEMPLARY MODALITIES

[021] Compounds, compositions and methods useful for treating cancer in a subject are provided in this document. In addition, useful pharmaceutical forms for such methods are provided. Definitions

[022] When referring to the compounds provided in this document, the following terms have the following meanings, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as normally understood by someone skilled in the art. In the case of multiple definitions for a term in this document, those in this section shall prevail, unless otherwise indicated.

[023] All publications, patent applications, patents and other references mentioned in this document are incorporated by reference in their entirety. In case of conflict, this application shall prevail.

[024] The articles “a”, “an” and “the”, as used in this document, not only include certain embodiments with a single member, but may also include embodiments with more than one member. For example, an aspect “comprising a compound of Formula Ib and an excipient” should be understood as presenting certain embodiments with at least one second compound of Formula Ib, at least one second excipient, or both.

[025] Similarly, the term “or”, as used in this document, is a Boolean “or”, unless the alternatives cannot be Petition 870260049430, dated 05 / 25 / 2026, p. 13 / 223 7 / 108 combined without logical incompatibility. For example, an aspect “comprising an excipient selected from A, B or C” should be understood as applicable to embodiments comprising A and B; B and C; A and C; or A, B and C.

[026] The term “about”, as used in this document to modify a numerical value, indicates a defined range around that value. If “X” were the value, “about X” would generally indicate a value from 0.95X to 1.05X. Any reference to “about X” specifically indicates at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” aims to teach and provide written description support for a claim limitation of, for example, “0.98X”. When “about” is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, “from about 5 to 20%” is equivalent to “from about 5% to about 20%”. When “about” is applied to the first value in a set of values, it applies to all values ​​in that set. Therefore, “about 7, 9, or 11%” is equivalent to “about 7%, about 9%, or about 11%”.

[027] The term “alkyl”, as used herein, and unless otherwise specified, refers to a linear or branched saturated hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes from one to ten carbon atoms, i.e., C1-10 alkyl. In certain embodiments, the alkyl group is C112 alkyl; C1-8 alkyl; or C1-6 alkyl. In certain embodiments, the alkyl group is selected from the group that includes methyl, CF3, CCl3, CFCl2, CF2Cl, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes substituted and unsubstituted alkyl groups, including halogenated alkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group. In certain embodiments, the alkyl group is unsubstituted. Non-limiting examples of... Petition 870260049430, dated 05 / 25 / 2026, page 14 / 223 8 / 108 chemical moieties with which the alkyl group can be substituted are selected from the group which includes halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, unprotected or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, incorporated herein by reference.

[028] The term “lower alkyl”, as used herein, and unless otherwise specified, refers to a saturated, linear or branched hydrocarbon having one to six carbon atoms, i.e., C1 to C6 alkyl. In certain embodiments, the lower alkyl group is a primary, secondary or tertiary hydrocarbon. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the lower alkyl group is unsubstituted.

[029] The term “alkylene”, as used herein, and unless otherwise specified, refers to divalent saturated aliphatic hydrocarbon groups (particularly having from one to eleven carbon atoms) which may be linear or branched chain. In certain embodiments, the alkylene group contains from 1 to 6 carbon atoms. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the alkylene group is unsubstituted. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.

[030] The term “alkenyl”, as used in this document, and unless otherwise specified, refers to monovalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which may be linear or branched chain and having at least 1 or from 1 to 2 olefinic unsaturation sites. The term includes substituted and unsubstituted chemical moieties. In certain Petition 870260049430, dated 05 / 25 / 2026, p. 15 / 223 In 9 / 108 forms, the alkenyl group is unsubstituted. Exemplary alkenyl groups include ethenyl (i.e., vinyl, or -CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), and the like.

[031] The term “alkenylene”, as used in this document, and unless otherwise specified, refers to divalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms that may be linear or branched chain and having at least 1 or 1 to 2 olefinic unsaturation sites. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the alkenylene group is unsubstituted. This term is exemplified by groups such as ethenylene (-CH=CH), propenylene isomers (e.g., -CH=CHCH2-; -C(CH3)=CH-; and CH=C(CH3)-), and the like.

[032] The term “alkynyl”, as used herein, and unless otherwise specified, refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which may be linear or branched chain and having at least 1 or 1 to 2 alkynyl unsaturation sites. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the alkynyl group is unsubstituted. Non-limiting examples of alkynyl groups include acetylenic, ethinyl (CΞCH), propargyl (-CH2CΞCH) and the like.

[033] The term “alkoxy”, as used herein, and unless otherwise specified, refers to the -OR' group wherein R' is alkyl or cycloalkyl. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like.

[034] The term “alkoxycarbonyl”, as used herein, and unless otherwise specified, refers to a -C(O)-alkoxy radical. The groups Petition 870260049430, dated 05 / 25 / 2026, page 16 / 223 10 / 108 alkoxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.

[035] The term “aryl”, as used in this document, and unless otherwise specified, refers to phenyl, biphenyl or naphthyl. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, an aryl group may be replaced by any described chemical moiety, including, but not limited to, one or more chemical moieties selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, unprotected or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, the complete contents of which are incorporated herein by reference in their entirety for all purposes.

[036] In certain embodiments, an aryl group refers to a phenyl or naphthyl group optionally mono- or disubstituted by a fluoro, chlorine, bromine, iodine, cyano, trifluoromethyl, nitro, carboxyl, aminocarbonyl, C1-3-alkyl (i.e., an alkyl group of one to three carbons) or C1-3-alkoxy group. In certain embodiments, the aryl group is unsubstituted.

[037] The term “amino” as used in this document, and unless otherwise specified, refers to the radical -NH2.

[038] The term “monoalkylamino” as used herein, and unless otherwise specified, refers to the alkyl-NR'- group, wherein R' is selected from hydrogen and alkyl or cycloalkyl.

[039] The term “alkylamino” or “arylamino”, as used herein, and unless otherwise specified, refers to an amino group having one or two alkyl or aryl substituents, respectively. In certain embodiments, the Petition 870260049430, dated 05 / 25 / 2026, p. 17 / 223 11 / 108 The alkyl substituent is a lower alkyl. In certain embodiments, the alkyl or lower alkyl is unsubstituted.

[040] The term “acyl”, as used herein, and unless otherwise specified, refers to a group of the formula C(O)R', wherein R' is alkyl or cycloalkyl (including lower alkyl) (i.e., “alkanoyl”), aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chlorine, bromine, fluoro, iodine, C1 to C4 alkyl or C1 to C4 alkoxy, sulfonate esters, such as alkyl or arylalkyl sulfonyl, including methanesulfonyl, mono-, di- or triphosphate esters, trityl or monomethoxytrityl, substituted benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl, such as phenoxymethyl. The aryl groups in the esters comprise a phenyl group. In particular, the acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl,butyryla, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-a-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitrobenzenoacetyl, 4-chloro-benzenoacetyl, 2-chloro-2,2-diphenylacetyla, 2-chloro-2phenylacetyla, trimethylacetyla, chlorodifluoroacetyla, perfluoroacetyla, fluoroacetyla, bromodifluoroacetyla, methoxyacetyla, 2-thiophenoacetyla, chlorosulfonylacetyla, 3methoxyphenylacetyla, phenoxyacetyla, terc-butylacetyla, trichloroacetyla, monochloroacetyla, dichloroacetyla, 7H-dodecafluoroheptanoyla, perfluoroheptanoyla, 7H-dodecafluoroheptanoyla, 7-chlorododecafluoroheptanoyla, 7-chloro-dodecafluoroheptanoyla, 7H-dodecafluoroheptanoyla, 7H-dodecafluoroheptanoyla, nona-fluoro-3,6-dioxaheptanoyla, nonafluoro-3,6-dioxaheptanoyla, perfluoroheptanoyla, methoxybenzoyla, methyl 3-amino-5-phenylthiophenol-2-carboxyla, 3,6-dichloro-2-methoxybenzoyla, 4-(1,1,2,2tetrafluoroethoxy)-benzoyla, 2-bromopropionyla, ômega-aminocaprila, decanoyl, npentadecanoyl,stearyl, 3-cyclopentylpropionyl, 1-benzenecarboxyl, O, Petition 870260049430, dated 05 / 25 / 2026, page 18 / 223 12 / 108 acetylmendyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1-methyl-1H-indazol-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl and 4-phenylbenzoyl.

[041] The term “carboxyl” or “carboxy” as used herein, and unless otherwise specified, refers to the radical -C(O)OH.

[042] The term “cycloalkyl”, as used herein, and unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group may be saturated, bridged or unbridged and / or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes from three to ten carbon atoms, i.e., C3 to C10 cycloalkyl. In some embodiments, the cycloalkyl has from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl or adamantyl. The term includes both substituted and unsubstituted chemical moieties. In certain embodiments, the cycloalkyl group is unsubstituted.

[043] The term “cycloalkenyl,” as used herein, and unless otherwise specified, refers to an unsaturated cyclic hydrocarbon. In certain embodiments, cycloalkenyl refers to mono- or multicyclic ring systems that include at least one double bond. In certain embodiments, the cycloalkenyl group may be a bridging, non-bridging, and / or fused bicyclic group. In certain embodiments, the cycloalkyl group includes three to ten carbon atoms, i.e., C3 to C10 cycloalkyl. In some embodiments, the cycloalkenyl has 3 to 7 (C3-7) or 4 to 7 (C4-7) carbon atoms. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the cycloalkenyl group is not Petition 870260049430, dated 05 / 25 / 2026, p. 19 / 223 13 / 108 replaced.

[044] The term “halogen” or “halo” as used herein, and unless otherwise specified, refers to chlorine, bromine, fluorine or iodine.

[045] The term “heterocyclyl” or “heterocyclic”, as used herein, and unless otherwise specified, refers to a monovalent non-aromatic monocyclic ring system or multicyclic ring system containing at least one non-aromatic ring, wherein one or more atoms of the non-aromatic ring are heteroatoms selected independently from O, S, or N; and the remaining atoms in the ring are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 atoms in the ring. The heterocyclic groups are linked to the rest of the molecule through the non-aromatic ring.In certain embodiments, the heterocycline is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridging ring system, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocycline may be attached to the main structure at any heteroatom or carbon atom, resulting in the creation of a stable compound.Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, cromanyl, chromonyl, cinolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,. Petition 870260049430, dated 05 / 25 / 2026, page 20 / 223 14 / 108 octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxanyl, piperazinyl, piperidinyl, 4-piperidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-tritianyl. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the heterocyclyl group is unsubstituted.

[046] The term “heteroaryl”, as used in this document, and unless otherwise specified, refers to a monovalent monocyclic aromatic group and / or a multicyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring. The heteroaryl groups are linked to the rest of the molecule through the aromatic ring. Each ring of a heteroaryl group may contain up to one or two O atoms, one or two S atoms, or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 atoms in the ring.Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopiridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopirimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl. Petition 870260049430, dated 05 / 25 / 2026, page 21 / 223 15 / 108 dibenzofuranyl, perimidinyl, phenanthrolinyl, phenantridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. The term includes substituted and unsubstituted chemical moieties. In certain embodiments, the heteroaryl group is unsubstituted.

[047] The term “protecting group”, as used in this document, and unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[048] The term “pharmaceutically acceptable salt” as used herein, and unless otherwise specified, refers to any salt of a compound provided herein that retains its biological properties and is not toxic or undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.These salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic and similar acids; or (2) salts formed when an acidic proton present in the original compound (a) is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion. Petition 870260049430, dated 05 / 25 / 2026, page 22 / 223 16 / 108 or hydroxides of alkali or alkaline-earth metals, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and the like.

[049] Pharmaceutically acceptable salts also include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and where the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, for example hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and similar substances.

[050] The term “substantially free of” or “substantially in the absence of”, as used herein, and unless otherwise specified, with respect to a composition, refers to a composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98%, 99% or 100% by weight, of Petition 870260049430, dated 05 / 25 / 2026, page 23 / 223 17 / 108 designated enantiomer of that compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of other enantiomers or diastereomers.

[051] Similarly, the term “isolate”, as used herein, and unless otherwise specified, with respect to a composition, refers to a composition that includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, the remainder comprising other chemical species or enantiomers.

[052] The term “solvate”, as used herein, and unless otherwise specified, refers to a compound provided herein or a salt thereof, which additionally includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[053] “Isotopic composition” refers to the amount of each isotope present in a given atom, and “natural isotopic composition” refers to the natural isotopic composition or abundance of a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “unenriched” atoms. Unless otherwise designated, the atoms of the compounds mentioned herein shall represent any stable isotope of that atom. For example, unless otherwise stated, when a position is specifically designated as H or hydrogen, it is understood that the position has hydrogen in its natural isotopic composition.

[054] “Isotopic enrichment” refers to the percentage of incorporation of a specific isotope into a given atom of a molecule in place of the natural isotopic abundance of that atom. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in Petition 870260049430, dated 05 / 25 / 2026, page 24 / 223 18 / 108 a sample contains deuterium at the specified position. Since the natural distribution of deuterium is about 0.0156%, the enrichment of deuterium at any position in a compound synthesized using unenriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided in this document can be determined using conventional analytical methods known to a person of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[055] “Isotopically enriched” refers to an atom that has an isotopic composition different from the natural isotopic composition of that atom. “Isotopically enriched” can also refer to a compound that contains at least one atom with an isotopic composition different from the natural isotopic composition of that atom.

[056] As used in this document, the groups “alkyl”, “cycloalkyl”, “alkenyl”, “cycloalkenyl”, “alkynyl”, “aryl”, “alkoxy”, “alkoxycarbonyl”, “carboxyl”, “alkylamino”, “arylamino”, “heterocyclyl”, “heteroaryl”, “acyl” and “carboxyl” optionally comprise deuterium in one or more positions where hydrogen atoms are present, and where the deuterium composition of the atom or atoms is different from the natural isotopic composition.

[057] Also as used in this document, the groups “alkyl”, “cycloalkyl”, “alkenyl”, “cycloalkenyl”, “alkynyl”, “aryl”, “alkoxy”, “alkoxycarbonyl”, “carboxyl”, “alkylamino”, “arylamino”, “heterocyclyl”, “heterocyclic”, “heteroaryl”, “acyl” and “carboxyl” optionally comprise carbon-13 in an amount different from the natural isotopic composition.

[058] As used in this document, the term “EC50” refers to a dosage, concentration, or amount of a test compound that elicits a dose-dependent response at 50% of the maximum expression of a specific response that is induced, elicited, or potentiated by the test compound. Petition 870260049430, dated 05 / 25 / 2026, p. 25 / 223 19 / 108

[059] As used in this document, the term “IC50” refers to an amount, concentration, or dosage of a specific test compound that achieves a 50% inhibition of a maximum response in an assay that measures such a response.

[060] The terms “subject” and “patient” are used interchangeably in this document. The terms “subject” and “subjects” refer to an animal, such as a mammal, including a non-primate (e.g., a cow, a pig, a horse, a cat, a dog, a rat, and a mouse) and a primate (e.g., a monkey, such as a cynomolgus monkey, a chimpanzee, and a human being) and, for example, a human being. In certain embodiments, the subject is immune or unresponsive to current treatments for a proliferative disease. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain embodiments, the individual is a human being.

[061] The terms “therapeutic agent” and “therapeutic agents” as used in this document, and unless otherwise specified, refer to any agent that may be used in the treatment of a disorder or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound provided in this document. In certain embodiments, a therapeutic agent is an agent that is known to be useful, has been, or is currently being used for the treatment of a disorder or one or more symptoms thereof.

[062] The term “therapeutically effective amount” or “effective amount” as used herein, and unless otherwise specified, refers to an amount of a compound or composition which, when administered to a subject to treat a disease, is sufficient to effect such treatment for the disease. A “therapeutically effective amount” may vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. Petition 870260049430, dated 05 / 25 / 2026, page 26 / 223 20 / 108

[063] “Treating” or “treatment” of any disease or disorder refers, in certain modalities, to the improvement of a disease or disorder that exists in a subject. In another modality, “treating” or “treatment” includes improving at least one physical parameter, which may be indiscernible to the subject. In certain modalities, “treating” or “treatment” refers to the modulation of the disease or disorder, either physically (e.g., stabilization of a discernible symptom), or physiologically (e.g., stabilization of a physical parameter) or both. In certain modalities, “treating” or “treatment” includes slowing the progression of the disease or disorder.

[064] As used in this document, the terms “prophylactic agent” and “prophylactic agents” refer to any agent that can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a compound provided in this document. In certain other embodiments, the term “prophylactic agent” does not refer to a compound provided in this document. For example, a prophylactic agent is an agent that is known to be useful, has been, or is currently being used to prevent or impede the onset, development, progression, and / or severity of a disorder.

[065] As used in this document, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) that is sufficient to result in the prevention or reduction of the development, recurrence, or onset of one or more symptoms associated with a disorder, or to increase or enhance the prophylactic effect (or effects) of another therapy (e.g., another prophylactic agent). Compounds

[066] In certain embodiments, compounds of Formula I are provided in this document: Petition 870260049430, dated 05 / 25 / 2026, p. 27 / 223 21 / 108 Cy-L2(R2>n R4R5 or (I) or a pharmaceutically acceptable salt thereof, where: Each R1 is selected independently of the group that includes H and R2; m is an integer from 0 to 4; A wavy linkage indicates a single-linkage attachment of L to a free site of a thiazole or benzothiazole ring. L1 is selected from the group that includes a single bond, C1-6 alkyl and -(C=O)-; L2 is selected from the group that includes -(C=O)(NR3)-, -(C=O)-alkyl-, and -(NR3)(C=O)-; Cy is selected from the group that includes C3-9-cycloalkyl, C3-9-heterocyclyl, C3-9-heteroaryl and C6-ioaryl; Each R2 is selected independently from the group that includes halo, Ci-3alkoxy, C1-3 alkyl, cyano and R5; n is an integer from 0 to 2; Each R3 is selected independently from the group that includes H and C13 alkyl; R4 is a C1-6 alkylene, in which R4 is substituted by 0 to 4 R7 groups; R5 is selected from the group consisting of -O(CO)R6, -N(R3)(CO)R3, Petition 870260049430, dated 05 / 25 / 2026, p. 28 / 223 22 / 108 -N(R3)(CO)R6, -OR6, -(CO)R6, -(CO)N(R3)R3, -(CO)N(R3)R6, C3-7Cycloalkyl, C3-9heterocyclyl, C6-ioaryl and C3-C9heteroaryl; or, alternatively, R4 and R5 join to form a 5- to 8-membered cycloalkyl, aryl, heterocyclic or heteroaryl ring that is optionally substituted by 0 to 4 R7 groups; Each R6 is selected independently from the group that includes C16 alkyl. C3-7cycloalkyl, C3-9heterocyclyl, C6-10aryl and C3-C9heteroaryl; where R6 is substituted by 0 to 4 R7 groups; and each R7 is selected independently from the group that includes halo, C1-3alkoxy, and C1-3 alkyl.

[067] In certain embodiments, compounds of Formula IB are provided in this document: (IB) or a pharmaceutically acceptable salt thereof, where: Each R1 is selected independently of the group that includes H and R2; m is an integer from 0 to 4; Cy is selected from the group that includes C3-9 heterocyclyl, C3C9 heteroaryl, and C6-10 aryl; Each R2 is selected independently of the group that includes halo. C1-3alkoxy, Petition 870260049430, dated 05 / 25 / 2026, p. 29 / 223 23 / 108 C1-3 alkyl and R5; n is an integer from 0 to 2; R3 is selected from the group that includes -H and C1-3 alkyl; R4 is a C1-6 alkylene, in which R4 is substituted by 0 to 4 R7 groups; each R5 is selected independently from the group that includes O(CO)R6, -NH(CO)R6, -OR6, -(CO)R6, C3-7Cycloalkyl, C3-9heterocyclyl, C6-waryl and C3-C9heteroaryl; Each R6 is selected independently from the group that includes C16 alkyl. C3-7cycloalkyl, C3-9heterocyclyl, C6-10aryl and C3-C9heteroaryl; where R6 is substituted by 0 to 4 R7 groups; and each R7 is selected independently from the group that includes halo, C1-3alkoxy, and C1-3 alkyl.

[068] In certain embodiments, Formula II compounds are provided in this document: or (II) or a pharmaceutically acceptable salt thereof, where: Y is selected from the group that includes CH, CR2, -N=CH-, -N=CR2-, O, S, and N; where Y and Z1 are not both N; and Z1 is selected from the group that includes CH, CR2, -N=CH-, -N=CR2-, and N; where Y and Z1 are not both N.

[069] In certain embodiments, compounds of Formula II-B are provided in this document: Petition 870260049430, dated 05 / 25 / 2026, p. 30 / 223 24 / 108 or a pharmaceutically acceptable salt thereof, where: Y is selected from the group that includes CH, CR2, O, S, and N; where Y and Z1 are not both N; and Z1 is selected from the group that includes CH, CR2, and N; where Y and Z1 are not both N.

[070] In certain modalities, Y is O and Z1 is N, CH or CR2. In certain modalities, Y is O and Z1 is CH or CR2 (for example, CH). In certain modalities, Y is O and Z1 is N.

[071] In certain embodiments, compounds are provided in this document, wherein the compounds are of Formula III: (III) or a pharmaceutically acceptable salt thereof, where: Z1 and Z2 are each selected from the group that includes CH, CR2, and N; where Z1 and Z2 are not both N.

[072] In certain modalities, Z1 is N and Z2 is CH or CR2 (e.g., CH). In certain modalities, Z1 is CH or CR2 (e.g., CH) and Z2 is N. In certain modalities, Z1 and Z2 are both selected independently of CH or CR2. In certain modalities, Z1 and Z2 are both CH. In certain modalities, Z1 and Z2 Petition 870260049430, dated 05 / 25 / 2026, p. 31 / 223 25 / 108 are each selected from the group that includes CH and N.

[073] In certain embodiments, compounds of Formula IV are provided in this document: or a pharmaceutically acceptable salt thereof, where: R1 is selected from the group that includes -H, halo and C1-3 alkyl; Each R2 is selected independently from the group that includes halo, C1-3 alkoxy, and C1-3 alkyl; R4 is C1-6 alkylene; R5 is selected from the group that includes -O(CO)R6, -NH(CO)R6, -OR6, (CO)R6, C3-7cycloalkyl and C3-9heterocyclyl; and R6 is selected from the group that includes C1-6 alkyl, C3-7 cycloalkyl, C39 heterocyclyl and C3-9 heteroaryl.

[074] In certain embodiments, R1 is selected independently of the group that includes H, F, Cl, methoxy, methyl, ethyl and acetoxy. In certain embodiments, R1 is selected independently of the group that includes H and methyl.

[075] In certain embodiments, R1 is H or methyl.

[076] In certain modes, R1 is 6-substituted. In certain modes, R1 is 5-substituted. In certain modes, R1 is 7-substituted. In certain modes, R1 is 4-substituted.

[077] In certain forms, m is an integer from 0 to 4 (for example, Petition 870260049430, dated 05 / 25 / 2026, p. 32 / 223 26 / 108 0, 1, 2, 3 or 4). In certain modalities, m is 0, 1, 2 or 3. In certain modalities, m is 0, 1 or 2. In certain modalities, m is 0 or 1. In certain modalities, m is 0.

[078] In certain embodiments, Cy is selected from the group that includes C3-9heterocyclyl, C3-C9heteroaryl and C6-10aryl. In certain embodiments, Cy is selected from the group that includes C3-C9heteroaryl and C6-10aryl. In certain embodiments, Cy is C6-10aryl (e.g., a phenyl ring). In certain embodiments, Cy is C3-C9heteroaryl (e.g., furanyl; pyridinyl; pyrimidinyl).

[079] In certain embodiments, each R2 is selected independently of the group that includes halo, C1-3 alkoxy, C1-3 alkyl and R5 is selected independently of the group that includes H, F, Cl, methoxy, methyl, ethyl and acetoxy. In certain embodiments, R1 is selected independently of the group that includes H and methyl.

[080] In certain modes, n is an integer from 0 to 2 (for example, 0, 1 or 2). In certain modes, n is 0 or 1. In certain modes, n is 0.

[081] In certain embodiments, each R3 is selected independently of the group that includes H and C1-3 alkyl. In certain embodiments, R3 is H. In certain embodiments, R3 is methyl. In certain embodiments, R3 is ethyl.

[082] In certain embodiments, R4 is C1-6 alkylene, wherein R4 is substituted by 0 to 4 R7 groups. In certain embodiments, R4 is methylene. In certain embodiments, R4 is ethylene, propylene or butylene. In certain embodiments, R4 is substituted by 0 R7 groups. In certain embodiments, R4 is substituted by 1 or 2 R7 groups (e.g., methyl).

[083] In certain modalities, R4 is replaced by 0 R2 groups.

[084] In certain embodiments, R5 is selected from the group that includes O(CO)R6, -N(R3)(CO)R3, -N(R3)(CO)R6, -OR6, -(CO)R6, -(CO)N(R3)R3, -(CO)N(R3)R6, C3-7cycloalkyl, C3-9heterocyclyl, C6-10aryl and C3-C9heteroaryl. In certain embodiments, R5 is selected from the group that includes -O(CO)R6, -N(R3)(CO)R6, -OR6, -(CO)R6, Petition 870260049430, dated 05 / 25 / 2026, page 33 / 223 27 / 108 -(CO)N(R3)R6, C3-7Cycloalkyl, C3-9heterocyclyl, C6-ioaryl and C3-C9heteroaryl.

[085] In certain embodiments, R5 is selected independently from the group which includes -O(CO)R6, -NH(CO)R6, -OR6, -(CO)R6, C3-7cycloalkyl, C39heterocyclyl, C6-waryl and C3-C9heteroaryl. In certain embodiments, R5 is -O(CO)R6 (e.g., acetoxy). In certain embodiments, R5 is -NH(CO)R6 (e.g., acetamido). In certain embodiments, R5 is -OR6 (e.g., methoxy, ethoxy or isopropoxy). In certain embodiments, R5 is -(CO)R6 (e.g., -(CO)Me). In certain embodiments, R5 is C3-7cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In certain embodiments, R5 is a C3-9 heterocyclyl (e.g., 1-substituted pyrrolidine-2,5-dione; 1-substituted pyrrolidin-2-one; 5-substituted pyrrolidin-2-one). In certain embodiments, R5 is a C6-10 aryl (e.g., phenyl; naphthyl).In certain embodiments, R5 is a C3-C9 heteroaryl (e.g., 1-, 2-, 4- or 5-imidazolyl; 1- or 4-triazolyl; 1-, 3-, 4- or 5-pyrazolyl; 2-, 4- or 5-oxazolyl; 2-, 3- or 4-pyridyl; 1-, 3-, 4-, 5- or 6-substituted pyridin-2-one; 2-, 4-, 5- or 6-pyrimidinyl).

[086] In certain embodiments, R5 is selected from the group that includes NH(CO)CH3, -O(CO)CH3, -(CO)CH3, and -OCH2CH3.

[087] In certain embodiments, each R6 is selected independently from the group that includes C1-6 alkyl (e.g., methyl, ethyl, or isopropyl), C37 cycloalkyl, C3-9 heterocyclyl, C6-10 aryl, and C3-C9 heteroaryl; wherein R6 is substituted by 0 to 4 R7 groups. In certain embodiments, R6 is C1-6 alkyl (e.g., methyl, ethyl, or isopropyl). In certain embodiments, R6 is C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, R6 is C39 heterocyclyl (e.g., 1-substituted pyrrolidine-2,5-dione; 1-substituted pyrrolidin-2-one; 5-substituted pyrrolidin-2-one). In certain embodiments, R6 is C6-10aryl (e.g., phenyl; naphthyl). In certain embodiments, R6 is C3-C9heteroaryl (e.g., 1-, 2-, 4- or 5-imidazolyl; 1- or 4-triazolyl; 1-, 3-, 4- or 5-pyrazolyl; 2-, 4- or 5-oxazolyl; 2-, 3- or 4-pyridyl; 1-, 3-, 4-, 5- or 6-substituted pyridin-2-one; Petition 870260049430, dated 05 / 25 / 2026, p. 34 / 223 28 / 108 pirimidinil).

[088] In certain modalities, R6 is replaced by 0 to 4 independently selected R7 groups. In certain modalities, R6 is replaced by 0 to 3 independently selected R7 groups. In certain modalities, R6 is replaced by 0 to 2 independently selected R7 groups. In certain modalities, R6 is replaced by 0 to 1 R7 groups. In certain modalities, R6 is replaced by no R7 groups.

[089] In certain embodiments, each R7 is independently selected from the group that includes halo, C1-3 alkoxy and C1-3 alkyl. In certain embodiments, each R7 is independently selected from the group that includes halo and C1-3 alkyl. In certain embodiments, each R7 is halo (e.g., F). In certain embodiments, each R7 is C1-3 alkyl (e.g., methyl). In certain embodiments, each R7 is C1-3 alkoxy (e.g., methoxy; ethoxy).

[090] In certain embodiments, a compound selected from the group which includes: Petition 870260049430, dated 05 / 25 / 2026, p. 35 / 223 29 / 108 Petition 870260049430, dated 05 / 25 / 2026, p. 36 / 223 30 / 108 Petition 870260049430, dated 05 / 25 / 2026, p. 37 / 223 31 / 108

[091] In certain embodiments, a compound selected from the group which includes: Petition 870260049430, dated 05 / 25 / 2026, p. 38 / 223 32 / 108 Petition 870260049430, dated 05 / 25 / 2026, p. 39 / 223 33 / 108 N H e

[092] In certain embodiments, the compound is selected from the group that includes the compounds in Table 6-1. In certain embodiments, the compound is any one of the compounds in Table 6-1.

[093] In certain embodiments, one or more variables of Formula (I) or Formula (IB) (i.e., R1, m, Cy, R2, n, R3, R4, R5, R6 or R7) correspond to those of a compound of Table 6-1.

[094] In certain embodiments, one or more variables of Formula (II) or Formula (II-B) (i.e., R1, m, Y, Z1, R2, n, R3, R4, R5, R6 or R7) correspond to those of a compound in Table 6-1.

[095] In certain embodiments, one or more variables of Formula (III) (i.e., R1, m, Z1, Z2, R2, n, R3, R4, R5, R6 or R7) correspond to those of a compound in Table 6-1.

[096] In certain embodiments, one or more variables of Formula (IV) (i.e., R1, Z1, Z2, R2, n, R3, R4, R5, R6 or R7) correspond to those of a compound in Table 6-1.

[097] In certain embodiments, the compound inhibits MBD3L2 RNA production at 11 mM (for example, as in the procedure of Example 7).

[098] In certain embodiments, the compound has an EC50 for DUX4 <10 mM (e.g., coded as “B” or “C” in Table 6-1). In certain embodiments, the compound has an EC50 for DUX4 <1 mM (e.g., coded as “C” in Table 6-1). Petition 870260049430, dated 05 / 25 / 2026, p. 40 / 223 34 / 108

[099] In some forms, the following are provided in this document: (a) (a) compounds as described in this document, for example, of Formula I, II, III or IV, and pharmaceutically acceptable salts and compositions thereof; (b) (b) compounds as described in this document, for example, of Formula I, II, III or IV, and pharmaceutically acceptable salts and compositions thereof for use in the treatment and / or prophylaxis of diseases characterized by the misexpression of DUX4; (c) (c) processes for the preparation of compounds as described herein, for example, of Formula I, II, III or IV, as described in more detail elsewhere herein; (d) pharmaceutical formulations comprising a compound as described herein, for example, of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent; and (e) pharmaceutical formulations comprising a compound as described herein, for example, of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, together with one or more other pharmaceutical agents effective for diseases characterized by the misexpression of DUX4, optionally in a pharmaceutically acceptable carrier or diluent. Optically Active Compounds

[0100] The compounds provided in this document may have multiple chiral centers and may exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. Any racemic, optically active, diastereomeric, polymorphic or stereoisomeric form, or mixtures thereof, of a compound provided in this document, possessing the useful properties described herein, is within the scope of the invention. The preparation Petition 870260049430, dated 05 / 25 / 2026, page 41 / 223 35 / 108 of optically active forms can be made by any methods known to a qualified professional (for example, by resolving the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by chromatographic separation using a chiral stationary phase).

[0101] Examples of methods for obtaining optically active materials are known in the art and include at least the following. i) Physical crystal separation - a technique by which macroscopic crystals of individual enantiomers are manually separated. This technique can be used if separate enantiomer crystals exist, i.e., the material is a conglomerate and the crystals are visually distinct; ii) Simultaneous crystallization - a technique by which individual enantiomers are crystallized separately from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) Enzymatic resolution - a technique by which partial or complete separation of a racemate is achieved due to different reaction rates of enantiomers with an enzyme; iv) Asymmetric enzymatic synthesis - a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain a synthetic precursor that is enantiomerically pure or enriched of the desired enantiomer; v) v) Asymmetric chemical synthesis - a synthetic technique by which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) Diastereomer separations - a technique by which a racemic compound reacts with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers into diastereomers. Diastereomers Petition 870260049430, dated 05 / 25 / 2026, page 42 / 223 The resulting 36 / 108 are then separated by chromatography or crystallization due to their now more distinct structural differences, and the chiral auxiliary is subsequently removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby the diastereomers of the racemate equilibrate to produce a preponderance in solution of the diastereomer of the desired enantiomer, or whereby the preferential crystallization of the diastereomer of the desired enantiomer disturbs the equilibrium in such a way that, in principle, all the material is converted into the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) Kinetic resolutions - this technique refers to obtaining partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to unequal reaction rates of enantiomers with a non-racemic chiral reagent or catalyst under kinetic conditions; ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique by which the desired enantiomer is obtained from non-chiral starting materials and in which stereochemical integrity is not or is only minimally compromised throughout the synthesis; x) Chiral liquid chromatography - a technique by which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase. The stationary phase may be made of chiral material or the mobile phase may contain additional chiral material to elicit the different interactions; xi) xi) Chiral gas chromatography - a technique by which the racemate is volatilized and the enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; Petition 870260049430, dated 05 / 25 / 2026, page 43 / 223 37 / 108 xii) xii) extraction with chiral solvents - a technique by which enantiomers are separated due to the preferential dissolution of one enantiomer in a specific chiral solvent; xiii) xiii) transport across chiral membranes - a technique whereby a racemate is brought into contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force, such as concentration or pressure differential, causes preferential transport across the membrane barrier. The separation occurs as a result of the non-racemic chiral nature of the membrane, which allows the passage of only one enantiomer of the racemate.

[0102] In some embodiments, the compositions of the inventive compounds are substantially free of a designated enantiomer of that compound. In certain embodiments, in the methods and compounds of this invention, the compounds are substantially free of enantiomers. In some embodiments, the composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, the remainder comprising other chemical species or enantiomers. Isotopically enriched compounds

[0103] Isotopically enriched compounds are also provided in this document.

[0104] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles has been previously demonstrated with some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999). Petition 870260049430, dated 05 / 25 / 2026, p. 44 / 223 38 / 108

[0105] Isotopic enrichment of a drug can be used, for example, (1) to reduce or eliminate unwanted metabolites, (2) to increase the half-life of the original drug, (3) to decrease the number of doses needed to achieve the desired effect, (4) to decrease the amount of a dose needed to achieve the desired effect, (5) to increase the formation of active metabolites, if any are formed, or (6) to decrease the production of deleterious metabolites in specific tissues or to create a more effective or safer drug for combination therapy, regardless of whether the combination therapy is intentional or not.

[0106] Replacing an atom with one of its isotopes generally results in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a CH bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest energy in the transition state), replacing the hydrogen with deuterium will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Fisiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0107] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a CH bond is broken and the same reaction in which deuterium is replaced by hydrogen. The DKIE can range from about 1 (no isotopic effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty times or more slower when deuterium is replaced by hydrogen. High DKIE values ​​may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is attributed to the small mass of a hydrogen atom and occurs because transition states involving a proton can sometimes form in the absence of the necessary activation energy. Because deuterium has more mass than hydrogen, the DKIE is more likely to be broken. Petition 870260049430, dated 05 / 25 / 2026, page 45 / 223 39 / 108 hydrogen, statistically it has a much lower probability of undergoing this phenomenon.

[0108] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in its nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a low-energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main risk associated with this isotope, but it must be ingested in large quantities to pose a significant health risk. Compared to deuterium, a smaller amount of tritium must be consumed before reaching a dangerous level. Replacing tritium (“T”) with hydrogen results in an even stronger bond than deuterium and provides numerically greater isotopic effects.Similarly, the substitution of isotopes by other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S, or 36S for sulfur, 15N for nitrogen, and 17O or 18O for oxygen, can lead to a similar kinetic isotopic effect.

[0109] For example, DKIE has been used to decrease the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all classes of drugs. For example, the incorporation of deuterium can lead to metabolic switching. The concept of metabolic switching states that xenogens, when sequestered by Phase I enzymes, can transiently bind and rebind in a variety of conformations before the chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different ratios Petition 870260049430, dated 05 / 25 / 2026, page 46 / 223 40 / 108 of known metabolites, as well as entirely new metabolites. This new metabolic profile may confer greater or lesser toxicity.

[0110] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulatory system. Examples of these enzymes include cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react and convert these foreign substances into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (CH) bond to a carbon-oxygen (CO) or carbon-carbon (CC) pi bond. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the original compounds. For many drugs, these oxidations are rapid.Therefore, these medications often require multiple or high daily doses.

[0111] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacological and / or toxicological profiles of a compound provided herein compared to a similar compound having a natural isotopic composition. COMPOUND PREPARATION

[0112] The compounds provided in this document can be prepared, isolated, or obtained by any method apparent to those skilled in the art. Exemplary methods of preparation are described in detail in the examples below. Pharmaceutical Compositions and Methods of Administration

[0113] In certain forms, they are provided in this document Petition 870260049430, dated 05 / 25 / 2026, page 47 / 223 41 / 108 pharmaceutical compositions comprising a compound as disclosed herein; and a pharmaceutically acceptable excipient, carrier or diluent.

[0114] In certain modalities, the composition is an oral formulation.

[0115] In certain embodiments, the compounds can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and administered by a suitable route of administration.

[0116] The methods provided in this document cover the administration of pharmaceutical compositions containing at least one compound as described in this document, including a compound of General Formula I, II, III or IV, if appropriate in salt form, used alone or in combination with one or more compatible and pharmaceutically acceptable carriers, as diluents or adjuvants, or with another pharmaceutical agent to treat diseases characterized by the misexpression of DUX4.

[0117] In certain embodiments, the second agent may be formulated or packaged with the compound provided herein. The second agent shall only be formulated with the compound provided herein when, in the judgment of those skilled in the art, such co-formulation does not interfere with the activity of the agent or the method of administration. In certain embodiments, the compound provided herein and the second agent are formulated separately. They may be packaged together or separately, for the convenience of the professional skilled in the field.

[0118] In clinical practice, the active agents provided in this document can be administered by any conventional route, such as orally, parenterally, rectally or by inhalation (e.g., in the form of aerosols). Petition 870260049430, dated 05 / 25 / 2026, page 48 / 223 42 / 108 In certain embodiments, the compound provided in this document is administered orally.

[0119] Tablets, pills, hard gelatin capsules, powders or granules may be used as solid compositions for oral administration. In these compositions, the active product is mixed with one or more inert diluents or excipients, such as sucrose, lactose or starch.

[0120] These compositions may comprise substances other than diluents, for example, a lubricant such as magnesium stearate, or a coating intended for controlled release.

[0121] Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin may be used as liquid compositions for oral administration. These compositions may also include substances other than diluents, for example, humectants, sweeteners or flavorings.

[0122] Compositions for parenteral administration may be sterile emulsions or solutions. Propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters, for example ethyl oleate, may be used as solvents or vehicles. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization may be carried out in various ways, for example, using a bacteriological filter, by radiation or by heating. They may also be prepared in the form of sterile solid compositions that can be dissolved at the time of use in sterile water or any other sterile injectable medium.

[0123] Compositions for rectal administration are rectal suppositories or capsules that contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. Petition 870260049430, dated 05 / 25 / 2026, page 49 / 223 43 / 108

[0124] The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, saline solution or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended for direct inhalation, the active ingredient is finely divided and combined with a diluent or water-soluble solid vehicle, for example, dextran, mannitol or lactose.

[0125] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit pharmaceutical form. The pharmaceutical compositions and single unit pharmaceutical forms provided herein comprise a prophylactic or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or another prophylactic or therapeutic agent) and typically one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term “pharmaceutically acceptable” means approved by a federal or state government regulatory agency, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans. The term “carrier” includes a diluent, excipient, or vehicle with which the therapeutic agent is administered.Pharmaceutical carriers such as water and oils can be sterile liquids, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a vehicle when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin. Petition 870260049430, dated 05 / 25 / 2026, page 50 / 223 44 / 108, the full content of which is incorporated herein by reference in its entirety for all purposes.

[0126] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. The suitability of a particular excipient for incorporation into a pharmaceutical composition or dosage form depends upon a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or dosage form may, if desired, also contain smaller amounts of wetting or emulsifying agents or pH buffering agents.

[0127] The lactose-free compositions provided herein may comprise excipients that are well known in the art and are listed, for example, in the US Pharmacopia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0128] Also covered in this document are anhydrous pharmaceutical compositions and pharmaceutical forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts. Petition 870260049430, dated 05 / 25 / 2026, page 51 / 223 45 / 108 as a means of simulating long-term storage to determine characteristics such as shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, NY, NY, 1995, p. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on a formulation can be of great importance, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, transport, and use of formulations.

[0129] The anhydrous pharmaceutical compositions and dosage forms provided herein may be prepared using anhydrous or low-moisture ingredients and under low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine may be anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging and / or storage.

[0130] An anhydrous pharmaceutical composition must be prepared and stored in such a way that its anhydrous nature is maintained. Consequently, anhydrous compositions may be packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, tightly sealed foils, plastics, unit dose containers (e.g., vials for injection), blisters, and plastic strips.

[0131] In addition, pharmaceutical compositions and pharmaceutical forms comprising one or more compounds that reduce the rate of decomposition of an active ingredient are provided. These compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. Petition 870260049430, dated 05 / 25 / 2026, page 52 / 223 46 / 108

[0132] Pharmaceutical compositions and single-unit dosage forms may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions and dosage forms shall contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain modalities, in purified form, together with an adequate amount of carrier to provide the form for proper administration to the subject. The formulation must be suitable for the mode of administration.In a given embodiment, the pharmaceutical compositions or single-unit pharmaceutical forms are sterile and in a form suitable for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject.

[0133] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, for example, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial, and rectal administration. In a specific embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In another embodiment, a pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are sterile isotonic aqueous buffer solutions.When necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocamne, to relieve discomfort. Petition 870260049430, dated 05 / 25 / 2026, page 53 / 223 47 / 108 pain at the injection site.

[0134] Examples of pharmaceutical forms include, but are not limited to: tablets; capsules; soft elastic gelatin capsules; wafers; trociscos; lozenges; dispersions; suppositories; ointments; poultices (cataplasms); pastes; powders; dressings; creams; plasters; solutions; adhesives; aerosols (e.g., nasal sprays or inhalers); gels; liquid pharmaceutical forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; liquid pharmaceutical forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid pharmaceutical forms suitable for parenteral administration to a subject.

[0135] The composition, form, and type of pharmaceutical forms provided herein generally vary depending on their use. For example, a pharmaceutical form used in the initial treatment of a viral infection may contain larger amounts of one or more of the active ingredients it comprises than a pharmaceutical form used in the maintenance treatment of the same infection. Similarly, a parenteral pharmaceutical form may contain smaller amounts of one or more of the active ingredients it comprises than an oral pharmaceutical form used to treat the same disease or disorder. These and other ways in which the specific pharmaceutical forms covered herein vary from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

[0136] Generally, the ingredients of the compositions are supplied separately or mixed in a unit pharmaceutical form, for example, as a Petition 870260049430, dated 05 / 25 / 2026, page 54 / 223 48 / 108 dry lyophilized powder or concentrate without water in a tightly closed container, such as an ampoule or sachet, indicating the amount of active agent. When the composition is administered by infusion, it may be dispensed with an infusion bottle containing sterile pharmaceutical-grade water or saline solution. When the composition is administered by injection, an ampoule of sterile water for injection or saline solution may be provided so that the ingredients can be mixed before administration.

[0137] Typical pharmaceutical forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, being within the range of about 0.1 mg to about 1000 mg per day, administered as a single daily dose in the morning or as divided doses throughout the day, taken with food. In certain embodiments, a pharmaceutical form may have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound. Oral pharmaceutical forms

[0138] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), capsules, and liquids (e.g., flavored syrups). Such pharmaceutical forms contain predetermined amounts of active ingredients and may be prepared by methods of pharmacy well known to those skilled in the art. See, in general, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (2000).

[0139] In certain embodiments, the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail in the sections above. However, the scope of the compositions provided herein extends beyond solid, anhydrous oral dosage forms. Thus, forms Petition 870260049430, dated 05 / 25 / 2026, page 55 / 223 49 / 108 additional details are described in this document.

[0140] Typical oral dosage forms are prepared by combining the active ingredients in an intimate mixture with at least one excipient in accordance with conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms, depending on the desired form of preparation for administration. For example, excipients suitable for use in liquid or aerosol oral dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and pods) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0141] Due to their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid excipients are used. If desired, tablets can be coated using standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmaceutical methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation, if necessary.

[0142] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredients in a free-flowing form, such as powder or granules, optionally mixed with an excipient, in a suitable machine. Molded tablets can be manufactured by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Petition 870260049430, dated 05 / 25 / 2026, page 56 / 223 50 / 108

[0143] Examples of excipients that may be used in oral pharmaceutical forms include, but are not limited to, binders, fillers, disintegrants and lubricants. Binders suitable for use in pharmaceutical compositions and pharmaceutical forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

[0144] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions provided herein is typically present in about 50 to about 99 percent by weight of the pharmaceutical composition or dosage form.

[0145] Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH101, AVICEL-PH103, AVICEL RC581, AVICEL-PH105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC581. Suitable anhydrous or low-moisture excipients or additives include AVICEL-PH103™ and Starch 1500 LM.

[0146] Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. The Petition 870260049430, dated 05 / 25 / 2026, page 57 / 223 51 / 108 tablets containing too much disintegrant may disintegrate during storage, while those containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant—that is, neither too much nor too little to detrimentally alter the release of the active ingredients—must be used to form solid oral dosage forms. The amount of disintegrant used varies based on the type of formulation and is readily discernible to those skilled in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 percent by weight of disintegrant, specifically from about 1 to about 5 percent by weight of disintegrant.

[0147] Disintegrants that may be used in pharmaceutical compositions and pharmaceutical forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums and mixtures thereof.

[0148] Lubricants that may be used in pharmaceutical compositions and pharmaceutical forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof. Additional lubricants include, for example, a silica siloid gel (AEROSIL 200, manufactured by WR Grace Co. of Baltimore, MD), a coagulated synthetic silica aerosol (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used, the lubricants are Petition 870260049430, dated 05 / 25 / 2026, page 58 / 223 52 / 108 are typically used in amounts less than about 1 percent by weight of the pharmaceutical compositions or pharmaceutical forms in which they are incorporated. Delayed-release pharmaceutical forms

[0149] Active ingredients, such as the compounds provided herein, may be administered by controlled-release means or by delivery devices that are well known to those with common knowledge in the field. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500; each of which is incorporated herein by reference in its entirety. Such pharmaceutical forms may be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those with common knowledge in the field, including those described herein, may be readily selected for use with the active ingredients provided herein.Thus, this includes single-unit pharmaceutical forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules, and coated tablets that are adapted for controlled release.

[0150] All controlled-release pharmaceutical products have the common goal of improving drug therapy in relation to their Petition 870260049430, dated 05 / 25 / 2026, page 59 / 223 53 / 108 uncontrolled equivalents. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by the use of a minimum amount of drug substance to cure or control the condition in a minimum period of time. The advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and greater subject adherence. Furthermore, controlled-release formulations can be used to affect the onset time of action or other characteristics, such as blood levels of the drug, and can therefore affect the occurrence of side effects (e.g., adverse effects).

[0151] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect and then gradually and continuously release other amounts of drug to maintain that level of therapeutic or prophylactic effect over a prolonged period. To maintain this constant level of drug in the body, the drug must be released from the pharmaceutical form at a rate that replenishes the amount of drug being metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0152] In certain embodiments, the drug may be administered by intravenous infusion, implantable osmotic pump, transdermal patch, liposomes, or other modes of administration. In certain embodiments, a pump may be used (see, for example, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials may be used. In another embodiment, a controlled-release system may be placed in a subject at an appropriate location determined by a qualified professional, i.e., requiring Petition 870260049430, dated 05 / 25 / 2026, page 60 / 223 54 / 108 thus only a fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled-release systems are discussed in Langer's review (Science 249:1527-1533 (1990)). The active ingredient may be dispersed in a solid inner matrix, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicon carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate, which is enclosed by an outer polymeric membrane, for example, polyethylene, polypropylene,Ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride / vinyl acetate copolymers, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, which is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a rate-control release step. The percentage of active ingredient in such parenteral compositions depends greatly on their specific nature as well as the subject's needs. Parenteral Pharmaceutical Forms

[0153] In certain embodiments, parenteral pharmaceutical forms are provided. Parenteral pharmaceutical forms may be administered to subjects by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. As their administration Petition 870260049430, dated 05 / 25 / 2026, page 61 / 223 55 / 108 typically ignores the subjects' natural defenses against contaminants; parenteral pharmaceutical forms are usually sterile or can be sterilized before administration to an individual. Examples of parenteral pharmaceutical forms include, but are not limited to, ready-to-inject solutions, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, ready-to-inject suspensions, and emulsions.

[0154] Suitable vehicles that can be used to deliver parenteral pharmaceutical forms are well known to those skilled in the art. Examples include, without limitation: Water for Injection USP; aqueous carriers, such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and Ringer's lactate injection; water-miscible carriers, such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0155] Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be incorporated into parenteral pharmaceutical forms. Transdermal, topical, and mucosal pharmaceutical forms

[0156] Transdermal, topical, and mucosal dosage forms are also provided. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to a specialist in the field. See, for example, Remington's Pharmaceutical Sciences, 16th, 18th, and 20th eds., Mack Publishing, Easton, PA (1980, 1990, and 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues in the oral cavity may be Petition 870260049430, dated 05 / 25 / 2026, page 62 / 223 56 / 108 formulated as mouthwashes or oral gels. In addition, transdermal pharmaceutical forms include “reservoir” or “matrix” type patches, which can be applied to the skin and used for a specific period to allow the penetration of a desired amount of active ingredients.

[0157] Suitable excipients (e.g., carriers and diluents) and other materials that may be used to provide topical and mucosal pharmaceutical forms covered in this document are well known to those skilled in the pharmaceutical art and depend on the specific tissue to which a given pharmaceutical composition or dosage form will be applied. With this fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels, or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms, if desired. Examples of such additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 16th, 18th and 20th editions., Mack Publishing, Easton PA (1980, 1990 & 2000).

[0158] Depending on the specific tissue to be treated, additional components may be used before, in conjunction with, or after treatment with the supplied active ingredients. For example, penetration enhancers may be used to assist in the delivery of the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to, acetone; various alcohols, such as ethanol, oleyl and tetrahydrofuryl; alkyl sulfoxides, such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones, such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polividone); urea; and various water-soluble or water-insoluble sugar esters, such as Tween 80 (polysorbate 80) and Span. Petition 870260049430, dated 05 / 25 / 2026, page 63 / 223 57 / 108 (sorbitan monostearate).

[0159] The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this respect, stearates can serve as a lipid carrier for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancer or penetration enhancer. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. Dosage and Unit-Dose Pharmaceutical Forms

[0160] In certain embodiments, methods for treating a patient are provided herein, comprising administering an effective treatment amount of a compound or composition, as disclosed herein. In some embodiments, the patient is a human being.

[0161] In human therapy, the physician will determine the dosage he considers most appropriate according to preventive or curative treatment and according to the age, weight, stage of infection and other specific factors of the subject to be treated. In certain modalities, doses are approximately 1 to approximately 1,000 mg per day for an adult, or approximately 5 to approximately 250 mg per day or approximately 10 to 50 mg per day for an adult. In certain modalities, doses are approximately 5 to approximately 400 mg per day or 25 to 200 mg per day per adult. In certain modalities, dosage rates of approximately 50 to approximately Petition 870260049430, dated 05 / 25 / 2026, p. 64 / 223 58 / 108 of 500 mg per day.

[0162] In other respects, methods are provided for the treatment or prevention of a disease characterized by the incorrect expression of DUX4 in a subject, by administering to a needy subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The amount of the compound or composition that will be effective in preventing or treating a disorder or one or more of its symptoms will vary according to the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage also vary according to factors specific to each subject, depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease or condition, the route of administration, as well as the subject's age, body weight, response and previous medical history.Effective doses can be extrapolated from dose-response curves derived from in vitro test systems or animal models.

[0163] In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of the subject's or sample's body weight (for example, about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in certain embodiments, the dosage administered to a subject is from 0.140 mg / kg to 3 mg / kg of the subject's body weight, based on the weight of the active compound. In certain embodiments, the dosage administered to a subject is between 0.20 mg / kg and 2.00 mg / kg, or between 0.30 mg / kg and 1.50 mg / kg of the subject's body weight.

[0164] In certain modalities, the recommended daily dosage range of Petition 870260049430, dated 05 / 25 / 2026, p. 65 / 223 59 / 108 A composition provided in this document for the conditions described herein falls within the range of approximately 0.1 mg to approximately 1000 mg per day, administered as a single once-daily dose or in divided doses throughout the day. In certain embodiments, the daily dose is administered twice daily in equally divided doses. In certain embodiments, the daily dose range should be approximately 10 mg to approximately 200 mg per day, in other embodiments, between approximately 10 mg and approximately 150 mg per day, in other embodiments, between approximately 25 mg and approximately 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will become evident to those with common knowledge in the field. Furthermore, it is important to emphasize that the attending clinician or physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the patient's response.

[0165] Different therapeutically effective amounts may be applicable to different diseases and conditions, as will be readily known to those with common knowledge in the field. Similarly, amounts sufficient to prevent, control, treat, or improve such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also covered by the dosage amounts and dosing frequency schedules described above. Furthermore, when a subject receives multiple dosages of a composition provided herein, not all dosages need to be equal. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or may be decreased to reduce one or more side effects that a specific subject is experiencing.

[0166] In certain embodiments, the dosage of the composition provided in this document, based on the weight of the active compound, administered to prevent, treat, control or improve a disorder, or one or more symptoms thereof in Petition 870260049430, dated 05 / 25 / 2026, page 66 / 223 60 / 108 a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg or 15 mg / kg or more of a subject's body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, control or improve a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 12 mg, 0.25 mg to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg or 1 mg to 2.5 mg.

[0167] In certain embodiments, treatment or prevention may be initiated with one or more loading doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the loading dose may be, for example, about 60 to about 400 mg per day, or about 100 to about 200 mg per day for one day to five weeks. The loading dose may be followed by one or more maintenance doses. In certain embodiments, each maintenance dose is independently about 10 mg to about 200 mg per day, between about 25 mg and about 150 mg per day, or between about 25 and about 80 mg per day. Maintenance doses may be administered daily and may be administered in single or divided doses.

[0168] In certain embodiments, a dose of a compound or composition provided in this document may be administered to achieve a steady-state concentration of the active ingredient in the blood or serum of the subject. The steady-state concentration may be determined by measurement according to techniques available to those qualified or may be based on the physical characteristics of the subject, such as height, weight, and age. In certain embodiments, a sufficient quantity of a compound or composition provided in this document Petition 870260049430, dated 05 / 25 / 2026, p. 67 / 223 61 / 108 document is administered to achieve a stable concentration in the subject's blood or serum of approximately 300 to approximately 4000 ng / ml, approximately 400 to approximately 1600 ng / ml, or approximately 600 to approximately 1200 ng / ml. In some embodiments, loading doses may be administered to achieve stable blood or serum concentrations of approximately 1200 to approximately 8000 ng / ml, or approximately 2000 to approximately 4000 ng / ml for one to five days. In certain embodiments, maintenance doses may be administered to achieve a stable concentration in the subject's blood or serum of approximately 300 to approximately 4000 ng / ml, approximately 400 to approximately 1600 ng / ml, or approximately 600 to approximately 1200 ng / ml.

[0169] In certain embodiments, the administration of the same composition may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, the administration of the same prophylactic or therapeutic agent may be repeated, while the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0170] In certain aspects, unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration are provided in this document. Such forms are described in detail above. In certain embodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250 mg, or 10 to 50 mg of active ingredient. In certain embodiments, the unit dosages comprise approximately 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. These unit dosages can be prepared according to techniques familiar to those skilled in the art.

[0171] The dosages of the second agents should be used in the combination therapies provided herein. In certain modalities, lower dosages than those that have been or are currently being used to prevent or treat a Petition 870260049430, dated 05 / 25 / 2026, page 68 / 223 62 / 108 disease characterized by the incorrect expression of DUX4 are used in the combination therapies provided in this document. Recommended dosages of second agents can be obtained with the knowledge of specialists. For those second agents that are approved for clinical use, recommended dosages are described, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Therapeutics 9th Ed., McGraw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in their entirety.

[0172] In various modalities, the therapies (for example, a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, approximately 1 hour apart, approximately 1 to approximately 2 hours apart, approximately 2 to approximately 3 hours apart, approximately 3 to approximately 4 hours apart, approximately 4 to approximately 5 hours apart, approximately 5 to approximately 6 hours apart, approximately 6 to approximately 7 hours apart, approximately 7 to approximately 8 hours apart, approximately 8 to approximately 9 hours apart, approximately 9 to approximately 10 hours apart, approximately 10 to approximately 11 hours apart, approximately 11 to approximately 12 hours apart, approximately 12 to 18 hours apart interval, 18 to 24 hours interval, 24 to 36 hours interval,36 to 48 hour intervals, 48 ​​to 52 hour intervals, 52 to 60 hour intervals, 60 to 72 hour intervals, 72 to 84 hour intervals, 84 to 96 hour intervals, or 96 to 120 hour intervals. In several modalities, therapies are administered with intervals of no more than 24 hours or no more than 48 hours. In certain modalities, two or more therapies are administered in the same patient consultation. In other modalities, the compound provided herein, Petition 870260049430, dated 05 / 25 / 2026, p. 69 / 223 63 / 108 document and the second agent are managed simultaneously.

[0173] In other embodiments, the compound provided herein and the second agent are administered with an interval of approximately 2 to 4 days, with an interval of approximately 4 to 6 days, with an interval of approximately 1 week, with an interval of approximately 1 to 2 weeks, or with an interval of more than 2 weeks.

[0174] In certain embodiments, the administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months. In other embodiments, the administration of the same agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months.

[0175] In certain embodiments, a compound provided herein and a second agent are administered to a patient, for example, a mammal such as a human, in a sequence and within a time range such that the compound provided herein can act in conjunction with the other agent to provide a greater benefit than if they were administered otherwise. For example, the second active agent may be administered at the same time or sequentially in any order at different times; however, if they are not administered at the same time, they must be administered sufficiently close in time to provide the desired therapeutic or prophylactic effect. In certain embodiments, the compound provided herein and the second active agent exert their effect at overlapping times. Each second active agent may be administered separately, in any appropriate form and by any suitable route.In other embodiments, the compound provided in this document is administered before, concurrently with, or after the administration of the second active agent.

[0176] In certain embodiments, a compound as provided herein Petition 870260049430, dated 05 / 25 / 2026, page 70 / 223 64 / 108 document and a second agent are administered cyclically to a patient. Cycling therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) for a period, followed by administering a second and / or third agent (e.g., a second and / or third prophylactic or therapeutic agent) for a second period, and repeating this sequential administration. Cycling therapy may reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment.

[0177] In certain embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days, or about once a week. A cycle may comprise administration of a compound provided herein and the second agent by infusion for about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle may comprise at least 1 week of rest, at least 2 weeks of rest, or at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and most typically from about 2 to about 8 cycles.

[0178] In other embodiments, courses of treatment are administered simultaneously to a patient, that is, individual doses of the second agent are administered separately, but within a time range such that the compound provided herein can work in conjunction with the second active agent. For example, one component may be administered once a week in combination with other components that may be administered once every two weeks or once every three weeks. In other words, dosing regimens are carried out concomitantly, even if the therapeutic agents are not administered simultaneously or on the same day. Petition 870260049430, dated 05 / 25 / 2026, page 71 / 223 65 / 108

[0179] The second agent may act additively or synergistically with the compound provided herein. In certain embodiments, the compound provided herein is administered concomitantly with one or more second agents in the same pharmaceutical composition. In another embodiment, a compound provided herein is administered concomitantly with one or more second agents in separate pharmaceutical compositions. In another embodiment, a compound provided herein is administered before or after the administration of a second agent. Administration of a compound provided herein and a second agent by the same or different routes of administration, for example, oral and parenteral, is also contemplated.In certain embodiments, when the compound provided herein is administered concomitantly with a second agent that potentially produces adverse side effects, including, but not limited to, toxicity, the second active agent may advantageously be administered at a dose that is below the threshold at which the adverse side effect is provoked. Kits

[0180] Kits are also provided for use in methods of treating diseases characterized by the misexpression of DUX4. The kits may include a compound or composition provided herein, a second agent or composition, and instructions providing information to a healthcare professional on its use in treating the disorder. Instructions may be provided in printed form or electronically, such as on a floppy disk, CD, or DVD, or in the form of a website address where such instructions can be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, may include a dosage such that, when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 day. In some Petition 870260049430, dated 05 / 25 / 2026, page 72 / 223 66 / 108 embodiments, a compound or composition may be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., composition (lyophilized)).

[0181] In some embodiments, suitable packaging is provided. As used herein, “packaging” includes a solid matrix or material commonly used in a system and capable of containing within fixed limits a compound provided herein and / or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene and polycarbonate bottles, vials, laminated paper, plastic and plastic foil envelopes and the like). If electron beam sterilization techniques are employed, the packaging must have sufficiently low density to permit sterilization of the contents. Methods of Use

[0182] In certain embodiments, methods for treating a patient are provided herein, comprising administering an effective treatment amount of a compound or composition, as disclosed herein. In some embodiments, the patient is a human being. In certain embodiments, the patient is a subject in need of treatment (i.e., a patient who needs it). In certain embodiments, the patient is a subject who has been previously treated with another chemotherapeutic compound or composition.

[0183] In certain embodiments, methods are provided herein for the treatment and / or prophylaxis of diseases characterized by the misexpression of DUX4, which include the administration of an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for treating a disease characterized by the misexpression of DUX4 in a subject. In certain embodiments, the methods encompass the step of administering to the subject in need an amount of a compound effective for treatment or Petition 870260049430, dated 05 / 25 / 2026, page 73 / 223 67 / 108 prevention of a disease characterized by the misexpression of DUX4 in combination with a second agent effective for the treatment or prevention of the disease. The compound may be any compound as described herein, and the second agent may be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or pharmaceutical form, as described elsewhere in this document.

[0184] In certain modalities, the subject has never received therapy or prophylaxis for a disease characterized by the incorrect expression of DUX4. In other modalities, the subject has previously received therapy or prophylaxis for a disease characterized by the incorrect expression of DUX4.

[0185] In certain modalities, the subject is a subject who has discontinued therapy for the disease characterized by incorrect expression of DUX4 due to one or more adverse events associated with the therapy. In certain modalities, the subject is a subject for whom the current therapy is not indicated.

[0186] In certain embodiments, the subject received therapy for a disease characterized by the misexpression of DUX4 and discontinued that therapy before administration of a method provided herein. In other embodiments, the subject received therapy and continues to receive it along with the administration of a method provided herein. The methods may be co-administered with other therapies for the disease, according to the judgment of a subject matter expert. In certain embodiments, the methods or compositions provided herein may be co-administered with a reduced dose of the other therapy for the disease characterized by the misexpression of DUX4.

[0187] In certain modalities, treatment methods are provided for a subject who is refractory to treatment with a disease characterized by the expression Petition 870260049430, dated 05 / 25 / 2026, page 74 / 223 68 / 108 incorrect expression of DUX4. For example, in some modalities, the subject may be a subject who did not respond to treatment with one or more agents for the disease characterized by incorrect expression of DUX4. In some modalities, the subject may be a subject who responded poorly to treatment with one or more agents for the disease characterized by incorrect expression of DUX4. Test Methods

[0188] The compounds can be analyzed for activity against the disease characterized by the misexpression of DUX4 according to any assay known to those skilled in the art. Second Therapeutic Agents

[0189] In certain embodiments, the compounds and compositions provided herein are useful in methods of treating a liver disorder, which comprise the additional administration of a second agent effective for treating the disorder in a subject in need thereof. The second agent may be any agent known to those skilled in the art to be effective for treating the disorder, including those currently approved by the FDA.

[0190] In certain embodiments, a compound provided herein is administered in combination with a second agent. In other embodiments, a second agent is administered in combination with two second agents. In other embodiments, a second agent is administered in combination with two or more second agents.

[0191] As used in this document, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided in this document) Petition 870260049430, dated 05 / 25 / 2026, page 75 / 223 69 / 108 can be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0192] As used in this document, the term “synergistic” includes a combination of a compound provided in this document and another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, control, or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows the use of lower dosages of one or more therapies and / or less frequent administration of said therapies to a subject with a disorder. The ability to use lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer said therapy less frequently reduces the toxicity associated with administering said therapy to a subject without reducing the effectiveness of said therapy in preventing or treating a disorder.Furthermore, a synergistic effect can result in greater efficacy of the agents in preventing or treating a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can prevent or reduce adverse or unwanted side effects associated with the use of any of the therapies alone.

[0193] The active compounds provided in this document may be Petition 870260049430, dated 05 / 25 / 2026, p. 76 / 223 70 / 108 administered in combination or alternating with another therapeutic agent. In combination therapy, effective dosages of two or more agents are administered together, while in alternating or sequential therapy, an effective dosage of each agent is administered serially or sequentially. The dosages administered will depend on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It is important to emphasize that dosage values ​​also vary according to the severity of the condition to be attenuated. It should also be understood that, for any specific subject, specific dosage regimens and schedules must be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions. In certain modalities, a compound for treatment against a disease characterized by the misexpression of DUX4 has an EC50 of 1 to 15 μM.In certain embodiments, a compound with an EC50 of less than 1 to 5 μM is desirable.

[0194] Examples of second agents include losmapimod, vitamin C, vitamin E, zinc gluconate, and selenomethionine. EXAMPLES

[0195] As used in this document, the symbols and conventions used in these processes, diagrams, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the descriptive report: g (grams); mg (milligrams); ml (milliliters); μl (microliters); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); h, hr, or hrs (hours); min (minutes); TLC (thin-layer chromatography); HPLC (high-performance liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); DCM Petition 870260049430, dated 05 / 25 / 2026, page 77 / 223 71 / 108 (dichloromethane); DMSO (dimethyl sulfoxide); DMSO-de (deuterated dimethyl sulfoxide); and EtOAc (ethyl acetate).

[0196] For all examples that follow, standard processing and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). All reactions are conducted at room temperature unless otherwise indicated. The synthetic methodologies illustrated in this document are intended to exemplify applicable chemistry through specific examples and are not indicative of the scope of disclosure. EXAMPLE 1

[0197] Synthesis of N-(6-(Benzo[d]thiazol-2-yl)pyridin-3-yl)-3-(2,5-dioxopyrrolidin-1yl)propenamide (AT003) (5a) COOH PPA, 130C, 4h Stage 1a 3a T3P, Et3N, DCM, RT Stage 2a

[0198] Synthesis of 6-(Benzo[d]thiazol-2-yl)pyridin-3-amine (3) / W\NH2 N 3a

[0199] To a mixture of 2-aminobenzenethiol (1a) (2 g, 15.98 mmol) and 5-aminopicolinic acid (2) (2.20 g, 15.98 mmol) polyphosphoric acid (30 g) was added at room temperature under a nitrogen atmosphere. The reaction was heated to 130 °C for 4 h. TLC analysis showed consumption of the starting material. The mixture of Petition 870260049430, dated 05 / 25 / 2026, page 78 / 223 72 / 108 reaction was rapidly cooled with water (50 ml) and the pH slowly adjusted to neutral using a saturated sodium hydroxide solution, and the resulting precipitate was filtered and washed with water. The solid obtained was ground with MTBE and dried under vacuum to provide 6-(benzo[d]thiazol-2-yl)pyridin-3-amine (3a) (1.9 g, 8.36 mmol, 52.3% yield) as a light yellow solid. LCMS (ESI, +ve mode): 83.94%, Observed: 228.2 (M+H) for C12H9N3S, RT: 1.74 min.

[0200] Synthesis of N-(6-(benzo[d]thiazol-2-yl)pyridin-3-yl)-3-(2,5-dioxopyrrolidin-1yl)propanamide (5a) (AT003)

[0201] To a stirred solution of 6-(benzo[d]thiazol-2-yl)pyridin-3-amine (3a) (100 mg, 0.440 mmol) in dichloromethane (10 ml) was added 3-(2,5dioxopyrrolidin-1-yl)propanoic acid (4a) (75 mg, 0.440 mmol) under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C, then triethylamine (0.307 ml, 2.200 mmol) and T3P in EtOAc (0.786 ml, 1.320 mmol, 50% solution) were added. The reaction mixture was stirred at room temperature for 16 h. TLC analysis showed consumption of the starting material. The reaction mixture was diluted with DCM (15 ml), washed with 10% sodium bicarbonate solution (10 ml) and brine solution (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue.The residue obtained was purified by preparative HPLC (0.1% HCOOH in ACN) and lyophilized to provide N-(6(benzo[d]thiazol-2-yl)pyridin-3-yl)-3-(2,5-dioxopyrrolidin-1-yl)propanamide (38 mg, 0.099 mmol, 22.50% yield) (5a) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.81 (s, 1H), 8.29 (s, 2H), 8.15 (d, J = 8.00 Hz, 1H), 8.07 (d, J = 8.00 Hz, 1H), 7.57-7.53 (m, 1H), 7.48 (t, J = 7.20 Hz, 1H), 3.71 (t, J = 7.20 Hz, 2H), 2.67-2.64 (m, 6H). LCMS (ESI, +ve mode): 99.61%, Observed: 381.1 (M + H) for. Petition 870260049430, dated 05 / 25 / 2026, p. 79 / 223 73 / 108 C21H19N3O3S, RT: 2.07 min. HPLC: 99.09%, RT: 3.55 min. EXAMPLE 2

[0202] Synthesis of 4-acetamido-N-(4-(benzo[b]thiophen-2-yl)-phenyl)-Nmethylbutanamide (AT037) (5a) ib K2CO3rDikis dioxane / H2O, 90 °C Step 1b 3b HATU, DIPEA, DMF, RT Stage 2b Synthesis of 4-(Benzo[b]thiophen-2-yl)-N-methylaniline (3b) 3b

[0204] In a sealed 25 ml tube containing a solution of benzo[b]thiophen-2-ylboronic acid (1b) (500 mg, 2.81 mmol) in a mixture of dioxane (6 ml) and water (2 ml), 4-bromo-N-methylaniline (2b) (523 mg, 2.81 mmol) and potassium carbonate (1165 mg, 8.43 mmol) were added at room temperature. The reaction mixture was degassed with nitrogen for 5 min, and then bis(triphenylphosphine)palladium(II) dichloride (197 mg, 0.281 mmol) was added. The reaction was stirred at 90 °C for 12 h. TLC analysis showed consumption of the starting material. The reaction mixture was dissolved in ethyl acetate (50 ml), washed with water (20 ml) and brine solution (20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue thus obtained was purified by silica gel column chromatography (230-400 Petition 870260049430, dated 05 / 25 / 2026, page 80 / 223 74 / 108 mesh) eluted with 0-15% EtOAc in petroleum ether to give 4-(benzo[b]thiophen-2-yl)-N-methylaniline (3b) (300 mg, 1.136 mmol, 40.5% yield) as a white solid. LCMS (ESI, mode + ve): 90.65%, Observed: 240.1 (M+H) for C15H13NS, RT: 3.00 min

[0205] Synthesis of 4-acetamido-N-(4-(benzo[b]thiophen-2-yl)-phenyl)-Nmethylbutanamide (AT037) (5b) I íí A oH\= / / 5b

[0206] To a stirred solution of 4-(benzo[b]thiophen-2-yl)-N-methylaniline (3b) (100 mg, 0.418 mmol) in N,N-dimethylformamide (6 ml) was added 4-acetamidobutanoic acid (4b) (60.7 mg, 0.418 mmol) and DIPEA (0.298 ml, 1.671 mmol) at 0 °C. Then HATU (318 mg, 0.836 mmol) was added and stirred for 12 h at room temperature. LCMS analysis showed consumption of the starting material. The reaction mixture was dissolved in DCM (15 ml), washed with 10% sodium bicarbonate solution (10 ml) and water (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue thus obtained was purified by HPLC prep. (0.1% NH4HCO3 in ACN) and lyophilized to provide 4-acetamido-N-(4-(benzo[b]thiophen-2-yl)phenyl)-N-methylbutanamide (16 mg, 0.041 mmol, 10% yield) (AT037) (5b) as a white solid.de1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 7.20 Hz, 1H), 7.92 (s, 1H), 7.88–7.84 (m, 3H), 7.73 (s, 1H), 7.42–7.36 (s, 3H), (3, 3H), 2.96-2.94 (m, 2H), 2.11 (s, 2H), 1.73 (s, 3H), 1.61 (t, J = 7.20 Hz, 2H). LCMS (ESI, +ve mode): 99.73%, Observed: 367.1(M+H) for C21H22N2O2S, RT: 2.51 min. HPLC: 99.92%, RT: 4.20 min. EXAMPLE 3

[0207] Synthesis of N-(4-(Benzo[d]thiazol-2-yl)phenyl)-4-propionamidobutanamide (AT045) (5c) Petition 870260049430, of 25 / 05 / 2026, p. 81 / 223 75 / 108 THEIR 2c DC M, Et3N, RT Step 1c NaOH THF / HnO RT Step 2c

[0208] Synthesis of 4-propionamidobutanoate from 4 methyl (2c)

[0209] To a solution of methyl 4-aminobutanoate hydrochloride (1c) (500 mg, 3.26 mmol) in DCM (10 ml) triethylamine (1.372 ml, 9.77 mmol) and propionyl chloride (301 mg, 3.26 mmol) were added at 0 °C. It was stirred for 16 h at room temperature. LCMS analysis showed consumption of the starting material. The reaction mixture was diluted with DCM (15 ml), washed with water (10 ml) and sodium bicarbonate solution (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-propionamidobutanoate (2c) (190 mg, 1.096 mmol, 33.7% yield) as a light yellow liquid. It was carried to the next step without further purification. LCMS (ELSD, +ve mode): 99.94%, Observed: 174.1 (M+H) for CsHisNOs, RT: 1.23 min.

[0210] Synthesis of 4-methylpropionamidobutanoate (4c)

[0211] To a stirred solution of methyl 4-propionamidobutanoate (3c) (180 mg, 1.039 mmol) in a mixture of water (4 ml) and THF (4 ml) was added Petition 870260049430, dated 05 / 25 / 2026, page 82 / 223 76 / 108 sodium hydroxide (125 mg, 3.12 mmol) at 0°C. It was stirred for 2 h at room temperature. LCMS analysis showed the completion of the starting material. The reaction mixture was concentrated under reduced pressure to remove THF and acidified (pH 3-4) using 1.5 N HCl and extracted with DCM (2 x 15 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-propionamidobutanoic acid (4c) (75 mg, 0.405 mmol, 38.9% yield) as a light yellow liquid. It was taken to the next step without further purification. LCMS (ESI, +ve mode): 86%, Observed: 160.3 (M+H) for C7H13NO3, RT: 0.94 min.

[0212] Synthesis of N-(4-(Benzo[d]thiazol-2-yl)phenyl)-4-propionamidobutanamide (AT045) (5c)

[0213] To a stirred solution of 4-(benzo[b]thiophen-2-yl)-N-methylaniline (3b) (100 mg, 0.418 mmol) in N,N-dimethylformamide (6 ml) was added 4-acetamidobutanoic acid (4b) (60.7 mg, 0.418 mmol) and DIPEA (0.298 ml, 1.671 mmol) at 0 °C. Then HATU (318 mg, 0.836 mmol) was added and stirred for 12 h at room temperature. LCMS analysis showed consumption of the starting material. The reaction mixture was dissolved in DCM (15 ml), washed with 10% sodium bicarbonate solution (10 ml) and water (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue thus obtained was purified by HPLC prep. (0.1% NH4HCO3 in ACN) and lyophilized to provide 4-acetamido-N-(4-(benzo[b]thiophen-2-yl)phenyl)-N-methylbutanamide (16 mg, 0.041 mmol, 10% yield) (AT037) (5b) as a white solid.RMN de1H (400 MHz, DMSO-d6): δ 8,00 (d, J = 7,20 Hz, 1H), 7,92 (s, 1H), 7,88-7,84 (m, 3H), 7,73 (s, 1H), 7,42-7,36 (m, 4H), 3,20 (s, 3H), 2,96-2,94 (m, 2H), 2,11 (s, 2H), 1,73 (s, 3H), 1,61 (t, J = 7,20 Hz, 2H). LCMS (ESI, modo +ve): 99,73%, Observado:. Petição 870260049430, de 25 / 05 / 2026, pág. 83 / 223 77 / 108 367,1(M+H) para C21H22N2O2S, RT: 2,51 min. HPLC: 99,92%, RT: 4,20 min.

[0214] To a stirred solution of 4-propionamidobutanoic acid (4c) (70 mg, 0.440 mmol) in DCM (5 ml) 4-(benzo[d]thiazol-2-yl)-aniline (3c) (100 mg, 0.440 mmol) and triethylamine (0.062 ml, 0.440 mmol) at 0°C were added. Then, T3P in EtOAc (0.259 ml, 0.440 mmol, 50%) was added and stirred for 12 h at room temperature. TLC analysis showed consumption of the starting material. The reaction mixture was diluted with DCM (20 ml), washed with 10% sodium bicarbonate solution (10 ml) and brine solution (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by HPLC prep. (0.1% NH4HCO3 in ACN) and lyophilized to provide N-(4-(benzo[d]thiazol-2-yl)phenyl)-4-propionamidobutanamide (63 mg, 0.171 mmol, 39.0% yield) (AT045) (5c) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.13 (d, J = 7.20 Hz, 1H), 8.06-8.02 (m, 3H), 7.827.80 (m, 3H), 7.56-7.51 (m, 1H), 7.46-7.42 (m, 1H), 3.10 (t, J = 6.80 Hz, 2H), 2.37 (t, J = 7.60 Hz, 2H), 2.07 (q, J = 7.60 Hz, 2H), 1.75-1.72 (m, 2H), 1.00 (t, J = 7.60 Hz, 2H). LCMS (ESI, +ve mode): 97.3%, Observed: 368.1(M+H) for C20H21N3O2S, RT: 2.40 min. HPLC: 99.94%, RT: 3.86 min. EXAMPLE 4 Cellular Cytotoxicity Assay Protocol 50 (CC50) Preparation

[0215] MB200 cells were cultured to 80% confluence in F10 medium supplemented with basic rhFGF (10 ng / ml), 15% fetal bovine serum, 1% streptomycin penicillin, 1% amphotericin B, and 1 μM dexamethasone. Adherent MB200 cells growing on a 10 cm plate were then trypsinized with 1 ml of trypsin. After the cells detached from the plate, F10 medium (10 ml) was added and the cells were filtered through a 70 μm cell filter.

[0216] The cells were counted using a 10 μl mixture of suspension Petition 870260049430, dated 05 / 25 / 2026, page 84 / 223 78 / 108 cells were treated with 10 μL of trypan blue. After counting the total number of cells, a 200 kJ / ml dilution was prepared, and the cells were seeded at a rate of 10 kJ / well in a 96-well plate in triplicate, taking care to avoid seeding cells at the edges of the plate to prevent edge effects. Using a multichannel pipette, the 200 kJ / ml cell dilution (50 μL / well) was added to wells B2-B11, C2-C11, and D2-D11 in triplicate. Cellular treatment with inhibitors

[0217] In a deep well block (DWB), the medium for the appropriate cell line (450 µl / well) was added to wells 1 to 10. In well 2 of the DWB, 10 mM of drug solution (13.5 µl) was added, followed by an additional volume of medium (225 µl). The well was pipetted up and down four times. A portion (225 µl) was transferred to well 3, and this process was repeated up to well 10. Using a multichannel pipette, a smaller portion (50 µl / well) was removed from all wells in the DWB and then dispensed onto the cells in each corresponding row. After drug addition, the plate was incubated at 37 °C for 72 h. Luminescence Reading

[0218] Using a multichannel pipette, pre-warmed cell titration glo reagent (Promega) (100 pl) was added to each well. After 5 minutes, total luminescence was measured with a luminometer. CC50 was determined with the GraphPad prism model. EXAMPLE 5 EC50 Protocol Preparation of the Transfection Complex

[0219] This example provides a representative protocol for a single well from a 96-well plate. It can be expanded as needed for the treatment of multiple wells.

[0220] For negative controls, a well containing reporter DNA was used, Petition 870260049430, dated 05 / 25 / 2026, page 85 / 223 79 / 108 Renilla and turbofect DNA (without expression vector). For positive controls, wells containing cells that were not treated with any inhibitor were used. These were transfected with the complete DNA-lipid complex, as set out below.

[0221] The DNA-lipid complex for a single well of a 96-well plate is prepared by adding to a tube 100 ng of transfection factor (TF) expression vector, 100 ng of TF reporter DNA, 10 ng of Renilla reporter DNA, 0.4 ml of Turbofect transfection reagent, and 25 ml of serum-free or penicillin / streptomycin-free medium. The mixture was mixed with gentle swirling of the tube, and the mixture was pipetted into a well of a 96-well plate. The plate was then gently tapped to spread the mixture evenly across the bottom of the well. The well was incubated for 30 min. Cell preparation

[0222] HEK293 cells were cultured to 80% confluence in DMEM supplemented with 10% fetal bovine serum, 1% streptomycin penicillin, and 1% amphotericin B. Adherent cells that grew in a 10 cm plate were trypsinized with 1 ml of pre-warmed trypsin. After the cells detached from the plate, 10 ml of medium were added, and the cells were filtered through a 70 mm cell strainer.

[0223] The cells were counted using a mixture of 10 ml of cell suspension with 10 ml of trypan blue. Once the total number of cells was counted, a dilution of 150 kJ / ml was prepared. Transfection

[0224] After completion of the transfection complex incubation, 155 ml of HEK293s (23.25 k total cells) were gently dispensed over the wells containing the 25 ml transfection complex, producing a total volume of approximately 180 ml. The mixture was then incubated for 24 h. Petition 870260049430, dated 05 / 25 / 2026, page 86 / 223 80 / 108 Cellular treatment with inhibitors

[0225] To treat the cells with each inhibitor, the inhibitors were prepared in the same growth medium. In a deep-well block, regular serum medium was added to well 1 (135 ml) and wells 2 to 10 (100 ml). 15 ml of 10 nM inhibitor was added to the first well. The final drug concentration in well 1 was 1 nM. The wells were pipetted up and down, and 50 ml were transferred from well 1 to well 2 (1 / 3 dilution). The well was mixed, and the serial dilution was repeated with the remaining wells. After the serial dilution was completed, using a multichannel pipette, 20 ml of each inhibitor were transferred to designated wells in a 96-well plate. After the inhibitor addition, the cells were incubated at 37 °C for 24 h. Measuring the relative activity of luciferase using a luciferase assay system.

[0226] Before the assay, a sufficient quantity of 1x passive lysis buffer was prepared. The luciferase substrate buffer (Promega) was completely thawed and then mixed with the lyophilized luciferase substrate. The stop buffer (Promega) was also completely thawed.

[0227] (1) Cell lysis: After the treatment of the cells was complete, all the culture medium was removed by turning the 96-well plate over and tapping it to dry on a dry paper towel. Immediately afterwards, 1x passive lysis buffer (25 μl) was added. The plates were then placed on a shaker for 15 minutes at medium speed.

[0228] (2) Luciferase signal measurement: The luciferase substrate solution for all wells was placed in a solution basin. The luciferase substrate solution was then added to each well (100 μl / well) using a multichannel pipette. The total luminescence was then read immediately using a plate reader. Petition 870260049430, dated 05 / 25 / 2026, page 87 / 223 81 / 108

[0229] (3) Renilla signal measurement: The “complete stop solution” was prepared in a solution basin by mixing the buffer with the 50X stop solution substrate (Promega) to produce the final 1x solution. The complete stop solution was added to each well (50 μl / well) using a multichannel pipette. The total luminescence was then read immediately using a plate reader. Measurement of relative luciferase units

[0230] Using a spreadsheet (e.g., Excel), the luciferase signal was divided by the renilla signal to obtain a relative unit of luciferase. EXAMPLE 6 Synthesis and Activity of Exemplary Compounds

[0231] Table 6-1 below shows additional exemplary compounds prepared according to the methods of the previous examples, as well as the activities of the compounds. Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibition at 11 mM 1 / —(\ / Vnh o K 0 9 o 1 BBA YES / =\ U 1 / ΧΛ / / NH 9 ° V 0 2 BBA NO o ZI Ó' 3 BBB NO Petition 870260049430, dated 05 / 25 / 2026, p. 88 / 223 82 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM H 0 0 kÂ^N 4 CAA NO II HH ° 5 CAA YES / Vx,s / =N [| 1 / )—(\ / )—NH OK 0 V o 6 BAA NO / =\ p í —4 #— χ / ~~ N '—' Η N —\ \ / / ° O^AX 7 AAA YES Οι γτ^ν9 A <UU o o 8 A A A SIM A^S / =\ I 1 / / NH AA . 0 / —\ / ° ' HNA 9 C A A SIM zk~w τ Οχ ^Σο 10 C A A SIM / =Ν zA^S / τ^ ΗΝ^ ί Σ A A 11 A A A SIM Petition 870260049430, dated 05 / 25 / 2026, p. 89 / 223 83 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM .O o ( / VN 12 CAA NO ll à / / NH / =N 0 x 13 CAA YES ll J / / —(\ / / NH O X--- < / H H 14 C A A SIM H H A—YN^y H O kçAyN 15 C A A SIM '—( o HNy y-y i \= / 16 B A A SIM H Π Ο V^N 17 C B B NÃO I J / ^NH rvp o 18 B A A SIM y° o J ZI z O 19 C A A NÃO Petition 870260049430, dated 05 / 25 / 2026, pp. 90 / 223 84 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mm 25 AAA NO / ^V^ / Ç^0 π γ NS^JLpí o H / tA » # yN 26 CBA YES / =\ 1 A ΑΛ / Anh rA^ / '-NH 0 Hn 27 CAA YES Petition 870260049430, dated 05 / 25 / 2026, pp. 91 / 223 85 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM H in? o H / r^ II ( / yN 28 AAA SIM . hn—d W 1 |l Q— V 0 29 CBA SIM V ^NH F\ / V^,N zmx HN^ 1 XW ΥΛ \^S \= / b 30 BAA SIM r^Xr'8 / =\ / / l J / XX\ \ Ο H H ^ ^ 31 CAA SIM ZI L IZ o \ 2 ω u 32 CAA SIM / =\ J / W\ / ^nh \\ 0·^ (j '—(\ η VN 33 CAA SIM ' 34 BAA SIM Η H 0 0 35 CAA NÃO Petition 870260049430, of 25 / 05 / 2026, p. 92 / 223 86 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM 9 H V9 o V^n 36 CAB SIM y Á 99 9nh o 0 v 0 37 BAA SIM Η HO 0 syK> 38 CAA SIM í 9 99 / 9nh Z^V / 9n o —< II H 39 CAA SIM S / =\ y 9 h 99 h O\\ <z II NN H 40 C A A SIM H / ? γύνυ^9 5^99 o yv ^9 Y o y-N 41 C A A SIM QHI u o H NA 42 B A A NÃO \\ / = N9 / )—(\ 9nh o ΑΛ 0 43 A A A NÃO Petition 870260049430, of 25 / 05 / 2026, p. 93 / 223 87 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM _ (D ^NH / =\ — / 1 |[ / Vnh 44 CAA YES Η 1 ^γ^Ν^-^ΝΗ sAXX 0 II 45 CAA NO cx ω z=^ ZI yz <À° 46 CAA YES 1 L >a / / nh °a \— / \—. / — 0 NH 47 BAA NO HM 0 Av-n 48 CAA NO ZI L TZ Az Az ω X) 49 CAA YES 0 O- UA,·. :> 0 50 BAA NO Petition 870260049430, dated 05 / 25 / 2026, pp. 94 / 223 88 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM Η ϊΠ zsAv o / r^ » A VN 51 CAA NO / Xnh \ Y ΥΛ Jr Y. °Y ZI ^=° IZ ^=z ω X) 56 CAA YES HH n Xx / NXXA / o A ii / / y^N 57 CAA NO Petition 870260049430, dated 05 / 25 / 2026, pp. 95 / 223 89 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM cy / Η 1 .sXX 0 58 CAA NÃO H lí NN n ayX ° H XX-n 59 BAA SIM ^0V''Q 60 CAA SIM H VA.......0 61 CAA SIM H 62 CAA SIM s^Xj NÃ-63 CAB / y CAB SIM yy ΛΆ l IL / XX\ / / NH \— / \ , Q c / '—X li VN 65 CAA SIM Qi......Qarm7 66 AAA SIM Petition 870260049430, dated 5 / 25 / 2026, p. 96 / 223 90 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM H „ rty χι / =\ li / Vn 67 BAA SIM Ρχι o Ο ΉΛ X^ JXN Οχ^'-Ν NH 68 CAA NÃO 0 0Λ0 0 0 t “ S X> 0 69 ABA Η0 H IIA NÃO < li. Οχ HVU 0 H 71 AAA SIM Οχ H 9 U o H 72 AAA SIM Η H ^γΝγ^^^-Ν s^M oo Oy-N 73 CAA SIM ooq LJHH / r^ li yN F 74 CAA SIM Petition 870260049430, dated 5 / 25 / 2026, p. 97 / 223 91 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM o=\ ZI 75 CAA YES o Γ ω IZ ZI 76 BAA YES 0 HH^ o Ay-N 77 CAA YES Η II Λ o HC|—< T vn 78 BAA NO ZI L 79 AAA NO H ° \_ / sr π π n \ à AA n H 80 AAA NO cAn o ,—' 7— / L 1 AA ANH N= / 81 CAA YES H / ? SN .. A / TÁ Y / / / VN 0 J— / \— / O 82 CAA NO 7—2 L 1 VNH N—' 83 CAA YES Petition 870260049430, dated 05 / 25 / 2026, pp. 98 / 223 92 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM H íí OH FH^HF 84 CAA YES Οχ / =\ J 0 LT AA anh HX 85 CAA YES OO . / — / =\ 7— í í ΆΑ / Anh 86 CAA SIM / ΤΑ Η θ < / Vq XY / \ / \ A \ / s fY π n \ A A J n HN γγ^ ° 87 B A A SIM XY T 0 \ AN 88 C A A SIM H / ? a 0 89 A A A SIM ArAn o A 1 II ? \ 1 ii / \ N n N H 0 90 A A A SIM o °Y JÍ / \ f YN H A Y / o 91 A A A SIM _ / s\xC3 AA A A^ o AAn hn^^nJ / s A 92 A A A SIM Petition 870260049430, dated 05 / 25 / 2026, pp. 99 / 223 93 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM 71 o IZ rz^° o=< JJ 93 BAA YES 0. S / =\ \ 1 / ? 1 L v 4 / / NH n-\ N cr7 94 CAA YES 0 tk, / =\ >< >NLL / XA # NH v 7 95 AAA NO 0 °» Λ 99 CAA NO 0 O\ z Ki ΞΕ 100 BAA NO Petition 870260049430, dated 05 / 25 / 2026, pp. 100 / 223 94 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM GH H 9 Νγηζ NN AU o H Cl 101 AAA YES FSHONN ' NUOH Cl 102 AAA YES 1 / )—4 Anh o X—\ 7— 0 NH 103 CAA YES Qs An II HHA o 104 CAA YES AA / ? °\ aAn hx ^nh 105 BAA YES Q ω ' < o H 106 AAA YES H í| sn^^nA £Vn oh 107 AAA YES H / ? Y / N .. Λ AYIA ( / Vn o A / \— / 0 108 AAA YES f T γγ A\ .o HNn; o M 109 BAA YES Petition 870260049430, dated 05 / 25 / 2026, pp. 101 / 223 95 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mm ..... Vy-N 110 AAA YES o / =\ XnH OH 114 AAA SIM ,^s ο V Γ LF\AA / mh IN H 115 AAA SIM O / =\ / Λ LL / ^NH o FN Ν-γ 116 BAA SIM C> ΗΝγ^ o XV 0 117 AAA SIM Qü H 0 2~~ / 0 118 AAA SIM Petition 870260049430, dated 05 / 25 / 2026, pp. 102 / 223 96 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM orr IZ 7=0 119 AAA YES HHN^|^^N\ / OO SV / ^V- N 120 AAA YES O ur / ii \ — / / II II Π H 11 121 AAA NO __ / S. / \ T 0 U>N HNy^N^ 122 AAA NO Ox ω ' r—ZK / T 123 AAA NO / = NO / —' S / =\ / — í li / W\ / )-nh N vk 124 CAA NO ç 125 CAA NO ,,S í / )-N” rrN °^-r hn-t 126 AAA YES o V-λ 1 Π / r \ 1 U 7 \ N NN . Petition 870260049430, dated 05 / 25 / 2026, pp. 103 / 223 97 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. at 11 mM or V 1 Π J u 7 \ H 0 128 AAA NÃO 0 ,χχ / =\ / —\ LL Aa / / NH \ / 9 xx^n M hnA 129 CAA SIM HHS^XxJ OH < II Vn 130 BAA SIM (D X-, s K \ 1 0 LX Anh nX ΧΧ^Ν Η x H 131 AAA SIM H II ΛΑ / γΧ2 ° HA / \χΝ 132 CAA NÃO o χχγ-s / —\ yx Ί LX / NH NH cY\ 133 AAA NÃO 0 y-ys, / —\ τ \ 1 L 1 Ά\ / 'NH NH XçX^-M \— / J 134 AAA SIM CXsAi r N '' Ν' , HL / ' zO HN-y 135 AAA NÃO Petition 870260049430, 05 / 25 / 2026, pág. 104 / 223 98 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. at 11 mM Η H zyN ηΛ—V VV 0 s^\ / 136 AAA NÃO 9 H zyN Λ—V V-Λ VA 0 s^\ / 137 AAA NÃO H ,S JJ 0 VA PF 138 AAB SIM HHZ\z N^^^^ s-χΣΣ 0 0 n 139 AAA no εΣΣ^ ° Λ » # yN 140 CAA SIM । the? fTNY^V sVv Ο Λα Y 0 # Λν 141 BAB SIM 1 II λ / αΣ ε^ΣΣ 0 H <αΣ^-ν 142 CAA SIM Petition 870260049430, 05 / 25 / 2026, pág. 105 / 223 99 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mm \X 0 oh Â~~y 143 AAA NO । ? SxAJ ° X^ / XT ° # yN F 144 AAA YES 1 O γγ V—AS·^ o H <xXh-- N F 145 B A A SIM χ<\ΧΊ II H X XXXXx / <ον n γ 1 0 146 A A A NÃO Οχ αΟ^Λί 0 ι—\ UXA-y । o 147 A A A NÃO ^NWá ° Y O-s yjvy H o 148 A A A NÃO / VS\ / Π Η H X χΧΟχ / νΌ yo ° Y Y O 0 149 A A A SIM y° IZ o. y-z yXo 150 A A A NÃO Petition 870260049430, dated 05 / 25 / 2026, pp. 106 / 223 100 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM O\__ Η 1 \ 0 o ^X^-N 151 AAA YES Η 1 \ XX''NNV SJ\J 0 o N 152 AAA NO XxX^XX ih XvX AL AL ​​ / Τ # yN F 155 CAB SIM X zy ZI oy z Λ HX\-NQ \ / V^xo / / Th )—' 7 x-^x A y J o nX O^X 158 AAA YES xx=° X~z J í ω z 159 AAA NO Petition 870260049430, dated 5 / 25 / 2026, p. 107 / 223 101 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. and 11 mM ^yS / yo o. L Jy 1 λ N 'N v^VN. / H 0 160 AAA NÃO I IZ^ Γ \ z° zy ογ 161 AAA SIM Y\=o Y~ZJQ ω^ζ 162 AAA SIM A zl ZI OY z Hxy A / AA S 16 ,.-Νχ^χζ-χν^ zS^xJ 0 LJ / =< TN / YN 164 AAA SIM YYS\Y} Η H / / \ΧνζΝχχΧζΝχ χ ΥΥ T Π5} A AA 0\ 16 / / \A zNx / X / Nx χ vn ry O 0 166 AAA NÃO xy^S / y O 0 íí \ / ) vY YX\ XX XQ Yn 0 NN \ H \J o^ 167 CAA SIM Οχ z^YxYX 0 H\A Nx1^ CA XNWil ° The information MxnA / \Y lo 169 AAA SIM Petition 870260049430, dated 5 / 25 / 2026, p. 108 / 223 102 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM 170 BAA SIM H II ( X n A*NN ^ςΑΧΧ sh 171 AAA SIM ^aXJ S h 172 AAA SIM / \ ,o hnA ΓΥ tXXh ° \— / HN^ A 173 AAA SIM— 17 HAA HAA / BAA 0 / o __ o ü / / V < A aa h AA~n H 175 CAA SIM H o N^u 0 / —< J zy^s / =\ / — í T Ta Anh 176 BBA NÃO H n N-^ü ° / —é J / =\ Ü J TA A\ 177 AAAX-A1 n SIM H,? SIM Petition 870260049430, dated 5 / 25 / 2026, p. 109 / 223 103 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inib. a 11 mM o IzA ° λ ZI ω xz 179 AAA SIM ys oo AHHF 180 AAA NO F Ά H 9 U o HF 181 AAA NO O. z^, χχ^-s í? 1 l[ Άνη xX-N H 182 AAA SIM O yvs >·θ ? 1 Anh ΎιΆ X^NH 183 AAA SIM O, Z-γ, Χγ5χ Ά<0. f 1 II Anh 'ζνΆ X^N Η 184 BAA SIM Ο X AW ACX ? 1 L ΆNH ^nA X^NH 185 AAA SIM H n Nx° 0 / —< J / —\ / — u í / W ANH XX^N x' 186 AAA NÃO H n NX° O / — / J XxS / —\ | I < \NH \I \— / 187 AAA NO Petition 870260049430, dated 05 / 25 / 2026, pp. 110 / 223 104 / 108 Structure ID EC50 for DUX4 at 6h CC50 MB200 (mM) CC50 HEK (mM) qPCR MBD3L2 Inhibit. at 11 mM FA As oo nA^An^^N^ A hh CN 188 AAA YES Keys: A = >10 mM; B = 1 to 10 mM; C = <1mM Example 7 Protocol for RNA isolation and qPCR to determine MBD3L2 RNA levels

[0232] The protocol describes the process of isolating RNA from cultured cells, converting RNA into complementary DNA (cDNA), and measuring the expression of the target gene using a quantitative polymerase chain reaction (qPCR). Cell Treatment with Compound

[0233] FSHD seed cells were distributed in a six-well plate. One day after seeding, the DUX4 inhibitor (11 μM or 3.6 μM / well) was added to the cells. After another 48 hours, the old medium was removed from the cells. The cells were washed with 2 ml of warm phosphate-buffered saline (PBS).

[0234] PBS was aspirated and cells were lysed in each well with 350 μl of RLT buffer and 3.5 μl of beta-mercaptoethanol (BME). The lysates were added to new, RNase-free, labeled Eppendorf tubes. The cells were then physically disrupted for 60 minutes at level 4 of the bead disruptor to ensure RNA release. RNA Collection

[0235] RNA was collected according to standard procedures (i.e., Qiagen kit instructions), as discussed below. Petition 870260049430, dated 05 / 25 / 2026, pages 111 / 223 105 / 108

[0236] RNA was precipitated by adding 350 μL of 70% ethanol to each sample in a separate Eppendorf tube. Each suspension was mixed by pipetting up and down.

[0237] The solution was transferred to the pink centrifuge column (700 μl). Up to 700 μl of the sample, including any precipitate formed, was transferred to an RNeasy centrifuge column placed in a 2 ml collection tube. The tube was centrifuged for 15 s 13K RPM and the flow was discarded.

[0238] RW1 buffer (700 μl) was added to the RNeasy centrifuge column. The tube was centrifuged for 15 s to 13K RPM and the flow was discarded.

[0239] RPE buffer (500 μl) was added to the RNeasy centrifuge column. The tube was centrifuged for 15 s 13K RPM and the flow was discarded.

[0240] Additional RPE buffer (500 μl) was added to the RNeasy centrifuge column. The tube was centrifuged for 15 s 13K RPM and the flow was discarded.

[0241] The column was placed in a new collector tube and centrifuged for 2 min at 13K RPMs.

[0242] The RNA was then eluted and collected from the column. Water (30 μl) was added to the center of the column and allowed to incubate for 5 min at room temperature. The column was then centrifuged for 1 min at 14K RPM, after which the RNA concentration was measured. Measuring RNA concentration

[0243] The nanodroplet measurement was calibrated with 2 μl of nuclease-free water as a blank. The RNA sample (2 μl) was added to the nanodroplet and the RNA concentration was measured. Once the concentration was determined, the samples were prepared for reverse transcription. Reverse transcription

[0244] RNA concentrations were standardized to 200 μg / μl. In a Petition 870260049430, dated 05 / 25 / 2026, pages 112 / 223 Using a 106 / 108 PCR tube, the RNA (2 μg) in a new Eppendorf tube was diluted with RNase-free water to a final volume of 9.5 μl of 200 μg / μl RNA.

[0245] DNase was used to remove any DNA contamination. A DNase master mix was prepared from 1.5 μl / reaction DNase solution (1 unit / μl, Promega), 3 μl / 5X RT reaction buffer (i.e., 250 mM Tris-HCl (pH 8.3), 375 mM KCl, 15 mM MgCl2, and 500 μl 0.1 M DTT; Promega MMLV), and 1 μl / reaction RNase inhibitor solution (RNasin, 40 units / μl, Promega). The DNase Master Mix was added to the standardized RNA samples (5.5 μl / sample). The samples were mixed by shaking and briefly centrifuged. The samples were heated to 37 °C for 60 min, 80 °C for 5 min, and then cooled to 4 °C. The samples were stored on ice until the addition of the next reagents.

[0246] An RT reaction master mix was prepared from 5 μl / reaction buffer 5X RT, 2 μl / reaction dNTP solution (2.5 mM at each nucleotide), 1 μl / reaction RNase inhibitor solution (RNasin, 40 units / μl, Promega), 1.6 μl / reaction M-MLV reverse transcriptase (200 units / μl, Promega), and 13.4 μl / reaction deionized RNase-free water. The RT Reaction Master Mix was cooled on ice until use.

[0247] A 50 μM solution of Random Primer 6 random hexanucleotides (2 μl) was added to each sample. The samples were mixed by stirring and briefly centrifuged. The samples were heated to 70 °C for 5 min and then cooled to 4 °C.

[0248] RT Reaction Main Mixture (23 μl) was added to each sample. The samples were mixed by shaking and briefly centrifuged. To convert RNA to cDNA, the samples were heated to 42 °C for 60 min, 95 °C for 5 min, and then cooled to 4 °C. The cDNA product mixture was diluted 5:1 with deionized water (40 μl 160 μl). Petition 870260049430, dated 05 / 25 / 2026, pages 113 / 223 107 / 108 Running qPCR

[0249] Samples were run in triplicate, with a methyl-CpG 3-like 2-binding protein target primer (MBD3L2) and a eukaryotic translation elongation factor 1-alpha control primer (EEF1A).

[0250] A qPCR Master Mix was prepared for each primer and stored on ice (4 °C) until use. The qPCR master mix included 10 μl / reaction of SYBR Green Mix (2X) (ThermoFisher), 1 μl / reaction of primer mix (i.e., MBD3L2 PCR primer mix or EEF1A primer mix), and 4 μl / reaction of deionized, RNase-free water.

[0251] To set up the qPCR plate, 15 μl of the appropriate qPCR Core Mixture were added to the appropriate wells for each target / primer. After all targets / primers were added to the wells, 5 μl of the sample were added to the corresponding wells, so that each well had 20 μl in total. The plate was covered with a transparent foil.

[0252] A qPCR series was set up (QuantStudio 5) with the following cycle: Holding stage (1 cycle): 50 °C - 2 min (1.6 °C / s); 95 °C - 10 min (1.6 °C / s). PCR stage (50 cycles): 95 °C - 15 s (1.6 °C / s) for denaturation; 60 °C - 1 min (1.6 °C / s) for amplification.

[0253] All publications and patent applications cited in this descriptive report are incorporated herein by reference, as if each individual publication or patent application were specifically and individually indicated for incorporation by reference. Although the claimed subject matter has been described in terms of various embodiments, the skilled technician will understand that various modifications, substitutions, omissions and alterations may be made without departing from its spirit. Consequently, it is intended that the Petition 870260049430, dated 05 / 25 / 2026, pp. 114 / 223 108 / 108 The scope of the matter is limited solely by the scope of the following claims, including equivalents thereof. Petition 870260049430, dated 05 / 25 / 2026, pp. 115 / 223

Claims

1 / 9 CLAIMS 1. Compound CHARACTERIZED in that it is of Formula I: Cy-L2 (R2>n r4-r5 or Cy-L2 (R2)n r4-R5 (I) or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of H and R2; m is an integer from 0 to 4; a wavy linkage indicates a single linkage attachment of L to a free site of a thiazole or benzothiazole ring; L1 is selected from the group including a single linkage, C1-6-alkyl and -(C=O)-; L2 is selected from the group including -(C=O)(NR3)-, -(C=O)-alkyl-, and -(NR3)(C=O)-; C3-C9-heteroaryl and C6-ioaryl; each R2 is independently selected from the group consisting of halo, C1-3-alkoxy, C1-3 alkyl, cyano and R5; n is an integer from 0 to 2; each R3 is independently selected from the group consisting of H and C1-3 alkyl;118 / 127 2 / 9 R4 is C1-6 alkylene, wherein R4 is substituted by 0 to 4 R7 groups; R5 is selected from the group consisting of -O(CO)R6, -N(R3)(CO)R3, -N(R3)(CO)R6, -O R6, -(CO)R6, -(CO)N(R3)R3, -(CO)N(R3)R6, C3-7 Cycloalkyl, C39 heterocyclyl, C6-waryl and C3-C9 heteroaryl; or, alternatively, R4 and R5 join to form a 5- to 8-membered cycloalkyl or heterocyclic ring that is optionally substituted by 0 to 4 R7 groups; Each R6 is independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, C3-9 heterocyclyl, C6-10 aryl, and C3-C9 heteroaryl; wherein R6 is substituted by 0 to 4 R7 groups; and each R7 is independently selected from the group consisting of halo, C1-3 alkoxy, and C1-3 alkyl.

2. Compound according to claim 1, wherein the compound is CHARACTERIZED in that it is of Formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from the group consisting of CH, CR2, -N=CH-, -N=CR2, O, S and N; wherein Y and Z1 are not both N; and Z1 is selected from the group consisting of CH, CR2, -N=CH-, N=CR2- and N; wherein Y and Z1 are not both N.

3. Compound according to claim 1, wherein the compound is CHARACTERIZED in that it is of Formula (III): Petition 870250054187, dated 06 / 27 / 2025, p. 119 / 127 3 / 9 (III) or a pharmaceutically acceptable salt thereof, wherein: Z1 and Z2 are each selected from the group consisting of CH, CR2, and N; wherein Z1 and Z2 are not both N.

4. Compound according to claim 3, wherein the compound is CHARACTERIZED in that it is of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of -H, halo and C1-3 alkyl; each R2 is independently selected from the group consisting of halo, C1-3 alkoxy, and C1-3 alkyl; R4 is C1-6 alkylene; R5 is selected from the group consisting of -O(CO)R6, -NH(CO)R6, OR6, -(CO)R6, C3-7 cycloalkyl and C3-9 heterocyclyl; and R6 is selected from the group consisting of C1-6 alkyl, C37 cycloalkyl, C3-9 heterocyclyl and C3-9 heteroaryl.

5. Compound, according to claim 3 or 4, CHARACTERIZED by Petition 870250054187, dated 06 / 27 / 2025, pp. 120 / 127 4 / 9 in that Z1 and Z2 are each selected from the group consisting of CH and N.

6. Compound, according to any one of claim 5, CHARACTERIZED in that R1 is H or methyl.

7. A compound, according to any one of claim 6, CHARACTERIZED in that n is 0.

8. A compound, according to any one of claim 7, CHARACTERIZED in that R4 is replaced by 0 R2 groups.

9. A compound according to any one of claims 1 to 8, CHARACTERIZED in that R5 is selected from the group consisting of -NH(CO)CH3, -O(CO)CH3, -(CO)CH3, and -OCH2CH3.

10. Compound, according to claim 1, CHARACTERIZED in that the compound is selected from the group consisting of: Petition 870250054187, dated 06 / 27 / 2025, p. 121 / 127 5 / 9 Petition 870250054187, dated 06 / 27 / 2025, p. 122 / 127 6 / 9 NH SNSNSJJ NH NH NJ NH JJ OO NH NH FF HN HN NSNHSNOJ Petition 870250054187, dated 06 / 27 / 2025, p. 123 / 127 7 / 9 11. Compound, according to claim 10, CHARACTERIZED in that the compound is selected from the group consisting of: Petition 870250054187, dated 06 / 27 / 2025, pp. 124 / 127 8 / 9 Petition 870250054187, dated 06 / 27 / 2025, pp. 125 / 127 9 / 9 12. Compound according to claim 1, wherein the compound is CHARACTERIZED in that it is selected from the group consisting of the compounds in Table 6-1.

13. Compound according to claim 12, wherein the compound is CHARACTERIZED in that it inhibits MBD3L2 RNA production at 11 mM.

14. Compound according to claim 12 or 13, wherein the compound is CHARACTERIZED in that it has an EC50 for DUX4 <10 mM.

15. Compound according to claim 14, CHARACTERIZED in that the compound has an EC50 for DUX4 <1 mM.

16. Pharmaceutical composition CHARACTERIZED in that it comprises: the compound, as defined in any one of claims 1 to 15, and a pharmaceutically acceptable excipient, carrier or diluent.

17. Pharmaceutical composition according to claim 16, wherein the composition is characterized by the fact that it is an oral formulation.

18. Method for treating a patient CHARACTERIZED in that it comprises administering an effective treatment amount of a compound or composition, as defined in any one of claims 1 to 17.

19. Method according to claim 18, CHARACTERIZED in that the host is a human being. Petition 870250054187, dated 06 / 27 / 2025, pp. 126 / 127