JAK2 v617f inhibitors

Abstract

A compound having the following structure of Formula (I) or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R5, R6, n, and A are as defined herein. Pharmaceutical compositions comprising the compounds, and their use in methods of treating diseases are also described.

Description

[0001] PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0002] Attorney Docket: CGB-028WO

[0003] JAK2 V617F INHIBITORS

[0004] RELATED APPLICATIONS

[0005] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 700,398, filed September 27, 2024, and U.S. Provisional Application No. 63 / 800,998, filed May 6, 2025, each of which is incorporated herein by reference in their entirety.

[0006] TECHNICAL FIELD

[0007] The disclosure relates to substituted imidazopyrrolopyridine compounds that act as Janus kinase (JAK), in particular JAK2 V617F, inhibitors. The disclosure also provides compounds (e.g., a compound of Formula (I -XIII)) or pharmaceutically acceptable salts thereof and uses of the compounds, or pharmaceutically acceptable salts thereof, for the treatment of a disease, disorder, or condition associated with inhibiting an activity of the V617F variant of JAK2 kinase, e.g., cancer., in a subject.

[0008] BACKGROUND

[0009] Janus kinase (JAK) 2 is a non-receptor tyrosine kinase, which is associated with several cytokine receptor families. This interaction is vital for the proper functioning of the immune system and the regulation of blood cell production. Mutations in JAK2 can lead to various health conditions. For example, the JAK2 V617F mutation has been associated with several myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis. Broad-spectrum JAK2 inhibitors can affect normal JAK2 function, leading to side effects.

[0010] BRIEF SUMMARY

[0011] In brief, the present disclosure provides compounds, including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0012] In one aspect, a compound having a structure of Formula (I) is provided:

[0013] 1

[0014] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R5, R6, n, and

[0015] A are as defined herein.

[0016] In another aspect, a compound having a structure of Formula (II) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R5, R6, n, and A are as defined herein.

[0017] In another aspect, a compound having a structure of Formula (III) is provided: io or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R5, R6, n, and

[0018] A are as defined herein.

[0019] In another aspect, a compound having a structure of Formula (IV) is provided:

[0020] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R5, R6, n, and A are as defined herein.

[0021] In another aspect, a compound having a structure of Formula (V) is provided:

[0022] 5 or a pharmaceutically acceptable salt thereof, wherein variables R1, R2, R3, R4, and R5are as defined herein.

[0023] In another aspect, a compound having a structure of Formula (VI) is provided:

[0024] 10 or a pharmaceutically acceptable salt thereof, wherein variables R1, R2, R3, and R4are as defined herein.

[0025] 3

[0026] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0027] In another aspect, a compound having a structure of Formula (VII) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, R8, R9, R10, and Raare as defined herein.

[0028] 5 In another aspect, a compound having a structure of Formula (VIII) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R1, R4, and R8are as defined herein.

[0029] In another aspect, a compound having a structure of Formula (IX) is provided:

[0030] 10 or a pharmaceutically acceptable salt thereof, wherein variables R1, R2, R3, and R4are as defined herein.

[0031] 4

[0032] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0033] In another aspect, a compound having a structure of Formula (X) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R2, R3, R4, R11, R12, and n are as defined herein.

[0034] In another aspect, a compound having a structure of Formula (XI) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R4, R11, R13, n, and m are as defined herein.

[0035] In another aspect, a compound having a structure of Formula (XII) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R4, R14, R15, R16, and R17are as defined herein.

[0036] 5

[0037] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0038] In another aspect, a compound having a structure of Formula (XIII) is provided: or a pharmaceutically acceptable salt thereof, wherein variables R2, R3, R4, R9, R10, R11, R12, Ra, and n are as defined herein.

[0039] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula (I-XIII)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.

[0040] In another aspect, the disclosure provides a method of inhibiting an activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a compound disclosed herein (e.g., a compound of Formula (I-XIII)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein, e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I-XIII)) or a pharmaceutically acceptable salt thereof).

[0041] In another aspect, the disclosure provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I-XIII)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I-XIII)) or a pharmaceutically acceptable salt thereof.

[0042] Various aspects and embodiments now will be described more fully hereinafter. Such aspects and embodiments may take many different forms, and the exemplary ones disclosed herein should not be construed as limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0043] DETAILED DESCRIPTION

[0044] As generally described herein, the present disclosure provides compounds and compositions useful for preventing and / or treating a disease or condition described herein,

[0045] 6

[0046] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) e.g., a disease, disorder, or condition associated with inhibiting an activity of the V617F variant of JAK2 kinase, e.g., cancer.

[0047] I. Definitions

[0048] Chemical Definitions

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0050] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 332 25 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0051] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure

[0052] 7

[0053] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0054] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0055] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an”

[0056] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0057] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, c5, c6, C1-6, Ci-5, Ci-4, Ci-3, Ci-2, C2-6, C2-5, C2-1, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs 6 alkyl.

[0058] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0059] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carboncarbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”).

[0060] As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carboncarbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”).

[0061] As used herein, “alkylene,” refers to a divalent radical of an alkyl. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0062] As used herein, “alkenylene,” refers to a divalent radical of an alkenyl.

[0063] 9

[0064] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0065] As used herein, “alkynylene,” refers to a divalent radical of an alkynyl.

[0066] As used herein, "alkoxyl" or "alkoxy" refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.

[0067] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl).

[0068] As used herein, “phenylene,” refers to a divalent radical of a phenyl.

[0069] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0070] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10

[0071] 10

[0072] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0073] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothi azolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0074] Examples of representative heteroaryls include the following:

[0075] 11

[0076] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, Ci-Cs alkyl, C3-C10 carbocyclyl, 4-10 membered heterocyclyl, Ce- C10 aryl, and 5-10 membered heteroaryl.

[0077] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).

[0078] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.

[0079] As used herein, “cycloalkylene,” refers to a divalent radical of a cycloalkyl. “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0080] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0081] “Deuterohaloalkyl” refers to an alkyl group where 1 or more hydrogen atoms of a haloalkyl are replaced with deuterium.

[0082] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. In some embodiments, the bicyclic heterocyclyl is a fused or spiro ring system. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl or cycloalkyl groups wherein the point of attachment is either on the carbocyclyl, cycloalkyl, or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring or aryl, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0083] In some embodiments, a heterocyclyl group is a 3-12 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-12 membered heterocyclyl”). In some embodiments, the 3-12 membered heterocyclyl has 1-4 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 3-12 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 3-12 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 3-12 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered

[0085] 13

[0086] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0087] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0088] As used herein, “heterocyclylene,” refers to a divalent radical of a heterocyclyl.

[0089] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen,

[0090] 14

[0091] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g.,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0092] As used herein, “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0093] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.

[0094] As used herein, “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms.

[0095] As used herein, “oxo” refers to -C=O.

[0096] In general, the term “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g, a carbon or nitrogen atom) is replaced with a permissible substituent, e.g, a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0097] Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0098] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group (such as an alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) are independently, for example, halogen; -(CH2)o-4R0; -(CH2)o-40R°; -0-(CH2)o-4C(0)OR°; -(CH2)o-4CH(OR°)2;

[0099] -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh, which may be substituted with R°; -CH=CHPh, which may be substituted with -NO2; -CN; -N3; - (CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(0)R°; -N(R°)C(S)R°;

[0100] -(CH2)O-4N(R°) C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)O-4N(R°)C(0)OR°; -N(R°)N(R°) C(O)R°; -N(R°)N(R°)C(0)NR°2; -N(R°)N(R°)C(0)0R°; -(CH2)O-4C(0)R°; -C(S)R°;

[0101] 15

[0102] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0103] -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)o-4C(0)OSiR°3; -(CH2)o-40C(0)R°;

[0104] -OC(0)(CH2)O-4SR°-, SC(S)SR°; -(CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -(CH2)O-4OC(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O-4OS(0)2R°;

[0105] -S(O)2NR°2; -(CH2)O-4S(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(N H)NRO2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; -SiRa; -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, where each R° may be substituted as defined below and is independently hydrogen, Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0106] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently, for example, deuterium, halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o-2OR*, -(CH2)O-2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)o-2C(0)R*, -(CH2)o-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*,

[0107] -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR*, where each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, -CHzPh, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0108] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where each independent occurrence of R* is selected from hydrogen, Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected 16

[0109] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(C(R*)2)2-3O-, where each independent occurrence of R* is selected from hydrogen, Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0110] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, where each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, -CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -:, -NR:'2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; where each R:is independently hydrogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, it should be understood that a substitutable nitrogen can be substituted with four substituents (or have four bonds to less than four substituents) such that the nitrogen atom will be positively charged or its cation, i.e., N+. Such substitution of a substitutable nitrogen can be of a ring nitrogen, for example, a ring nitrogen of a heterocyclic group containing nitrogen as a ring atom. In particular embodiments, where one of the substituents of a cationic nitrogen atom is a hydroxyl group, the hydroxyl group can be deprotonated and represented by a negatively charged oxygen atom, i.e., O'. In such cases, a general formula for the substitution can be represented by RN+(0')(R’)R”, where R, R’ and R” represent carbon or other atoms, groups and / or moieties to which the nitrogen atom is bound.

[0112] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R:are independently, for example, halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*),

[0113] 17

[0114] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0115] -CN, -C(O)OH, -C(O)OR , -NH2, -NHR*, -NR% or -NO2, where each R is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, -CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0116] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0117] Other Definitions

[0118] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. Also contemplated are embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. Also contemplated are embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0119] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0120] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0121] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0122] The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” are used interchangeably herein and refer to buffers, carriers, and excipients

[0123] 18

[0124] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g. Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23 d ed. 2020).

[0125] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19, and Gould, Salt selection for basic drugs, International Journal of Pharmaceutics, 33 (1986) 201-217. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when

[0126] 19

[0127] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0128] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0129] Disease, disorder, and condition are used interchangeably herein.

[0130] As used herein, “treat”, “treating”, and “treatment” refer to the treatment of a disease, disorder, or symptom or manifestation of such in a subject, e.g., in a human, for instance, in reference, for example, to methods of treating a disease, disorder, or condition associated with inhibiting an activity of the V617F variant of JAK2 kinase, e.g., cancer, in a subject. This generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition (e.g., cancer) in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition. In the case of oncology, “treating” can be ameliorative (slowing or reducing symptoms) or curative (reversing or eliminating symptoms).

[0131] As used herein, “prevent”, “preventing” and “prevention” refer to causing a disease, disorder, or symptom or manifestation of such not to occur for at least a period of time in at least some subjects.

[0132] The term “effective amount” as used herein refers to the amount of a compound, e.g., a compound or composition described herein, sufficient to elicit a beneficial or desired result or biological effect. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound or composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0133] 20

[0134] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0135] For example, an effective amount may be an amount of a compound or composition sufficient to achieve one or more of the following: (i) modulate an activity of the V617F variant of JAK2 kinase, (ii) modulate an activity of JAK2, or (ii) treat or prevent a disease or condition associated with the V617F variant of JAK2 kinase, e.g., cancer, or a symptom or manifestation thereof.

[0136] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. As will be appreciated by those of ordinary skill in this art, a therapeutically effective amount of a compound or composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A therapeutically effective amount of a compound or composition can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. A therapeutically effective amount of a compound or composition also includes an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. In addition, a therapeutically effective amount can encompass an amount of a compound or composition that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0137] At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0138] Throughout the description, where compounds or compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compounds or compositions of the present invention that consist

[0139] 21

[0140] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. Similarly, throughout the description, where compounds or compositions are described as consisting essentially of specific components, or where processes and methods are described as consisting essentially of specific steps, it is contemplated that, additionally, there are compounds or compositions of the present invention that consist of the recited components, and that there are processes and methods according to the present invention that consist of the recited processing steps.

[0141] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0142] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0143] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0144] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional

[0145] 22

[0146] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0147] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0148] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0149] The claims encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0150] IL Compounds

[0151] The compounds described herein are JAK inhibitors, in particular, JAK2 V617F inhibitors. In one aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0152] A is selected from the group consisting of -C3 and -C5-10 cycloalkylene, RA-3-12 membered heterocyclylene, and phenylene, wherein RAis a bond or O;

[0153] R1is selected from the group consisting of hydrogen, -C2-6 alkynyl, halo, Rla-(3-12

[0154] 23

[0155] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) membered heterocyclyl), -C3-10 cycloalkyl, 5-10 membered heteroaryl, and phenyl optionally fused to C3-8 cycloalkyl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, -C2-6 alkynyl, 5-10 membered heteroaryl, and C3-8 cycloalkyl are optionally substituted with 1, 2, 3, or 4 Rlb, wherein R1is not one of the following groups:

[0156] Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene;

[0157] 10 each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, oxo, -C(O)(Ci-6 alkyl), -OH, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, phenyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), - OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl),-O- (C3-10 cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents

[0158] 20 each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy; each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkyl-O(Ci-6 alkyl), -Ci-6alkylene-C(O)ORa, -C(O)ORa, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6

[0159] 25 alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl),- -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered

[0160] 24

[0161] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) heteroaryl), -0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl),-0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, -CN, and - Ci -6 alkoxy;

[0162] R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -Ci- 6 alkoxy, -C1-6 haloalkoxy, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, and -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo; wherein R6is not hydrogen when R1is hydrogen;

[0163] R6ais bond or -C1-6 alkylene;

[0164] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -C1-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), - NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(C2-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -C(0)NRa(C3-io cycloalkyl), - NRaS(O)2(Ci-6 alkyl), -NRa(Ci-6 haloalkyl), (C1-6 alkylene)-NRaC(O)O(Ci-6 alkyl), (C1-6 alkylene)-NRaC(0)(C3-io cycloalkyl), -OC(O)N(Ra)2, -C(O)N(Ra)2, -NRaC(0)N(Ra)2, - N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, -C1-6 haloalkyl and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; n is 0, 1, 2, or 3, wherein when A is cyclopentyl, n is 1, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

[0165] In another aspect, provided is a compound of Formula (II):

[0166] 25

[0167] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0168] A is selected from the group consisting of: C3-5 and C7-10 cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein RAis a bond or O;

[0169] R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;

[0170] Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;

[0171] R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is 26 IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -Ci-6 alkyl, halo, -Ci-6 haloalkyl, -Ci-6 deuteroalkyl, -Ci-6 deuterohaloalkyl, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, wherein R6is not hydrogen when R1is hydrogen;

[0172] 5 R6ais bond or -C1-6 alkylene;

[0173] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, oxo, -C1-6 alkoxy, halo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), - NRaC(O)O(C2-6 alkyl), -N(CI-6 alkyl)C(O)O(methyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(Ci-6

[0174] 10 alkenyl), -NRaC(0)(C3-io cycloalkyl), -C(0)NRa(C3-io cycloalkyl), -NRaS(O)2(Ci-6alkyl), NRa(Ci-6 haloalkyl), (Ci-6alkylene)-NRaC(0)(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), (Ci-6alkylene)-NRaC(O)O(Ci-6 alkyl), -0C(0)N(Ra)2, -C(0)N(Ra)2, - NRaC(0)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-io cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, C1-6 haloalkyl, and -C1-6 haloalkoxy, wherein the -C3-io cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl, and wherein when A is C4 cycloalkylene, R5is not -NRaC(O)O(ethyl) or -N(Ra)2; n is 0, 1, 2, or 3, wherein when A is cyclopentyl or RA-3-12 membered

[0175] 20 heterocyclylene, n is 1, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

[0176] In another aspect provided is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein:

[0177] 25 A is selected from the group consisting of: C3-4 and Ce-io cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein

[0178] 27

[0179] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0180] RAis a bond or O;

[0181] R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;

[0182] Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-ealkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;

[0183] R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -Ci- 6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, wherein R6is not hydrogen when R1is hydrogen;

[0184] R6ais bond or -C1-6 alkylene;

[0185] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -C1-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), - NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(Ci-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), -C(0)NRa(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -

[0186] 28

[0187] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0188] NRaS(O)2(Ci-6 alkyl), NRa(Ci-6 haloalkyl), (Ci-6alkylene)-NRaC(0)(C3-io cycloalkyl), (Ci-6 alkylene)-NRaC(O)O(Ci-6alkyl), -0C(0)N(Ra)2, -C(0)N(Ra)2, -NRaC(0)N(Ra)2, - N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -Ci-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, C1-6 haloalkyl, and -C1-6 haloalkoxy, wherein -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; wherein: when n is 2 and one R5is methyl, the other R5is selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -C1-6 alkoxy, -N(Ra)2, -NRaC(O)O(Ci-6 alkyl), -NRa(Ci-6 haloalkyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(C4-8 cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -NRaS(O)2(Ci-6 alkyl), (Ci-6alkylene)-NRaC(0)(C3-io cycloalkyl), - OC(O)N(Ra)2, -NRaC(0)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy; or the other wherein R6bis selected from the group consisting of: halo, -C1-6 alkyl, -C1-6 haloalkyl and -CN; wherein one R6cis -C1-6 alkoxy and the other R6cis hydrogen or each R6cis selected from halogen, -C1-6 alkyl, and -C1-6 alkoxy, wherein when A is C4 cycloalkylene, R5is not -NRaC(O)O(ethyl) or -N(Ra)2; n is 0, 1, 2, or 3, wherein when A is RA-3-12 membered heterocyclylene, n is 1, 2, or

[0189] 3; and each Rais independently hydrogen or -C1-6 alkyl.

[0190] In another aspect, provided is a compound of Formula (IV):

[0191] 29

[0192] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0193] A is selected from the group consisting of: C3 and C5-10 cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein RAis a bond or O;

[0194] R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;

[0195] Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;

[0196] R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is 30 IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -Ci- 6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and - N(Ra)2, , wherein R6is not hydrogen when R1is hydrogen and wherein the 5-6 membered heteroaryl is not one of the following groups: each R2is independently selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and -Ci-6 deuterohaloalkyl; each R3is independently selected from the group consisting of hydrogen, -CN, halo, - Ci-6 alkyl, -Ci-6 haloalkyl, -Ci-6 alkoxy, and -C3-10 cycloalkyl;

[0197] R3ais selected from the group consisting of -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, and -C1-6 alkoxy;

[0198] R3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl;

[0199] R6ais bond or -C1-6 alkylene;

[0200] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -C1-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), - NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(Ci-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), -C(0)NRa(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), - NRaS(O)2(Ci-6alkyl), NRa(Ci-6 haloalkyl), (Ci-6alkylene)-NRaC(0)(C3-io cycloalkyl), (C1-6 alkylene)-NRaC(O)O(Ci-6alkyl), -OC(O)N(Ra)2, -C(O)N(Ra)2, -NRaC(0)N(Ra)2, - N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group

[0201] 31

[0202] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) consisting of: halo, -OH, -C1-6 alkoxy, C1-6 haloalkyl, and -C1-6 haloalkoxy, wherein the -Oslo cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; n is 0, 1, 2, or 3, wherein when A is cyclopentyl or RA-3-12 membered heterocyclylene, n is 1, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

[0203] In some embodiments, A is selected from cyclopentyl ene, cyclohexylene, and 3-12 membered heterocyclylene. In some embodiments, A is selected from cyclopentylene, cyclohexylene, and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene. In some embodiments, A is selected from cyclopentyl ene and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene. In some embodiments, A is selected from cyclohexylene and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene.

[0204] In some embodiments, A is cyclopentylene or cyclohexylene. In some embodiments, A is cyclopentylene. In some embodiments, A is cyclohexylene. In some embodiments, A is 3-12 membered heterocyclylene. In some embodiments, A is 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene. In some embodiments, A is 10-membered heterocyclylene. In some embodiments, A is:

[0205] In some embodiments, R1is selected from the group consisting of: 3-12 membered heterocyclyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, phenyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is not indazolyl or dihydrobenzofuranyl. In some embodiments, R1is 3-12 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is phenyl optionally fused to C3-8 cycloalkyl, wherein the phenyl and C3-8 cycloalkyl are optionally substituted with 1, 2, 3, or 4 Rlb.

[0206] In some embodiments, R1is phenyl optionally fused to C3-8 cycloalkyl, wherein the phenyl is substituted with 1 Rlcand 0, 1, 2, or 3 Rlband C3-8 cycloalkyl is optionally substituted with 1, 2, 3, or 4 Rlb, wherein each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkyl-O(Ci-6 alkyl), -Ci-ealkylene-C(O)ORa, - C(O)ORa, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io

[0207] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) cycloalkyl), -NHS(0)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci- 6 alkyl),- -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered

[0208] 5 heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, -CN, and -C1-6 alkoxy.

[0209] In some embodiments, R1is selected from the group consisting of:

[0210] 10

[0211] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0212] In some embodiments, R1is selected from the group consisting of:

[0213] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0214] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0215] In some embodiments, R4is -C1-3 alkyl or -C1-3 deuteroalkyl. In some embodiments, R4is -C1-3 alkyl. In some embodiments, R4is -C1-3 deuteroalkyl. In some embodiments, R4is methyl or -CD3. In some embodiments, R4is methyl. In some embodiments, R4is -CD3.

[0216] In some embodiments, each R5is selected from the group consisting of: - NRaC(O)O(Ci-6alkyl), -NRaC(O)(C2-6 alkenyl), -C1-6 alkyl, -NRaC(O)(3-10 membered heterocyclyl), -NRaC(0)(C3-io cycloalkyl), NRaC(O)(Ci-6 alkyl), and oxo, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, or -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with -C1-6 alkyl.

[0217] In some embodiments, each R5is selected from the group consisting of: - NHC(O)O(methyl), -NHC(O)O(ethyl), -NHC(O)O(isopropyl), -NRaC(O)(C2alkenyl), methyl, -NHC(O)(cyclopropyl), NRaC(O)(methyl), NRaC(O)(ethylene-OH), - NHC(O)(oxetanyl), and oxo, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy, wherein the methyl, ethyl, or isopropyl is optionally substituted with -OH.

[0218] In some embodiments, the -NHC(O)(cyclopropyl) optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -Ci-6 alkyl, halo, - OH, -Ci-6 alkoxy, and -Ci-6 haloalkoxy is selected from the group consisting of:

[0219] In some embodiments, when n is 2, one R5is methyl, and the other R5is selected from the group consisting of:

[0220] 36

[0221] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0222] In some embodiments, when n is 2, one R5is methyl, and the other R5is wherein R6bis selected from the group consisting of: halo, -C1-6 alkyl, -

[0223] Ci-6 haloalkyl and -CN; wherein one R6cis -Ci-6 alkoxy and the other R6cis hydrogen or each

[0224] R6Cis selected from halogen, -Ci-6 alkyl, and -Ci-6 alkoxy.

[0225] In some embodiments, when n is 2, one R5is methyl, and the other R5is

[0226] In some embodiments, R5is -NHC(0)0(m ethyl). In some embodiments, R5is - NRaC(O)O(C2-6 alkyl), wherein the -C2-6 alkyl is optionally substituted with -OH. In some embodiments, R5is -NHC(O)O(ethyl) or -NHC(O)O(isopropyl), wherein the ethyl or isopropyl is optionally substituted with -OH. In some embodiments, R5is -NHC(O)O(ethyl), wherein the ethyl is optionally substituted with -OH. In some embodiments, R5is - NHC(O)O(isopropyl), wherein the isopropyl is optionally substituted with -OH.

[0227] In some embodiments, R6is selected from: wherein: each of R2and R3is independently selected from the group consisting of: hydrogen, - Ci-6 alkyl, halo, -Ci-6 haloalkyl, -Ci-6 deuteroalkyl, -Ci-6 deuterohaloalkyl, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2; and

[0228] R3ais selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2; or

[0229] (b) -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH,

[0230] 37

[0231] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2.

[0232] In some embodiments, R6is selected from:

[0233] R2ais -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo,

[0234] R3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl, each of R2and R3is independently selected from the group consisting of: hydrogen, -

[0235] C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2; and

[0236] R3ais selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2; or

[0237] (b) -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2.

[0238] In some embodiments, R6is selected from:

[0239] R2ais -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo;

[0240] 38

[0241] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) each R2is independently selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and -Ci-6 deuterohaloalkyl; each R3is independently selected from the group consisting of hydrogen, -CN, halo, - Ci-6 alkyl, -Ci-6 haloalkyl, -Ci-6 alkoxy, and -C3-10 cycloalkyl;

[0242] R3ais selected from the group consisting of -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, and -C1-6 alkoxy; and

[0243] R3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl; or

[0244] (b) C3-10 cycloalkyl.

[0245] In some embodiments, R6is selected from:

[0246] R2is -C1-6 alkyl or -C1-6 deuteroalkyl; and

[0247] R3is halo or -C1-6 alkoxy; or

[0248] (b) C3-8 cycloalkyl.

[0249] In some embodiments, R6is selected from:

[0250] R2is -C1-6 alkyl or -C1-6 deuteroalkyl; and

[0251] R3is halo; or

[0252] (b) C3-8 cycloalkyl.

[0253] In some embodiments, R6is selected from the group consisting of:

[0254] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0255] In some embodiments, R6is selected from the group consisting of:

[0256] In some embodiments, R6is selected from the group consisting of:

[0257] In some embodiments, R6is selected from the group consisting of:

[0258] In some embodiments, R6is selected from the group consisting of:

[0259] In some embodiments, R6is -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2.

[0260] In some embodiments, R6is -C3-8 cycloalkyl. In some embodiments, R6is:'^^^.

[0261] In some embodiments, n is 0, 1, or 2.

[0262] In some embodiments, Rais hydrogen. In some embodiments, Rais -C1-6 alkyl. In some embodiments, Rais methyl.

[0263] In another aspect, provided is a compound of Formula (V):

[0264] 40

[0265] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0266] R1is selected from the group consisting of:

[0267] 5 R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl; each R5is independently selected from the group consisting of: hydrogen, halo, -Ci-6 alkyl, -CN, -Ci-6 haloalkyl, -OH, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;

[0268] R2is selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and -Ci-6 deuterohaloalkyl; and

[0269] 10 R3is selected from the group consisting of halo, -Ci-6 alkyl, and -Ci-6 alkoxy.

[0270] In some embodiments, the compound is of Formula (Va): pharmaceutically acceptable salt thereof.

[0271] In another aspect, provided is a compound of Formula (VI):

[0272] 41

[0273] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0274] R1is selected from the group consisting of:

[0275] 42

[0276] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0277] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: hydrogen, -C1-6 alkyl,

[0278] -Ci-6 haloalkyl, -OH, -CN, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;

[0279] 5 R2is selected from the group consisting of -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, and -Ci-6 deuterohaloalkyl; and

[0280] R3is selected from the group consisting of halo, -Ci-6 alkyl, -Ci-6 alkoxy, and -Ci-6 haloalkoxy.

[0281] In some embodiments, the compound is of Formula (Via): io pharmaceutically acceptable salt thereof.

[0282] In another aspect, provided is a compound of Formula (VII): pharmaceutically acceptable salt thereof, wherein:

[0283] R1is selected from the group consisting of: 5-10 membered heteroaryl, phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12

[0284] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) membered heteroaryl, and 5-10 membered heteroaryl fused to 4-12 membered heterocyclyl, wherein the 5-10 membered heteroaryl, C3-8 cycloalkyl, 4-12 membered heterocyclyl, and 4-12 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb, and wherein when the phenyl is not fused to C3-8 cycloalkyl or 4-12 membered heterocyclyl or 4-12 membered heteroaryl, the phenyl is substituted with 1 Rlcand 0, 1, 2, or 3 Rlb, and wherein when the phenyl is fused to C3-8 cycloalkyl or 4-12 membered heterocyclyl or 4-12 membered heteroaryl, the phenyl is optionally substituted with 0, 1, 2, or 3 Rlb; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, Ci-4 heteroalkyl, -C1-6 haloalkyl, oxo, -C(O)(Ci-6 alkyl), -OH, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-ealkylene-C(O)ORa, Ci-4 alkylene-CN, - C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), - S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, - C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, phenyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3- 10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O-(Ci-6 alkylene)-(3-10 membered heterocyclyl), -S-(3-10 membered heterocyclyl), -S-(C3-io cycloalkyl), -S-(5-6 membered heteroaryl), and -S-(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy; wherein each Rais independently hydrogen, -C1-6 alkyl, -C1-6 deuteroalkyl, and -C1-6 haloalkyl; wherein Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; wherein k is 1 or 2, each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkoxy, -C1-6 alkyl-O(Ci-6 alkyl), -Ci-ealkylene-C(O)ORa, Ci-4 alkylene-CN, -C(O)ORa, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci- 6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered

[0285] 44

[0286] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), -S-(3-10 membered heterocyclyl),-S-(C3-io cycloalkyl), -S-(5-6 membered heteroaryl), and -S-(Ci-6 alkylene)-(3- 10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, - C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, - CN, and -C1-6 alkoxy;

[0287] R4is -C1-6 alkyl or -C1-6 deuteroalkyl;

[0288] R8is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to C3-8 cycloalkyl, 5-6 membered heteroaryl fused to 4-12 membered heterocyclyl, 5-6 membered heteroaryl fused to 4-12 membered heteroaryl, R8a-(3-10 membered heterocyclyl), phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12 membered heteroaryl, wherein the -C3-8 cycloalkyl, -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, 4-12 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -OH, halo, oxo, -CN, -N(Ra)2, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C2- 6 alkenyl, -C2-6 alkynyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -O-(Ci-6 alkyl), -O-(C 1-6 alkyl ene)-O- (C1-6 alkyl), -O-(C2-6 alkenyl), -O-(C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), -(Ci- e alkylene)-O-(Ci-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkylene)-(C3-io cycloalkyl), -(C1-6 alkylene)-(3-10 membered heterocyclyl), -(C1-6 alkylene)-(5-6 membered heteroaryl), or -(C1-6 alkylene)-(phenyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, - (C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(O)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl;

[0289] R8ais bond, -C(O)-, -C1-6 alkylene, -C2-6 alkenylene, -C2-6 alkynylene, -(C2-6 alkynylene)-(Ci-6 alkylene), -(C2-6 alkenylene)-(Ci-6 alkylene), -(C2-6 alkylene)-(Ci-6 alkynylene), -(C2-6 alkylene)-(Ci-6 alkenylene), wherein the -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH;

[0290] R9is independently selected from the group consisting of: H, D, -C1-6 alkyl, -C1-6 deuteroalkyl, -OH, -C1-6 alkoxy, -(C1-6 alkyl)-O-(Ci-6 alkyl), wherein the -C1-6 alkyl and -C1-6

[0291] 45

[0292] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) alkoxy are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH;

[0293] R10is independently selected from the group consisting of: -OH, -N(Ra)2, -(Ci-6 alkyl), -(C2-6 alkenyl), -(C2-6 alkynyl), -O(Ci-6 alkyl), -O-(Ci-6 alkylene)-O-(Ci-6 alkyl), - O(C2-6 alkenyl), -O(C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), -(C1-6 alkylene)-O- (C1-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, -Ci- 6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(O)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl, wherein when R10is -(Cs-cycloalkyl) and R8is substituted with halo, Ci-

[0294] 6 alkoxy, or C1-6 alkyl, then R1is not phenyl or indazolyl optionally substituted with 1 or 2 substituents that are C1-6 alkyl, C1-6 alkoxy, or deuterated C1-6 alkyl.

[0295] In some embodiments, R1is phenyl not fused to C3-8 cycloalkyl or 4-12 membered heterocyclyl, and the phenyl is substituted with 1 Rlcand optionally substituted with 0, 1, 2, or 3 Rlb. In some embodiments, Rlcis -C1-6 alkoxy. In some embodiments, Rlcis -C1-3 alkoxy. In some embodiments, Rlcis -Ci alkoxy. In some embodiments, R1is phenyl optionally substituted with 0, 1, 2, or 3 Rlbeach independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, oxo, -C(O)(Ci-6 alkyl), -OH, - CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -N(Ra)2, 3-10 membered heterocyclyl, phenyl, and -C3-10 cycloalkyl, wherein the -C1-6 alkyl, -C1-6 alkoxy, -N(Ra)2, 3-10 membered heterocyclyl, phenyl, and -C3-10 cycloalkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, -D, Ci-4 deuterohaloalkyl, Ci-4 heteroalkyl, oxo, CN, Ci-4 alkylene-CN, C1-3 alkylalcohol, (Ci-4 alkylene)-O-(Ci-4 alkyl), halo, hydroxyl, -C(=O)-Ci-3 alkyl, -N(Ra)2, wherein each Ra is independently selected from the group consisting of: hydrogen, -Ci-4 alkyl, -C1-4 deuteroalkyl, and -Ci-4 haloalkyl;

[0296] In some embodiments, R1is phenyl fused to C3-8 cycloalkyl, and the C3-8 cycloalkyl is optionally substituted.

[0297] In some embodiments, R1is phenyl fused to 4-12 membered heterocyclyl, and the 4- 46

[0298] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0299] 12 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is phenyl fused to 4-12 membered heterocyclyl, and the phenyl is optionally substituted with 1, 2, or 3 Rlb, and the 4-12 membered heterocyclyl is optionally substituted with 1, 2, or 3 Rlb. In some embodiments, the optionally substituted 4-12 membered

[0300] 5 heterocyclyl is an optionally substituted 5-6 membered heterocyclyl. In some embodiments,

[0301] H the 5-6 membered heterocyclyl is selected from the group consisting of:

[0302] In some embodiments, R1is 5-10 membered heteroaryl fused to 4-12 membered heterocyclyl, wherein the 4-12 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is 5-6 membered heteroaryl fused to a 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 Rlb. In some embodiments, R1is a 5- membered heteroaryl fused to a 6 membered heterocyclyl.

[0303] In some embodiments, R1is selected from the group consisting of:

[0304] 15 , each optionally substituted. In some

[0305] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) , wherein the phenyl is optionally substituted each independently with 1, 2, or

[0306] 3 Rlband the fused heterocyclyl is optionally substituted each independently with 1, 2, or 3

[0307] 5 optionally substituted each independently with Ci alkyl and / or F, and the fused heterocyclyl is optionally substituted each independently with 1, 2 or 3 substituents selected from the group consisting of Ci alkyl, cyclopropyl, and halo. In some embodiments, R1is selected from the group consisting of: , wherein the phenyl fused to the heterocyclyl can be optionally substituted with 1, 2, or 3 substituents that are Ci alkyl and F.

[0308] In some embodiments, R8is 5-6 membered heteroaryl, phenyl, or phenyl fused to 4-

[0309] 48

[0310] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0311] 12 membered heterocyclyl, wherein the phenyl, 5-6 membered heteroaryl, or 4-12 membered heterocyclyl or is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -OH, oxo, -CN, -N(Ra)2, -Ci-6 alkyl, -Ci-6 haloalkyl, -Ci-6 deuteroalkyl, -Ci-6 deuterohaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -O-(Ci-6 alkyl), - O-(Ci-6alkyl)-O-(Ci-6alkyl), -O-(C2-6 alkenyl), -O-(C2-6 alkynyl), -O-(Ci-6 alkyl)-0-(C3-io cycloalkyl), -(C1-6 alkyl)-O-(Ci-6 alkyl), -(C1-6 alkyl)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkyl)-(C3-io cycloalkyl), -(C1-6 alkyl)-(3-10 membered heterocyclyl), -(C1-6 alkyl)-(5-6 membered heteroaryl), or -(C1-6 alkyl)-(phenyl), wherein the - C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, -(C2-6 alkenyl), -(C2-6 alkynyl), - C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(C 1-6 alkyl), - C(O)N(Ra)2, - N(Ra)C(O)(Ci-6 alkyl. In some embodiments, R8is 5-6 membered heteroaryl substituted with 1 or 2 substituents selected from F and -CH3. In some embodiments, R8is 5-6 membered heteroaryl or phenyl substituted with 1 substituent selected from the group consisting of: -O-

[0312] (C1-6 alkyl), -O-(Ci-6 alkyl)-O-(Ci-6 alkyl), -O-(C2-6 alkenyl), -O-(C2-6 alkynyl), -O-(Ci-6 alkyl)-0-(C3-io cycloalkyl), -(C1-6 alkyl)-O-(Ci-6 alkyl), -(C1-6 alkyl)-0-(C3-io cycloalkyl), - (C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkyl)-(C3-io cycloalkyl), -(C1-6 alkyl)-(3-10 membered heterocyclyl), -(C1-6 alkyl)-(5-6 membered heteroaryl), or -(C1-6 alkyl)-(phenyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, - (C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(O)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl. In some embodiments, R8is selected from the

[0313] 49

[0314] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0315] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0316] In some embodiments, R9is -C1-3 alkyl, -OH, -C1-3 alkoxy, or -(C1-3 alkyl)-O-(Ci-3 alkyl), wherein the -C1-3 alkyl and -C1-3 alkoxy are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: halo, -D, and -OH. In some embodiments, R9is -C1-3 alkyl optionally substituted with 1, 2, or 3 F. In some embodiments, R9is -C1-3

[0317] VOH

[0318] In some embodiments, in Formula (VII), R10is -N(Ra)2, -(C1-3 alkyl), -O-(Ci-3 alkyl), - O-(Ci-3 alkyl)-O-(Ci-3 alkyl), -O-(Ci-3 alkyl)-O-(C3-5 cycloalkyl), -(C1-3 alkyl)-O-(Ci-3 alkyl),

[0319] 15 -(C1-3 alkyl)-O-(C3-5 cycloalkyl), -(C3-5 cycloalkyl), -(3-6 membered heterocyclyl), wherein the -C1-3 alkyl, -C3-5 cycloalkyl, or 3-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting

[0320] 51

[0321] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) of: F, CN, -OH, -N(Ra)2, -Ci-6 alkyl, -(C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl and -C1-6 haloalkoxy, -C(O)(Ci-3 alkyl), -C(O)N(Ra)2, -N(Ra)C(O)(Ci-3 alkyl); and wherein Rais independently hydrogen, -C1-3 alkyl, -C1-3 deuteroalkyl, and -C1-3 haloalkyl.

[0322] In some embodiments, in Formula (VIII), R10is -N(Ra)2, -(C1-3 alkyl), -O-(C2-3 alkyl), -O-(Ci-3 alkyl)-O-(Ci-3 alkyl), -O-(Ci-3 alkyl)-O-(C3-5 cycloalkyl), -(C1-3 alkyl)-O-(Ci-3 alkyl), -(C1-3 alkyl)-O-(C3-5 cycloalkyl), -(C3-5 cycloalkyl), -(3-6 membered heterocyclyl), wherein the -C1-3 alkyl, -C3-5 cycloalkyl, or 3-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: F, CN, -OH, -N(Ra)2, -C1-6 alkyl, -(C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl and -C1-6 haloalkoxy, -C(O)(Ci-3 alkyl), -C(O)N(Ra)2, -N(Ra)C(O)(Ci-3 alkyl); and wherein Rais independently hydrogen, -C1-3 alkyl, -C1-3 deuteroalkyl, and -C1-3 haloalkyl.

[0323] In some embodiments, R10is selected from the group consisting of:

[0324] In some embodiments, the compound is of Formula (Vila): (Vila), or a pharmaceutically acceptable salt thereof.

[0325] In another aspect, provided is a compound of Formula (VIII):

[0326] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0327] R1is selected from the group consisting of: R1is selected from the group consisting of:

[0328] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0329] R4is -C1-6 alkyl or -C1-6 deuteroalkyl; and

[0330] R8is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to C3-8 cycloalkyl, 5-6 membered heteroaryl fused to 4-12 membered heterocyclyl, 5-6 membered heteroaryl fused to 4-12 membered heteroaryl, R8a-(3-10 membered heterocyclyl), phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12 membered heteroaryl, wherein the -C3-8 cycloalkyl, -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, 4-12 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -OH, halo, oxo, -CN, -N(Ra)2, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C2- 6 alkenyl, -C2-6 alkynyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -O-(Ci-6 alkyl), -O-(C 1-6 alkyl ene)-O- (C1-6 alkyl), -O-(C2-6 alkenyl), -O- (C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), - (Ci-e alkylene)-O-(Ci-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkylene)-(C3-io cycloalkyl), -(C1-6 alkylene)-(3-10 membered heterocyclyl), -(C1-6 alkylene)-(5-6 membered heteroaryl), or -(C1-6 alkylene)-(phenyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, - (C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(0)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl, wherein each Rais independently selected from the group consisting of: hydrogen, -Ci-4 alkyl, -Ci-4 deuteroalkyl, and -Ci-4 haloalkyl; and

[0331] R8ais bond, -C(O)-, -C1-6 alkylene, -C2-6 alkenylene, -C2-6 alkynylene, -(C2-6 alkynylene)-(Ci-6 alkylene), -(C2-6 alkenylene)-(Ci-6 alkylene), -(C2-6 alkylene)-(Ci-6 alkynylene), -(C2-6 alkylene)-(Ci-6 alkenylene), wherein the -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH,

[0332] 54

[0333] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) wherein when R1is phenyl, indazolyl, or dihydroisobenzofuranyl and R8is 5-6 membered heteroaryl, then R8is -(Ci-6 alkylene)-(3-10 membered heterocyclyl), -(Ci-6 alkylene)-(5-6 membered heteroaryl), or -(Ci-6 alkylene)-(phenyl), each optionally substituted, and wherein when R1is phenyl, indazolyl, dihydrobenzofuranyl, or dihydroisobenzofuranyl, then R8cannot be a phenyl substituted with the following: - C(0)N(Ra)2, -Ci-6 alkyl substituted with -N(Ra)2, -(Ci-6 alkylene)-(3-10 membered nitrogencontaining heterocyclyl), or -C(O)-(3-10 membered nitrogen-containing heterocyclyl).

[0334] In some embodiments, the compound is of Formula (Villa): (Villa), or a pharmaceutically acceptable salt thereof.

[0335] In another aspect, provided is a compound of Formula (IX): or a pharmaceutically acceptable salt thereof, wherein:

[0336] R1is selected from the group consisting of: each optionally substituted with 1, 2, 3 or 4 substituents

[0337] 55

[0338] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) selected from: D, -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, -OH, oxo, -CN, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;

[0339] R2is selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and -Ci-6 deuterohaloalkyl;

[0340] 5 R3is selected from the group consisting of halo, -Ci-6 alkyl, and -Ci-6 alkoxy; and

[0341] R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl.

[0342] In some embodiments, R1is selected from the group consisting of:

[0343] In some embodiments, R2is -CH3. In some embodiments, R3is F.

[0344] In some embodiments, the compound is of Formula (IXa): pharmaceutically acceptable salt thereof.

[0345] In another aspect, provided is a compound of Formula (X):

[0346] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein:

[0347] R2is selected from the group consisting of: hydrogen, D, Ci-6 alkyl, Ci-6 deuteroalkyl, Ci-6 haloalkyl, Ci-6 deuterohaloalkyl, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -C1-6 alkylene-C3-8 cycloalkyl, and -C1-6 alkylene-3-10 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, and NRX1RX2;

[0348] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;

[0349] R3is selected from the group consisting of: hydrogen, D, halo, C1-6 alkyl, and C1-6 alkoxy;

[0350] R4is C1-6 alkyl or C1-6 deuteroalkyl; each R11is independently selected from the group consisting of: D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, NRX1RX2, and - C1-6 alkylene-OH;

[0351] R12is selected from the group consisting of: hydrogen, D, halo, C1-6 alkyl, and C1-6 alkoxy; and n is 0, 1, 2, 3, 4, 5, or 6.

[0352] In some embodiments, R4is methyl or trideuteromethyl.

[0353] In some embodiments, R12is hydrogen. In some embodiments, R12is D. In some embodiments, R12is fluoro. In some embodiments, R12is methyl.

[0354] In some embodiments, each R11is independently D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, halo, CN, C1-6 alkoxy, NRX1RX2, or -C1-6 alkylene-OH.

[0355] In some embodiments, each R11is independently D, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, OH, fluoro, chloro, CN, C1-3 alkoxy, C1-3 haloalkoxy, NH2, NHMe, NMe2, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, C1-3 alkyl, fluoro, or -C1-3 alkylene-OH.

[0356] In some embodiments, each R11is independently D, fluoro, chloro, methoxy, ethoxy, isopropoxy, OH, CN, methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-l -propyl, 2 -butyl, 2-methyl-2-propyl, 1 -pentyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2-butyl, 3- methyl-2-butyl, 3 -methyl- 1-butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-

[0357] 57

[0358] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, -CF3, - CHF2, -CH2F, -CC13, -CHCh, -CH2CI, -NH2, -NHMe, -NMe2, -NEt2, -CH2OH, or - CH2CH2OH.

[0359] In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, or 3.

[0360] In some embodiments, R2is Ci-4 alkyl, Ci-4 deuteroalkyl, Ci-4 haloalkyl, Ci-4 deuterohaloalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -C1-3 alkylene-C3-6 cycloalkyl, and -C1-3 alkylene-3-6 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with 1 to 3 RA, wherein each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuteroalkyl, D, CN, fluoro, chloro, OH, or NH2.

[0361] In some embodiments, R2is C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, 4-6 membered heterocyclyl, or -C1-2 alkylene-C3-4 cycloalkyl. In some embodiments R2is methyl or trideuteromethyl.

[0362] In some embodiments, R3is selected from the group consisting of: hydrogen, halo, Ci- 3 alkyl, and C1-3 alkoxy. In some embodiments, R3is selected from the group consisting of: fluoro, C1-3 alkyl, and C1-3 alkoxy. In some embodiments, R3is fluoro.

[0363] In some embodiments, the compound is of Formula (Xa): pharmaceutically acceptable salt thereof.

[0364] The disclosed compounds also embrace combinations of the specific R2, R3, R4, R11, R12, and n groups disclosed above.

[0365] In some embodiments, the compound is of Formula (Xb), (Xc), or (Xd):

[0366] 58

[0367] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) wherein:

[0368] R2is Ci-2 alkyl, C1-2 deuteroalkyl, C1-2 fluoroalkyl, or tetrahydrofuranyl, wherein alkyl 5 and tetrahydrofuranyl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, and NRX1RX2;

[0369] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or 10 Ci-4 deuteroalkyl;

[0370] R4is methyl or trideuteromethyl; each R11is independently selected from the group consisting of: D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, NRX1RX2, and - C1-6 alkylene-OH;

[0371] 15 R11Ais hydrogen, methyl, fluoro, or -CF3; and n is 0, 1, 2, or 3.

[0372] In some embodiments, R2is C1-2 alkyl, C1-2 deuteroalkyl, C1-2 fluoroalkyl, or tetrahydrofuranyl .

[0373] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0374] In some embodiments, each R11is independently fluoro, C1-3 alkyl, C1-3 deuteroalkyl, Ci-3 haloalkyl, C1-3 alkoxy, D, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, fluoro, methoxy, ethoxy, methyl, ethyl, -CF3, -CHF2, -CH2F, -CCI3, - CHCh, -CH2CI, -CH2OH, or -CH2CH2OH.

[0375] In another aspect, provided is a compound of Formula (XI): or a pharmaceutically acceptable salt thereof, wherein:

[0376] R4is C1-6 alkyl or C1-6 deuteroalkyl; each R11is independently selected from the group consisting of: D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, NRX1RX2, and - C1-6 alkylene-OH;

[0377] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;

[0378] R13is selected from the group consisting of: D, OH, halo, CN, NRX1RX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, C1-6 deuteroalkoxy, C3-8 cycloalkyl, -O-C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -C1-6 alkylene-Cs-8 cycloalkyl, -C1-6 alkylenes' 10 membered heterocyclyl, and -C1-6 alkylene-Ci-6 deuteroalkoxy, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, or NRxlRX2; n is 0, 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, 4, or 5.

[0379] In some embodiments, R4is methyl or trideuteromethyl.

[0380] In some embodiments, each R11is independently D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6

[0381] 60

[0382] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) haloalkyl, OH, halo, CN, Ci-6 alkoxy, NRX1R , or -Ci-6 alkylene-OH.

[0383] In some embodiments, each R11is independently D, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, OH, fluoro, chloro, CN, C1-3 alkoxy, C1-3 haloalkoxy, NH2, NHMe, NMe2, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, C1-3 alkyl, fluoro, or -C1-3 alkylene-OH.

[0384] In some embodiments, each R11is independently D, fluoro, chloro, methoxy, ethoxy, isopropoxy, OH, CN, methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-l -propyl, 2 -butyl, 2-methyl-2-propyl, 1 -pentyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2-butyl, 3- methyl-2-butyl, 3 -methyl- 1-butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, -CF3, - CHF2, -CH2F, -CCI3, -CHCh, -CH2CI, -NH2, -NHMe, -NMe2, -NEt2, -CH2OH, or - CH2CH2OH.

[0385] In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, or 3.

[0386] In some embodiments, each R13is independently D, OH, fluoro, chloro, CN, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 deuteroalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, Ci-4 deuterohaloalkyl, Ci-4 deuteroalkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -C1-3 alkylene-C3-6 cycloalkyl, -C1-3 alkylene-3-6 membered heterocyclyl, and -C1-3 alkylene-Ci-4 deuteroalkoxy, wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with 1 to 3 RA, wherein each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuteroalkyl, D, CN, fluoro, chloro, OH, or NH2.

[0387] In some embodiments, each R13is independently D, OH, halo, Ci-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuteroalkoxy, C3-4 cycloalkyl, and -O-C3-4 cycloalkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more RA, wherein each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, D, CN, halo, OH, or NRX1RX2. In some embodiments, each RAis independently C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, C1-2 haloalkoxy, D, CN, fluoro, chloro, OH, or NH2.

[0388] In some embodiments, the compound is of Formula (Xia):

[0389] 61

[0390] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) pharmaceutically acceptable salt thereof.

[0391] The disclosed compounds also embrace combinations of the specific R4, R11, R13, n, and m groups disclosed above.

[0392] In some embodiments, the compound is of Formula (Xlb), (XIc), or (Xld): wherein:

[0393] R4is methyl or trideuteromethyl; each R11is independently selected from the group consisting of: D, Ci-6 alkyl, Ci-6

[0394] 10 deuteroalkyl, Ci-6 haloalkyl, OH, oxo, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, NRX1RX2, and - Ci-6 alkylene-OH;

[0395] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4

[0396] 62

[0397] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) deuteroalkyl;

[0398] R11Ais hydrogen, methyl, fluoro, or -CF3; each R13is independently selected from the group consisting of: D, OH, halo, CN, NRXiRX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, C1-6 deuteroalkoxy, C3-8 cycloalkyl, -O-C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10-membered aryl, 5- to 11-membered heteroaryl, -C1-6 alkylene-C3-8 cycloalkyl, -C1-6 alkylene-3-10 membered heterocyclyl, and -C1-6 alkylene-Ci-6 deuteroalkoxy, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, or NRxlRX2;

[0399] R13Ais C1-3 alkyl, C1-3 haloalkyl, or C1-3 deuteroalkyl; n is 0, 1, 2, or 3; and m is 1, 2, or 3.

[0400] In some embodiments, each R11is independently fluoro, C1-3 alkyl, C1-3 alkoxy, D, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, fluoro, methoxy, ethoxy, methyl, ethyl, -CF3, -CHF2, -CH2F, -CCI3, -CHCh, -CH2CI, -CH2OH, or - CH2CH2OH.

[0401] In some embodiments, each R13is independently fluoro, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, C1-3 alkoxy, D, or -C1-3 alkylene-OH. In some embodiments, each R13is independently D, fluoro, methoxy, ethoxy, methyl, ethyl, -CF3, -CHF2, -CH2F, -CCI3, - CHCh, -CH2CI, -CH2OH, or -CH2CH2OH.

[0402] In another aspect, provided is a compound of Formula (XII): or a pharmaceutically acceptable salt thereof, wherein:

[0403] R4is C1-6 alkyl or C1-6 deuteroalkyl;

[0404] 63

[0405] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0406] R14is -OMe or -OCD3;

[0407] R15is selected from the group consisting of: D, OH, halo, CN, NRX1RX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, C1-6 deuteroalkoxy, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10-membered aryl, and 5- to 11 -membered heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, or NRxlRX2;

[0408] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl; or

[0409] R15and R16, together with the atoms to which they are attached, form a 5- or 6- membered heteroaryl optionally substituted with one or more RA;

[0410] R16is selected from the group consisting of: hydrogen, D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, -C1-6 alkoxy, C1-6 haloalkoxy, and NRX1RX2; and

[0411] R17is selected from the group consisting of: hydrogen, D, OH, halo, CN, NRX1RX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, and C1-6 deuteroalkoxy.

[0412] In some embodiments, R4is methyl or trideuteromethyl.

[0413] In some embodiments, R15is D, OH, fluoro, chloro, CN, NH2, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 deuteroalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, Ci-4 deuterohaloalkyl, Ci-4 deuteroalkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with one or more RA, each RAis independently C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, C1-2 haloalkoxy, C1-2 deuteroalkyl, D, C1-2 deuterohaloalkyl, oxo, CN, fluoro, chloro, OH, or NH2.

[0414] In some embodiments, R15is monocyclic, bridged, fused, or spiro 4- to 9-membered N-containing heterocyclyl, wherein the point of attachment is on N, or C3-8 cycloalkyl, wherein heterocyclyl and cycloalkyl is optionally substituted with 1 to 3 RA.

[0415] In some embodiments, R16is hydrogen, D, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, OH, fluoro, chloro, CN, C1-3 alkoxy, C1-3 haloalkoxy, or NH2.

[0416] In some embodiments, R17is hydrogen, D, OH, fluoro, chloro, CN, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 deuteroalkyl, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterohaloalkyl, or C1-3 deuteroalkoxy.

[0417] 64

[0418] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0419] In some embodiments, the compound is of Formula (Xlla): (Xlla), or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the compound is of Formula (Xllb), (XIIc), or (Xlld): (Xlld), or a pharmaceutically acceptable salt thereof

[0421] The disclosed compounds also embrace combinations of the specific R4, R14, R15, R16, and R17groups disclosed above.

[0422] In another aspect, provided is a compound of Formula (XIII):

[0423] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) or a pharmaceutically acceptable salt thereof, wherein: each Rais independently hydrogen, D, Ci-6 alkyl, Ci-6 deuteroalkyl, and Ci-6 haloalkyl;

[0424] R2is selected from the group consisting of: hydrogen, D, Ci-6 alkyl, Ci-6 deuteroalkyl, Ci-6 haloalkyl, Ci-6 deuterohaloalkyl, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -C1-6 alkylene-Cs-8 cycloalkyl, and -C1-6 alkylene-3-10 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, and NRX1RX2;

[0425] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;

[0426] R3is selected from the group consisting of: hydrogen, D, halo, C1-6 alkyl, and C1-6 alkoxy;

[0427] R4is C1-6 alkyl or C1-6 deuteroalkyl;

[0428] R9is selected from the group consisting of: hydrogen, D, C1-6 alkyl, C1-6 deuteroalkyl, OH, C1-6 alkoxy, halo, or CN, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: C1-3 alkyl, halo, CN, and OH;

[0429] R10is selected from the group consisting of: 0H,-N(Ra)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -O-C2-6 alkenyl, -O-C2-6 alkynyl, -O-C1-6 alkylene-0-C3-io cycloalkyl, -C1-6 alkylene-0-C3-io cycloalkyl, -C1-6 alkylene-C3-io cycloalkyl, -C1-6 alkylene-0-C3-io cycloalkyl, C3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: D, halo, CN, OH, N(Ra)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C(O)Ci-6 66

[0430] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) alkyl, -C(O)N(Ra)2, and -N(Ra)C(O)Ci-6 alkyl; each R11is independently selected from the group consisting of: D, -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, -OH, oxo, halo, -CN, -Ci-6 alkoxy, -Ci-6 haloalkoxy, NRX1RX2, - Ci-6 alkylene-OH, -Ci-6 alkylene-Ci-6 alkoxy, C3-8 cycloalkyl and 3-8 membered heterocyclyl, or two R11, together with the atom(s) which they are attached, form a C3-8 cycloalkyl or 3-8 membered heterocyclyl;

[0431] R12is selected from the group consisting of: hydrogen, halo, -C1-6 alkyl, and -C1-6 alkoxy; and n is 0, 1, 2, 3, 4, 5, or 6.

[0432] In some embodiments, R4is methyl or trideuteromethyl.

[0433] In some embodiments, R12is hydrogen. In some embodiments, R12is D. In some embodiments, R12is fluoro. In some embodiments, R12is methyl.

[0434] In some embodiments, each R11is independently D, -Ci-4 alkyl, -Ci-4 deuteroalkyl, - Ci-4 haloalkyl, -OH, halo, -CN, -Ci-4 alkoxy, -Ci-4 haloalkoxy, NRX1RX2, -C 1-4 alkylene-OH, - Ci-4 alkylene-Ci-4 alkoxy, C3-6 cycloalkyl, or 3-6 membered heterocyclyl.

[0435] In some embodiments, each R11is independently D, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, OH, fluoro, chloro, CN, C1-3 alkoxy, C1-3 haloalkoxy, NH2, NHMe, NMe2, cyclopropyl, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, C1-3 alkyl, fluoro, or cyclopropyl.

[0436] In some embodiments, each R11is independently D, fluoro, chloro, methoxy, ethoxy, isopropoxy, OH, CN, methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-l -propyl, 2 -butyl, 2-methyl-2-propyl, 1 -pentyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2-butyl, 3- methyl-2-butyl, 3 -methyl- 1-butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, -CF3, - CHF2, -CH2F, -CCI3, -CHCh, -CH2CI, -NH2, -NHMe, -NMe2, -NEt2, -CH2OH, -CH2CH2OH, cyclopropyl, aziridinyl, or oxiranyl.

[0437] In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1 or 2.

[0438] In some embodiments, R2is Ci-4 alkyl, Ci-4 deuteroalkyl, Ci-4 haloalkyl, Ci-4 deuterohaloalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -C1-3 alkylene-C3-6 cycloalkyl, and -C1-3 alkylene-3-6 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted

[0439] 67

[0440] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) with 1 to 3 R , wherein each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuteroalkyl, D, CN, fluoro, chloro, OH, or NH2.

[0441] In some embodiments, R2is selected from the group consisting of: Ci-4 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, C3-5 cycloalkyl, and -C1-2 alkylene-5-7 membered heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with 1 to 3 RA. In some embodiments, each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuteroalkyl, D, CN, fluoro, chloro, OH, or NH2.

[0442] In some embodiments, R2is C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, 4-6 membered heterocyclyl, or -C1-2 alkylene-C3-4 cycloalkyl. In some embodiments R2is methyl or trideuteromethyl.

[0443] In some embodiments, R3is selected from the group consisting of: hydrogen, halo, Ci- 3 alkyl, and C1-3 alkoxy. In some embodiments, R3is fluoro, C1-3 alkyl, or C1-3 alkoxy. In some embodiments, R3is fluoro.

[0444] In some embodiments, R9is hydrogen, D, C1-3 alkyl, C1-3 deuteroalkyl, OH, C1-3 alkoxy, fluoro, chloro, or CN. In some embodiments, R9is hydrogen, D, C1-3 alkyl, OH, C1-3 alkoxy, fluoro, chloro, or CN. In some embodiments, R9is methyl, ethyl, OH, fluoro, chloro, CN, or OH.

[0445] In some embodiments, R10is Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy, -O-C2-4 alkenyl, -O-C2-4 alkynyl, -O-C1-4 alkylene-O-C3-6 cycloalkyl, -Ci-4 alkylene-O-C3-6 cycloalkyl, -Ci-4 alkylene-C3-6 cycloalkyl, -Ci-4 alkylene-O- C3-6 cycloalkyl, C3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: D, fluoro, chloro, CN, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C(O)Ci-3 alkyl, -C(O)NH2, and - NHC(O)CI-3alkyl.

[0446] In some embodiments, R10is C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-5 cycloalkyl, and 3-5 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: D, halo, CN, OH, N(Ra)2, methyl, and ethyl.

[0447] In some embodiments, the compound is of Formula (Xllla):

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[0450] The disclosed compounds also embrace combinations of the specific R2, R3, R4, R9, R10, R11, R12, Ra, and n groups disclosed above.

[0451] In some embodiments, the compound is of Formula (Xlllb), (XIIIc), or (Xllld): wherein:

[0452] R2is Ci-2 alkyl, C1-2 deuteroalkyl, or C1-2 fluoroalkyl, wherein alkyl is optionally substituted with one or more RA;

[0453] 10 each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, and

[0454] 69

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[0456] NRX1R ,

[0457] RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;

[0458] R4is methyl or trideuteromethyl;

[0459] R9is hydrogen, methyl, fluoro, or -CF3;

[0460] R10Ais hydrogen, methyl, fluoro, or -CF3; each R11is independently selected from the group consisting of: D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, NRX1RX2, and - C1-6 alkylene-OH;

[0461] R11Ais hydrogen, methyl, fluoro, or -CF3; and n is 0, 1, 2, or 3.

[0462] In some embodiments, R2is C1-2 alkyl, C1-2 deuteroalkyl, or C1-2 fluoroalkyl.

[0463] In some embodiments, each R11is independently fluoro, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, C1-3 alkoxy, D, or -C1-3 alkylene-OH. In some embodiments, each R11is independently D, fluoro, methoxy, ethoxy, methyl, ethyl, -CF3, -CHF2, -CH2F, -CCI3, - CHCh, -CH2CI, -CH2OH, or -CH2CH2OH.

[0464] In another aspect, provided is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0465] Table 1. List of Compounds of Formula (I-XIII)

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[0518] As can be appreciated, the compounds described herein provide new therapies for disease without the need for exotic chemistry or specialized reagents or manufacturing techniques.

[0519] Ill Pharmaceutical compositions

[0520] Other embodiments are directed to pharmaceutical compositions. In an embodiment, the pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such additional therapeutic agents are described herein below.

[0521] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, optical, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0522] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[0523] In treatment methods according to embodiments of the disclosure, an effective amount of at least one compound of Formula (I-XIII) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective

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[0525] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.

[0526] The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.001 to 0.1 mg, 0.01 to 0.1 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.01-10 mg, 0.1 to 10 mg, 10 to 5000 mg, 100 to 5000 mg, 1000 mg to 4000 mg per day, or 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0527] In some embodiments, compounds of the disclosure are administered in a single dose. In an embodiment, the single dose is administered orally. In another embodiment, the single dose is administered by injection. However, other routes are used as appropriate. In some embodiments, compounds of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment compounds of the disclosure and another agent (e.g., an additional anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of compounds of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0528] Administration of compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0529] In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

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[0532] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0533] Provided herein are pharmaceutical compositions comprising one or more compounds of Formula (I-XIII), and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I-XIII) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Formula (I-XIII) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula (I-XIII).

[0534] A pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Formula (I-XIII) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, therapeutically effective amounts of one or more compounds selected from compounds of Formula (I-XIII) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the

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[0536] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0537] In one embodiment, one or more compounds selected from compounds of Formula (I- XIII) are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, one or more compounds selected from compounds of Formula (I-XIII) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0538] In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0539] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a pharmaceutically acceptable salt thereof such as sodium alginate.

[0540] In one embodiment, the oral dosage forms, such as a pill, capsule or tablet, comprises one or more suitable layers or coatings. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain

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[0542] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) additional components, such as by way of example only, gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0543] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0544] In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. In additional embodiments, suspensions of one or more compounds selected from compounds of Formula (I-XIII) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or

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[0546] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0547] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from compounds of Formula (I- XIII) as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, pharmaceutically acceptable salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0548] Methods for the preparation of compositions comprising the compounds described herein include formulating the compound(s) with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid composition. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, ointments, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0549] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I-XIII) illustratively takes the form of a

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[0551] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0552] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0553] Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Formula (I-XIII). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0554] Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0555] Compositions also, optionally, include one or more pharmaceutically acceptable salts in an amount required to bring osmolality of the composition into an acceptable range. Such pharmaceutically acceptable salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable pharmaceutically acceptable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0556] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such

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[0558] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0559] Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0560] Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0561] In certain embodiments, aqueous suspension compositions are packaged in singledose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0562] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials are useful herein. In some embodiments, sustained release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0563] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0564] In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I-XIII) provided in the pharmaceutical compositions is greater than

[0565] 122

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[0567] 90%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v. In another embodiment, the amount of a compound selected from compounds of Formula (I-XIII) in the pharmaceutical compositions is an amount between about any two of the values recited in the preceding sentence, for example, between about 2- 70 w / w%, 3.5-80 w / w%, 1-30 w / w%, etc.

[0568] In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I-XIII) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0569] In some embodiments, the amount the one or more compounds selected from compounds of Formula (I-XIII) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g,

[0570] 123

[0571] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0572] 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0573] In some embodiments, the amount of the one or more compounds selected from compounds of Formula (I-XIII) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0574] Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0575] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser

[0576] 124

[0577] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) device is accompanied by instructions for administration, or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0578] In some embodiments, a pharmaceutical composition has a compound described above and a pharmaceutically acceptable carrier including, for example, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0579] In one embodiment, a pharmaceutical composition comprising the compounds of Formula (I-XIII) and a therapeutic agent is disclosed. In some embodiments, the compounds of Formula (I-XIII) or the pharmaceutical composition comprising the compounds of Formula (I-XIII) for use in a method of inhibiting an activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a compound (e.g., a compound of Formula (I- XIII)).

[0580] IV. Methods of Use

[0581] The compounds described herein can inhibit the activity of the V617F variant of the protein-tyrosine kinase JAK2 (i.e., “V617F” or “JAK2V617F” or “JAK2 V617F”). Compounds which inhibit V617F are useful in providing a means of preventing the growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore anticipated that the compounds of the disclosure are useful in treating or preventing proliferative disorders such as cancers. In particular tumors with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to the inhibitors.

[0582] In certain embodiments, the present disclosure provides a method of inhibiting an activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a

[0583] 125

[0584] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) compound (e.g., a compound of Formula (I-XIII)), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a method for treating a V617F-related disorder in a patient in need thereof, comprising the step of administering to said patient a compound of the disclosure, or a pharmaceutically acceptable composition thereof.

[0585] In certain embodiments, the present disclosure provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound (e.g., a compound of Formula (I-XIII)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a myeloproliferative disease or disorder (e.g., a myeloproliferative neoplasm).

[0586] Myeloproliferative diseases (MPD) are multipotent hematopoietic stem cell disorders characterized by excess production of various blood cells. MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). JAK2 V617F mutation is reported in about 95% of patients with PV, in 35% to 70% of patients with ET, and 50% of patients with IMF. Also, JAK2 exon 12 mutations are detected in some of the V617F -negative PV patients (Ma et al., J. Mol. Diagn., 11 : 49-53, 2009). In some embodiments, the compounds of the disclosure can be useful in the treatment of myeloproliferative disorders (e.g., myeloproliferative neoplasms) in a patient in need thereof, such as polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.

[0587] In some embodiments, the myeloproliferative disorder is a myeloproliferative neoplasm.

[0588] In some embodiments, the myeloproliferative disorder is myelofibrosis (e.g., primary myelofibrosis (PMF) or post polycythemia vera / essential thrombocythemia myelofibrosis (Post-PV / ET MF)). In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF). In some embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative

[0589] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) neoplasm is polycythemia vera (PV). In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia (ET).

[0590] Myeloproliferative diseases include disorders of a bone marrow or lymph nodederived cell type, such as a white blood cell. A myeloproliferative disease can manifest by abnormal cell division resulting in an abnormal level of a particular hematological cell population. The abnormal cell division underlying a proliferative hematological disorder is typically inherent in the cells and not a normal physiological response to infection or inflammation. Leukemia is a type of myeloproliferative disease. Exemplary myeloproliferative diseases include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), hairy cell leukemia, leukemic manifestations of lymphomas, multiple myeloma, polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), and unclassified myeloproliferative diseases (UMPD or MPD-NC). Lymphoma is a type of proliferative disease that mainly involves lymphoid organs, such as lymph nodes, liver, and spleen. Exemplary proliferative lymphoid disorders include lymphocytic lymphoma (also called chronic lymphocytic leukemia), follicular lymphoma, large cell lymphoma, Burkitt's lymphoma, marginal zone lymphoma, lymphoblastic lymphoma (also called acute lymphoblastic lymphoma).

[0591] For example, the compounds of the disclosure are useful in the treatment of cancer. Example cancers include bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma), breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumors), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth, squamous head and neck cancers), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic), liver angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial

[0592] 127

[0593] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell cancer, neuroendocrine carcinoma), skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuro- ectodermal tumors, pineal tumors).

[0594] Further example cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia (AML), B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin’s or non-Hodgkin’s lymphoma, myeloproliferative neoplasms (e.g., 8pl 1 myeloproliferative syndrome, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt's lymphoma.

[0595] In certain embodiments, provided herein is a method of treating cancer comprising administering to a patient in need thereof a therapeutically effect amount of a compound of the disclosure. In certain embodiments, the cancer is selected from T lymphoblastic lymphoma, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, and osteosarcoma.

[0596] Other cancers treatable with the compounds of the disclosure include tumors of the eye, glioblastoma, melanoma, leiomyosarcoma, and urothelial carcinoma (e.g., ureter, urethra, bladder, urachus).

[0597] The compounds of the disclosure can also be useful in the inhibition of tumor metastases.

[0598] In some embodiments, the compounds of the disclosure as described herein can be used to treat Alzheimer’s disease, HIV, or tuberculosis.

[0599] In some embodiments, the compounds of the disclosure can be useful in the treatment of myelodysplastic syndrome (MDS) in a patient in need thereof. In some embodiments, said patient having the myelodysplastic syndrome (MDS) is red blood cell transfusion dependent.

[0600] As used herein, myelodysplastic syndromes are intended to encompass heterogeneous and clonal hematopoietic disorders that are characterized by ineffective hematopoiesis on one or more of the major myeloid cell lineages. Myelodysplastic syndromes are associated with

[0601] 128

[0602] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) bone marrow failure, peripheral blood cytopenias, and a propensity to progress to acute myeloid leukemia (AML). Moreover, clonal cytogenetic abnormalities can be detected in about 50% of cases with MDS. In 1997, The World Health Organization (WHO) in conjunction with the Society for Hematopathology (SH) and the European Association of

[0603] 5 Hematopathology (EAHP) proposed new classifications for hematopoietic neoplasms (Harris, et al., J Clin Oncol 1999;17:3835-3849; Vardiman, et al., Blood 2002;100:2292-2302). For MDS, the WHO utilized not only the morphologic criteria from the French- American-British (FAB) classification but also incorporated available genetic, biologic, and clinical characteristics to define subsets of MDS (Bennett, et al., Br. J. Haematol. 1982;51 : 189-199). io In 2008, the WHO classification of MDS (Table 2) was further refined to allow precise and prognostically relevant subclassification of unilineage dysplasia by incorporating new clinical and scientific information (Vardiman, et al., Blood 2009;114:937-951; Swerdlow, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.4th Edition. Lyon France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic

[0604] 15 syndromes / neoplasms” in Chapter 5, Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (ed.4th edition): Lyon, France: IARC Press;2008:88-103).

[0605] Table 2. 2008 WHO Classification for De Novo Myelodysplastic Syndrome

[0606] 129

[0607] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0608] In some embodiments, the myelodysplastic syndrome is refractory cytopenia with unilineage dysplasia (RCUD). In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS). In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts associated with thrombocytosis (RARS- T). In some embodiments, the myelodysplastic syndrome is refractory cytopenia with multilineage dysplasia. In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1). In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2). In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome, unclassified (MDS-U). In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome associated with isolated del(5q). In some embodiments, the myelodysplastic syndrome is refractory to erythropoiesis-stimulating agents. In some embodiments, the compounds of the disclosure can be useful in the treatment of myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome). In some embodiments, the compounds of the disclosure can be useful in the treatment of leukemia. In some embodiments, the compounds of the disclosure can be useful in the treatment of acute myeloid leukemia (AML).

[0609] In addition to oncogenic neoplasms, the compounds of the disclosure can be useful in the treatment of skeletal and chondrocyte disorders including, but not limited to, achrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare- Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndromes.

[0610] The compounds provided herein may further be useful in the treatment of fibrotic diseases, such as where a disease symptom or disorder is characterized by fibrosis. Example

[0611] 130

[0612] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) fibrotic diseases include liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0613] In some embodiments, the compounds provided herein can be used in the treatment of a hypophosphatemia disorder such as, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteromalacia.

[0614] V. Methods of Preparation

[0615] Preparation methods for the above compounds and compositions are described herein below and / or known in the art.

[0616] It will be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include — C(O) — R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

[0617] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention. In some embodiments, for example, a phosphate bearing compound of Formula (I-XIII) is a prodrug and the structure of such example is described in the disclosure.

[0618] Furthermore, all compounds of the invention which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate

[0619] 131

[0620] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the invention can be converted to their free base or acid form by standard techniques.

[0621] 5

[0622] 132

[0623] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0624] EXAMPLES

[0625] The following section describes abbreviations used in the examples and includes examples for making intermediate compounds 11-162 (Examples 1-51) and examples for making compounds 1-49 (Examples 52-88).

[0626] 5 Abbreviations:

[0627] ACN acetonitrile

[0628] AC2O acetic anhydride

[0629] Br2 bromine ca. circa; approximately

[0630] CDI 1,1 ‘-carbonyldiimidazole

[0631] CH3I iodomethane

[0632] CO2 carbon dioxide

[0633] CS2CO3 caesium carbonate

[0634] DCM dichloromethane

[0635] DMF dimethylformamide

[0636] DMSO dimethyl sulfoxide DMSO-de deuterated dimethyl sulfoxide DTT dithiothreitol EDTA ethylenediaminetetraacetic acid eq. equivalent(s) EtOAc ethyl acetate EtOH ethanol FA formic acid Fe iron h hour(s) HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3 -oxide hexafluorophosphate

[0637] 'H-NMR proton nuclear magnetic resonance

[0638] H2O water

[0639] HC1 hydrochloric acid

[0640] HEPES 4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid

[0641] HTRF homogenous time resolved fluorescence

[0642] 133

[0643] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0644] IC50 half maximal inhibitory concentration IPA isopropyl alcohol z-PrMgBr isopropylmagnesium bromide K2CO3 potassium carbonate KOAc potassium acetate LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide M molar MeMgBr methylmagnesium bromide MeOH methanol MeOH-d4deuterated methanol MgCh magnesium chloride min. minute(s) MS mass spectrometry m / z mass-to-charge ratio N2 nitrogen (gas) NaBHsCN sodium cyanoborohydride NaHCO3sodium bicarbonate NaOH sodium hydroxide Na2SO3sodium sulfite Na2SO4sodium sulfate NH4CI ammonium chloride NH4OAc ammonium acetate Pd(dppf)C12 (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) pet ether petroleum ether POC13 phosphoryl chloride prep-HPLC preparative high performance liquid chromatography rt room temperature RT retention time sat. saturated SiO2silicon dioxide; silica sol. solution

[0645] 134

[0646] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0647] TEA tnethylamine

[0648] THF tetrahydrofuran

[0649] TLC thin-layer chromatography

[0650] UV ultraviolet

[0651] Preparation of Intermediates

[0652] Example 1: Preparation of 5-Fluoro-l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole and 3-fluoro-l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-1 and Intermediate 1-2)

[0653] To a stirred solution of 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (1.0 g, 4.716 mmol, 1.0 equiv.) in tetrahydrofuran (dry) (20.0 mL) was added potassium carbonate (1.1 g, 8.0 mmol) followed by iodomethane-d3 (1.2 g, 8.1 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 24 h. The reaction mixture was poured into ice water (20 mL) and then extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the product as mixture of 3-fluoro-l- (methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-1) and 5-fluoro-l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-2) 0.7 g, 69% yield) as a colorless oil. MS m / z: [M+H]+= 229.47.

[0654] Example 2: Preparation of l-ethyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole and l-ethyl-5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- IH-pyrazole (Intermediate 1-3 and Intermediate 1-4)

[0655] To a stirred solution of 3-fhioro-4-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-lH-

[0656] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) pyrazole (0.5 g, 2.5 mmol, 1 equiv.) in tetrahydrofuran (dry) (10 mL) at rt was added potassium carbonate (1.4 g, 10 mmol). The resulting reaction mixture was stirred for 15 min. To this was added ethyl iodide, 98% (0.81 mL, 10 mmol). The reaction mixture was stirred at 60 °C for 24 h. The reaction mixture filtered, and filtrate was concentrated under reduced pressure to get crude mixture of l-ethyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-3) and l-ethyl-5-fluoro-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-4) (0.5 g, 2.1 mmol, 82% yield) as a yellow solid. MS m / z: [M+H]+= 158.87.

[0657] Example 3: Preparation of tert-Butyl ((lR,3R)-3-((5-nitro-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Intermediate 1-5)

[0658] To a solution of 4-chloro-5-nitro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (3.0 g, 8.9 mmol, 1.0 equiv.) in isopropyl alcohol (30 mL) was added trimethylamine (2.5 mL, 17 mmol) followed by tert-butyl ((lR,3R)-3-aminocyclopentyl)carbamate (1.9 g, 9.3 mmol). The reaction mixture was heated to 70 °C for three hours, then cooled to room temperature. The reaction mixture was diluted with 50 mL of water, and stirred for 20 minutes. The precipitates were filtered, washed with water and dried under reduced pressure to obtain tert- butyl((lR,3R)-3-((5-nitro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4- yl)amino)cyclopentyl) carbamate. (Intermediate 1-5, 4.2 g, 94%) as a yellow color solid. MS m / z: [M+H]+= 502.32.

[0659] Example 4: Preparation of tert-Butyl((lR,3R)-3-((5-amino-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Intermediate 1-6)

[0660] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0661] To a solution of tert-butyl ((lR,3R)-3-((5-nitro-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridin-4-yl)amino)cyclopentyl)carbamate (Intermediate 1-5, 4.2 g, 8.4 mmol) in tetrahydrofuran (84 mL) and ethanol (25 mL) was added iron powder (4.2 g, 75 mmol), ammonium chloride (4.0 g, 75 mmol) and water (25 mL) at room temperature. The reaction mixture was heated to 70 °C and stirred for 3 h at 70 °C. and then cooled to room temperature. The catalyst was removed by filtration through a Celite® bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was diluted with 50 mL water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl((lR,3R)-3-((5-amino-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4- yl)amino)cyclopentyl)carbamate (Intermediate 1-6, 3.9 g, 99%) as a brown solid. MS m / z: [M+H]+= 472.33.

[0662] Example 5: Preparation of tert-Butyl ((lR,3R)-3-(2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyr idin- 1 (2H)-yl)cyclopentyl)car bamate

[0663] (Intermediate 1-7)

[0664] To a solution of tert-butyl ((lR,3R)-3-((5-amino-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b] pyridin-4-yl)amino)cyclopentyl)carbamate (Intermediate 1-6, 5.0 g, 11 mmol) in acetonitrile (25 mL) was added l,l'-carbonyldiimidazole (6.9 g, 42 mmol). The reaction mixture was heated at 70 °C for 2 h, and then cooled to room temperature. The reaction

[0665] 137

[0666] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) mixture was diluted with 50 mL water & extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain yellow color solid. The residue was purified by combi-flash column chromatography using 100-200 mesh silica gel and the desired product was eluted at 50% of ethyl acetate in pet ether as the eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to afford desired product tert-butyl ((lR,3R)-3-(2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl) carbamate (4.0 g, 75%) as a pale brown solid. MS m / z: [M+H]+= 498.34.

[0667] Example 6: Preparation of tert-Butyl((lR,3R)-3-(3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Intermediate 1-8)

[0668] To a stirred solution of tert-butyl ((lR,3R)-3-(2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (1.0 g, 2.0 mmol) in dimethylformamide (5 mL) was added potassium carbonate (Intermediate 1-7, 0.860 g, 6.2 mmol), followed by the drop-wise addition of iodomethane-di (0.388 mL, 6.2 mmol,) at room temperature. The resulting reaction mixture was stirred at 50 °C for 3 h. After completion of the reaction, the reaction mixture was diluted with water. The mixture was stirred for 20 minutes and filtered through a Buchner funnel. The solid was dried under reduced pressure to give tert-butyl ((lR,3R)-3-(3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.7 g, 14 mmol, 67% yield) as a yellow solid. MS m / z: [M+H]+= 515.34.

[0669] Example 7: Preparation of tert-Butyl ((lR,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Intermediate 1-9)

[0670] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0671] To a stirred solution of tert-butyl((lR,3R)-3-(3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-8, 1.0 g, 1.9 mmol) in THF / n-heptane / ethylbenzene (20.0 mL) was added lithium diisopropylamide, 2 M in THF (2.9 mL, 5.8 mmol) drop wise at -78 °C. The reaction mixture was stirred at -78 °C for 45 min. To this was added l,2-dibromo-l,l,2,2- tetrachloroethane (0.95 g, 2.93 mmol) in tetrahydrofuran (dry) (10.0 mL) at -78 °C and the reaction mixture was maintained at -78 °C for 30 min, and then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution (30 mL) and then extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (100-200 mesh silica gel, 30 to 80% ethyl acetate in pet ether as an eluent) to obtain the product tert-butyl ((lR,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-9, 0.75 g, 65 % yield) as a pale yellow solid. LCMS: 63.4% at RT: 2.21 mins; MS m / z: [M]+= 593.09.

[0672] Example 8: Preparation of tert-Butyl ((lR,3R)-3-(3-methyl-2-oxo-6-(phenylsulfonyl)- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-10)

[0673] To a stirred solution of tert-butyl ((lR,3R)-3-(2-oxo-6-(phenylsulfonyl)-3,6-

[0674] 139

[0675] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyndin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-7, 1.0 g, 2.0 mmol) in dimethylformamide (5 mL) was added potassium carbonate (1.1 g, 8.0 mmol). To this was added iodomethane (0.50 mL, 8.0 mmol) at room temperature and stirred for 3 h. After completion of the reaction, the reaction mixture was diluted with water. The precipitate formed was stirred for 30 minutes solids collected by filtration, and dried under reduced pressure to get tert-butyl ((lR,3R)-3-(3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-10, 87% ) as a yellow solid. MS m / z: [M+H]+= 512.38.

[0676] Example 9: Preparation of tert-Butyl ((lR,3R)-3-(7-bromo-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Intermediate 1-11)

[0677] A solution of tert-butyl ((lR,3R)-3-(3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-10, 0.70 g, 1.4 mmol, ) in tetrahydrofuran (dry) (20 mL) was cooled to -78 °C. To this was added drop-wise lithium diisopropylamide 2 M solution in THF / n-heptane / ethylbenzene (2.1 mL, 4.1 mmol). The resulting reaction mixture was stirred at -78 °C for 30 min. To this was added a solution of l,2-dibromo-l,l,2,2-tetrachloroethane (0.67 g, 2.0 mmol) in THF (0.5 mL) dropwise. The reaction mixture was stirred at -78 °C for 30 min followed by stirring at ambient temperature for 1 h. The reaction was quenched by addition of saturated NH4Q solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude material. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. Pure fractions were concentrated to afford tert-butyl ((lR,3R)-3-(7- bromo-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (Intermediate 1-11, 0.7 g, 1.2 mmol, 87% yield) as a yellow solid. MS m / z: [M+H]+= 590.06, 592.07.

[0678] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0679] Example 10: Preparation of tert-Butyl ((ls,4s)-l-methyl-4-((5-nitro-l-(phenylsulfonyl)- lH-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-12)

[0680] To a 40 mL vial equipped with a magnetic stir bar were added l-(benzenesulfonyl)-4- chloro-5-nitro-pyrrolo[2,3-b]pyridine (1.20 g, 3.6 mmol) and tert-butyl N-(4-amino-l- methyl-cyclohexyl)carbamate (1.0 g, 3.8 mmol, HC1) followed by the addition of IPA (15 mL). Then TEA (1.1 g, 11 mmol) was added into the mixture. The mixture was heated to 80 °C and stirred for 1 h. After completion of the reaction as indicated by LCMS (RT: 0.862 min, MS (ESI) m / z: [M+H]+= 530.2). The mixture was concentrated under reduced pressure affording the crude product as a yellow solid. The crude product was diluted with DCM (50 mL) and H2O (30 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure affording tert-butyl ((ls,4s)-l-methyl-4-((5-nitro-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-12, 2.0 g, 95% yield) as a yellow solid. LCMS m / z: [M+H]+= 530.2.

[0681] Example 11: Preparation of tert-Butyl ((ls,4s)-4-((5-amino-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridin-4-yl)amino)-l-methylcyclohexyl)carbamate (Intermediate 1-13)

[0682] To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tertbutyl ((ls,4s)-l-methyl-4-((5-nitro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-

[0683] 141

[0684] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) yl)amino)cyclohexyl)carbamate (Intermediate 1-12, 1.9 g, 3.5 mmol) followed by the addition of THF (10 mL) and EtOH (30 mL). Then Fe (1.94 g, 35 mmol) and HC1 (1 M, 1.22 mL) were added into the mixture. The mixture was heated to 70 °C and stirred for 3 h. The suspension was filtered and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure affording the crude product. The crude product was purified by flash silica gel chromatography (0% to 70% ethyl acetate / petroleum ether). Compound tert-butyl ((ls,4s)-4-((5-amino-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridin-4-yl)amino)-l-methylcyclohexyl)carbamate (Intermediate 1-13, 1.8 g, 98% yield) was obtained as a blue solid. LCMS m / z: [M+H]+= 500.2.

[0685] Example 12: Preparation of tert-Butyl ((ls,4s)-l-methyl-4-(2-oxo-6-(phenylsulfonyl)- 3,6-dihydr oimidazo [4,5-d] pyrr olo [2,3-b] pyr idin- 1 (2H)-yl)cyclohexyl)carbamate (Intermediate 1-14)

[0686] To an 100 mL round-bottom flask equipped with a magnetic stir bar were added tertbutyl ((ls,4s)-4-((5-amino-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)amino)-l- methylcyclohexyl)carbamate (Intermediate 1-13, 1.76 g, 3.5 mmol) and CDI (1.7 g, 10 mmol) followed by the addition of THF (20 mL). The mixture was heated to 50 °C and stirred for 1 h. After completion of the reaction as indicated by LCMS (RT: 0.540 min, MS (ESI) m / z: [M+H]+= 526.2). The mixture was quenched by slow addition of H2O (20 mL). The resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure affording tertbutyl ((ls,4s)-l-methyl-4-(2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclohexyl)carbamate (Intermediate 1-14, 1.8 g, 98% yield) as a blue solid. LCMS m / z: [M+H]+= 526.2.

[0687] Example 13: Preparation of tert-Butyl ((ls,4s)-l-methyl-4-(3-methyl-2-oxo-6-

[0688] 142

[0689] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0690] (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyndin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-15)

[0691] To an 8 mL vial equipped with a magnetic stir bar was added tert-butyl ((ls,4s)-l- methyl-4-(2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-14, 0.85 g, 1.6 mmol) followed by the addition of DMF (5 mL). Then CH3I (0.69 g, 4.9 mmol) and K2CO3 (0.67 g, 4.9 mmol) were added into the mixture. The mixture was heated to 50 °C and stirred for 16 h. After completion of the reaction as indicated by LCMS (RT: 0.559 min, MS (ESI) m / z: [M+H]+= 540.2). The mixture was quenched by slow addition of H2O (20 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure affording the residue as a colorless oil. The residue was purified by flash silica gel chromatography (0% to 50% ethyl acetate / petroleum ether) to afford tert-butyl ((ls,4s)-l-methyl-4-(3-methyl- 2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-15, 1.4 g, 75% yield) as a white solid. LCMS m / z: [M+H]+= 540.2.

[0692] Example 14: Preparation of tert-butyl ((ls,4s)-l-methyl-4-(3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-16)

[0693] 143

[0694] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0695] To a 100 mL three-necked round-bottom flask equipped with a magnetic stir bar was added tert-butyl ((ls,4s)-l-methyl-4-(3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclohexyl)carbamate (Intermediate 1-15, 1.0 g, 74 mmol) followed by the addition of THF (8 mL). The flask was then evacuated and backfilled with nitrogen for three times. The solution was cooled to -78 °C. Next, LDA (2 M, 2.61 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h. Then 1,2- dibromo-l,l,2,2-tetrachloro-ethane (0.74 g, 2.3 mmol) in THF (3 mL) was added into the mixture at -78 °C. The mixture was stirred at -78 °C for 0.5 h. The mixture was quenched by slow addition of saturated aqueous ammonium chloride (5 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (47% to 77% 0.05% aqueous formic acid / acetonitrile). After lyophilization, compound tert-butyl ((ls,4s)-l-methyl-4-(3-methyl-2-oxo- 6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-16, 0.63 g, 35% yield) was obtained as a gray solid. LCMS m / z: [M+H]+= 619.9.

[0696] Example 15: Preparation of l-isopropyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,5-a]pyridine (Intermediate 1-17)

[0697] Step 1: To a solution of 5-bromopyridine-2-carbonitrile (5 g, 27.32 mmol) in THF (250 mL) were added z-PrMgBr (2.9 M, 11.78 mL) and CuBr (195.96 mg, 1.37 mmol, 41.61 pL) at 0 °C. The mixture was stirred at 40 °C for 2 h under N2 atmosphere. The reaction mixture was quenched using sat. NH4Q (20 mL) at 0 °C, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 1 / 0 to 1 / 1) to give l-(5-bromo- 2-pyridyl)-2-methyl-propan-l-one (3 g, 37% yield) as a yellow oil. LCMS: RT; 0.527 min; MS m / z: [M+H]+= 229.9.

[0698] 144

[0699] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0700] Step 2: To a solution of l-(5-bromo-2-pyndyl)-2-methyl-propan-l-one (1.9 g, 8.33 mmol) in MeOH (20 mL) were added NaBHsCN (4.19 g, 66.64 mmol) and NFLOAc (6.42 g, 83.30 mmol). The mixture was stirred at 60 °C for 12 h under a N2 atmosphere. The reaction mixture was quenched using water (20 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 1 / 0 to 1 / 1) to give l-(5-bromo-2- pyridyl)-2-methyl-propan-l -amine (1 g, 3.53 mmol, 42% yield) as a yellow oil. LCMS: RT; 0.321 min; MS m / z: [M-NH2]+= 213.9.

[0701] Step 3: A mixture of AC2O (1.34 g, 13.09 mmol, 1.23 mL) and FA (2.01 g, 43.65 mmol, 1.65 mL) was stirred at 60 °C for 4 h under N2 atmosphere. Then the mixture was added into a solution of l-(5-bromo-2-pyridyl)-2-methyl-propan-l -amine (1 g, 4.36 mmol) and TEA (441.65 mg, 4.36 mmol, 607.50 pL) in THF (10 mL) at -10 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 12 h. The mixture was poured into sat. NaHCOi (80 mL) and extracted with EtOAc (80 mL x 3). The organic phase was separated, washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give N-[l-(5-bromo-2-pyridyl)-2-methyl-propyl]formamide (1.12 g, crude) as a yellow oil. It was used directly into the next step without further purification. LCMS: RT; 0.424 min; MS m / z: [M+H]+= 256.9.

[0702] Step 4: A mixture of N-[l-(5-bromo-2-pyridyl)-2-methyl-propyl]formamide (1.12 g, 4.36 mmol) in POCI3 (10 mL) was stirred at 100 °C for 1 h under a N2 atmosphere. The reaction mixture was quenched using saturated aqueous NaHCOi (20 mL) at 0 °C, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-bromo-l-isopropyl-imidazo[l,5-a]pyridine (868 mg, crude) as a yellow oil. It was used directly into the next step without further purification. LCMS: RT; 0.381 min; MS m / z: [M+H]+= 241.0.

[0703] Step 5: To a solution of 6-bromo-l-isopropyl-imidazo[l,5-a]pyridine (768 mg, 3.21 mmol) and 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.63 g, 6.42 mmol) in 1,4-dioxane (8 mL) were added KOAc (945.65 mg, 9.64 mmol) and Pd(dppf)C12 (235.01 mg, 321.19 pmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL x 3). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under

[0704] 145

[0705] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 1 / 0 to 3 / 1) to give l-isopropyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,5-a]pyridine (Intermediate 1-17, 680 mg, 52 % yield) as a yellow solid.

[0706] Example 16: Preparation of 6-bromo-3-isopropyl-imidazo [4, 5-b] pyridine (Intermediate 1-18)

[0707] To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1 g, 5.05 mmol) and 2- iodopropane (4.29 g, 25.25 mmol, 2.52 mL) in DMSO (5.5 mL) was added K2CO3 (2.09 g, 15.15 mmol). The mixture was stirred at 15 °C for 12 h. The reaction mixture was partitioned between water and EtOAc (20 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 1 / 0 to 80 / 20) to give 6-bromo-3-isopropyl-imidazo[4,5-b]pyridine (Intermediate 1-18, 670 mg, 2.77 mmol, 55% yield) as a yellow oil. LCMS: RT; 0.415 min; MS m / z: [M+H]+= 239.9.

[0708] Example 17: Intermediates Prepared According to Example 15, Step 5 (Intermediates I- 19 through 1-24)

[0709] The intermediates described herein may be prepared according to the scheme described in Example 15 (in particular from Example 15, Step 5), for example, from an intermediate as prepared in “Preparation of Intermediates,” an intermediate that is commercially available, an intermediate as prepared elsewhere in this application, or an intermediate that can be synthesized via a method known to those skilled in the art. An exemplary full synthesis is provided in any of the previous Examples, such as Example 15. Compounds prepared in accordance with the scheme described in Example 15, Step 5 are provided in Table 3 below.

[0710] Table 3. Structures of intermediates.

[0711] 146

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[0713] AMass corresponds to boronic acid

[0714] Example 18: Preparation of 2-(2-cyclopropyl-2,3-dihydro-l,4-benzodioxin-6-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (Intermediate 1-25)

[0715] Step 1: Preparation of l-cyclopropyl-2-(2-fluoro-5-nitrophenoxy)ethanone

[0716] 147

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[0718] A solution of 2-fluoro-5-nitrophenol (5.00 g, 31.8 mmol) in DMF (50 mL) was treated with 2-bromo-l -cyclopropyl ethanone (5.19 g, 31.8 mmol) and K2CO3 (8.80 g, 63.7 mmol). The mixture was stirred at 80 °C for 2 hours, diluted with H2O (100 mL), and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-17% ethyl acetate in petroleum ether) to afford 1-cyclopropyl- 2-(2-fluoro-5-nitrophenoxy)ethanone (6.00 g, 79% yield) as a yellow oil. LCMS m / z: [M+H]+= 240.1.

[0719] A solution of l-cyclopropyl-2-(2-fluoro-5-nitrophenoxy)ethanone (6.00 g, 25.1 mmol) in THF (60 mL) was treated with NaBH4 (2.57 g, 67.9 mmol). The mixture was stirred at 0 °C for 2 hours, diluted with 1 M HC1 (100 mL), and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford l-cyclopropyl-2-(2-fluoro-5- nitrophenoxy)ethanol (7 g, crude) as a yellow oil. It was used directly in the next step without further purification. LCMS m / z: [M+H-H2O] = 224.1.

[0720] Step 3: Preparation of 2-cyclopropyl-6-nitro-2,3-dihydro-l,4-benzodioxine

[0721] A solution of l-cyclopropyl-2-(2-fluoro-5-nitrophenoxy)ethanol (6.00 g, 24.9 mmol) in DMF (60 mL) was treated with CS2CO3 (16.2 g, 49.8 mmol). The mixture was stirred at 80 °C for 1 hour, diluted with H2O (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography

[0722] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0723] (0-25% ethyl acetate in petroleum ether) to afford 2-cyclopropyl-6-mtro-2,3-dihydro-l,4- benzodioxine (1.00 g, 18% yield) as a yellow oil. LCMS m / z: [M+H]+= 222.1.

[0724] Step 4: Preparation of 2-cyclopropyl-2,3-dihydro-l ,4-benzodioxin-6-amine

[0725] 2-cyclopropyl-6-nitro-2,3-dihydro-l,4-benzodioxine (800 mg, 3.62 mmol), NH4Q (967 mg, 18.1 mmol), and H2O (6 mL) were combined in a round-bottom flask, followed by EtOH (10 mL) and Fe (1.01 g, 18.1 mmol). The mixture was stirred at 80 °C for 2 hours, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50-75% ethyl acetate in petroleum ether) to afford 2-cy cl opropyl-2, 3 -dihydro- 1,4- benzodioxin-6-amine (630 mg, 70% yield) as a yellow oil. LCMS m / z: [M+H]+= 192.2.

[0726] Step 5: Preparation of 2-(2-cyclopropyl-2, 3-dihydro-l,4-benzodioxin-6-yl)-4, 4,5,5- tetramethyl-1 , 3, 2-dioxaborolane

[0727] A solution of 2-cy cl opropyl-2, 3 -dihydro- l,4-benzodioxin-6-amine (600 mg, 3.14 mmol) in acetonitrile (10 mL) was treated dropwise with LBuONO (485 mg, 4.71 mmol) at 0 °C. After stirring for 30 minutes, JLPi (956 mg, 3.77 mmol) in acetonitrile (10 mL) was added dropwise at 0 °C. The mixture was stirred at 80 °C for 1.5 hours, quenched with H2O (150 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1-25% ethyl acetate in petroleum ether) to afford 2-(2-cyclopropyl-2,3-dihydro-l,4-benzodioxin-6-yl)-4, 4,5,5- tetramethyl-1, 3, 2-dioxaborolane (Intermediate 1-25) (320 mg, 32% yield) as a yellow oil. LCMS m / z: [M+H]+= 303.1.

[0728] Example 19: Preparation of 2-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-

[0729] 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate 1-26) and 2-(3,3-dimethyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate

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[0732] 1-27)

[0733] Step 1: Preparation of 4-bromo-2-(2-methylallyloxy)phenol and -bromo-2-(2- methylallyloxy)phenol

[0734] To a solution of 4-bromobenzene-l,2-diol (1.00 g, 5.29 mmol) and 3 -bromo-2-m ethylpropene (587 pL, 5.82 mmol) in DMF (10 mL) was added Li2COs (978 mg, 13.3 mmol). The mixture was stirred at 60 °C for 12 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. Purification by silica gel chromatography (10-20% ethyl acetate in petroleum ether) afforded a mixture of 4-bromo-2-(2-methylallyloxy)phenol (350 mg, 21% yield) and 5- bromo-2-(2-methylallyloxy)phenol (350 mg, 27% yield) as a colorless oil. 'H NMR of the mixture: (400 MHz, DMSO-t / e) 5 9.26 (s, 1H), 7.04 (d, J= 2.4 Hz, 1H), 6.93 (dd, J= 4.4, 2.4 Hz, 1H), 6.74 (d, J= 8.8 Hz, 1H), 5.07 (s, 1H), 4.94 (s, 1H), 4.47 (s, 2H), 1.76 (s, 3H).

[0735] Step 2: Preparation of 6-bromo-2,2-dimethyl-3H-l, 4-benzodioxine and 6-bromo-3,3- dimethyl-2H-l, 4-benzodioxine

[0736] A mixture of 4-bromo-2-(2-methylallyloxy)phenol (350 mg, 1.44 mmol) and 5-bromo-2-(2- methylallyloxy)phenol (350 mg, 1.44 mmol) in formic acid (7 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. Purification by silica gel chromatography (10-30% ethyl acetate in petroleum ether) afforded a mixture of 6-bromo- 2, 2-dimethyl-3H-l, 4-benzodioxine (120 mg, 31% yield) and 6-bromo-3,3-dimethyl-2H-l,4-

[0737] 150

[0738] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) benzodioxine (120 mg, 34% yield) as a colorless oil. H NMR of the mixture: (400 MHz, DMSO-fifc) 5 7.10 - 6.94 (m, 2H), 6.87 - 6.76 (m, 1H), 3.95 - 3.92 (m, 2H), 1.27 (s, 6H).

[0739] Step 3: Preparation of 2-(2,2-dimethyl-2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)-4,4,5,5- tetramethyl-1 , 3, 2-dioxaborolane and 2-( 3, 3-dimethyl-2, 3-dihydrobenzo[b ][ 1, 4 ]dioxin-6-yl)~

[0740] 4.4.5.5-tetramethyl-l, 3, 2-dioxaborolane

[0741] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 2-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-

[0742] 4.4.5.5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate 1-26) and 2-(3,3-dimethyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate I- 27).

[0743] Example 20: Preparation of 2-(7-fluoro-8-methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-

[0744] 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate 1-28)

[0745] Step 1: Preparation of 5-methyl-2,3-dihydro-l,4-benzodioxine-6-diazonium tetrafluoroborate

[0746] To a mixture of 5-methyl-2,3-dihydro-l,4-benzodioxin-6-amine (1.00 g, 6.05 mmol) in THF (10 mL) was added HBF4 (6.64 g, 30.27 mmol, 40% purity). Next, isopentyl nitrite (1.63 mL, 12.11 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h, then concentrated under reduced pressure to afford 5-methyl-2,3-dihydro-l,4-benzodioxine-6-diazonium tetrafluoroborate (1.59 g, crude) as a yellow suspension. This material was used directly in the next step without further purification.

[0747] Next, 5-methyl-2,3-dihydro-l,4-benzodioxine-6-diazonium tetrafluoroborate (1.59 g, 6.02

[0748] 151

[0749] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) mmol) was dissolved in toluene (50 mL) at room temperature. The mixture was heated to 120 °C for 1 h, then concentrated under reduced pressure to afford a residue. Purification by silica gel chromatography (0-85% ethyl acetate in petroleum ether) afforded 6-fluoro-5- methyl-2,3-dihydro-l,4-benzodioxine (683 mg, 67% yield) as a colorless oil.

[0750] Step 3: Preparation of 7-bromo-6-fluoro-5-methyl-2,3-dihydro-l,4-benzodioxine

[0751] To a mixture of 6-fluoro-5-methyl-2,3-dihydro-l,4-benzodioxine (683 mg, 4.06 mmol) in MeOH (6 mL) was added NBS (722.88 mg, 4.06 mmol) in portions, and the mixture was stirred at 70 °C for 3 h. The mixture was concentrated under reduced pressure to afford a residue. Purification by silica gel chromatography (0-20% ethyl acetate in petroleum ether) afforded 7-bromo-6-fluoro-5-methyl-2,3-dihydro-l,4-benzodioxine (816 mg, 81% yield) as a colorless solid. 'H NMR: (400 MHz, DMSO-t / e) 5 6.87 (d, J= 6.8 Hz, 1H), 4.26 - 4.24 (m, 2H), 4.18 - 4.16 (m, 2H), 2.11 (d, J = 2.4 Hz, 3H).

[0752] Step 4: Preparation of 2-(7-fluoro-8-methyl-2,3-dihydrobenzo[b] [1,4] dioxin-6-yl)-

[0753] 4.4.5.5-tetramethyl-l, 3, 2-dioxaborolane

[0754] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 2-(7-fhioro-8-methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-

[0755] 4.4.5.5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate 1-28).

[0756] Example 21: Preparation of (S)-2-(2-(methoxymethyl)-2,3-dihydrobenzo[b][l,4]dioxin- 6-yl)-4,4,5,5-tetr amethyl- 1 ,3, 2-dioxaborolane (Intermediate 1-29)

[0757] Step 1: Preparation of (S)-6-bromo-2-(methoxymethyl)-2,3- dihydrobenzo b ][ 1, 4 [dioxine

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[0760] (S)-(6-bromo-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methanol (0.90 g, 3.67 mmol) and THF (10 mL) were combined, followed by NaH (0.29 g, 7.34 mmol, 60% purity) at 0 °C. The flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 0 °C under nitrogen for 15 min, then Mel (0.522 g, 3.67 mmol) was added at 0 °C. After stirring at 25 °C for 15 min under nitrogen, the reaction was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-25% ethyl acetate in petroleum ether) gave (S)-6-bromo-2- (methoxymethyl)-2,3-dihydrobenzo[b][l,4]dioxine (0.90 g, 95% yield) as a colorless solid.

[0761] Step 2: Preparation of (S)-2-(2-(methoxymethyl)-2,3-dihydrobenzo[b] [l,4]dioxin-6- yl)-4, 4, 5, 5 -tetramethyl- 1 , 3, 2-dioxaborolane

[0762] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (S)-2-(2-(methoxymethyl)-2,3-dihydrobenzo[b][l,4]dioxin-6- yl)-4, 4, 5, 5-tetramethyl- 1,3, 2-dioxaborolane (Intermediate 1-29).

[0763] Example 22: Preparation of 4,4,5,5-tetramethyl-2-(3H-spiro[benzo[b][l,4]dioxine-2,l'- cyclopropan]-6-yl)-l, 3, 2-dioxaborolane (Intermediate 1-30) l-(4-bromo-2-hydroxyphenyl)ethan-l-one (5.00 g, 23.3 mmol), DMF (50 mL), K2CO3 (6.43 g, 46.5 mmol), and l-(chloromethyl)-4-methoxybenzene (3.64 g, 23.3 mmol) were combined and stirred at 20 °C for 16 h. The mixture was quenched with H2O (50 mL) and extracted

[0764] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) with ethyl acetate (3 x 50 mL). The combined organic layers were washed with H2O (2 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-17% ethyl acetate in petroleum ether) afforded l-(4-bromo-2-((4-methoxybenzyl)oxy)phenyl)ethan-l-one (6.30 g, 80% yield) as a colorless oil. 'H NMR: (400 MHz, CDCh) 5 7.65 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 1.6 Hz, 1H), 7.16 (dd, J = 8.4, 1.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 3.84 (s, 3H), 2.53 (s, 3H). l-(4-bromo-2-((4-methoxybenzyl)oxy)phenyl)ethan-l-one ethanone (3.30 g, 9.85 mmol) and DCM (40 mL) were combined and treated with m-CPBA (5.00 g, 24.61 mmol, 85% purity) in portions at 20 °C. The mixture was stirred at 20 °C for 72 h, filtered, and the filter cake was washed with ethyl acetate (40 mL). The filtrate was diluted with H2O (40 mL), extracted with ethyl acetate (3 x 200 mL), and the combined organic layers were washed with saturated sodium sulfite solution (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (9-25% ethyl acetate in petroleum ether) afforded 4-bromo-2-((4-methoxybenzyl)oxy)phenyl acetate (2.20 g, 64% yield) as a colorless solid.

[0765] 4-bromo-2-((4-methoxybenzyl)oxy)phenyl acetate (2.20 g, 6.26 mmol) and THF (22 mL) were combined followed by addition of aqueous NaOH (4 M, 11.0 mL). The mixture was stirred at 20 °C for 2 h, then acidified to pH 3 using 1 M HC1. The mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (9-25% ethyl acetate in petroleum ether) afforded 4-bromo-2-((4-methoxybenzyl)oxy)phenol (1.90 g, 80% yield) as a colorless solid.

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[0768] Step 4: Preparation of methyl 4-bromo-2-(4-bromo-2-((4- methoxybenzyl) oxy)phenoxy) butanoate

[0769] 4-bromo-2-((4-methoxybenzyl)oxy)phenol (1.90 g, 6.15 mmol), DMF (20 mL), K2CO3 (1.70 g, 12.3 mmol), and methyl 2,4-dibromobutanoate (3.19 g, 12.3 mmol) were combined and stirred at 20 °C under nitrogen for 3 h. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with H2O (2 x 30 mL) and brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (9-17% ethyl acetate in petroleum ether) afforded methyl 4-bromo-2-(4-bromo-2-((4- methoxybenzyl)oxy)phenoxy)butanoate (2.50 g, 77% yield) as a colorless oil. LCMS m / z: [M+Na]+= 511.1.

[0770] Step 5: Preparation of methyl l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy) cyclopropane- 1 -carboxylate

[0771] Methyl 4-bromo-2-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)butanoate (2.50 g, 5.12 mmol) and THF (30 mL) were combined followed by addition of t-BuOK (0.862 g, 7.68 mmol) at 0 °C. The mixture was stirred at 20 °C under nitrogen for 3 h, then quenched with saturated aqueous ammonium chloride (30 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-17% ethyl acetate in petroleum ether) afforded methyl l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)cyclopropane-l -carboxylate (0.90 g, 38% yield) as a colorless oil. LCMS m / z: [M+Na]+= 429.0.

[0772] Step 6: Preparation of (l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl) methanol

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[0775] Methyl l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)cyclopropane-l -carboxylate (0.90 g, 2.21 mmol) and THF (5 mL) were combined at room temperature. The flask was evacuated and backfilled with nitrogen three times. Next, DIBAL-H (1 M, 11.05 mL) was added

[0776] 5 dropwise at -78 °C under nitrogen. The mixture was stirred at 20 °C for 3 h, then quenched with saturated aqueous ammonium chloride (10 mL). The mixture was filtered through a Celite® bed and eluted with ethyl acetate (20 mL). The filtrate was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

[0777] 10 Purification by silica gel chromatography (9-50% ethyl acetate in petroleum ether) afforded (l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl)methanol (0.80 g, 72% yield) as a colorless solid.

[0778] LCMS m / z: [M+Na]+= 403.0.

[0779] (l-(4-bromo-2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl)methanol (600 mg, 1.58 mmol), EtOH (60 mL), and HC1 (6 mL) were combined and stirred at 60 °C for 1 h. The mixture was diluted with H2O (20 mL) and brine (50 mL) then extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous

[0780] 20 sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (17-50% ethyl acetate in petroleum ether) afforded 5-bromo-2-(l- (hydroxymethyl)cyclopropoxy)phenol (270 mg, 55% yield) as a colorless oil. LCMS m / z: [M+H-H20]+= 240.9.

[0781] Step 8: Preparation of 6-bromo-3H-spiro [benzo [b] [1,4] dioxine-2, 1 '-cyclopropane /

[0782] 25

[0783] 156

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[0785] 5-bromo-2-(l-(hydroxymethyl)cyclopropoxy)phenol (320 mg, 1.24 mmol), PPI13 (0.356 g, 1.36 mmol), and DCM (3 mL) were combined, followed by DIAD (0.300 g, 1.48 mmol, 287.33 pL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h and concentrated under reduced pressure. Purification by preparative TLC (17% ethyl acetate in petroleum ether) gave 6-bromo-3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropane] (290 mg, 97% yield) as a colorless solid.

[0786] 'H NMR: (400 MHz, CDCI3) 5 7.07 (d, J= 2.0 Hz, 1H), 6.93 (dd, J= 8.8, 2.4 Hz, 1H), 6.67 (d, J= 8.4 Hz, 1H), 4.13 (s, 2H), 1.11 - 1.08 (m, 2H), 0.82 - 0.79 (m, 2H).

[0787] Step 9: Preparation of 4,4,5,5-tetramethyl-2-(3H-spiro[benzo[b] [l,4]dioxine-2,P- cyclopropan ]-6-yl)-l, 3, 2-dioxaborolane

[0788] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 4,4,5,5-tetramethyl-2-(3H-spiro[benzo[b][l,4]dioxine-2,l'- cyclopropan]-6-yl)-l, 3, 2-dioxaborolane (Intermediate 1-30).

[0789] Example 23: Preparation of 4,4,5,5-tetramethyl-2-(2-methyl-2,3- dihydrobenzo[b] [l,4]dioxin-6-yl)-l, 3, 2-dioxaborolane (Intermediate 1-31)

[0790] 5-bromo-2-iodophenol (10.00 g, 33.46 mmol) and l-bromopropan-2-ol (5.58 g, 40.15 mmol) were dissolved in DMF (100 mL), followed by the addition of K2CO3 (11.56 g, 83.64 mmol) and KI (2.78 g, 16.73 mmol). The mixture was stirred at 120 °C for 12 h. The reaction mixture was partitioned between H2O (70 mL) and ethyl acetate (210 mL). The organic phase was separated, washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate in petroleum ether) afforded l-(5-bromo-2-iodophenoxy)propan-2-ol (5.60 g, 47% yield) as a yellow oil.

[0791] Step 2: Preparation of 6-bromo-2-methyl-2,3-dihydrobenzo[b] [l,4]dioxine

[0792] 157

[0793] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) l-(5-bromo-2-iodophenoxy)propan-2-ol (5.60 g, 15.69 mmol) and toluene (50 mL) were combined, followed by CS2CO3 (10.22 g, 31.37 mmol), / -BuXPhos (1.33 g, 3.14 mmol), and Pd(OAc)2 (0.176 g, 0.784 mmol). The mixture was degassed and purged with nitrogen three times, then stirred at 110 °C for 12 h under nitrogen. The mixture was filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate in petroleum ether) afforded 6-bromo-2-methyl-2,3-dihydrobenzo[b][l,4]dioxine (1.90 g, 53% yield) as a colorless solid.

[0794] Step 3: Preparation of 4,4,5,5-tetramethyl-2-(2-methyl-2,3- dihydrobenzo b ][ 1, 4 ]dioxin-6-yl)-l, 3, 2-dioxaborolane

[0795] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 4,4,5,5-tetramethyl-2-(2-methyl-2,3- dihydrobenzofb] [ 1 ,4]dioxin-6-yl)- 1 ,3 , 2-dioxaborolane (Intermediate 1-31).

[0796] Example 24: Preparation of 4,4,5,5-tetramethyl-2-(3-methyl-2,3- dihydrobenzo[b] [l,4]dioxin-6-yl)-l, 3, 2-dioxaborolane (Intermediate 1-32)

[0797] Step 1: Preparation of l-(4-bromo-2-iodophenoxy)p , l-bromopropan-2-ol (2.79 g, 20.1 mmol), K2CO3 (5.78 g, 41.82 mmol), KI (1.39 g, 8.36 mmol), and 4-bromo-2-iodophenol (5.00 g, 16.73 mmol) were combined in DMF (50 mL) and stirred at 120 °C for 12 h. The reaction mixture was partitioned between H2O (70 mL) and ethyl acetate (210 mL). The organic phase was separated, washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate in petroleum ether) afforded l-(4-bromo-2- iodophenoxy)propan-2-ol (4.30 g, 63% yield) as a yellow oil. LCMS m / z: [M+H]+= 340.8.

[0798] 158

[0799] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) 4-benzodioxine l-(4-bromo-2-iodophenoxy)propan-2-ol (4.30 g, 12.05 mmol) and toluene (40 mL) were combined, followed by CS2CO3 (7.85 g, 24.09 mmol), tert-butyl XPhos (1.02 g, 2.41 mmol), and Pd(OAc)2 (0.135 g, 0.602 mmol). The mixture was stirred at 110 °C for 3 h under nitrogen, then filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate in petroleum ether) afforded 6-bromo-3-methyl-2,3- dihydro-l,4-benzodi oxine (1.20 g, 41% yield) as a colorless solid. 'H NMR: (400 MHz, DMSO-tL) 5 7.07-7.04 (m, 1H), 6.99-6.96 (m, 1H), 6.84-6.80 (m, 1H), 4.31-4.26 (m, 2H), 3.83-3.78 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H).

[0800] Step 3: Preparation of 4,4,5,5-tetramethyl-2-(3-methyl-2,3- dihydrobenzo b ][ 1, 4 ]dioxin-6-yl)-l, 3, 2-dioxaborolane

[0801] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 4,4,5,5-tetramethyl-2-(3-methyl-2,3- dihydrobenzofb] [ 1 ,4]dioxin-6-yl)- 1 ,3 , 2-dioxaborolane (Intermediate 1-32).

[0802] Example 25: Preparation of 2-(7,8-difluoro-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)- 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (Intermediate 1-33)

[0803] Step 1: Preparation of 4-bromo-2,3-difluoro-6-methoxyphenol

[0804] 2,3-Difluoro-6-methoxyphenol (1.00 g, 6.25 mmol) was dissolved in DCM (10 mL), and NBS (1.22 g, 6.87 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure. Purification by silica gel chromatography (0-12% ethyl acetate in petroleum ether) afforded 4-bromo-2,3-difluoro-6-methoxyphenol (1.30 g, 87%

[0805] 159

[0806] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) yield) as a yellow solid. ’H NMR: (400 MHz, CDCh) 5 6.80 - 6.78 (m, 1H), 5.54 (s, 1H), 3.90 (s, 3H).

[0807] Step 2: Preparation of 5-bromo-3,4-difluorobenzene-l ,2-diol

[0808] 4-Bromo-2,3-difluoro-6-methoxyphenol (1.30 g, 5.44 mmol) was dissolved in DCM (13 mL), and BBn (2 M, 4.08 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 h under nitrogen and quenched by addition of MeOH (2 mL). The mixture was diluted with DCM (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-30% ethyl acetate in petroleum ether) afforded 5-bromo-3,4-difluorobenzene-l,2-diol (1.22 g, 88% yield) as a yellow solid.

[0809] Step 3: Preparation of 7-bromo-5,6-difluoro-2,3-dihydro-l,4-benzodioxine 100 C, 2 h

[0810] 5-Bromo-3,4-difluorobenzene-l,2-diol (1.22 g, 5.42 mmol) and 1,2-dibromoethane (614 pL, 8.13 mmol) were dissolved in DMF (15 mL) followed by addition of K2CO3 (1.65 g, 11.93 mmol). The mixture was stirred at 100 °C for 2 h then cooled to room temperature. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-30% ethyl acetate in petroleum ether) afforded 7-bromo-5,6-difluoro-2,3-dihydro-l,4- benzodioxine (320 mg, 20% yield) as a yellow solid.

[0811] Step 4: Preparation of 2-(7,8-difluoro-2,3-dihydrobenzo[b] [1, 4]dioxin-6-yl)-4, 4,5,5- tetramethyl-1 , 3, 2-dioxaborolane

[0812] 160

[0813] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0814] 7-Bromo-5,6-difluoro-2,3-dihydro-l,4-benzodioxine (300 mg, 1.20 mmol) was dissolved in THF (3 mL), and z-PrMgCl LiCl (1.3 M, 4.60 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 h under nitrogen. 2-Isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.11 g, 5.98 mmol, 1.22 mL) was added, and the mixture was stirred at 25 °C for 1 h under nitrogen. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% ethyl acetate in petroleum ether) afforded 2-(5,6-difluoro-2,3- dihydro-l,4-benzodioxin-7-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1-33) (279 mg, 78% yield) as a yellow solid.

[0815] 'H NMR: (400 MHz, DMSO-fifc) 5 6.83 - 6.81 (m, 1H), 4.37 - 4.35 (m, 2H), 4.28 - 4.26 (m, 2H), 1.27 (s, 12H).

[0816] Example 26: Preparation of 3-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)methyl)-4-methylmorpholine (Intermediate 1-34) o uene, ,

[0817] A mixture of 4-bromo-3-fluoro-lH-pyrazole (0.90 g, 5.46 mmol) and (4-methylmorpholin-3- yl)methanol (787 mg, 6.00 mmol) was dissolved in toluene (10 mL). Next, triphenylphosphine (1.72 g, 6.55 mmol) and DIAD (1.27 mL, 6.55 mmol) were added at 20 °C. The flask was evacuated and backfilled with nitrogen three times. The reaction mixture was stirred at 20 °C under nitrogen for 12 h and then concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC (Phenomenex Luna 161

[0818] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0819] C18, 150 x 25 mm, 10 pm; flow rate: 25 mL / min; gradient: 5%-30% B over 15 mm; mobile phase A: 0.225% aqueous formic acid, mobile phase B: acetonitrile). After lyophilization, 3- [(4-bromo-3-fluoropyrazol-l-yl)methyl]-4-methylmorpholine was obtained as a red oil (250 mg, 746 pmol, 14% yield). LCMS m / z: [M+H]+= 280.0.

[0820] Step 2: Preparation of 3-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)methyl)-4-methylmorpholine

[0821] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 3-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)methyl)-4-methylmorpholine (Intermediate 1-34).

[0822] Example 27: Preparation of (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid (Intermediate 1-35)

[0823] Step 1: Preparation of 4-bromo-3-fluor o-l -(2,2, 2-trifluoroethyl)pyr azole

[0824] 4-Bromo-3 -fluoro- IH-pyrazole (2.00 g, 12.2 mmol) was dissolved in DMF (20 mL). 2,2,2- Trifluoroethyl trifluoromethanesulfonate (3.38 g, 14.6 mmol) and CS2CO3 (7.90 g, 24.3 mmol) were added, and the mixture was stirred at 80 °C for 1 h under nitrogen. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0- 7% ethyl acetate in petroleum ether) to afford 4-bromo-3-fluoro-l-(2,2,2- trifhioroethyl)pyrazole (1.75 g, 58% yield) as a colorless oil. LCMS m / z: [M+H]+= 248.8.

[0825] Step 2: Preparation of (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid (Intermediate 1-35).

[0826] Example 28: Preparation of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-

[0827] 162

[0828] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) lH-pyrazol-l-yl)methyl)-4-methylmorpholine (Intermediate 1-36)

[0829] Step 1: Preparation of tert-butyl 2-[(4-bromo-3-fluoro-lH-pyrazol-l- yl)methyl]morpholine-4-carboxylate

[0830] 4-Bromo-3 -fluoro- IH-pyrazole (1.50 g, 9.09 mmol) was dissolved in DMF (20 mL) followed by addition of tert-Butyl 2-(bromomethyl)morpholine-4-carboxylate (2.80 g, 10.0 mmol) and CS2CO3 (8.89 g, 27.3 mmol) at 20 °C. The mixture was heated to 80 °C for 1 h, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-33% ethyl acetate in petroleum ether) to afford tert-butyl 2-[(4-bromo-3- fluoro-lH-pyrazol-l-yl)methyl]morpholine-4-carboxylate (2.80 g, 84% yield) as a colorless oil.

[0831] LCMS m / z: [M+H - Boc]+= 265.9.

[0832] Step 2: Preparation o f2-[(4-bromo-3-fluoro-lH-pyrazol-l-yl)methyl]morpholine

[0833] Tert-butyl 2-[(4-bromo-3-fluoro-lH-pyrazol-l-yl)methyl]morpholine-4-carboxylate (2.60 g, 7.14 mmol) was dissolved in DMF (20 mL), and TFA (11.1 g, 97.3 mmol, 7.22 mL) was added at 20 °C. The mixture was stirred at 20 °C for 16 h and concentrated under reduced pressure to afford 2-[(4-bromo-3-fluoro-lH-pyrazol-l-yl)methyl]morpholine (2 g, crude, TFA salt) as a yellow solid. It was used directly in the next step without further purification.

[0834] Step 3: Preparation of 2- [(4-bromo-3-jluor o-lH-pyrazol-1 -yl)methyl] -4- methylmorpholine

[0835] 163

[0836] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0837] 2-[(4-Bromo-3-fluoro-lH-pyrazol-l-yl)methyl]morpholine (1.90 g, 7.19 mmol, TFA salt), AcOH (30.2 mg, 0.503 mmol, 28.8 pL), and formaldehyde (2.85 g, 35.2 mmol, 2.62 mL, 37% purity) were dissolved in MeOH (20 mL). NaBH(OAc)s (3.19 g, 15.1 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 2 h, quenched with brine (200 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated under reduced pressure to afford 2-[(4-bromo-3-fluoro-lH-pyrazol-l-yl)methyl]-4- methylmorpholine (1.6 g, crude) as a yellow solid. It was used directly in the next step without further purification.

[0838] LCMS m / z: [M+H]+ = 278.0.

[0839] Step 4: Preparation of 2-((3-jluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)methyl)-4-methylmorpholine

[0840] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)methyl)-4-methylmorpholine (Intermediate 1-36).

[0841] Example 29: Preparation of (R)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-37)

[0842] Step 1: Preparation of 4-bromo-3-fluoro-l-[(3R)-tetrahydrofuran-3-yl]pyrazole , - , .

[0843] 4-Bromo-3 -fluoro- IH-pyrazole (1.00 g, 6.06 mmol), (3S)-tetrahydrofuran-3-ol (550 mg, 6.24 mmol), and PPhi (2.38 g, 9.09 mmol) were dissolved in THF (10 mL) at room temperature. Next, DIAD (1.84 g, 9.09 mmol, 1.76 mL) was added at 0 °C. The mixture was stirred at 20 °C for 0.5 h and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in petroleum ether) to afford 4-bromo-3- 164 IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) fhioro-l-[(3R)-tetrahydrofuran-3-yl]pyrazole (1.70 g, 95% yield) as a yellow oil. LCMS m / z: [M+H]+= 235.0.

[0844] Step 2: Preparation of (R)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-

[0845] 1.3.2 -dioxaborolan-2-y I)- IH-pyrazole

[0846] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (R)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-

[0847] 1.3.2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-37).

[0848] Example 30: Preparation of (S)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-38)

[0849] To a solution of 4-bromo-3 -fluoro- IH-pyrazole (1.00 g, 6.06 mmol), (3R)-tetrahydrofuran-3- ol (550 mg, 6.24 mmol, 502 pL) and PPhi (2.38 g, 9.09 mmol) in THF (10 mL) was added DIAD (1.84 g, 9.09 mmol, 1.76 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in petroleum ether) to afford 4-bromo-3- fhioro-l-[(3S)-tetrahydrofuran-3-yl]pyrazole (1.10 g, 62% yield) as a yellow oil. LCMS m / z: [M+H]+= 235.0.

[0850] Step 2: Preparation of (S)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-

[0851] 1.3.2 -dioxaborolan-2-y I)- IH-pyrazole

[0852] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (S)-3-fluoro-l-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-

[0853] 1.3.2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-38).

[0854] Example 31: Preparation of l-(cyclopropylmethyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-39)

[0855] 165

[0856] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0857] 4-bromo-3-fluoro-lH-pyrazole (0.500 g, 3.03 mmol) was dissolved in DMF (10 mL). K2CO3 (0.964 g, 6.97 mmol) and bromomethylcyclopropane (0.347 mL, 3.64 mmol) were added at 25 °C, and the reaction mixture was stirred for 4 h. The mixture was quenched by slow addition of H2O (15 mL), transferred to a separatory funnel, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-5% ethyl acetate in petroleum ether) to afford 4-bromo- 1 -(cy cl opropylmethyl)-3 -fluoro- IH-pyrazole (0.548 g, crude) as a colorless oil. ’H NMR: (400 MHz, DMSO-t / e) 5 7.99-7.94 (m, 1H), 3.83 (d, J = 7.2 Hz, 2H), 1.21-1.14 (m, 1H), 0.55-0.49 (m, 2H), 0.36-0.29 (m, 2H).

[0858] Step 2: Preparation of l-(cyclopropylmethyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0859] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide l-(cyclopropylmethyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-39).

[0860] Example 32: Preparation of l-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)-2-methylpropan-2-ol (Intermediate 1-40)

[0861] A mixture of 4-bromo-3-fluoro-lH-pyrazole (2 g, 12.12 mmol), CS2CO3 (11.85 g, 36.37

[0862] 166

[0863] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) mmol), and CH3CN (20 mL) was treated dropwise with 2,2-dimethyloxirane (1.31 g, 18.19 mmol, 1.61 mL) at 25 °C. The mixture was heated to 80 °C and stirred for 5 h, then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford l-(4- bromo-3-fluoropyrazol-l-yl)-2-methylpropan-2-ol (2.4 g, crude) as a yellow oil. LCMS m / z: [M+H]+= 238.9.

[0864] Step 2: Preparation of l-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)~ lH-pyrazol-l-yl)-2-methylpropan-2-ol

[0865] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide l-(3-fhioro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)-2-methylpropan-2-ol (Intermediate 1-40).

[0866] Example 33: Preparation of (lS,2S)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropane-l-carbonitrile (Intermediate 1-41) 2-(4-bromophenyl)cyclopropane-l -carboxamide

[0867] A solution of (lS,2S)-2-(4-bromophenyl)cyclopropane-l-carboxylic acid (1.00 g, 4.15 mmol) and NH4CI (2.22 g, 41.5 mmol) in DMF (10 mL) was treated with DIEA (20.7 mmol, 3.61 mL) and HATU (2.37 g, 6.22 mmol) at 25 °C. The mixture was stirred for 1 h, then quenched with H2O (15 mL), extracted with ethyl acetate (2 x 15 mL), washed with brine (2 x 20 mL), dried over Na?SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-33% ethyl acetate in petroleum ether) to afford (lS,2S)-2-(4-bromophenyl)cyclopropane-l-carboxamide (1.00 g, >95% yield) as a colorless solid. LCMS m / z: [M+H]+ = 240.0, 242.0.

[0868] Step 2: Preparation of (lS,2S)-2-(4-bromophenyl)cyclopropane-l -carbonitrile

[0869] 167 IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0870] A solution of (lS,2S)-2-(4-bromophenyl)cyclopropane-l-carboxamide (920 mg, 3.83 mmol) in ACN (15 mL) was treated with POCI3 (9.98 mmol, 930 pL) at 25 °C. The mixture was heated to 80 °C and stirred for 0.5 h, then added dropwise to JLO (30 mL). The pH was adjusted to 8 using saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 30 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-9% ethyl acetate in petroleum ether) to afford (lS,2S)-2-(4- bromophenyl)cyclopropane-l -carbonitrile (805 mg, 95%) as a colorless solid. 'H NMR: (400 MHz, DMSO-fifc) 5 7.49 (d, J= 8.4 Hz, 2H), 7.17 (d, J= 8.4 Hz, 2H), 2.72 (ddd, J= 4.8, 6.4, 9.2 Hz, 1H), 2.12 - 2.00 (m, 1H), 1.62 (td, J= 5.6, 9.2 Hz, 1H), 1.54 - 1.41 (m, 1H).

[0871] Step 3: Preparation of (lS,2S)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropane-l-carbonitrile

[0872] The aryl bromide obtained above was subjected to the borylation procedure described in example 15, step 5 to provide (lS,2S)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropane-l -carbonitrile (Intermediate 1-41).

[0873] Example 34: Preparation of 3-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)azetidine-3-carbonitrile (Intermediate 1-

[0874] A mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.50 g, 8.83 mmol), 3 -methylazetidine-3 -carbonitrile hydrochloride (1.52 g, 11.5 mmol), XantPhos Pd G3 (838 mg, 0.883 mmol), and CS2CO3 (8.64 g, 26.5 mmol) in dioxane (30 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100 °C for 1 h under nitrogen then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether), followed by a second

[0875] 168

[0876] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) purification (0-18% ethyl acetate in petroleum ether), to afford 3 -methyl- 1-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine-3-carbonitrile (Intermediate 1-42) (1.00 g, 29% yield) as a colorless solid. LCMS m / z: [M+H]+= 299.2.

[0877] Example 35: Preparation of 6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-

[0878] 2-oxa-6-azaspiro [3.3] heptane (Intermediate 1-43)

[0879] A solution of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.00 g, 3.53 mmol) in dioxane (15 mL) was treated with cesium carbonate (3.45 g, 10.6 mmol), XantPhos Pd G3 (335 mg, 0.353 mmol), and 2-oxa-6-azaspiro[3.3]heptane HCl (719 mg, 5.30 mmol) at 25 °C. The flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 100 °C under nitrogen for 1 h, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-25% ethyl acetate in petroleum ether) to afford 6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- oxa-6-azaspiro[3.3]heptane (Intermediate 1-43) (500 mg, 47% yield) as a colorless solid. LCMS m / z: [M+H]+ = 302.1.

[0880] Example 36: Preparation of (R)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidine-3-carbonitrile (Intermediate 1-44)

[0881] A mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.00 g, 3.53 mmol), (3R)-pyrrolidine-3 -carbonitrile hydrochloride (937 mg, 7.07 mmol), CS2CO3 (3.45 g, 10.6 mmol), and XantPhos Pd G3 (335 mg, 0.353 mmol) in dioxane (15 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 1 h under nitrogen, then concentrated under reduced pressure. The crude product was purified by silica

[0882] 169

[0883] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) gel chromatography (0-13% ethyl acetate in petroleum ether) to afford (R)-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-3-carbonitrile (Intermediate 1-44) (240 mg, 19% yield) as a pink solid. LCMS m / z: [M+H]+= 299.1.

[0884] Example 37: Preparation of 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 6-oxa-2-azaspiro [3.4] octane (Intermediate 1-45)

[0885] Step 1: Preparation / 2-(4-bromophenyl)-6-oxa-2-azaspiro[3.4]octane

[0886] A solution of 6-oxa-2-azaspiro[3.4]octane HCl (600 mg, 4.01 mmol), (4- bromophenyl)boronic acid (966 mg, 4.81 mmol), and TEA (20.0 mmol, 2.79 mL) in DCM (10 mL) was treated with Cu(OAc)2 (728 mg, 4.01 mmol). The flask was evacuated and backfilled with oxygen three times. The mixture was stirred at 25 °C under oxygen for 12 h, then filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-9% ethyl acetate in petroleum ether) to afford 2-(4-bromophenyl)-6-oxa-2-azaspiro[3.4]octane (466 mg, 40% yield) as a colorless solid. LCMS m / z: [M+H]+= 268.0.

[0887] Step 2: Preparation of 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-6- oxa-2-azaspiro[ 3.4 ] octane

[0888] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-6- oxa-2-azaspiro[3.4]octane (Intermediate 1-45).

[0889] Example 38: Preparation of l-ethyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-

[0890] 2-yl)-lH-pyrazole (Intermediate 1-46)

[0891] Step 1: Preparation of 4-bromo-l-ethyl-3-fluoro-pyr azole

[0892] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0893] A solution of 4-bromo-3 -fluoro- IH-pyrazole (150 g, 303 mmol) in DMF (1500 mL) was treated with EtI (56.7 g, 364 mmol, 29.1 mL) and K2CO3 (126 g, 909 mmol). The reaction mixture was stirred at 60 °C for 1 h, then diluted with JLO (1000 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with H2O (200 mL) and brine (3 x 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. 4- bromo-l-ethyl-3-fluoro-pyrazole (150 g, 85% yield) was obtained as a yellow oil. LCMS m / z: [M+H]+= 195.1.

[0894] Step 2: Preparation of l-ethyl-3-jluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyr azole

[0895] A mixture of 4-bromo-l-ethyl-3-fluoro-pyrazole (12.0 g, 62.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (19.0 g, 74.6 mmol), dioxane (120 mL), Pd(dppf)C12 (4.55 g, 6.22 mmol), and KOAc (12.2 g, 124 mmol) was combined at 25 °C. The reaction vessel was evacuated and backfilled with nitrogen three times, then the reaction mixture was stirred at 100 °C under nitrogen for 1 h. The reaction mixture was diluted with JLO (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-8% ethyl acetate in petroleum ether) to afford l-ethyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole (Intermediate 1-46) (5.01 g, 48% yield) as a yellow oil. LCMS m / z: [M+H]+= 241.1.

[0896] Example 39: Preparation of 3-fluoro-l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-47)

[0897] 171

[0898] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0899] Step 1: Preparation of 4-bromo-3-fluoro-l-(methyl-d3)-lH-pyrazole

[0900] A solution of 4-bromo-3 -fluoro- IH-pyrazole (197.0 g, 1.19 mol), K2CO3 (330.0 g, 2.39 mol) and DMF (985 mL) was treated with CD3I (258.7 g, 1.78 mol) at 20 °C. After 1 hour, the reaction mixture was poured into water (3 L) and extracted with ethyl acetate (3 x 2 L). The combined organic extracts were washed with 5 wt.% aq. LiCl (3 x 1 L) and brine (3 x 1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was dissolved in hexane (1 L) at 20 °C and cooled to ~ -20 to -30 °C until large quantities of solids began to precipitate. The solids were filtered and washed with cold (ca. -20 to -30 °C) hexane (200 mL). The solids (low melting point) were dried at 35 °C under reduced pressure to afford 4-bromo-3-fluoro-l-(methyl-d3)-lH-pyrazole (164 g, 73% yield) as a yellow oil.

[0901] Step 2: Preparation of 3-fluoro-l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0902] A solution of 4-bromo-3-fhioro-l-(methyl-d3)-lH-pyrazole (194.8 g, 1.07 mol) and B(OPr)3 (300.9 g, 1.60 mol) in THF (1.95 L) was cooled to between -90 to -100 °C. Next, the mixture was treated with w-BuLi (1.39 mol) and allowed to react at -90 to -100 °C for 30 minutes. At this point, 2M aq. NaOH (975 mL) was added to the mixture, and it was allowed to warm to room temperature. The layers were separated, and the aqueous phase was extracted with MTBE (975 mL). The organic phase was discarded. The aqueous phase was acidified with concentrated HC1 to pH ~7 and then 2M aq. HC1 to pH 5-6. Next, this mixture was extracted with ethyl acetate (2 x 1.95 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo at 35 °C. This afforded crude material which was used in the next step without further purification.

[0903] To the crude material obtained above was added pinacol (126.4 g, 1.07 mol) and THF (1.95 L) at room temperature. The resulting mixture was stirred for 18 hours, concentrated in 172

[0904] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) vacuo at 35 °C, and subsequently azeotropically distilled with heptane (400 mL). The solids obtained were slurried with heptane (400 mL) and filtered to afford 3-fluoro-l-(methyl-d3)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-47) (181.5 g, 76% yield) as a colorless solid. LCMS m / z: [M+H]+= 230.1.

[0905] Example 40: Preparation of 2-(6-fluoro-2,3-dihydro-l,4-benzodioxin-7-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (Intermediate 1-48)

[0906] A solution of 6-bromo-7-fluoro-2,3-dihydro-l,4-benzodioxine (700 mg, 3.00 mmol) in THF (8 mL) was treated with z-PrMgCl (2 M, 3.75 mL, 7.50 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h, then 2-methoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (1.42 g, 9.01 mmol) in THF (8 mL) was added at 25 °C under N2. After stirring at 25 °C for 50 min, the mixture was poured into NH4Q solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-11% ethyl acetate in petroleum ether) to afford 2-(6-fluoro-2,3- dihydro-l,4-benzodioxin-7-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1-48) (0.45 g, 53% yield) as a colorless solid.

[0907] >H NMR: (400 MHz, CDCh) 5 7.13 (d, J = 5.6 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 4.22-4.16 (m, 2H), 4.15-4.11 (m, 2H), 1.26 (s, 12H).

[0908] Example 41: Preparation of l-cyclopropyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-49)

[0909] Step 1: Preparation of 4-bromo-l-cyclopropyl-3-jluoro-lH-pyrazole

[0910] 173

[0911] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0912] To a solution of 4-bromo-3 -fluoro- IH-pyrazole (6.0 g, 36.4 mmol) in 1,4-dioxane (60 mL) was added cyclopropylboronic acid (7.81 g, 90.9 mmol), Cu(OAc)2 (6.61 g, 36.4 mmol), DMAP (17.8 g, 145.5 mmol), and pyridine (7.34 mL, 90.9 mmol) at 25 °C. Next, the reaction vessel was evacuated and backfilled with oxygen (3x), and the mixture was heated to 95 °C for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (200 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0-9% ethyl acetate in petroleum ether) to afford 4- bromo-l-cyclopropyl-3-fluoro-lH-pyrazole (4.3 g, 52% yield) as a yellow oil. LCMS m / z: [M+H]+= 206.8.

[0913] Step 2: Preparation of l-cyclopropyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0914] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide l-cyclopropyl-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- IH-pyrazole (Intermediate 1-49).

[0915] Example 42: Preparation of (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid (Intermediate 1-50)

[0916] Step 1: Preparation of 4-bromo-3-fluor o-l -(2,2, 2-trifluoroethyl)pyr azole

[0917] 4-Bromo-3 -fluoro- IH-pyrazole (2.00 g, 12.2 mmol) was dissolved in DMF (20 mL). 2,2,2- Trifluoroethyl trifluoromethanesulfonate (3.38 g, 14.6 mmol) and CS2CO3 (7.90 g, 24.3 mmol) were added, and the mixture was stirred at 80 °C for 1 h under nitrogen. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The 174

[0918] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0- 7% ethyl acetate in petroleum ether) to afford 4-bromo-3-fluoro-l-(2,2,2- trifhioroethyl)pyrazole (1.75 g, 58% yield) as a colorless oil. LCMS m / z: [M+H]+= 248.8.

[0919] Step 2: Preparation of (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid

[0920] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (3-fluoro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)boronic acid (Intermediate 1-50). ^Isolation afforded the boronic acid and not the boronic ester.

[0921] Example 43: Preparation of (S)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-51)

[0922] A solution of (2R)-butan-2-ol (3.00 g, 40.5 mmol) in DCM (20 mL) was treated with TEA (121 mmol, 16.9 mL), 4-methylbenzenesulfonyl chloride (9.26 g, 48.6 mmol), and DMAP (989 mg, 8.09 mmol) at 25 °C. The flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 25 °C under nitrogen for 2 h, then quenched by slow addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with DCM (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-1% ethyl acetate in petroleum ether) to afford (R)-sec-butyl 4-methylbenzenesulfonate (2.78 g, 24%) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 = 0.83 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.51-1.58 (m, 1H), 1.59-1.68 (m, 1H), 2.45 (s, 3H), 4.57 (sxt, J = 6.0 Hz, 1H), 7.34 (br d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H).

[0923] Step 2: Preparation of (S)-4-bromo-l-(sec-butyl)-3-fluoro-lH-pyrazole

[0924] 175

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[0926] A solution of 4-bromo-3 -fluoro- IH-pyrazole (1.50 g, 9.09 mmol) and (R)-sec-butyl 4- (2.49 g, 10.9 mmol) in DMF (45 mL) was treated with CS2CO3 (8.89 g, 27.28 mmol) at 50 °C and stirred for 1 h. The mixture was quenched with H2O (80 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-1% ethyl acetate in petroleum ether) to afford (S)-4-bromo- l-(sec-butyl)-3 -fluoro- IH-pyrazole (1.40 g, 64%) as a yellow oil. LCMS m / z: [M+H]+= 221.1, 223.1.

[0927] Step 3: Preparation of (S)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0928] The aryl bromide obtained above was subjected to the borylation procedure described in example 15, step 5 to provide (S)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- IH-pyrazole (Intermediate 1-51).

[0929] Example 44: Preparation of (R)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-52)

[0930] A solution of (2S)-butan-2-ol (2.00 g, 27.0 mmol) in DCM (50 mL) was treated with TEA (81.0 mmol, 11.3 mL), 4-methylbenzenesulfonyl chloride (6.17 g, 32.4 mmol), and DMAP (659 mg, 5.40 mmol) at 25 °C. The flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 25 °C under nitrogen for 1 h then quenched with H2O (35 mL). The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with H2O (3 x 35 mL) and brine (2 x 35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to afford (S)-sec-butyl 4- methylbenzenesulfonate (3.20 g, 52%) as a colorless oil. 'H NMR: (400 MHz, CDCI3) 5 = 7.80 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.61-4.51 (m, 1H), 2.45 (s, 3H), 1.68-1.52 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H).

[0931] 176

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[0933] A solution of (S)-sec-butyl 4-methylbenzenesulfonate (2.49 g, 10.9 mmol) in DMF (40 mL) was treated with CS2CO3 (8.89 g, 27.3 mmol) and 4-bromo-3-fluoro-lH-pyrazole (1.50 g, 9.09 mmol) at 25 °C. The flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 50 °C under nitrogen for 2 h, then quenched with H2O (35 mL). The mixture was extracted with ethyl acetate (2 x 30 mL), washed with H2O (3 x 35 mL), then washed with brine (2 x 35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-15% ethyl acetate in petroleum ether), followed by preparative HPLC (Phenomenex Luna C 18, 150 x 25 mm, 10 pm; flow rate: 25 mL / min; 38-68% acetonitrile in 0.1% aqueous formic acid over 12 min). The mixture was concentrated under reduced pressure to afford (R)-4-bromo-l-(sec- butyl)-3-fhioro-lH-pyrazole (1.80 g, 84%) as a yellow oil. LCMS m / z: [M+H]+= 220.9.

[0934] Step 3: Preparation of (S)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0935] The aryl bromide obtained above was subjected to the borylation procedure described in Example 15, Step 5 to provide (R)-l-(sec-butyl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (Intermediate 1-52).

[0936] Example 45: Intermediates Prepared According to Example 15, Step 5 (Intermediates I- 53 through 1-56)

[0937] The intermediates described herein may be prepared according to the scheme described in Example 15 (in particular from Example 15, Step 5), for example, from an intermediate as prepared in “Preparation of Intermediates,” an intermediate that is commercially available, an intermediate as prepared elsewhere in this application, or an intermediate that can be synthesized via a method known to those skilled in the art. An exemplary full synthesis is provided in any of the previous Examples, such as Example 15. Compounds prepared in accordance with the scheme described in Example 15, Step 5 are provided in Table 4 below.

[0938] Table 4. Structures of intermediates.

[0939] 177

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[0941] Example 46: Preparation of tert-butyl ((ls,4s)-4-(8-bromo-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)carbamate (Intermediate 1-57)

[0942] To a round bottom flask was added tert-butyl ((ls,4s)-l-methyl-4-(3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclohexyl)carbamate (Intermediate 1-15, 1.0 g, 1.9 mmol) and dichloromethane (50 mL). The reaction vessel was cooled to 0 °C and bromine (0.12 mL, 2.2 mmol) was added

[0943] 10 dropwise. The reaction mixture was brought to room temperature and stirred for 16 h. The mixture was quenched with saturated aqueous sodium thiosulfate (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 - 100% EtOAc in hexanes) to afford tert-butyl ((ls,4s)-4-(8-bromo-3-

[0944] 15 methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-

[0945] 178

[0946] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) l-methylcyclohexyl)carbamate (Intermediate 1-57, 0.62 g, 54%) as a white solid. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 618.2 / 620.2.

[0947] Example 47: Preparation of tert-butyl ((ls,4s)-4-(8-(4-methoxyphenyl)-3-methyl-2-oxo- 6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)carbamate (Intermediate 1-58)

[0948] To a 8 mL vial was added tert-butyl ((ls,4s)-4-(8-bromo-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)carbamate (Intermediate 1-57, 1.0 g, 1.6 mmol), 1,4-di oxane (10 mL), and H2O (2 mL). CS2CO3 (1.6 g, 4.9 mmol), Pd(dppf)C12 (0.24 g, 0.32 mmol) and 2-(4- methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.76 g, 3.2 mmol) were added and the mixture was sparged with nitrogen for 5 min then stirred at 100 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 - 15% EtOAc in petroleum ether) to give tert-butyl ((ls,4s)-4-(8-(4- methoxyphenyl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)-l-methylcyclohexyl)carbamate (Intermediate 1-58, 1.0 g, 75% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 646.0.

[0949] Example 48: Preparation of tert-butyl ((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)-l-methylcyclohexyl)carbamate (Intermediate 1-59)

[0950] 179

[0951] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0952] To a solution of tert-butyl ((ls,4s)-4-(8-(4-methoxyphenyl)-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)carbamate (Intermediate 1-58, 0.90 g, 1.4 mmol) in DCE (10 mL) was added NBS (0.25 g, 1.4 mmol). The mixture was stirred at 60 °C for 0.5 h. The reaction mixture was quenched with sodium bicarbonate (10 mL) at 25 °C, diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 - 20% EtOAc in petroleum ether) to give tert-butyl ((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)carbamate (Intermediate 1-59, 0.47 g, 47% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 724.2 / 726.2.

[0953] Example 49: Preparation of l-((ls,4s)-4-amino-4-methylcyclohexyl)-7-bromo-8-(4- methoxyphenyl)-3-methyl-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2(lH)-one (Intermediate 1-60)

[0954] To a 50 mL flask was added tert-butyl ((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)- l-methylcyclohexyl)carbamate (Intermediate 1-59, 0.80 g, 1.1 mmol) and DCM (5 mL).

[0955] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0956] TFA (0.41 mL, 5.5 mmol) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give l-((ls,4s)-4-amino-4- methylcyclohexyl)-7-bromo-8-(4-methoxyphenyl)-3-methyl-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one, Trifluoroacetic acid (Intermediate 1-60) as a black oil that was used directly in the next step. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 624.2 / 626.2.

[0957] Example 50: Preparation of N-((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3-methyl-2- oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)cyclopropanecarboxamide (Intermediate 1-61)

[0958] To a solution of l-((ls,4s)-4-amino-4-methylcyclohexyl)-7-bromo-8-(4- methoxyphenyl)-3-methyl-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2(lH)-one (Intermediate 1-60, 6.0 g, 9.6 mmol) in DCM (40 mL) was added TEA (6.0 mL, 43 mmol) and cyclopropanecarbonyl chloride (1.0 mL, 11 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, warmed to 25 °C and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 - 11% EtOAc in petroleum ether) to give N-((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)- l-methylcyclohexyl)cyclopropanecarboxamide (Intermediate 1-61, 4.0 g, 60% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 692.2 / 694.2.

[0959] Example 51: Preparation of N-((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3-methyl-2- oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)cyclopropanecarboxamide (Intermediate 1-62)

[0960] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0961] To an 8 mL vial was added N-((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3-methyl-2- oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)-l- methylcyclohexyl)cyclopropanecarboxamide (Intermediate 1-61, 0.15 g, 0.22 mmol), MeOH (2 mL) and K2CO3 (0.090 g, 0.65 mmol). The mixture was stirred at 80 °C for 1 h and cooled to 25 °C. The suspension was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (35% - 65% MeCN in 0.05% aqueous formic acid). The fractions containing the product were lyophilized to obtain N-((ls,4s)-4-(7-bromo-8-(4-methoxyphenyl)-3-methyl-2-oxo-3,6- dihydroimidazo[4, 5-d]pyrrolo[2,3 -b]pyridin- 1 (2H)-yl)- 1 - methylcyclohexyl)cyclopropanecarboxamide (Intermediate 1-62, 0.050 g, 42% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos) m / z: [M+H]+= 552.2 / 554.2.

[0962] Preparation of Compounds of the Disclosed Formulas

[0963] Example 52: Preparation of Ethyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4- yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and Ethyl ((lR,3R)-3-(7-(3- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2- oxo-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 1 and Compound 2)

[0964] 182

[0965] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[0966] Step 1: To a solution of tert-butyl ((lR,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (prepared according to Intermediate 1-11, 0.8 g, 1.348 mmol, 1.0 equiv.) in 1,4-dioxane (5 mL), water (2.0 mL) was added a mixture of 3-fhioro-l-(methyl- d3)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole and 5-fluoro-l-(methyl-d3)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.28 g, 1.2 mmol). To this was added cesium carbonate (1.3 g, 4.0 mmol) and the resulting mixture was degassed with argon for 10 min. Tetrakis(triphenylphosphine)palladium (0) (0.16 g, 0.14 mmol) was added to the resulting reaction mixture and stirred at 105 °C for 3 h under argon atmosphere. The resulting reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL), washed with saturated brine solution, dried over sodium sulfate, concentrated under reduced pressure to obtain 1 g of crude product. The crude was purified by Combi-Flash column chromatography (100-200 mesh silica gel, 40-80% ethyl acetate in pet ether as an eluent) to obtain the product as a mixture of tert-butyl ((lR,3R)-3-(7-(3-fhioro-l-(methyl-d3)- lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H) yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(7-(5- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate. (0.250 g, 30% yield) as a pale yellow solid.

[0967] LCMS m / z: [M+H]+= 616.24, 616.24.

[0968] Step 2: To a stirred solution of tert-butyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H) yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl- d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.25 g, 0.41 mmol) in DCM (4.0 183

[0969] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) mL) was added bromine, (71 mg, 0.447 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and then extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine solution (30 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude mixture of tert-butyl ((lR,3R)-3-(8- bromo-7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and tertbutyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-

[0970] 6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.25 g, 89%) as a pale yellow solid. LCMS m / z: [M+H]+= 694.18, 696.11.

[0971] Step 3: To a stirred solution of tert-butyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-(methyl- d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(8-bromo-

[0972] 7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.25 g, 0.36 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.55 mL, 7.2 mmol, 20 equiv.) drop wise at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. After completion, volatiles were removed under reduced pressure. The residue was dissolved in 10% methanol / DCM, washed with saturated sodium bicarbonate solution followed by brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude as mixture of l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(3-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2(lH)-one and l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(5-fluoro-l-(methyl- d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2(lH)-one (0.20 g, 93.4%) as pale brown gum. LCMS m / z: [M+H]+= 594.03, 596.02.

[0973] Step 4: To a stirred solution of l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(3- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one and l-((lR,3R)-3-aminocyclopentyl)-

[0974] 8-bromo-7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one (0.20 g, 0.34 mmol) in dichloromethane (2.0 mL) was added triethylamine (0.14 mL, 1.0 mmol) followed by ethyl

[0975] 184

[0976] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) chloroformate (55 mg, 0.51 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and then extracted with 10% methanol / DCM (2 x 10 mL). The combined organic layer was washed with brine solution (20 mL). The organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude as a mixture of ethyl ((lR,3R)-3-(8- bromo-7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and ethyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.18 g, 80%) as a pale yellow gum. LCMS m / z: [M+H]+= 666.13, 668.09.

[0977] Step 5: To a stirred solution of ethyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-(methyl-d3)- lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and ethyl ((lR,3R)-3-(8-bromo-7- (5 -fluoro- 1 -(methyl -ds)- 1 H-pyrazol-4-yl)-3 -(methyl-d3)-2-oxo-6-(phenyl sulfonyl)-3 , 6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (170 mg, 0.255 mmol, 1.0 equiv.) in 1,4-dioxane (3.0 mL), water (1.0 mL) was added ( 1 -isopropyl- 1H- indazol-5-yl)boronic acid (52.038 mg, 0.255 mmol, 1.0 equiv.) and cesium carbonate (249 mg, 0.765 mmol, 3.0 equiv.) and the resulting mixture was degassed with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (29.472 mg, 0.026 mmol, 0.1 equiv.) was added to the resulting reaction mixture and stirred at 105 °C for 3 h under argon atmosphere. The resulting reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), washed with saturated brine solution, dried over sodium sulfate, concentrated under reduced pressure to obtain 250 mg of crude product. The crude was purified by column chromatography (100-200 mesh silica gel, 35-70% ethyl acetate in pet ether as an eluent) to obtain the product as mixture of ethyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4- yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and ethyl ((lR,3R)-3-(7-(5-fhioro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3- (methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (180 mg, 94.6 %) as a pale yellow gum. LCMS m / z: [M+H]+= 746.31, 746.35.

[0978] Step 6 : A stirred solution of ethyl ((lR,3R)-3-(7-(3-fhioro-l-(methyl-d3)-lH-

[0979] 185

[0980] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and ethyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3- (methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (0.24 g, 0.32 mmol) in tetrahydrofuran (dry) (5.0 mL) was cooled at 0 °C. To this was added drop-wise tetra butylammonium fluoride (1.3 mL, 1.3 mmol). The resulting reaction mixture was heated at 60 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to obtain the crude material. The residue was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (4 x 20 mL). The organic extract was dried over sodium sulphate filtered and concentrated under reduced pressure to obtain a desired product (190 mg) as pale yellow oil. The crude compound was purified by prep-HPLC reverse phase to obtain pure compounds Peak-1 ethyl ((lR,3R)-3-(7-(5-fhioro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Compound 1, 10 mg, 5.3%) and Peak-2 ethyl ((lR,3R)-3-(7-(3- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 2, 16 mg, 8.1%) as a white solid. Compound 1: Peak 1, LCMS m / z: [M+H]+= 606.53; Compound 2: Peak 2, LCMS m / z: [M+H]+= 606.49.

[0981] Example 53: Preparation of Methyl ((lR,3R)-3-(7-(5-fluoro-l-methyl-lH-pyrazol-4-yl)- 8-(l-isopropyl-lH-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 3)

[0982] Step 1: To a stirred solution of tert-butyl ((lR,3R)-3-(7-bromo-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (prepared according to Intermediate 1-11, 0.7 g, 1.179 mmol, 1

[0983] 186

[0984] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) equiv.) and a mixture of 3-fluoro-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- IH-pyrazole, 5-fluoro-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.27 g, 1.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at rt was added tri-potassium phosphate (0.75 g, 3.5 mmol). The reaction mixture was purged with argon for 15 mins, followed by addition of tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol). The resulting reaction mixture was heated at 105 °C for 3 h. The reaction mixture was filtered through a Celite® bed and filtrate was dried over Na2SO4. The volatiles were removed under reduced pressure to get the crude product. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. Pure fractions were concentrated to afford a mixture of tert-butyl ((lR,3R)-3-(7-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(7-(5-fluoro-l-methyl-lH-pyrazol-4-yl)- 3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.33 g, 0.54 mmol, 45% yield) as a yellow solid. LCMS m / z: [M+H]+= 610.12.

[0985] Step 2: A stirred solution of a mixture of tert-butyl ((lR,3R)-3-(7-(3-fluoro-l- methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(7-(5- fluoro-l-methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.30 g, 0.49 mmol) in dichloromethane (10 mL) was cooled to 0 °C. To this was added bromine (0.093 g, 0.59 mmol) dissolved in DCM (0.1 mL). The resulting reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into saturated sodium thiosulphate solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material as a mixture of tert-butyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-3-methyl- 2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l-methyl-lH- pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.30 g, 0.44 mmol, 88% yield) as yellow solid. LCMS m / z: [M+H]+= 688.30, 690.31.

[0986] Step 3: A stirred solution of tert-butyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-

[0987] 187

[0988] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) b]pyndin-l(2H)-yl)cyclopentyl)carbamate and tert-butyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l- methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.35 g, 0.51 mmol, ) in methylene chloride (5 mL) was cooled at 0 °C. To this was dropwise added trifluoroacetic acid (0.78 mL, 10 mmol). The resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to get the crude material dissolved in 20% MeOH- DCM and washed with saturated NaHCCh solution. The organic extracts were dried over sodium sulphate filtered and concentrated under reduced pressure to get a mixture of 1- ((lR,3R)-3-aminocy cl opentyl)-8-bromo-7-(3-fluoro-l -methyl- lH-pyrazol-4-yl)-3-methyl-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one and 1-((1R,3R)- 3-aminocyclopentyl)-8-bromo-7-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-3-methyl-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one (0.28 g, 0.48 mmol, 93% yield) as a yellow semi-solid. LCMS m / z: [M]+= 588.08, 589.94.

[0989] Step 4: To a stirred solution of l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(3- fluoro-l-methyl-lH-pyrazol-4-yl)-3-methyl-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2(lH)-one and l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(5- fluoro-l-methyl-lH-pyrazol-4-yl)-3-methyl-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2(lH)-one (280 mg, 0.476 mmol, 1 equiv.) in methylene chloride (5 mL) at room temperature was added triethylamine (0.33 mL, 2.4 mmol,). To this was added methyl carbonochloridate (90 mg, 0.95 mmol) at 0 °C. The resulting reaction mixture was stirred for 1 h. The progress of reaction was monitored by LCMS and TLC (SiCh, 100% Ethyl acetate / Hexane, UV active) The reaction mixture poured into water (50 mL) and extracted with DCM (2 x 50 mL). The organic layer was dried over Na2SO4 volatiles were removed under reduced pressure to get crude product. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. Pure fractions were concentrated to afford mixture of methyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l- methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.3 g, 0.46 mmol, 97%) as a yellow solid. LCMS m / z: [M+2H]+= 647.99, 648.03.

[0990] Step 5: To a stirred solution of methyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-

[0991] 188

[0992] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) b]pyndin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l- methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (80 mg, 0.124 mmol, 1 equiv.) was added (l-isopropyl-lH-indazol-5-yl) boronic acid (64 mg, 0.309 mmol, 2.5 equiv.) in 1,4- dioxane (4 mL) water (0.5 mL) at rt. To this was added cesium carbonate (0.12 g, 0.37 mmol). The resulting reaction mixture was purged with argon for 15 min followed by addition of tetrakis(triphenylphosphine)palladium (14.3 mg, 0.012 mmol). The resulting reaction mixture was heated at 100 °C for 3 h. The reaction mixture was filtered through a Celite® bed and filtrate was dried over Na2SO4. The volatiles were removed under reduced pressure to get the crude material. The crude material was purified by flash chromatography (silica gel 100-200 mesh size, MeOH-DCM gradient from 5%- 10% MeOH-DCM). The pure fractions were concentrated to afford a mixture of methyl ((lR,3R)-3-(7-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-8-(l -isopropyl- lH-indazol-5-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3, 6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(5-fluoro- 1 -methyl- lH-pyrazol-4-yl)-8-(l -isopropyl- lH-indazol-5-yl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.08 g, 0.11 mmol, 89% yield) as a brown solid. LCMS m / z: [M+H]+= 726.23, 726.23.

[0993] Step 6: A solution of methyl ((lR,3R)-3-(7-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-8- (l-isopropyl-lH-indazol-5-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(5- fluoro-1 -methyl-lH-pyrazol-4-yl)-8-(l -isopropyl- lH-indazol-5-yl)-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.16 g, 0.22 mmol) in tetrahydrofuran (dry) (2 mL) was cooled at 0 °C. To this was added tetrabutylammonium fluoride (1 mol / L in tetrahydrofuran) (0.33 mL, 0.331 mmol, 2 equiv.). The reaction mixture was heated at 60 °C for 2 h. The progress of reaction was monitored by LCMS and TLC (SiCh, 80% Ethyl acetate / Hexane, UV active). The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with saturated NELCl solution and dried over sodium sulphate filtered and concentrated under reduced pressure to obtain crude material. The crude was purified by prep-HPLC and the pure fractions were lyophilized to afford methyl ((lR,3R)-3-(7-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)- 3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-

[0994] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) yl)cyclopentyl)carbamate (Compound 3, 0.0025 g, 0.004 mmol, 1.94% yield) as a white solid. LCMS m / z: [M+H]+= 586.45.

[0995] Example 54: Preparation of Isopropyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6- dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyr idin- 1 (2H)-yl)cyclopentyl)car bamate and Isopropyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (Compound 4 and Compound 5)

[0996] Step 1: To a stirred solution of l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(3-fluoro- l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2(lH)-one and l-((lR,3R)-3-aminocyclopentyl)-8-bromo-7-(5- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(lH)-one (0.20 g, 0.34 mmol, 1 equiv.) (prepared according to Example 16) in methylene chloride (5 mL) at room temperature was added triethylamine (0.236 mL, 1.682 mmol, 5 equiv.). This mixture was chilled to 0 °C and isopropyl chloroformate (ca. 30% in toluene, ca. 2 mol / L) (1.5 mL, 1.009 mmol, 3 equiv.) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by adding water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude material. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. The pure fractions were concentrated to afford a mixture of isopropyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2- oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate and isopropyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l-(methyl-d3)-lH- 190

[0997] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.2 g, 0.294 mmol, 87.35% yield) as a yellow solid. LCMS m / z: [M+2H]+= 682.08’ 682.12.

[0998] Step 2: To a stirred solution of isopropyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l- (methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and isopropyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3- (methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (0.20 g, 0.29 mmol, 1 equiv.), (l-isopropyl-lH-indazol-5- yl)boronic acid (0.15 g, 0.74 mmol, 2.5 equiv.) in 1,4-dioxane (10 mL) water ( 2 mL) and cesium carbonate (0.287 g, 0.882 mmol, 3 equiv.). The resulting reaction mixture was purged with argon for 15 min. followed by addition of tetrakis(triphenylphosphine)palladium (0.033 g, 0.029 mmol, 0.1 equiv.). The resulting reaction mixture was heated at 105 °C for 3 h. The reaction mixture was filtered through a Celite® bed, filtrate was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. The pure fractions were concentrated to afford mixture of isopropyl ((lR,3R)-3-(7-(3-fluoro-l- (methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate and isopropyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4- yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl) carbamate. (0.15 g, 0.197 mmol, 67.17% yield) as a yellow solid. LCMS m / z: [M+H]+= 760.33.

[0999] Step 3: To a stirred solution of isopropyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and isopropyl ((lR,3R)-3-(7-(5-fhioro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3- (methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl)carbamate (0.150 g, 0.20 mmol) in tetrahydrofuran (4 mL) was cooled to 0 °C. To this was added tetrabutylammonium fluoride (ca. 1 mol / L in tetrahydrofuran) (0.40 mL, 0.40 mmol ). The reaction mixture was heated at 60 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated NH4Q solution, dried over sodium

[1000] 191

[1001] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) sulfate, and concentrated under reduced pressure to give the crude material. Reverse phase purification and lyophilization of the pure fractions afforded isopropyl ((lR,3R)-3-(7-(3- fluoro-l-(rnethyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3-(methyl-d3)-2-oxo- 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate

[1002] 5 (Compound 4, 0.030 g, 0.0.048 mmol, 24.52% yield) as a white solid and isopropyl ((lR,3R)-3-(7-(5-fhioro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-indazol-5-yl)-3- (methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Compound 5, 0.0093 g, 0.016 mmol, 8.2% yield) as white solid. Compound 4: Peak 1, LCMS m / z: [M+H]+= 620.56; 'H NMR: (400 MHz, DMSO-tfc @ 363

[1003] 10 K) 5 11.60 (s, 1H), 8.05 (d, J = 11.20 Hz, 2H), 7.73 (d, J= 8.80 Hz, 2H), 7.36 (d, J= 8.00 Hz, 1H), 7.12 (d, J= 3.20 Hz, 1H), 6.10-5.20 (m, 1H), 5.03-4.98 (m, 1H), 4.70-4.65 (m, 1H), 3.90-3.84 (m, 1H), 3.75 (s, 1H), 2.07-1.87 (m, 3H), 1.53 (d, J = 7.60 Hz, 6H), 1.20-0.80 (m, 9H); Compound 5: Peak 2, LCMS m / z: [M+H]+= 620.56; 'H NMR: (400 MHz, DMSO-tfc @ 363 K) 5 11.56-11.48 (m, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.71 (m, 2H), 7.36-7.35 (d, J=

[1004] 15 2Hz, 1H), 7.12-7.11(d, J= 3.2Hz, 1H), 5.67-5.56 (m, 1H), 5.07-4.97 (m, 1H), 4.70-4.65 (m, 1H), 3.92-3.82 (m, 1H), 3.72 (m, 1H), 2.09-1.87 (m, 3H), 1.65 (d, J = 5.60 Hz, 6H), 1.20-1.00 (m, 9H).

[1005] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[1006] Example 55: Preparation of Methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol- 4-yl)-8-(l-isopropyl-lH-benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-3,6- dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyr idin- 1 (2H)-yl)cyclopentyl)car bamate and Methyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- benzo [d] imidazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo [4,5-d] pyrrolo [2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 6 and Compound 7)

[1007] Step 1: To a solution of methyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l- (methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (prepared according to Example 16, 150 mg, 0.230 mmol) in 1,4-dioxane (3.0 mL) was added (1- isopropyl-lH-benzo[d]imidazol-5-yl)boronic acid (94 mg, 0.460 mmol) and potassium phosphate tribasic (0.15 g, 0.69 mmol). The resulting mixture was degassed with argon for 10 min followed by addition of [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with di chloromethane (19 mg, 0.023 mmol). The reaction mixture stirred at 105 °C for 3 h under argon atmosphere. To the resulting reaction mixture, water (20 mL) was added and extracted with ethyl acetate (2 x 20 mL), washed with saturated brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give 170 mg of crude product. The crude was purified by column chromatography (100-200 mesh silica gel, 45-70% ethyl acetate in pet ether as an eluent) to obtain the product mixture of methyl ((lR,3R)-3-(7-(3- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH-benzo[d]imidazol-5-yl)-3-(methyl- d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(5-fhioro-l-(methyl-d3)-lH-pyrazol-4- yl)-8-(l-isopropyl-lH-benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.14 g, 83 %) 193

[1008] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) as a pale yellow gum. LCMS m / z: [M+H] = 732.28.

[1009] Step 2: To a solution of methyl ((lR,3R)-3-(7-(3-fhroro-l-(methyl-d3)-lH-pyrazol-4- yl)-8-(l-isopropyl-lH-benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4, 5-d]pyrrolo[2,3 -b]pyridin- 1 (2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.2 g, 0.27 mmol, 1.0 equiv.) in tetrahydrofuran (2 mL), was added tetrabutylammonium fluoride (0.55 mL, 0.55 mmol) at room temperature. The reaction mixture was heated to 70 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to obtained the crude material. The residue was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (4 x 20 mL). The organic extract was dried over sodium sulfate filtered and concentrated under reduced pressure to obtain the crude product (150 mg) as pale yellow oil. The crude compound was purified by prep-HPLC reverse phase to obtain pure compound methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 6, 0.004 g, 2.47%) as off-white solid and methyl ((lR,3R)-3-(7-(3-fhioro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(l-isopropyl-lH- benzo[d]imidazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 7, 0.009 g, 5.57%) as a white solid. Compound 6: Peak 1, LCMS m / z: [M+H]+= 592.41; 'H NMR (400 MHz, DMSO-tL @ 298K) 5 11.89 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.67-7.59 (m, 1H), 7.30-7.23 (m, 1H), 7.17-7.11 (m, 1H), 6.63-6.03 (m, 1H), 4.84-4.81 (m, 1H), 3.84-3.83 (m, 1H), 3.70-3.60 (m, 1H), 3.46-3.42 (m, 4H), 2.01-1.96 (m, 2H), 1.73-1.71 (m, 1H), 1.62-1.50 (m, 6H), 1.35-1.30 (m, 1H), 1.20-1.15 (m, 1H). Compound 7: Peak 2, LCMS m / z: [M+H]+= 592.41; ‘H NMR: (400 MHz, DMSO-tL @ 298K) 5 11.85 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.64-7.57 (m, 1H), 7.47 (s, 1H), 7.26-7.20 (m, 1H), 6.63-6.02 (m, 1H), 4.83-4.81 (m, 1H), 3.85-3.83 (m, 1H), 3.46 (s, 4H), 1.98-1.95 (m, 2H), 1.75-1.71 (m, 1H), 1.61-1.50 (m, 7H), 1.35-1.31 (m, 1H), 1.14-1.08 (m, 1H).

[1010] Example 56: Preparation of Methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol- 4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and Methyl ((lR,3R)-3-(7-(3- fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-(methyl-d3)-2-

[1011] 194

[1012] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) oxo-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate

[1013] (Compound 8 and Compound 9)

[1014] Step 1: To a stirred solution of methyl ((lR,3R)-3-(8-bromo-7-(3-fhioro-l-(methyl- d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(8-bromo-7- (5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (0.09 g, 0.138 mmol, 1 equiv.) (prepared according to Example 16) and (2-isopropyl-2H-indazol-5- yl)boronic acid (0.028 g, 0.14 mmol) in dioxane (2 mL) and water (0.3 mL) at room temperature was added cesium carbonate (0.14 g, 0.41 mmol). The reaction mixture was purged with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol, 0.1 equiv.) was added, the mixture purged with argon gas for 5 minutes, and the mixture was heated at 105 °C for 3 hours. The reaction mixture was filtered through a Celite® bed and filtrate was dried over Na2SO4. The solvent was concentrated under reduced pressure to give the crude product. The crude was purified by flash chromatography by using 100-200 silica gel, eluent: 70% EtOAc in pet ether. The pure fractions were concentrated to afford mixture of methyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2- isopropyl-2H-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(5-fluoro- l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-(methyl-d3)-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl) carbamate (0.08 g, 0.109 mmol, 79.26 % yield) as a yellow solid. MS m / z: [M+H]+= 732.29, 732.29.

[1015] Step 2: To a stirred solution of methyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH- pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-

[1016] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyndin-l(2H)-yl)cyclopentyl)carbamate (3) and methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3- (methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- l(2H)-yl)cyclopentyl) carbamate (0.1 g, 0.137 mmol, 1 equiv.) in tetrahydrofuran (dry) (2 mL) cooled at 0 °C was added drop-wise tetrabutylammonium fluoride (ca. 1 mol / L in tetrahydrofuran) (0.11 g, 0.41 mmol). The reaction mixture was heated at 60 °C for 1 h. The progress of reaction was monitored by LCMS and TLC (SiCh, 50% Ethyl acetate / Hexane; UV active). The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2 x 30 mL). The combined organic layer was washed with saturated NELCl solution and dried over sodium sulphate and concentrated under reduced pressure to get crude material. The crude was purified by prep-HPLC. Pure fractions were lyophilized to afford methyl ((lR,3R)-3-(7-(5-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5- yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Compound 8, 0.007 g, 0.012 mmol, 2.71 % yield) as off white solid and methyl ((lR,3R)-3-(7-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-8-(2-isopropyl-2H- indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (Compound 9, 0.014 g, 0.024 mmol, 5.4 % yield) as a off white solid. Compound 8: Peak 1, LCMS m / z: [M+H]+= 592.50; 'H NMR: (400 MHz, DMSO-tL) 5 11.90 (bs, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.68 (m, 2H), 7.20 -7.13 (m, 2H), 4.85-4.82 (m, 1H), 3.92-3.87 (m, 2H), 3.49 (s, 3H), 2.11 (m, 1H), 1.95-1.80 (m, 1H), 1.60 (m, 6H), 1.53 (m, 1H), 1.25 (m, 2H), 1.25-1.02 (m, 1H). Compound 9: Peak 2, LCMS m / z: [M+H]+= 592.41; ‘H NMR: (400 MHz, DMSO-tL) 5 11.47 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.74-7.65 (m, 2H), 7.48 (s, 1H), 7.17 (dd, J = 8.40, 23.40 Hz, 1H), 60.50-6.10 (m, 1H), 4.88-4.81 (m, 1H), 4.10-3.66 (m, 2H), 3.48-3.45 (m, 3H), 2.03-1.95 (m, 2H), 1.75 (m, 1H), 1.58-1.55 (m, 7H), 1.49 (m, 1H), 1.27(m, 1H), 1.16 (m, 1H).

[1017] Example 57: Preparation of Methyl ((lR,3R)-3-(7-(5-fluoro-l-methyl-lH-pyrazol-4-yl)- 8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo [4,5-d] pyrrolo [2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate and Methyl ((lR,3R)-3-(7-(3-fluoro-l- methyl-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-3,6- dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyr idin- 1 (2H)-yl)cyclopentyl)car bamate (Compound 10 and Compound 11)

[1018] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025)

[1019] Step 1: To a stirred solution of methyl ((lR,3R)-3-(8-bromo-7-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(8-bromo-7-(5-fluoro-l- methyl-lH-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (prepared according to Example 17, 0.12 g, 0.19 mmol), in 1,4-dioxane (4 mL) water (0.5 mL) at room temperature was added 2- isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole (0.0796 g, 0.278 mmol, 1.5 equiv.) and cesium carbonate (0.181 g, 0.557 mmol, 3 equiv.). The resulting reaction mixture was purged with argon for 15 minutes followed by addition of tetrakis(triphenylphosphine)palladium (0.022 g, 0.019 mmol). The reaction mixture was heated at 105 °C for 3 h. The reaction mixture was filtered through a Celite® bed and filtrate was dried over Na2SO4. The volatiles were removed under reduced pressure to get the crude material. The crude material was purified by flash chromatography (silica gel 100-200 mesh size, MeOH-DCM gradient from 5%- 10% MeOH-DCM). Pure fractions were concentrated to afford a mixture of methyl ((lR,3R)-3-(7-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-8-(2- i sopropyl-2H-indazol-5 -y 1 )- 3 -methyl -2-oxo-6-(phenyl sulfonyl)-3 , 6-dihy droimidazo[4, 5 - d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(3-fluoro- 1 -methyl- lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-6- (phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)- yl)cyclopentyl)carbamate (0.12 g, 0.17 mmol, 89% yield) as a brown solid. LCMS m / z: [M+H]+= 726.42.

[1020] Step 2: To a stirred solution of methyl ((lR,3R)-3-(7-(3-fhioro-l-methyl-lH-pyrazol- 4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4, 5-d]pyrrolo[2,3 -b]pyridin- 1 (2H)-yl)cyclopentyl)carbamate and methyl ((lR,3R)-3-(7-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3- methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-

[1021] 197

[1022] IPTS / 200134983.3 PCT / US25 / 48136 26 September 2025 (26.09.2025) yl)cyclopentyl)carbamate (0.14 g, 0.21 mmol, ) in tetrahydrofuran (2 mL) at 0 °C was added dropwise tetrabutylammonium fluoride (ca. 1 mol / L in tetrahydrofuran) (0.39 mL, 0.41 mmol). The reaction mixture was heated at 60 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with saturated NH4Q solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude material. Prep-HPLC purification gave pure fractions that were lyophilized to afford methyl ((lR,3R)-3-(7-(3-fluoro-l-methyl-lH- pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 11, 0.0093 g, 0.016 mmol, 8.23% yield) as a white solid and methyl ((lR,3R)-3-(7-(5-fhioro-l-methyl-lH- pyrazol-4-yl)-8-(2-isopropyl-2H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-l(2H)-yl)cyclopentyl)carbamate (Compound 10, 0.00486 g, 0.008 mmol, 4.30% yield) as a white solid. Compound 10: Peak 1, LCMS m / z: [M+H]+= 586.44; ‘H NMR: (400 MHz, DMSO-^ @ 363 K) 5 11.53 (s, 1H), 8.33 (s, 1H), 8.06 (s, 1H), 7.69 (m, 2H), 7.20-7.17 (m, 2H), 6.10-5.01 (m, 1H), 4.87-4.80 (m, 1H), 3.90-3.86 (m, 2H), 3.60 (s, 3H), 3.49 (s, 3H), 3.35 (s, 3H), 2.11-1.65 (m, 3H), 1.59 (d, J= 6.40 Hz, 6H), 1.07-0.84 (m, 3H). Compound 11: Peak 2, LCMS m / z: [M+H]+= 586.44; ‘H NMR: (400 MHz, DMSO-tL @ 363 K) 5 11.54 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.68 (m, 2H), 7.37 (d...

Claims

PCT / US25 / 48136 26 September 2025 (26.09.2025)Listing of Claims:5 A is selected from the group consisting of: -C3 and -C5-10 cycloalkylene, RA-3-12 membered heterocyclylene, and phenylene, wherein RAis a bond or O;R1is selected from the group consisting of: hydrogen, -C2-6 alkynyl, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, 5-10 membered heteroaryl, and phenyl optionally fused to C3-8 cycloalkyl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, -C2-610 alkynyl, 5-10 membered heteroaryl, and C3-8 cycloalkyl are optionally substituted with 1, 2, 3, or 4 Rlb, wherein R1is not one of the following groups:15 Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, oxo, -C(O)(Ci-6 alkyl), -OH, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6303IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, phenyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), - 0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl),-O- (C3-10 cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy; each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkyl-O(Ci-6alkyl), -Ci-6alkylene-C(O)ORa, -C(O)ORa, -N(Ra)2, -P(O)(Ci-6 alkyl)2, - S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, - S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl),- -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -O- (C3-10 cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, -CN, and -C1-6 alkoxy;R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, - C1-6 haloalkoxy, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, and -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo; wherein R6is not hydrogen when R1is hydrogen; R6ais bond or -C1-6 alkylene;R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, - OH, -C1-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), -NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6alkyl), -NRaC(O)(C2-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), - NRaC(O)(3-10 membered heterocyclyl), -C(0)NRa(C3-io cycloalkyl), -NRaS(O)2(Ci-6 alkyl), -304IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)NRa(Ci-6haloalkyl), (Ci-6 alkylene)-NRaC(O)O(Ci-6 alkyl), (Ci-6 alkylene)-NRaC(0)(C3-io cycloalkyl), -0C(0)N(Ra)2, -C(0)N(Ra)2, -NRaC(0)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), - N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -Ci-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, -C1-6 haloalkyl and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; n is 0, 1, 2, or 3, wherein when A is cyclopentyl, n is 1, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:A is selected from the group consisting of: C3-5 and C7-10 cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein RAis a bond or O;R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10305IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, - C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, wherein R6is not hydrogen when R1is hydrogen;R6ais bond or -C1-6 alkylene;R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, - OH, oxo, -C1-6 alkoxy, halo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), -NRaC(O)O(C2-6 alkyl), -N(CI-6alkyl)C(O)O(methyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(Ci-6 alkenyl), - NRaC(0)(C3-io cycloalkyl), -C(0)NRa(C3-io cycloalkyl), -NRaS(O)2(Ci-6 alkyl), NRa(Ci-6 haloalkyl), (Ci-6alkylene)-NRaC(0)(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), (Ci-6alkylene)-NRaC(O)O(Ci-6 alkyl), -OC(O)N(Ra)2, -C(O)N(Ra)2, - NRaC(0)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, C1-6 haloalkyl, and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl, and wherein when A is C4 cycloalkylene, R5is not -NRaC(O)O(ethyl) or -N(Ra)2; n is 0, 1, 2, or 3, wherein when A is cyclopentyl or RA-3-12 membered heterocyclylene, n is 1, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

3. A compound of Formula (III):306IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)or a pharmaceutically acceptable salt thereof, wherein:A is selected from the group consisting of: Cs-4 and Ce-io cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein RAis a bond or O;R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 membered heteroaryl, R6a-(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally307IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, - C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, wherein R6is not hydrogen when R1is hydrogen;R6ais bond or -C1-6 alkylene;R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -Ci-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), -NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6alkyl), -NRaC(O)(Ci-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), - C(0)NRa(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -NRaS(O)2(Ci-6 alkyl), NRa(Ci-6 haloalkyl), (Ci-ealkylene)-NRaC(0)(C3-io cycloalkyl), (Ci-6 alkylene)-NRaC(O)O(Ci-6alkyl), -OC(O)N(Ra)2, -C(O)N(Ra)2, -NRaC(O)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -Ci-6 alkoxy, Ci-6 haloalkyl, and -Ci-6 haloalkoxy, wherein -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; wherein: when n is 2 and one R5is methyl, the other R5is selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, -OH, -C1-6 alkoxy, -N(Ra)2, -NRaC(O)O(Ci-6 alkyl), -NRa(Ci-6 haloalkyl), -NRaC(O)(Ci-6 alkyl), -NRaC(O)(C4-8 cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -NRaS(O)2(Ci-6 alkyl), (Ci-ealkylene)-NRaC(0)(C3-io cycloalkyl), - OC(O)N(Ra)2, -NRaC(O)N(Ra)2, -N(Ra)C(O)O(C2-6 alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -C1-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy; or the otherwherein R6bis selected from the group consisting of: halo, -C1-6 alkyl, -C1-6 haloalkyl and -CN; wherein one R6cis -C1-6 alkoxy and the other R6cis hydrogen or each R6cis selected from halogen, -C1-6 alkyl, and -C1-6 alkoxy, wherein when A is C4 cycloalkylene, R5is not -NRaC(O)O(ethyl) or -N(Ra)2; n is 0, 1, 2, or 3, wherein when A is RA-3-12 membered heterocyclylene, n is 1, 2, or 3; and308IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) each Rais independently hydrogen or -Ci-6 alkyl.or a pharmaceutically acceptable salt thereof, wherein:A is selected from the group consisting of: C3 and C5-10 cycloalkylene, RA-3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene, and phenylene, wherein RAis a bond or O;R1is selected from the group consisting of: hydrogen, halo, Rla-(3-12 membered heterocyclyl), -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, -C3-10 cycloalkyl, phenyl optionally fused to C3-8 cycloalkyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb;Rlais selected from the group consisting of: bond, -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, -C(O)(Ci-6 alkyl), -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-6alkylene-C(O)ORa, -C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6alkyl, -S(O)k(Ci-6alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, phenyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, OH, -C1-6 alkyl, -CN, and -C1-6 alkoxy;R6is selected from the group consisting of: hydrogen, -C1-6 alkyl, -CN, -C3-10 cycloalkyl, 5-6 309IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) membered heteroaryl, R -(3-10 membered heterocyclyl), and phenyl wherein the -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, - C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -CN, -C(O)- (C1-6 alkyl), and -N(Ra)2, , wherein R6is not hydrogen when R1is hydrogen and wherein the 5-6 membered heteroaryl is not one of the following groups:R2ais -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo, each R2is independently selected from the group consisting of -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, and -C1-6 deuterohaloalkyl; each R3is independently selected from the group consisting of hydrogen, -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 alkoxy, and -C3-10 cycloalkyl;R3ais selected from the group consisting of -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, and -C1-6 alkoxy;R3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl;R6ais bond or -C1-6 alkylene;R4is -C1-6 alkyl or -C1-6 deuteroalkyl; each R5is independently selected from the group consisting of: -C1-6 alkyl, -C1-6 haloalkyl, - OH, -C1-6 alkoxy, halo, oxo, -N(Ra)2, -C(O)(Ci-6 alkyl), -C(O)O(Ci-6 alkyl), -NRaC(O)O(Ci-6alkyl), -NRaC(O)(Ci-6alkyl), -NRaC(O)(Ci-6 alkenyl), -NRaC(0)(C3-io cycloalkyl), - C(0)NRa(C3-io cycloalkyl), -NRaC(O)(3-10 membered heterocyclyl), -NRaS(O)2(Ci-6 alkyl), NRa(Ci-6 haloalkyl), (Ci-ealkylene)-NRaC(0)(C3-io cycloalkyl), (C1-6 alkylene)- NRaC(O)O(Ci-6alkyl), -0C(0)N(Ra)2, -C(0)N(Ra)2, -NRaC(0)N(Ra)2, -N(Ra)C(O)O(C2-6310IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) alkenyl), -N(Ra)C(O)(C2-6 alkenyl), and 3-10 membered heterocyclyl, wherein the -Ci-6 alkyl, -C2-6 alkenyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, - C1-6 alkoxy, C1-6 haloalkyl, and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 -C1-6 alkyl; n is 0, 1, 2, or 3, wherein when A is cyclopentyl or RA-3-12 membered heterocyclylene, n isI, 2, or 3; and each Rais independently hydrogen or -C1-6 alkyl.

5. The compound of claim 1, wherein A is selected from cyclopentylene, cyclohexylene, and 3-12 membered heterocyclylene.

6. The compound of claim 4, wherein A is selected from cyclopentylene, cyclohexylene, and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene7. The compound of claim 2, wherein A is selected from cyclopentylene and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene.

8. The compound of claim 3, wherein A is selected from cyclohexylene and 3-12 membered, monocyclic or bicyclic fused or spiro, heterocyclylene.

9. The compound of claim 1 or 4, wherein A is cyclopentylene or cyclohexylene.

10. The compound of any one of claims 1-3 and 5-9, wherein A is cyclopentylene.I I. The compound of any one of claims 1, 2, and 4-9, wherein A is cyclohexylene.

12. The compound of any one of claims 1-8, wherein A is 10-membered heterocyclylene.

13. The compound of any one of claims 1-8 and 12, wherein A is:

14. The compound of any one of claims 2-13, wherein R1is selected from the group consisting of: 3-12 membered heterocyclyl, phenyl optionally fused to C3-8 cycloalkyl, and 5- 10 membered heteroaryl, wherein the 3-12 membered heterocyclyl, phenyl, C3-8 cycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb.

15. The compound of any one of claims 1-14, wherein R1is not indazolyl or dihydrobenzofuranyl .

16. The compound of any one of claims 1-15, wherein R1is 3-12 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 Rlb.311IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)17. The compound of any one of claims 1-15, wherein R1is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 Rlb.

18. The compound of any one of claims 2-15, wherein R1is phenyl optionally fused to C3- 8 cycloalkyl, wherein the phenyl and C3-8 cycloalkyl are optionally substituted with 1, 2, 3, or 4 Rlb.

19. The compound of any one of claims 1-14 and 18, wherein R1is phenyl optionally fused to C3-8 cycloalkyl, wherein the phenyl is substituted with 1 Rlcand 0, 1, 2, or 3 Rlband C3-8 cycloalkyl is optionally substituted with 1, 2, 3, or 4 Rlb, wherein each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkyl- O(Ci-6 alkyl), -Ci-6alkylene-C(O)ORa, -C(O)ORa, -N(Ra)2, -P(O)(Ci-6 alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NHS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci-6 alkyl),- -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -O- (C3-10 cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, -CN, and -C1-6 alkoxy.

20. The compound of any one of claims 2-14, wherein R1is selected from the group consisting of:312IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)313IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)21. The compound of any one of claims 1-13, wherein R1is selected from the group consisting of:314IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)22. The compound of any one of claims 1-21, wherein R4is -C1-3 alkyl or -C1-3 deuteroalkyl.

23. The compound of any one of claims 1-22, wherein R4is methyl or -CD3.

24. The compound of any one of claims 1 and 4-23, wherein each R5is selected from the group consisting of: -NRaC(O)O(Ci-6 alkyl), -NRaC(O)(C2-6 alkenyl), -C1-6 alkyl, - NRaC(O)(3-10 membered heterocyclyl), -NRaC(0)(C3-io cycloalkyl), NRaC(O)(Ci-6 alkyl), and oxo, wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, or -C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy, wherein the -C3-10 cycloalkyl is optionally substituted with -C1-6 alkyl.

25. The compound of any one of claims 1 and 3-24, wherein each R5is selected from the group consisting of: -NHC(0)0(m ethyl), -NHC(O)O(ethyl), -NHC(O)O(isopropyl), - NRaC(O)(C2 alkenyl), methyl, -NHC(O)(cyclopropyl), NRaC(O)(methyl), NRaC(O)(ethylene-OH), -NHC(O)(oxetanyl), and oxo, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -OH, -C1-6 alkoxy, and -C1-6 haloalkoxy, wherein the methyl, ethyl, or315IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) isopropyl is optionally substituted with -OH.

26. The compound of any one of claims 1, 2, and 4-25, wherein the - NHC(O)(cyclopropyl) optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -Ci-6 alkyl, halo, -OH, -Ci-6 alkoxy, and -Ci-6 haloalkoxy is selected from the group consisting of:

27. The compound of any one of claims 1, 2, and 4-26, wherein when n is 2, one R5is methyl, and the other R5is selected from the group consisting of:

28. The compound of any one of claims 1, 2, and 4-25, wherein when n is 2, one R5is methyl, and the otherwherein R6bis selected from the group consisting of: halo, -Ci-6 alkyl, -Ci-e haloalkyl and -CN; wherein one R6cis -Ci-6 alkoxy and the other R6cis hydrogen or each R6cis selected from halogen, -Ci-6 alkyl, and -Ci-6 alkoxy.

29. The compound of any one of claims 1-28, wherein when n is 2, one R5is methyl, and the other R5is30. The compound of any one of claims 1 and 3-29, wherein R5is -NHC(0)0(m ethyl).

31. The compound of any one of claims 1-29, wherein R5is -NRaC(O)O(C2-6 alkyl), wherein the -C2-6 alkyl is optionally substituted with -OH.

32. The compound of any one of claims 1-29, wherein R5is -NHC(O)O(ethyl) or - NHC(O)O(isopropyl), wherein the ethyl or isopropyl is optionally substituted with -OH.

33. The compound of any one of claims 1-3, and 5-32, wherein R6is selected from:IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) each of R2and R3is independently selected from the group consisting of: hydrogen, -Ci-6 alkyl, halo, -Ci-6 haloalkyl, -Ci-6 deuteroalkyl, -Ci-6 deuterohaloalkyl, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2; andR3ais selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2; or(b) -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, - C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)-(Ci-6 alkyl), and -N(Ra)2.

34. The compound of any one of claims 1-33, wherein R6is selected from:wherein:R2ais -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo,R3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl, each of R2and R3is independently selected from the group consisting of: hydrogen, -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2; andR3ais selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2; or(b) -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, - C1-6 deuterohaloalkyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (Ci- 6 alkyl), and -N(Ra)2.

35. The compound of any one of claims 1-34, wherein R6is selected from:317IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)wherein:R2ais -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 halo; each R2is independently selected from the group consisting of -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, and -C1-6 deuterohaloalkyl; each R3is independently selected from the group consisting of hydrogen, -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 alkoxy, and -C3-10 cycloalkyl;R3ais selected from the group consisting of -CN, halo, -C1-6 alkyl, -C1-6 haloalkyl, and -C1-6 alkoxy; andR3bis selected from the group consisting of halo, -C1-6 haloalkyl, -C1-6 haloalkoxy, and -C3-10 cycloalkyl; or(b) -C3-10 cycloalkyl.

36. The compound of any one of claims 1-3 and 5-35, wherein R6is selected from:R2is -C1-6 alkyl or -C1-6 deuteroalkyl; andR3is halo or -C1-6 alkoxy; or(b) C3-8 cycloalkyl.

37. The compound of any one of claims 1-36, wherein R6is selected from:R3is halo; or(b) C3-8 cycloalkyl.318IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)38. The compound of any one of claims 1-3 and 5-34, wherein R6is selected from the group consisting of:5 39. The compound of any one of claims 1-38, wherein R6is selected from the group consisting of:

40. The compound of any one of claims 1-3, 5-34, and 38, wherein R6is selected from the group consisting of: io41. The compound of any one of claims 1-40, wherein R6is selected from the group consisting of:1542. The compound of any one of claims 1-41, wherein R6is selected from the group consisting of:319IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)43. The compound of any one of claims 1-34, wherein R6is -C3-10 cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -C1-6 alkyl, halo, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C1-6 alkoxy, - C1-6 haloalkoxy, -C3-10 cycloalkyl, -OH, oxo, -C(O)- (C1-6 alkyl), and -N(Ra)2.

44. The compound of any one of claims 1-34 and 43, wherein R6is -C3-8 cycloalkyl.

45. The compound of any one of claims 1-39, 43, and 44, wherein R6is:

46. The compound of any one of claims 1-44, wherein n is 0, 1, or 2.

47. The compound of any one of claims 1-45, wherein Rais hydrogen.or a pharmaceutically acceptable salt thereof, wherein:320IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl; each R5is independently selected from the group consisting of: hydrogen, halo, -Ci-6 alkyl, -CN, -Ci-6 haloalkyl, -OH, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;5 R2is selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and-Ci-6 deuterohaloalkyl; andR3is selected from the group consisting of halo, -Ci-6 alkyl, and -Ci-6 alkoxy.

49. A compound of Formula (VI):io or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of:321IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)5R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl; each R5is independently selected from the group consisting of: hydrogen, -Ci-6 alkyl, -Ci-6 haloalkyl, -OH, -CN, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;R2is selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and10 -Ci-6 deuterohaloalkyl; andR3is selected from the group consisting of halo, -Ci-6 alkyl, -Ci-6 alkoxy, and -Ci-6 haloalkoxy.

50. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

51. A compound of Formula (VII):322IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of: 5-10 membered heteroaryl, phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12 membered heteroaryl, and 5-10 membered heteroaryl fused to 4-12 membered heterocyclyl, wherein the 5-10 membered heteroaryl, C3-8 cycloalkyl, 4-12 membered heterocyclyl, and 4-12 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 Rlb, and wherein when the phenyl is not fused to C3-8 cycloalkyl or 4-12 membered heterocyclyl or 4-12 membered heteroaryl, the phenyl is substituted with 1 Rlcand 0, 1, 2, or 3 Rlb, and wherein when the phenyl is fused to C3-8 cycloalkyl or 4-12 membered heterocyclyl or 4-12 membered heteroaryl, the phenyl is optionally substituted with 0, 1, 2, or 3 Rlb; each Rlbis independently selected from the group consisting of: -C1-6 alkyl, -C1-6 deuteroalkyl, Ci-4 heteroalkyl, -C1-6 haloalkyl, oxo, -C(O)(Ci-6 alkyl), -OH, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, -C1-6 alkyl-ORa, -Ci-ealkylene-C(O)ORa, Ci-4 alkylene-CN, - C(O)ORa, halo, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), - S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, - C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, phenyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -0C(0)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3- 10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O-(Ci-6 alkylene)-(3-10 membered heterocyclyl), -S-(3-10 membered heterocyclyl), -S-(C3-io cycloalkyl), -S-(5-6 membered heteroaryl), and -S-(Ci-6 alkylene)-(3-10 membered heterocyclyl), wherein the -C1-6 alkyl, 3-10 membered heterocyclyl, -C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently323IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) selected from the group consisting of: oxo, halo, OH, -Ci-6 alkyl, -CN, and -Ci-6 alkoxy; wherein each Rais independently hydrogen, -Ci-6 alkyl, -Ci-6 deuteroalkyl, and -Ci-6 haloalkyl; wherein Rlais selected from the group consisting of: bond, -Ci-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene; wherein k is 1 or 2, each Rlcis independently selected from the group consisting of: -OH, -CN, -C1-6 haloalkoxy, -C1-6 alkoxy, -C1-6 alkyl-O(Ci-6 alkyl), -Ci-ealkylene-C(O)ORa, Ci-4 alkylene-CN, -C(O)ORa, -N(Ra)2, -P(O)(Ci-6alkyl)2, -S(O)k(Ci-6 alkyl), -S(O)k(Ci-6 haloalkyl), -S(0)k(C3-io cycloalkyl), -NRaS(O)k-Ci-6 alkyl, -S(O)k(Ci-6 alkylene)N(Ra)2, -S(O)kN(Ra)2, -S(O)(NRa)(Ci- 6 alkyl), -C(O)-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, -C3-10 cycloalkyl, Rla-(5-6 membered heteroaryl), -OC(O)N(Ra)2, -OC(O)(3-10 membered heterocyclyl), -O-(3-10 membered heterocyclyl), -0-(C3-io cycloalkyl), -O-(5-6 membered heteroaryl), -O(Ci-6 alkylene)-(3-10 membered heterocyclyl), -S-(3-10 membered heterocyclyl), -S-(C3-io cycloalkyl), -S-(5-6 membered heteroaryl), and -S-(Ci-6 alkylene)-(3- 10 membered heterocyclyl), wherein k is 1 or 2, wherein the 3-10 membered heterocyclyl, - C3-10 cycloalkyl, or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: oxo, halo, -C1-6 alkyl, - CN, and -C1-6 alkoxy;R4is -C1-6 alkyl or -C1-6 deuteroalkyl;R8is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to C3-8 cycloalkyl, 5-6 membered heteroaryl fused to 4-12 membered heterocyclyl, 5-6 membered heteroaryl fused to 4-12 membered heteroaryl, R8a-(3-10 membered heterocyclyl), phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12 membered heteroaryl, wherein the -C3-8 cycloalkyl, -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, 4-12 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -OH, halo, oxo, -CN, -N(Ra)2, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C2- 6 alkenyl, -C2-6 alkynyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -O-(Ci-6 alkyl), -O-(C 1-6 alkyl ene)-O- (C1-6 alkyl), -O-(C2-6 alkenyl), -O-(C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), -(Ci- e alkylene)-O-(Ci-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkylene)-(C3-io cycloalkyl), -(C1-6 alkylene)-(3-10 membered324IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) heterocyclyl), -(Ci-6 alkylene)-(5-6 membered heteroaryl), or -(Ci-6 alkylene)-(phenyl), wherein the -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, - (C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(O)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl;R8ais bond, -C(O)-, -C1-6 alkylene, -C2-6 alkenylene, -C2-6 alkynylene, -(C2-6 alkynylene)-(Ci-6 alkylene), -(C2-6 alkenylene)-(Ci-6 alkylene), -(C2-6 alkylene)-(Ci-6 alkynylene), -(C2-6 alkylene)-(Ci-6 alkenylene), wherein the -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH;R9is independently selected from the group consisting of: H, D, -C1-6 alkyl, -C1-6 deuteroalkyl, -OH, -C1-6 alkoxy, -(C1-6 alkyl)-O-(Ci-6 alkyl), wherein the -C1-6 alkyl and -C1-6 alkoxy are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH;R10is independently selected from the group consisting of: -OH, -N(Ra)2, -(C1-6 alkyl), -(C2-6 alkenyl), -(C2-6 alkynyl), -O(Ci-6 alkyl), -O-(Ci-6 alkylene)-O-(Ci-6 alkyl), - O(C2-6 alkenyl), -O(C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), -(C1-6 alkylene)-O- (C1-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, or 3-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, -Ci- 6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(O)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl, wherein when R10is -(C3-cycloalkyl) and R8issubstituted with halo, C1-6 alkoxy, or C1-6 alkyl, then R1is not phenyl or indazolyl optionally substituted with 1 or 2 substituents that are C1-6 alkyl, C1-6 alkoxy, or deuterated C1-6 alkyl.

52. A compound of Formula (VIII):325IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of: R1is selected from the group consisting of:326IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl; andR8is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to C3-8 cycloalkyl, 5-6 membered heteroaryl fused to 4-12 membered heterocyclyl, 5-6 membered heteroaryl fused to 4-12 membered heteroaryl, R8a-(3-10 membered heterocyclyl), phenyl, phenyl fused to C3-8 cycloalkyl, phenyl fused to 4-12 membered heterocyclyl, phenyl fused to 4-12 membered heteroaryl, wherein the -C3-8 cycloalkyl, -C3-10 cycloalkyl, 5-6 membered heteroaryl, 3-10 membered heterocyclyl, 4-12 membered heterocyclyl, or phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: -OH, halo, oxo, -CN, -N(Ra)2, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 deuteroalkyl, -C1-6 deuterohaloalkyl, -C2- 6 alkenyl, -C2-6 alkynyl, -C1-6 alkoxy, -C1-6 haloalkoxy, -O-(Ci-6 alkyl), -O-(C 1-6 alkyl ene)-O- (C1-6 alkyl), -O-(C2-6 alkenyl), -O- (C2-6 alkynyl), -O-(Ci-6 alkylene)-0-(C3-io cycloalkyl), - (Ci-e alkylene)-O-(Ci-6 alkyl), -(C1-6 alkylene)-0-(C3-io cycloalkyl), -(C3-10 cycloalkyl), -(3-10 membered heterocyclyl), -(C1-6 alkylene)-(C3-io cycloalkyl), -(C1-6 alkylene)-(3-10 membered heterocyclyl), -(C1-6 alkylene)-(5-6 membered heteroaryl), or -(C1-6 alkylene)-(phenyl), wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, 3-10 membered heterocyclyl, or phenyl are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halo, CN, -OH, -N(Ra)2, -C1-6 alkyl, - (C2-6 alkenyl), -(C2-6 alkynyl), -C1-6 alkoxy, -C1-6 haloalkyl, -C1-6 haloalkoxy, -C(O)(Ci-6 alkyl), - C(0)N(Ra)2, -N(Ra)C(O)(Ci-6 alkyl, wherein each Rais independently selected from the group consisting of: hydrogen, -Ci-4 alkyl, -Ci-4 deuteroalkyl, and -Ci-4 haloalkyl; andR8ais bond, -C(O)-, -C1-6 alkylene, -C2-6 alkenylene, -C2-6 alkynylene, -(C2-6 alkynylene)-(Ci-6 alkylene), -(C2-6 alkenylene)-(Ci-6 alkylene), -(C2-6 alkylene)-(Ci-6 alkynylene), -(C2-6 alkylene)-(Ci-6 alkenylene), wherein the -C1-6 alkylene, -C2-6 alkenylene, and -C2-6 alkynylene are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: C1-3 alkyl, halo, CN, and -OH, 327 IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) wherein when R1is phenyl, indazolyl, or dihydroisobenzofuranyl and R8is 5-6 membered heteroaryl, then R8is -(Ci-6 alkylene)-(3-10 membered heterocyclyl), -(Ci-6 alkylene)-(5-6 membered heteroaryl), or -(Ci-6 alkylene)-(phenyl), each optionally substituted, and wherein when R1is phenyl, indazolyl, dihydrobenzofuranyl, or dihydroisobenzofuranyl, then R8cannot be a phenyl substituted with the following: - C(O)N(Ra)2, -Ci-6 alkyl substituted with -N(Ra)2, -(Ci-6 alkylene)-(3-10 membered nitrogencontaining heterocyclyl), or -C(O)-(3-10 membered nitrogen-containing heterocyclyl).

53. A compound of Formula (IX):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of:each optionally substituted with 1, 2, 3 or 4 substituents selected from: D, -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, -OH, oxo, -CN, -Ci-6 alkoxy, and -Ci-6 haloalkoxy;R2is selected from the group consisting of -Ci-6 alkyl, -Ci-6 deuteroalkyl, -Ci-6 haloalkyl, and -Ci-6 deuterohaloalkyl;R3is selected from the group consisting of halo, -Ci-6 alkyl, and -Ci-6 alkoxy; and R4is -Ci-6 alkyl or -Ci-6 deuteroalkyl.

54. A compound of Formula (X):328IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)or a pharmaceutically acceptable salt thereof, wherein:R2is selected from the group consisting of: hydrogen, D, Ci-6 alkyl, Ci-6 deuteroalkyl,Ci-6 haloalkyl, Ci-6 deuterohaloalkyl, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -(C1-6 alkylene)-C3-8 cycloalkyl, and -(C1-6 alkylene)-3-10 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, and NRX1RX2;RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;R3is selected from the group consisting of: hydrogen, D, halo, C1-6 alkyl, and C1-6 alkoxy;R4is C1-6 alkyl or C1-6 deuteroalkyl; each R11is independently selected from the group consisting of: D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, oxo, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, NRX1RX2, and - (C1-6 alkylene)-OH;R12is selected from the group consisting of: hydrogen, D, halo, C1-6 alkyl, and C1-6 alkoxy; and n is 0, 1, 2, 3, 4, 5, or 6.

55. The compound of claim 54, which is of Formula (Xa):329IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)pharmaceutically acceptable salt thereof.

56. The compound of claim 54 or 55, wherein R4is methyl or trideuteromethyl.

57. The compound of any one of claims 54-56, wherein R12is hydrogen.

58. The compound of any one of claims 54-57, wherein each R11is independently D, C1-3 alkyl, fluoro, or -(C1-3 alkylene)-OH.

59. The compound of any one of claims 54-58, wherein n is 1, 2, 3, 4, or 5.

60. The compound of any one of claims 54-57, wherein n is 0.

61. The compound of any one of claims 54-60, wherein R2is selected from the group consisting of: C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, 4-6 membered heterocyclyl, and - (Ci-2 alkylene)-C3-4 cycloalkyl.

62. The compound of claim 61, wherein R2is methyl or trideuteromethyl.

63. The compound of any one of claims 54-62, wherein R3is selected from the group consisting of: fluoro, C1-3 alkyl, and C1-3 alkoxy.

64. The compound of claim 63, wherein R3is fluoro.

65. A compound of Formula (XI):or a pharmaceutically acceptable salt thereof, wherein:R4is Ci-6 alkyl or Ci-6 deuteroalkyl; each R11is independently selected from the group consisting of: D, Ci-6 alkyl, Ci-6330IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) deuteroalkyl, Ci-6 haloalkyl, OH, oxo, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, NRX1R , and - (Ci-6 alkylene)-OH;RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl;R13is selected from the group consisting of: D, OH, halo, CN, NRX1RX2, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 deuteroalkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, Ci-6 deuterohaloalkyl, Ci-6 deuteroalkoxy, C3-8 cycloalkyl, -O-C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -(C1-6 alkylene)-C3-8 cycloalkyl, -(C1-6 alkylene)-3-10 membered heterocyclyl, and -(C1-6 alkylene)-Ci-6 deuteroalkoxy, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, or NRX1RX2; n is 0, 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, 4, or 5.

66. The compound of claim 65, which is of Formula (Xia):pharmaceutically acceptable salt thereof67. The compound of claim 65 or 66, wherein R4is methyl or trideuteromethyl.

68. The compound of any one of claims 65-67, wherein each R11is independently D, C1-3 alkyl, fluoro, or -(C1-3 alkylene)-OH.

69. The compound of any one of claims 65-68, wherein n is 1, 2, 3, 4, or 5.

70. The compound of any one of claims 65-67, wherein n is 0.

71. The compound of any one of claims 65-70, wherein R13is selected from the group consisting of: D, OH, halo, Ci-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuteroalkoxy, C3-4 cycloalkyl, and -O-C3-4 cycloalkyl, wherein alkyl and cycloalkyl are each331IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) optionally substituted with one or more R , each RAis independently C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, D, CN, halo, OH, or NRxlRX2.

72. A compound of Formula (XII):or a pharmaceutically acceptable salt thereof, wherein:R4is C1-6 alkyl or C1-6 deuteroalkyl;R14is -OMe or -OCD3;R15is selected from the group consisting of: D, OH, halo, CN, NRX1RX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, C1-6 deuteroalkoxy, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10-membered aryl, and 5- to 11 -membered heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, or NRX1RX2;RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, or Ci-4 deuteroalkyl; orR15and R16, together with the atoms to which they are attached, form a 5- or 6- membered heteroaryl optionally substituted with one or more RA;R16is selected from the group consisting of: hydrogen, D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, OH, halo, CN, -C1-6 alkoxy, C1-6 haloalkoxy, and NRX1RX2; andR17is selected from the group consisting of: hydrogen, D, OH, halo, CN, NRX1RX2, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterohaloalkyl, and C1-6 deuteroalkoxy.

73. The compound of claim 72, which is of Formula (Xlla):332IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)(Xlla), or a pharmaceutically acceptable salt thereof.

74. The compound of claim 72 or 73, wherein R4is methyl or trideuteromethyl.

75. The compound of any one of claims 72-74, wherein R15is monocyclic, bridged, fused, or spiro 4- to 9-membered N-containing heterocyclyl, wherein the point of attachment5 is on N, or C3-8 cycloalkyl, wherein heterocyclyl and cycloalkyl is optionally substituted with 1 to 3 RA.or a pharmaceutically acceptable salt thereof, wherein:10 each Rais independently hydrogen, D, C1-6 alkyl, C1-6 deuteroalkyl, and C1-6 haloalkyl;R2is selected from the group consisting of: hydrogen, D, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 deuterohaloalkyl, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 6- to 10- membered aryl, 5- to 11-membered heteroaryl, -(C1-6 alkylene)-C3-8 cycloalkyl, and -(C1-615 alkylene)-3-10 membered heterocyclyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more RA; each RAis independently Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 deuteroalkyl, D, Ci-4 deuterohaloalkyl, oxo, CN, halo, OH, andNRX1RX2;333IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)RX1and RX2are each independently hydrogen, D, Ci-4 alkyl, Ci-4 haloalkyl, orCi-4 deuteroalkyl;R3is selected from the group consisting of: hydrogen, D, halo, Ci-6 alkyl, and Ci-6 alkoxy;R4is Ci-6 alkyl or Ci-6 deuteroalkyl;R9is selected from the group consisting of: hydrogen, D, Ci-6 alkyl, Ci-6 deuteroalkyl, OH, Ci-6 alkoxy, halo, or CN, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: C1-3 alkyl, halo, CN, and OH;R10is selected from the group consisting of: 0H,-N(Ra)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -O-C2-6 alkenyl, -O-C2-6 alkynyl, -O-(Ci- 6 alkylene)-0-C3-io cycloalkyl, -(C1-6 alkylene)-0-C3-io cycloalkyl, -(C1-6 alkylene)-C3-io cycloalkyl, -(C1-6 alkylene)-0-C3-io cycloalkyl, C3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: D, halo, CN, OH, N(Ra)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C(O)Ci-6 alkyl, -C(O)N(Ra)2, and -N(Ra)C(O)Ci-6 alkyl; each R11is independently selected from the group consisting of: D, -C1-6 alkyl, -C1-6 deuteroalkyl, -C1-6 haloalkyl, -OH, oxo, halo, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy, NRX1RX2, - (C1-6 alkylene)-OH, -(C1-6 alkylene)-Ci-6 alkoxy, C3-8 cycloalkyl, and 3-8 membered heterocyclyl, or two R11, together with the atom(s) which they are attached, form a C3-8 cycloalkyl or 3-8 membered heterocyclyl;R12is selected from the group consisting of: hydrogen, halo, -C1-6 alkyl, and -C1-6 alkoxy; and n is 0, 1, 2, 3, 4, 5, or 6.

77. The compound of claim 76, which is of Formula (XHIa):334IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025)78. The compound of claim 76 or 77, wherein R4is methyl or trideuteromethyl.

79. The compound of any one of claims 76-78, wherein R12is hydrogen.

80. The compound of any one of claims 76-79, wherein each R11is independently D, C1-3 alkyl, fluoro, and cyclopropyl.

81. The compound of any one of claims 76-80, wherein n is 1, 2, 3, or 4.

82. The compound of any one of claims 76-79, wherein n is 0.

83. The compound of any one of claims 76-82, wherein R2is selected from the group consisting of: Ci-4 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl, C3-5 cycloalkyl, and -(C1-2 alkylene)-5-7 membered heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with 1 to 3 RA.

84. The compound of any one of claims 76-83, wherein R3is selected from the group consisting of: fluoro, C1-3 alkyl, and C1-3 alkoxy.

85. The compound of any one of claims 76-84, wherein R9is methyl, ethyl, OH, fluoro, chloro, CN, or OH.

86. The compound of any one of claims 76-85, wherein R10is C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-5 cycloalkyl, and 3-5 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: D, halo, CN, OH, N(Ra)2, methyl, and ethyl.

87. A pharmaceutical composition, comprising a compound of any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

88. A method of inhibiting an activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a compound of any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 87.

89. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, or the pharmaceutical335IPTS / 200134983.3PCT / US25 / 48136 26 September 2025 (26.09.2025) composition of claim 87.

90. The method of claim 89, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skin cancer, and brain cancer.

91. The method of claim 89, wherein the cancer is a hematological cancer.

92. The method of claim 89, wherein the cancer is selected from leukemia, lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin’s or non-Hodgkin’s lymphoma, a myeloproliferative neoplasm), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

93. A method of treating a myeloproliferative disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 87.

94. The method of claim 93, wherein the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post- essential thrombocythemia myelofibrosis, post polycythemia vera myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

95. A method of treating myelodysplastic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 87.336IPTS / 200134983.3

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