Compounds derived from substituted indazole propionic acid and their uses as AMPK activators.

Description

1 / 160 Compounds derived from substituted indazoline propionic acid and their uses as AMPK activators. BACKGROUND OF THE INVENTION

[001] Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a highly conserved serine / threonine kinase that acts as a central regulator of energy homeostasis. AMPK has been shown to mediate multiple pathways within intestinal epithelial cells, including the direct modulation of substrates involved in tight junction stability, polarity, differentiation, nutrient transport, and autophagy. Strengthening the intestinal barrier may have therapeutic potential for metabolic and inflammatory diseases associated with intestinal permeability or leaky gut. Considering the functional attributes of AMPK in energy and tissue homeostasis, there is a need for potent and direct, gut-targeted AMPK activators to treat conditions associated with AMPK activation. SUMMARY OF THE INVENTION

[002] The present invention provides, in part, a compound of Formula (I): Rb1 Formula (I) a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, wherein: - A1 is CR8, or N; - A2 is CH2, CHD, CD2, S, O, or NH; Petition 870250087244, dated 09 / 26 / 2025, p. 14 / 190 2 / 160 - A3 is CH, CD, or N; - R1 is H, D, C1-8 alkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted; - R2, R3, R5, and R6 are each independently H, D, OH, or halogen; - R4 is a monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with R9, R10, R11, R12, or R13, wherein R9, R10, R11, R12, and R13 are each independently H, D, halogen, CN, oxo, C1-8 alkyl, C3-6 cycloalkyl, C0-6 alkylene ORx, C1-6 haloalkylene ORx, C0-6 alkylene(C0-6haloalkyl)NRxRy, C1-6 alkylene(C1-6haloalkyl)NRxRy, 4- to 6-membered heterocycloalkyl, C(O)ORx, C0-6 alkylene-C(O)NRxRy, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkylene-C(O)NRxRy, O(Ci-6 alkyl)SO2NRxNRy, NRxRy, NHSO2Rx, SRx, S-C1-6 alkylene-C(O)NRxRy, S(O)RxRy, SO2Rx, SO2NRxRy, S(O)(NRx)Ry, S(O)(NRx)Ry, or SO2Rx; wherein each Rxe Ry is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C36 cycloalkyl, C1-6 alkylene-amide, OC0-2 alkylene-heterocycloalkyl, 4- to 6-membered alkyl heterocycle, C(O)C1-6 alkyl, imino, or C1-6 alkylsulfonyl; or Rxe Ry together with the atoms to which Rxe Ry are attached may form an optionally substituted ring; - R7 is C1-3 alkyl, C3-6 cycloalkyl, cyano or halogen; - Rb1, Rb2 and Rb3 are each independently H or D; - R8 is H, D, or halogen; and - n is 0, 1, or 2.

[003] Also described herein is 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof. The present invention also provides 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3 Petition 870250087244, dated 09 / 26 / 2025, page 15 / 190 3 / 160 yl]propanoic. A compound with the following structure is described here:

[004] The present invention provides a method for treating a condition, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of Formula (I), a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, wherein the condition is an inflammatory condition, an autoimmune condition or a functional gastrointestinal disorder. The present invention also provides a method for treating a condition, comprising: a) administering to an individual in need thereof a therapeutically effective amount of the compound of Formula (I), a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof; and b) administering a therapeutically effective amount of an additional therapeutic agent.

[005] The present invention further provides a compound of Formula (I), a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, for use as a medicament. The present invention also provides a compound of Formula (I), a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, for use in the treatment of an inflammatory condition, an autoimmune condition or a functional gastrointestinal disorder. The present invention provides the use of a compound of Formula (I), a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, in the manufacture of a medicament for the treatment Petition 870250087244, dated 09 / 26 / 2025, page 16 / 190 4 / 160 of an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder. The present invention further provides the use of a compound of Formula (I), a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, as a medicament. The present invention further provides the use of a compound of Formula (I), a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, in the treatment of an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[006] The present invention provides crystalline 3-[6-chloro-5-(2'hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof.

[007] It should be understood that both the previous general description and the detailed description below are merely illustrative and explanatory and are not restrictive of the invention, as claimed. BRIEF DESCRIPTION OF THE FIGURES

[008] FIG. 1 shows the PXRD of the compound of Ex. 1, form 1. DETAILED DESCRIPTION OF THE INVENTION

[009] The present invention can be more easily understood by reference to the following detailed description of the embodiments of the invention and to the Examples included herein. It should be understood that this invention is not limited to specific synthetic manufacturing methods, which may, of course, vary. It should also be understood that the terminology used herein is intended to describe only specific embodiments and is not intended to be limiting.

[0010] Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a highly conserved serine / threonine kinase that functions as a central regulator of energy homeostasis (Herzig, S. et al. Nat Rev Mol Cell Biol 19:121-135 (2018)). AMPK exists Petition 870250087244, dated 09 / 26 / 2025, page 17 / 190 5 / 160 as a heterotrimeric protein complex consisting of a catalytic α subunit, a structural β subunit, and a regulatory γ subunit. Multiple isoforms (e.g., two α, two β, three γ) encoded by different genes allow for up to twelve possible heterotrimeric AMPK complexes, with each heterotrimeric AMPK complex exhibiting a distinct cellular and tissue expression profile. AMPK is activated by upstream kinases, including hepatic kinase β1 (LKB1) and calcium / calmodulin-dependent protein kinase β (CamKKe), which phosphorylate the active site residue Thr172 within the α subunit of AMPK. AMPK is also activated when the intracellular ratio of adenosine monophosphate (AMP):adenosine triphosphate (ATP) or, to a lesser extent, adenosine diphosphate (ADP):ATP increases under conditions of energy stress, such as nutrient deprivation, inflammation, and hypoxia (Xiao, B. et al. Nature 449:496-500 (2007)).After activation, AMPK phosphorylates direct substrates involved in pathways that promote ATP production (e.g., fatty acid oxidation, glycolysis, glucose uptake, autophagy, and mitophagy) and inhibit ATP consumption (e.g., glucose, lipid, and protein synthesis; cell growth) to restore energy balance. Furthermore, AMPK can regulate and reprogram metabolism through transcriptional changes, phosphorylating factors that induce or repress gene transcription.

[0011] There are several approaches to the pharmacological activation of AMPK, both direct and indirect (Kim, J. et al. Exp Mol Med 48:e224 (2016)). 5-aminoimidazole-4-carboxamide-1-ε-Dribofuranoside (AICAR) and metformin increase cytosolic AMP. AICAR acts as an AMP mimetic, while metformin indirectly increases cytosolic AMP by inhibiting mitochondrial respiration and ATP release. AMP can bind to the γ subunit of AMPK to allosterically activate AMPK. In contrast, agonis Petition 870250087244, dated 09 / 26 / 2025, p. 18 / 190 6 / 160 Direct AMPK agonists can bind to the drug and metabolism allosteric site (ADaM) between the α and β subunits of AMPK to activate and protect AMPK from dephosphorylation. Selective AMPK pan-β and β1 agonists have been described.

[0012] AMPK activity can be altered due to pathological conditions, including metabolic and inflammatory diseases such as obesity, diabetes, cardiovascular disease, and cancer. Furthermore, there is evidence that AMPK can promote and maintain intestinal barrier function (Sahoo, S. et al. Nat Commun 12: 4246 (2021); Wu, Z. et al. J Cell Physiol 237: 3705-3716 (2022)). AMPK has been shown to mediate multiple pathways within intestinal epithelial cells, including direct modulation of substrates involved in tight junction stability, polarity, differentiation, nutrient transport, and autophagy (Sun, X. et al. Open Biol 7: 170104 (2017); Rowart, P. et al. Int J Mol Sci 13: 2040 (2018); Zhu, MJ. et al. Tissue Barrier 6: 1-13 (2018); Tsukita, K. et al.Strengthening the intestinal barrier may have therapeutic potential for metabolic and inflammatory diseases associated with intestinal permeability or a leaky gut (Odenwald, MA. et al. Clin Gastrenterol Hepatol 11:1075-1083 (2013)). AMPK activators have been developed for systemic administration. Considering the functional attributes of AMPK in energy and tissue homeostasis, there is a need for potent and direct AMPK activators, targeting the gut, to treat conditions associated with AMPK activation.

[0013] AMPK activating compounds, pharmaceutically acceptable salts, tautomers or pharmaceutically acceptable salts of tautomers thereof are described herein. AMPK activating pharmaceutical compositions comprising AMPK activating compounds, pharmaceutically acceptable salts, tautomers or pharmaceutically acceptable salts of tautomers thereof are also described herein. Petition 870250087244, dated 09 / 26 / 2025, page 19 / 1907 / 160 the same and at least one pharmaceutically acceptable excipient. Methods for synthesizing AMPK activating compounds or pharmaceutically acceptable salts, tautomers or pharmaceutically acceptable salts of tautomers thereof, and methods for administering the AMPK activating compounds, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof, to an individual in need thereof to treat a condition are further described herein. In some embodiments, the AMPK activating compounds, pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers described herein may be used to treat a metabolic disorder, an inflammatory disorder, an autoimmune disorder, a gastrointestinal barrier dysfunction disorder, a functional gastrointestinal disorder, a central nervous system disorder, an eating disorder, a nutritional disorder, or an allergy.In a preferred embodiment, the AMPK-activating compounds, pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of the tautomers described herein may be used to treat a metabolic disorder, an inflammatory disorder, an autoimmune disorder, a gastrointestinal barrier dysfunction disorder, or a functional gastrointestinal disorder. Definitions

[0014] Unless defined otherwise herein, the scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those skilled in the art. The invention described herein can be properly practiced in the absence of any element not specifically described herein.

[0015] Compounds of the invention or compounds of the description include compounds of Formula I, 1a, II, III, IVa-c and V, and the Petition 870250087244, dated 09 / 26 / 2025, page 20 / 190 8 / 160 new intermediates used in their preparation. Anyone skilled in the art will understand that the compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemics, diastereomers and other mixtures of such isomers, tautomers thereof, where they may exist. Those skilled in the art will also understand that the compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs and isotopically labeled versions thereof, where they may be formed.

[0016] As used herein, the singular forms a, an, an and the include plural references unless otherwise indicated. For example, the substituent a, an includes one or more substituents.

[0017] As used herein, the term about, when used to modify a numerically defined parameter (e.g., the dose of an AMPK activator compound, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof), means that the parameter may vary by up to 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0018] The term and / or means one or more. For example, X and / or Y should be understood as X and Y or X or Y and should be considered as providing explicit support for both meanings or for either meaning. Similarly, when more than two expressions are listed, as in X, Y and / or Z, they should be understood to mean i) X and Y, X, Y and Z, X and Z or Y and Z, or ii) X or Y or Z, and should be considered as explicit support for all meanings. Petition 870250087244, dated 09 / 26 / 2025, page 21 / 190 9 / 160

[0019] Any open valence appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures described herein indicates the presence of a hydrogen atom, unless otherwise indicated.

[0020] If substituents are described as being selected independently of a group, each substituent is selected independently of the other. Each substituent, therefore, can be identical to or different from the other substituent(s).

[0021] Optionally or optionally means that the event or circumstance subsequently described may, but does not necessarily, occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0022] The terms optionally substituted and substituted or unsubstituted are used interchangeably to indicate that the specific group described may have no non-hydrogen substituents (i.e., unsubstituted), or may have one or more non-hydrogen substituents (i.e., substituted). Unless otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the group described. When an optional substituent is linked via a double bond, such as an oxo substituent (=O), the group occupies two available valences, so the total number of other substituents included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different.Throughout the invention, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to someone skilled in the art.

[0023] Halogen or halo refers to fluorine, chlorine, bromine, and iodine (F, Cl, Br, I). In a preferred embodiment, halo refers to fluorine. Petition 870250087244, dated 09 / 26 / 2025, p. 22 / 190 10 / 160 In a preferred embodiment, halo refers to chlorine.

[0024] Cyan refers to a substituent with a carbon atom bonded to a nitrogen atom by a triple bond, i.e., CeN.

[0025] Hydroxy refers to an -OH group.

[0026] Oxo refers to an oxygen with a double bond (=O).

[0027] The term C1-C2 includes C1-C3... C1-C3. By way of example only, a group designated as C1-C4 indicates that there are from one to four carbon atoms in the portion, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. For example, C1-C4 alkyl indicates that there are from one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0028] The terms carbocyclic or carbocycle refer to a ring or system of rings in which the atoms forming the ring structure are all carbon atoms. The term is distinguished from heterocyclic rings or heterocycles, in which the ring structure contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. For example, carbocycle includes cycloalkyl and aryl.

[0029] Alkyl refers to a monovalent, saturated aliphatic hydrocarbon radical that has a specific number of carbon atoms, including linear or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 8 carbon atoms (C1-C5 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 5 carbon atoms (C1-C5 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to Petition 870250087244, dated 09 / 26 / 2025, p. 23 / 190 11 / 160 carbon atoms (C1-C3 alkyl) or 1 to 2 carbon atoms (C1-C2 alkyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like. The alkyl groups may be optionally substituted, unsubstituted or substituted, as defined herein.

[0030] The term haloalkyl refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by at least one of the same halogen atoms or by different halogen atoms. For example, fluoroalkyl means an alkyl, as defined herein, substituted with one, two, or three fluorine atoms. Exemplary fluoroalkyl (C1) compounds include fluoromethyl, difluoromethyl, and trifluoromethyl; exemplary fluoroalkyl (C2) compounds include 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,2-trifluoroethyl, and the like. Examples of fully substituted fluoroalkyl groups (also called perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0031] Alkoxy refers to an alkyl group, as defined herein, that is single-bonded to an oxygen atom. The point of attachment of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be represented as alkyl-O- or O(C1-x alkyl). Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (C1-C8 alkoxy), 1 to 6 carbon atoms (C1-C6 alkoxy), 1 to 4 carbon atoms (C1-C4 alkoxy), or 1 to 3 carbon atoms (C1-C3 alkoxy). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

[0032] Alkoxyalkyl refers to an alkyl group, as defined herein, that is substituted by an alkoxy group, as defined herein. Alkoxyalkyl can be represented as C1-x alkylene-O-C1-y alkyl. Petition 870250087244, dated 09 / 26 / 2025, p. 24 / 190 12 / 160 Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-.

[0033] Cycloalkyl refers to a system of fully saturated hydrocarbon rings having a specified number of carbon atoms, which may be a system of monocyclic, bicyclic, or polycyclic bridging or fused rings, connected to the base molecule via a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to: 3 to 12 carbon atoms (C3-C12 cycloalkyl), 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). Representative cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantanyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraenyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2,2]pentyl, norbornyl and bicyclo[1,1,1]pentyl.Cycloalkyl groups may be optionally substituted, unsubstituted, or substituted, as defined herein.

[0034] Cycloalkoxy refers to a cycloalkyl group, as defined herein, that is single-bonded to an oxygen atom. The point of attachment of a cycloalkoxy radical to a molecule is through the oxygen atom. A cycloalkoxy radical may be represented as cycloalkyl-O- or OC1-cycloalkyl. Cycloalkoxy groups may contain, but are not limited to, 3 to 8 carbon atoms (C3-C8 cycloalkoxy), 3 to 6 carbon atoms (C3-C6 cycloalkoxy), and 3 to 4 carbon atoms (C3-C4 cycloalkoxy). Representative cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-di Petition 870250087244, dated 09 / 26 / 2025, p. 25 / 190 13 / 160 hydronaphthalenyl, tetraenyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2,2]pentyl, norbornyl and bicyclo[1,1,1]pentyl.

[0035] Heterocycloalkyl refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O, and S as a ring member, wherein the S atoms of the ring are optionally replaced by one or two oxo groups (i.e., S(O)q, where q is 0, 1, or 2) and wherein the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. Heterocycloalkyl rings include rings that are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, wherein such spirocyclic, bridged, or fused rings may be saturated, partially unsaturated, or aromatic to the extent that unsaturation or aromaticity makes chemical sense, provided that the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system.Heterocycloalkyl rings may contain from 1 to 4 heteroatoms selected from N, O, and S(O)q as ring members, or from 1 to 2 heteroatoms in the ring, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms. Heterocycloalkyl rings may be optionally substituted, unsubstituted, or substituted, as defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic ring, bridged or fused, attached to it. Heterocycloalkyl rings may include, but are not limited to, 3- to 8-membered heterocycloalkyl groups, for example, 4- to 7- or 4- to 6-membered heterocycloalkyl groups, according to the definition presented herein.Illustrative examples of heterocycloalkyl rings include, but are not limited to, a monovalent radical of oxirane (oxiranyl), thirane (thiranyl), aziridine (aziridinyl), oxetane (oxetanyl), thiethane (thietanyl), azetidine (azetidinyl), tetrahydrofuran (tetrahydroPetição 870250087244, dated 09 / 26 / 2025, page 26 / 190. 14 / 160 furanyl), tetrahydrothiophene (tetrahydrothiophenyl), pyrrolidine (pyrrolidinyl), tetrahydropyran (tetrahydropyranyl), tetrahydrothiopyran (tetrahydrothiopyranyl), piperidine (piperidinyl), 1,4-dioxane (1,4-dioxanyl), 1,4-oxathiarane (1,4-oxathiaran), morpholine (morpholinyl), 1,4-dithiane (1,4-dithianyl), piperazine (piperazinyl), thiomorpholine (thiomorpholinyl), oxepane (oxepanil), thiepane (thiepanil), azepane (azepanil), 1,4-dioxepane (1,4dioxepanil), 1,4-oxathiepane (1,4-oxathiepanil), 1,4-oxaazepane (1,4oxaazepanil), 1,4-thiazepane (1,4-thiazepanyl), 1,4-diazepane (1,4-diazepanyl) or 1,4-ditepane (1,4-ditepanyl). Illustrative examples of bridged and fused heterocycloalkyl groups include, but are not limited to, a monovalent radical of 1-oxa-5-azabicyclo[2,2,1]heptane, 3-oxa-8-azabicyclo-[3,2,1]octane, 3-azabicyclo[3,1,0]hexane or 2-azabicyclo-[3,1,0]hexane.

[0036] Aryl refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems containing the specified number of atoms in the ring, in which all carbon atoms in the ring are sp2 hybridized and in which the pi electrons are conjugated. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms (C6-C20 aryl), 6 to 14 carbon atoms (C6-C14 aryl), 6 to 12 carbon atoms (C6-C12 aryl) or 6 to 10 carbon atoms (C6-C10 aryl). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted, or substituted, as further defined in this document.

[0037] Similarly, heteroaryl or heteroaromatic refers to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one selected heteroatom. Petition 870250087244, dated 09 / 26 / 2025, page 27 / 190 15 / 160 of N, O, and S as a ring member in a ring in which all carbon atoms in the ring are sp2 hybridized and in which the pi electrons are conjugated. Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms (5 to 20 member heteroaryl), 5 to 14 ring atoms (5 to 14 member heteroaryl), 5 to 12 ring atoms (5 to 12 member heteroaryl), 5 to 10 ring atoms (5 to 10 member heteroaryl), 5 to 9 ring atoms (5 to 9 member heteroaryl), or 5 to 6 ring atoms (5 to 6 member heteroaryl). Heteroaryl rings are linked to the base molecule via a ring atom of the heteroaromatic ring. Thus, 5- or 6-membered heteroaryl rings, alone or in a fused structure, can be linked to the base molecule through a C or N atom of the ring.Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted, or substituted, as defined herein.Illustrative examples of monocyclic heteroaryl groups include, but are not limited to a monovalent pyrrole radical (pyrrolyl), furan (furanyl), thiophene (thiophenyl), pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoxazolyl), oxazole (oxazolyl), isothiazole (isothiazolyl), thiazolyl (thiazolyl), 1,2,3-triazole (1,2,3-triazolyl), 1,3,4-triazole (1,3,4-triazolyl), 1-oxa-2,3-diazole (1-oxa2,3-diazolyl), 1-oxa-2,4-diazole (1-oxa-2,4-diazolyl), 1-oxa-2,5-diazole. Petition 870250087244, 09 / 26 / 2025, p. 28 / 1 16 / 160 (1-oxa-2,5-diazolyl), 1-oxa-3,4-diazol (1-oxa-3,4-diazolyl), 1-thia-2,3diazol (1-thia-2,3-diazolyl), 1-thia-2,4-diazol (1-thia-2,4-diazolyl), 1-thia2,5-diazol (1-thia-2,5-diazolyl), 1-thia-3,4-diazol (1-thia-3,4-diazolyl), tetrazol (tetrazolyl), pyridine (pyridinyl), pyridazine (pyridazinyl), pyrimidine (pyrimidinyl) or pyrazine (pyrazinyl). Illustrative examples of fused ring heteroaryl groups include, but are not limited to, benzofuran (benzofuranila), benzothiofeno (benzotiofenila), indole (indolila), benzimidazole (benzimidazolila), indazol (indazolila), benzotriazole (benzotriazolila), pyrrolo[2,3-b]pyridine (pyrrolo[2,3-b]pyridine), pyrrolo[2,3-c]pyridine. (pyrrolo[2,3c]pyridinila), pyrrolo[3,2-c]pyridina (pyrrolo[3,2-c]pyridinila), pyrrolo[3,2b]pyridina (pyrrolo[3,2-b]pyridinila), imidazo[4,5-b]pyridina (imidazo[4,5b]pyridinila), imidazo[4,5-c]pyridina (imidazo[4,5-b]pyridinila), pyrazolo[4,3-d]pyridine (pyrazolo[4,3-d]pyridinila), pyrazolo[4,3-c]pyridine (pyrazolo[4,3-c]pyridinyl), pyrazolo[3,4-c]pyridine (pyrazolo[3,4-c]pyridinyl), pyrazolo[3,4-b]pyridine (pyrazolo[3,4-b]pyridinyl), isoindole (isoindolyl), indazole (indazolyl), purine (purinyl), indolizine (indolizinyl), imidazo[1,2-a]pyridine (imidazo[1,2-a]pyridinyl), imidazo[1,5-a]pyridine (imidazo[1,5-a]pyridinyl), pyrazolo[1,5-a]pyridine (pyrazolo[1,5a]pyridinyl), pyrrolo[1,2-b]pyridazine (pyrrolo[1,2-b]pyridazinyl), imidazo[1,2-c]pyrimidine (imidazo[1,2-c]pyrimidinyl), quinoline (quinolinyl), isoquinoline (isoquinolinyl), cinoline (cinnolinyl), quinazoline (azaquinazoline), quinoxaline (quinoxalinyl), phthalazine (phthalazinyl), 1,6naphthyridine (1,6-naphthyridinyl), 1,7-naphthyridine (1,7-naphthyridinyl), 1,8naphthyridine (1,8-naphthyridinyl), 1,5-naphthyridine (1,5-naphthyridinyl), 2,6naphthyridine (2,6-naphthyridinyl), 2,7-naphthyridine (2,7-naphthyridinyl), pyrido[3,2d]pyrimidine (pyrido[3,2-d]pyrimidinyl), pyrido[4,3-d]pyrimidine (pyrido[4,3d]pyrimidinyl), pyrido[3,4-d]pyrimidine (pyrido[3,4-d]pyrimidinyl), pyrido[2,3-d]pyrimidine (pyrido[2,3-d]pyrimidinyl), pyrido[2,3-b]pyrazine (pyrido[2,3-b]pyrazinyl), pyrido[3,4-b]pyrazine (pyrido[3,4-b]pyrazinyl), pyrimide, Petition 870250087244, 09 / 26 / 2025, p. 29 / 1 17 / 160 do[5,4-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl), pyrazino[2,3-b]pyrazine (pyrazino[2,3-b]pyrazinyl), or pyrimido[4,5-d]pyrimidine (pyrimido[4,5d]pyrimidinyl).

[0039] Amino refers to an unsubstituted -NH2 group. When amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rx and Ry are independently defined as described herein. For example, alkylamino refers to an -NRxRy group, where one of Rx and Ry is an alkyl moiety and the other is H, and dialkylamino refers to NRxRy, where both Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2).

[0040] The term alkylamino or aminoalkyl refers to a radical of the formula -NHRx or -NRxRy, where each Rx and Ry is independently H, an alkyl group, or an alkylene group. For example, alkylamino may refer to an -NRxRy group, where one of Rx and Ry is an alkyl moiety and the other is H; and dialkylamino may refer to -NRxRy, where both Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2). In some embodiments, aminoalkyl refers to -NH-alkylene or alkylene-NH-alkylene, where each alkylene is independently substituted or unsubstituted.

[0041] The term pharmaceutically acceptable means that the substance (for example, the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention, is suitable for administration to an individual or patient.

[0042] Deuterium enrichment factor, as used herein, means the ratio of deuterium abundance to natural deuterium abundance, each relative to hydrogen abundance. Petition 870250087244, dated 09 / 26 / 2025, page 30 / 190 18 / 160 An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0043] The term treating, treating or treatment, as used herein, encompasses both preventive, i.e., prophylactic, treatment and palliative, i.e., relieving, attenuating or delaying the progression of the patient's disease (or condition) or any tissue damage associated with the disease.

[0044] As used herein, the terms subject, individual, or patient, used interchangeably, refer to any animal, including mammals. Mammals, according to the invention, include canines, felines, bovines, caprines, equines, ovines, swine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In one embodiment, humans are suitable individuals. Human individuals may be of any gender and be at any stage of development.

[0045] As used herein, the expression therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that induces the biological or medicinal response in a tissue. Petition 870250087244, dated 09 / 26 / 2025, page 31 / 190 19 / 160 of the system, animal, individual, or human being sought by a researcher, veterinarian, physician, or other clinician, which may include one or more of the following: (1) to prevent disease; for example, to prevent a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder, but does not yet experience or exhibit the pathology or symptoms of the disease; (2) to inhibit the disease; for example, to inhibit a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder (i.e., to interrupt (or delay) the further development of the pathology or symptomatology, or both); and (3) to improve the disease; for example, to improve a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder (i.e., to reverse the pathology or symptomatology, or both). Compounds of the Invention

[0046] AMPK activating compounds are described here. In some embodiments, the compounds described here are pan-AMPK activating compounds.

[0047] The present invention provides a compound of Formula (I): Formula (I) a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, wherein: - A1 is CR8, or N; Petition 870250087244, dated 09 / 26 / 2025, p. 32 / 190 20 / 160 - A2 is CH2, CHD, CD2, S, O, or NH; - A3 is CH, CD, or N; - R1 is H, D, C1-8 alkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted; - R2, R3, R5, and R6 are each independently H, D, OH, or halogen; - R4 is a monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with R9, R10, R11, R12, or R13, wherein R9, R10, R11, R12, and R13 are each independently H, D, halogen, CN, oxo, C1-8 alkyl, C3-6 cycloalkyl, C0-6 alkylene-ORx, C1-6 haloalkylene-ORx, C0-6 alkylene(C0-6haloalkyl)NRxRy, C1-6 alkylene(C1-6 haloalkyl)NRxRy, 4- to 6-membered heterocycloalkyl, C(O)ORx, C0-6 alkylene-C(O)NRxRy, OC1-3 alkyleneheterocycloalkyl, OC1-3 alkylene-C(O)NRxRy, O(C1-6 alkyl)SO2NRxNRy, NRxRy, NHSO2Rx, SRx, S-C1-6 alkylene-C(O)NRxRy, S(O)RxRy, SO2Rx, SO2NRxRy, S(O)(NRx)Ry, S(O)(NRx)Ry, or SO2Rx; wherein each Rx and Ry is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 alkylene-amide, OC0-2 alkylene-heterocycloalkyl, 4- to 6-membered heterocycloalkyl, C(O)C1-6 alkyl, imino, or C1-6 alkylsulfonyl;or Rxe Ry together with the atoms to which Rxe Ry are attached can form an optionally substituted ring; - R7 is C1-3 alkyl, C3-6 cycloalkyl, cyano, or halogen; - Rb1, Rb2, and Rb3 are each independently H or D; - R8 is H, D, or halogen; and - n is 0, 1, or 2.

[0048] In some forms, the compound is of Formula (Ia): Petition 870250087244, dated 09 / 26 / 2025, p. 33 / 190 21 / 160 Formula (Ia), or a pharmaceutically acceptable salt, tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

[0049] In some embodiments, A1 is CR8. In some embodiments, A1 is N. In some embodiments, R8 is H. In some embodiments, R8 is a halogen. In a preferred embodiment, A1 is CH or CF.

[0050] In some embodiments, A2 is O or NH. In a preferred embodiment, A2 is CH2 or S. In a preferred embodiment, A2 is CH2. In a preferred embodiment, A2 is S.

[0051] In some forms, A3 is CH. In a preferred form, A3 is N. In a preferred form, A1 is N and A3 is N.

[0052] In some embodiments, R1 is H, D, or C1-8 alkyl. In some embodiments, R1 is C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl. In some embodiments, R1 is -6-O-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid. In a preferred embodiment, R1 is H.

[0053] In some embodiments, R2 is H. In some embodiments, R2 is halogen. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R3 is H. In some embodiments, R3 is halogen. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R5 is H. In some embodiments, R5 is halogen. In some embodiments, R5 is F. In some embodiments, R5 is Cl. In some embodiments, R6 is H. In some embodiments, R6 is halogen. In some embodiments, R6 is OH. In some embodiments, R6 is F. In some embodiments, R6 is Cl. In a preferred embodiment, R2 is halogen; and R3, Petition 870250087244, dated 09 / 26 / 2025, p. 34 / 190 22 / 160 R5 and R6 are each independently H. In a preferred embodiment, R2, R3, R5, and R6 are each independently H.

[0054] In some embodiments, R4 is a 6-membered monocyclic aryl. In some embodiments, R4 is a 6-membered monocyclic aryl substituted with 1, 2, or 3 Ra. In some embodiments, R4 is a 5- or 6-membered monocyclic heteroaryl substituted with 1, 2, or 3 Ra. In a preferred embodiment, R4 is phenyl, wherein R9, R10, R11, R12, and R13 are each independently H, D, Cl, F, CN, C1-3 alkyl, C1-6 alkylene-OH, C1-6 alkylene-OC1-6 alkyl, OH, OC1-6 alkyl, OC16 haloalkyl, O(C1-3 alkylene)heterocycloalkyl, O(C1-3 alkylene)C(O)NRxRy, C1-3 alkylene-NRxRy, C(O)OH, C(O)OC1-3 alkyl, CO2-2 alkylene-C(O)NRxRy, SO2NRxRy, S(O)(NRx)Ry, NRxRy, SRx, or SO2Rx. In a preferred embodiment, R4 is a 6-membered monocyclic heteroaryl compound, wherein at least one of R9, R10, R11, R12, and R13 is a C1-3 alkoxy, halogen, hydroxyl, or C(O)NH2.

[0055] In some embodiments, R7 is C1-3 alkyl. In some embodiments, R7 is C3-6 cycloalkyl. In some embodiments, R7 is cyclopropyl. In some embodiments, R7 is cyano. In some embodiments, R7 is halogen. In a preferred embodiment, R7 is Cl. In a preferred embodiment, R7 is F.

[0056] The present invention also provides a compound of Formula (II): a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein: R2 is H, D or halogen; Petition 870250087244, dated 09 / 26 / 2025, p. 35 / 190 23 / 160 - R7 is Cl or CN; - A2 is CH2, CHD, CD2, S, or NH; - A4 is CR9 or N; - R9 is H, F, Cl, C1-3 alkyl, C1-3 alkylene-O-C1-3 alkyl, C1-3 alkylene-NH2, COOH, C(O)OC1-3 alkyl, C1-3 alkylene-C(O)NH2, C(O)NHC1-3 alkyl, C(O)N(C1-3 alkyl)2, C1-6 alkylene(C1- 6haloalkyl)NH2, C0-2 alkylene-NH(C(O)C1-3 alkyl), OC1-3 alkyl, OC1-3haloalkyl, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkyleneC(O)NH2, NHSO2C1-3 alkyl, N(C1-3 alkyl)(C(O)C1-3 alkyl), SC1-3 alkyl, S-C1-3 alkylene-C(O)NH2, SO(NH)Ci-3 alkyl, SO2NH2, or SO2C1-3 alkyl; - R10 is H, D, or OH; - R11 is H, D, halogen, CN, O(C1-3 alkyl), or O(C13 haloalkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring; - R12 is H, OC1-3 alkyl, or C1-3 alkylene-OH; - R13 is H, F, Cl, or C1-3 alkyl; and - n is 1 or 2.

[0057] In some forms, R7 is CN. In a preferred form, R7 is Cl.

[0058] In some embodiments, R9 is H, F, Cl, C1-3 alkyl, C1-3 alkylene-O-C1-3 alkyl, C1-3 alkylene-NH2, COOH, C(O)OC1-3 alkyl, C1-3 alkylene-C(O)NH2, C(O)NHC1-3 alkyl, C(O)N(C1-3 alkyl)2, C13haloalkylene-NH2, C0-2 alkylene-NH(C(O)C1-3 alkyl), OC1-3 alkyl, OC1-3haloalkyl, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkyleneC(O)NH2, NHSO2C1-3 alkyl, N(C1-3 alkyl)(C(O)C1-3 alkyl), SC1-3 alkyl, S-C1-3 alkylene-C(O)NH2, SO(NH)C1-3 alkyl, SO2NH2, or SO2C1-3 alkyl. In some embodiments, R9 is H, C1-3 alkylene-OC1-3 alkyl, C1-3 alkylene-NH2, C1-3 alkylene-C(O)NH2, C1-3 alkylene(C1-3haloalkyl)NH2, or C0-2 alkylene-NH(C(O)C1-3 alkyl). In al Petition 870250087244, dated 09 / 26 / 2025, page 36 / 190 24 / 160 In some embodiments, R9 is NHSO2C1-3 alkyl or N(C1-3 alkyl)(C(O)C1-3 alkyl). In some embodiments, R9 is SC1-3 alkyl, SC1-3 alkylene-C(O)NH2, SO(NH)C1-3 alkyl, SO2NH2, or SO2C1-3 alkyl. In a preferred embodiment, R9 is H. In a preferred embodiment, R9 is C(O)NH2. In a preferred embodiment, R9 is C1-3 alkylene-NH2.

[0059] In some forms, R10 is H or D. In a preferred form, R10 is OH.

[0060] In some embodiments, R11 is H, F, Cl, or CN. In some embodiments, R11 is O(C1-3 alkyl) or O(C1-3 haloalkyl). In a preferred embodiment, R11 is H.

[0061] The present invention also provides a compound of Formula (III): Formula (III), a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein: - R9 is H, D, halogen, C1-3 alkyl, C(O)NH2, C1-3 alkyleneNH2, C1-3 alkylene-O-C1-3 alkyl, C(O)OCi-3 alkyl, C(O)OH, OC1-3 alkyl, OC1-3haloalkyl, -O(Ci-3 alkyl)SO2NH2, C1-6alkylene(C1-6 haloalkyl)NH2, SC1-3 alkyl, or -C(O)NRxRy, where each Rx and Ry are independently H or C1-6 alkyl; and - R11 is H, D, halogen, CN, or -O(C1-3 alkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring.

[0062] In a preferred embodiment, R9 is H or -C(O)NRxRy, wherein each Rx and Ry are independently H or C1-6 alkyl; and R11 is H or -O(C1-3 alkyl); or R9 and R11 together with the carbon atom. Petition 870250087244, dated 09 / 26 / 2025, p. 37 / 190 25 / 160 to which R9 and R11 are connected form an optionally replaceable ring.

[0063] The present invention also provides compounds of Formula (IVa), Formula (IVb), or Formula (IVc): Formula (IVc) a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein each R9, R10, and R11 are independently H, C1-3 alkyl, C1-3 alkylene-OH, or OC1-3 alkyl.

[0064] In a preferred embodiment, R9, R10, and R11 are each independently H. In a preferred embodiment, R10 is C1-3 alkyl, C1-3 alkylene-OH, or OC1-3 alkyl.

[0065] The present invention also provides a compound of Formula (V): a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, where: - R10 is H, D, or OH; - R9e R11 together with the carbon atom to which R9e Petition 870250087244, dated 09 / 26 / 2025, p. 38 / 190 26 / 160 R11 are linked to form an optionally substituted ring, wherein the ring is a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the ring is optionally substituted with C1-3 alkyl, OH, or oxo.

[0066] In some embodiments, the ring is a 6-membered heterocycloalkyl. In a preferred embodiment, the ring is a 5-membered heterocycloalkyl. In some embodiments, the ring is a 6-membered heteroaryl. In a preferred embodiment, the ring is a 5-membered heteroaryl.

[0067] In a preferred embodiment, the ring is substituted with C13 alkyl. In a preferred embodiment, the ring is substituted with OH. In a preferred embodiment, the ring is substituted with oxo.

[0068] In some embodiments, the compound of the invention, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, is selected from the group consisting of: 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran-6-yl)phenyl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; Petition 870250087244, dated 09 / 26 / 2025, page. 39 / 190 27 / 160 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)butanoic acid; 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoyl)oxy)-3,4,5-tri-hydroxytetrahydro-2H-pyran-2carboxylic acid; e 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazol-5-yl)-[1,1'biphenyl]-2-yl)oxy)-3,4,5-tri-hydroxytetrahydro-2H-pyran-2-carboxylic acid.

[0069] In a preferred embodiment, the compound is 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In a preferred embodiment, the compound is 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl]propanoic acid. In a preferred embodiment, the compound has the structure:

[0070] Any compound here can be purified. A compound here can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure. Petition 870250087244, dated 09 / 26 / 2025, p. 40 / 190 28 / 160 pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure,at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least, Petition 870250087244, dated 09 / 26 / 2025, page 41 / 190 29 / 160 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Pharmaceutically Acceptable Salts

[0071] The salts covered by the term pharmaceutically acceptable salts refer to compounds of this invention that are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention suitable for administration to an individual or patient. For a review of suitable salts, see Paulekun, GS et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0072] In addition, the compounds of the invention may also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparation of compounds of Formula I, Ia, II, III, IVa-c and V; 2) purification of compounds of Formula I, Ia, II, III, IVa-c and V; 3) separation of enantiomers of compounds of Formula I, Ia, II, III, IVa-c and V; or 4) separation of diastereomers of compounds of Formula I, Ia, II, III, IVa-c and V.

[0073] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzate, hydrochloride / chloride, hydrobromide / bromide, iodate / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate Petition 870250087244, dated 09 / 26 / 2025, page 42 / 190 30 / 160 to, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonic acid and xinafoate.

[0074] Suitable basic salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0075] Hemissals of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

[0076] Pharmaceutically acceptable salts of compounds of the invention can be prepared by methods well known to one skilled in the art, including, but not limited to, the following procedures: (i) by the reaction of a compound of the invention with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting a salt of a compound of the invention into another. This can be accomplished by reaction with an appropriate acid or base or by means of a suitable ion-exchange procedure.

[0077] These procedures are typically performed in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. Solvatos

[0078] The compounds of the invention and pharmaceutically accepted salts Petition 870250087244, dated 09 / 26 / 2025, page 43 / 190 31 / 160 The compounds of the invention may exist in non-solvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising the compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof, and one or more molecules of pharmaceutically acceptable solvent, for example, ethanol. The term hydrate is employed when said solvent is water.

[0079] In addition, compounds of Formula I, Ia, II, III, IVa-c and V may also include other solvates of such compounds that are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I, Ia, II, III, IVa-c and V; 2) purifying compounds of Formula I, Ia, II, III, IVa-c and V; 3) separating enantiomers of compounds of Formula I, Ia, II, III, IVa-c and V; or 4) separating diastereomers of compounds of Formula I, Ia, II, III, IVa-c and V.

[0080] A currently accepted classification system for organic hydrates is one that defines isolated-site, channel, or metal-ion-coordinated hydrates—see Polymorphism in Pharmaceutical Solids, by KR Morris (Ed. HG Brittain, Marcel Dekker, 1995). Isolated-site hydrates are those in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are found in cross-linked channels, where they are close to other water molecules. In metal-ion-coordinated hydrates, water molecules are linked to the metal ion.

[0081] When the solvent or water is strongly bound, the complex can have a well-defined stoichiometry, independent of moisture. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the content Petition 870250087244, dated 09 / 26 / 2025, p. 44 / 190 The 32 / 160 water / solvent ratio may depend on humidity and drying conditions. In these cases, non-stoichiometry will be the norm. Complexes

[0082] Also included within the scope of the invention are multicomponent complexes (excluding salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular constituents that are joined by non-covalent interactions; for example, a hydrogen-bonded complex (cocrystal) can be formed with a neutral molecule or with a salt. Cocrystals can be prepared by melt crystallization, by recrystallization from solvents, or by physical grinding of the components – see Chem Commun, 17;1889-1896, by O. Almarsson and MJ Zaworotko (2004). For a general review of multicomponent complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975). Solid form

[0083] The compounds of the invention can exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term amorphous refers to a state in which the material lacks long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or a liquid. Typically, such materials do not exhibit distinct X-ray diffraction patterns and, although they exhibit the properties of a solid, are more formally described as a liquid. Upon heating, a change of properties from solid to liquid occurs, characterized by a change of state, typically of second order (glass transition). The term crystalline refers Petition 870250087244, dated 09 / 26 / 2025, page 45 / 190 33 / 160 refers to a solid phase in which the material has a regular and ordered internal structure at the molecular level and exhibits a distinct X-ray diffraction pattern with defined peaks. Such materials, when sufficiently heated, will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of first order ('melting point').

[0084] The compounds of the invention can also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (molten or in solution) and consists of a two-dimensional order at the molecular level. Mesomorphism that arises as a result of a temperature change is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules that possess an ionic polar group (such as -COO-Na+, COO-K+ or -SO3-Na+) or a non-ionic group (such as -N-N+(CH3)3). For more information, see Crystals and the Polarizing Microscope, by N.H. Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970).

[0085] In a preferred embodiment, a compound of the invention is a crystalline form of the compound. In a preferred embodiment, the compound is crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In a preferred embodiment, the compound is crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, with a pattern of Petition 870250087244, dated 09 / 26 / 2025, page 46 / 190 34 / 160 X-ray powder diffraction comprising diffraction peaks of about 12.6 ± 0.2, about 18.8 ± 0.2, about 19.7 ± 0.2 and about 24.4 ± 0.2 degrees two theta. Stereoisomers

[0086] The compounds of the invention may exist as two or more stereoisomers. The stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Cis / trans isomers may also exist for saturated rings. The cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0087] Pharmaceutically acceptable salts, tautomers or pharmaceutically acceptable salts of tautomers of the compounds of the invention may also contain an optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine) contraion.

[0088] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography, crystallization Petition 870250087244, dated 09 / 26 / 2025, page 47 / 190 35 / 160 fractional chromatography or using both techniques, and one or both diastereoisomers can be converted into the corresponding pure enantiomer(s) by means well known to those skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC. The concentration of the eluate provides the enriched mixture. Chiral chromatography using sub- and supercritical fluids can be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited).

[0089] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which a homogeneous crystal form is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate, in which two crystalline forms are produced in equimolar amounts, each comprising a single enantiomer. Although both crystalline forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art – see, for example, Stereochemistry of Organic Compounds, by EL Eliel and SH Wilen (Wiley, 1994). Tautomerism

[0090] Where structural isomers are interconvertible through Petition 870250087244, dated 09 / 26 / 2025, p. 48 / 190 36 / 160 of a low-energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino / amino, keto / enol or oxime / nitroso, lactam / lactim group, or so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound can exhibit more than one type of isomerism.

[0091] It should be emphasized that, although, for the sake of brevity, the compounds of the invention have been presented here in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention. Isotopes

[0092] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention, in which one or more atoms are replaced by atoms having the same atomic number, but with an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0093] Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as 2H (D, deuterium) and 3H (T, tritium), carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.

[0094] Certain isotopically labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in either or both studies of tissue distribution of the drug or substrate. Radioactive isotopes, such as tritium and 14C, are particularly useful for this purpose due to their ease of incorporation and ease of detection. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in studies of Petition 870250087244, dated 09 / 26 / 2025, page 49 / 190 37 / 160 Positron Emission Tomography (PET) to examine substrate receptor occupancy. Deuterium substitution may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosing requirements, reduced CYP450 inhibition (competitive or time-dependent), or an improvement in the therapeutic index or tolerability.

[0095] In some embodiments, the invention provides deuterium-labeled (or deuterated) compounds and salts, wherein the formula and variables of such compounds and salts are each independently as described herein. Deuterated means that at least one of the atoms in the compound is deuterium in greater abundance than the natural abundance of deuterium (typically approximately 0.015%). One skilled in the art has recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of the invention can be defined by the deuterium enrichment factor. It is understood that one or more deuteriums can exchange with hydrogen under physiological conditions.

[0096] In some embodiments, the deuterium compound is selected from any of the compounds presented in Table 5, shown in the Examples section. In some embodiments, one or more hydrogen atoms at certain metabolic sites of the compounds of the invention are deuterated. In some embodiments, the deuterium compound is selected from the group consisting of: Petition 870250087244, dated 09 / 26 / 2025, page 50 / 190 38 / 160

[0097] The isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0098] Pharmaceutically acceptable solvates, according to the invention, include those in which the crystallization solvent can be isotopically substituted, for example, D2O, d6-acetone, d6DMSO. Propharmaceuticals

[0099] A compound of the invention can be administered in the form of a prodrug. Thus, certain derivatives of a compound of the invention, which may have little or no pharmacological activity, can, when administered into or on the body, be converted into a compound of the invention with the desired activity, for example, by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives are called prodrugs. More information on the use of prodrugs Petition 870250087244, dated 09 / 26 / 2025, page 51 / 190 39 / 160 cos can be found in The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio et al.).

[00100] Prodrugs according to the invention can, for example, be produced by replacing appropriate functionalities present in compounds of the invention with certain portions known to those skilled in the art as pro-portions, as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[00101] Thus, a prodrug according to the invention may be (a) an ester or amide derivative of a carboxylic acid when present in a compound of the invention; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in a compound of the invention; (c) an amide, imine, carbamate or amine derivative of an amino group when present in a compound of the invention; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivative of a thiol group when present in a compound of the invention; or an oxime or imine derivative of a carbonyl group when present in a compound of the invention.

[00102] Some specific examples of prodrugs according to the invention include: (I) when a compound of the invention contains a carboxylic acid functionality (-COOH), an ester thereof, such as a compound in which the hydrogen of the carboxylic acid functionality of the compound is replaced by C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g., tBuC(=O)OCH2-); (ii) when a compound of the invention contains an alcohol functionality (-OH), an ester thereof, such as a compound in which the hydrogen of the alcohol functionality of the compound is replaced by -CO(C1-C8 alkyl) (e.g., methyl carbonyl) or the alcohol is es Petition 870250087244, dated 09 / 26 / 2025, p. 52 / 190 40 / 160 certified with an amino acid; (iii) when a compound of the invention contains an alcohol functionality (-OH), an ether thereof, such as a compound in which the hydrogen of the alcohol functionality of the compound is replaced by (C1-C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2; (iv) when a compound of the invention contains an alcohol functionality (-OH), a phosphate thereof, such as a compound in which the hydrogen of the alcohol functionality of the compound is replaced by -P(=O)(OH)2 or -P(=O)(O-Na+)2 or -P(=O)(O-)2Ca2+; (v) when a compound of the invention contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amide thereof, for example, a compound in which, as the case may be, one or both hydrogens of the amino functionality of the compound are replaced by (C1-Cw)alkanol, -COCH2NH2 or the amino group is derivatized with an amino acid; (vi) when a compound of the invention contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amine thereof, for example, a compound in which, as the case here, one or both hydrogens of the amino functionality of the compound are replaced by -CH2OP(=O)(OH)2.

[00103] Certain compounds of the invention can themselves act as prodrugs of other compounds of the invention. It is also possible that two compounds of the invention may be joined in the form of a prodrug. In certain circumstances, a prodrug of a compound of the invention may be created by the internal linkage of two functional groups in a compound of the invention, for example, by the formation of a lactone. Metabolites

[00104] Also included within the scope of the invention are the active metabolites of the compounds of the invention, that is, compounds formed Petition 870250087244, dated 09 / 26 / 2025, p. 53 / 190 41 / 160 in vivo after drug administration, often by oxidation or dealkylation. Some examples of metabolites according to the invention include, but are not limited to, (I) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH > -COH): (ii) where the compound of the invention contains an alkoxy group, a hydroxyl derivative thereof (-OR -> -OH); (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR' -> -NHR or -NHR'); (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); (vi) when the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and (vii) when the compound contains a hydroxyl or carboxylic acid group, the compound can be metabolized by conjugation, for example, with glucuronic acid to form a glucuronide. There are other conjugative metabolism pathways. These pathways are often known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also undergo conjugation.

[00105] In a preferred embodiment, a metabolite of a compound described herein may comprise a moiety of O-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. In a preferred embodiment, the metabolite is 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4yl)-1H-indazol-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In a Petition 870250087244, dated 09 / 26 / 2025, page 54 / 190 42 / 160 preferred mode, the metabolite has the following structure: a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

[00106] In a preferred embodiment, the metabolite is 6((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazol-5-yl)-[1,1'-biphenyl]-2-yl)oxy)3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In a preferred embodiment, the metabolite has the structure: a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

[00107] In a preferred embodiment, the metabolite is 3-(6-chloro-5-(2'-(sulfoxy)-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In some embodiments, the metabolite is 3-(6-chloro-5-(2'-(sulfoxy)-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid, further comprising a hydroxyl group, or a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. In some embodiments, the metabolite has the structure: Petition 870250087244, dated 09 / 26 / 2025, page 55 / 190 43 / 160 OH oo H or a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof. Pharmaceutical Compositions

[00108] In another embodiment, the invention comprises pharmaceutical compositions. For the purposes of pharmaceutical composition, the compound itself, the pharmaceutically acceptable salts, the tautomers or the pharmaceutically acceptable salts of the tautomers thereof shall simply be referred to as the compounds of the invention. A pharmaceutical composition refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or prodrug thereof as the active ingredient, and at least one pharmaceutically acceptable excipient.

[00109] The term excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will depend largely on factors such as the route of administration, the effect of the excipient on solubility and stability, and the nature of the pharmaceutical form.

[00110] As used herein, excipient includes any and all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline solution, phosphate-buffered saline solution, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride or polyalcohols such as mannitol or sorbitol, in the composition. Examples of excipients also include various organic solvents (such as hydrates and Petition 870250087244, dated 09 / 26 / 2025, page 56 / 190 44 / 160 solvates). Pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / linking agents, lubricants, disintegrants, sweeteners or flavorings, colorants and the like. For example, for oral administration, tablets containing various excipients, such as citric acid, may be used together with various disintegrants, such as starch, alginic acid and certain complex silicates, and with binders, such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tablet-forming purposes. Solid compositions of a similar type may also be used in soft and hard gelatin capsules.Examples of excipients, therefore, do not include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound contained therein may be combined with various sweetening or flavoring agents, colorants or coloring matter and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin or combinations thereof.

[00111] Examples of excipients also include pharmaceutically acceptable substances, such as wetting agents, or small amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the shelf life or effectiveness of the compound.

[00112] The compositions of this invention may be in a variety of forms. These include, for example, pharmaceutical forms. Petition 870250087244, dated 09 / 26 / 2025, page 57 / 190 45 / 160 liquid, semi-solid and solid forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended route of administration and the therapeutic application.

[00113] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[00114] Oral administration of a solid pharmaceutical form may, for example, be presented in discrete units such as hard or soft capsules, pills, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, oral administration may be in the form of powder or granules. In another embodiment, the oral pharmaceutical form is sublingual, such as, for example, a lozenge. In such solid pharmaceutical forms, the compounds of the invention are normally combined with one or more excipients. Such capsules or tablets may comprise a controlled-release formulation. In the case of capsules, tablets, and pills, the pharmaceutical forms may also comprise buffering agents or may be prepared with enteric coatings. In a preferred embodiment, a compound of the invention is administered orally.In a preferred embodiment, a compound of the invention is administered orally as a soft capsule, pill, or tablet. In a preferred embodiment, a compound of the invention is administered. Petition 870250087244, dated 09 / 26 / 2025, page 58 / 190 46 / 160 orally in immediate-release form. In a preferred embodiment, a compound of the present invention is administered orally in extended-release form.

[00115] In another embodiment, oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the technique (e.g., water). Such compositions may also comprise adjuvants, such as one or more humectants, emulsifiers, suspending agents, flavorings (e.g., sweeteners), or fragrances.

[00116] In another embodiment, the invention comprises a parenteral dosage form. Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal, intramuscular, intrasternal injections and infusion. Injectable preparations (i.e., sterile aqueous or oily injectable suspensions) may be formulated according to known techniques, using one or more suitable dispersing, wetting or suspending agents.

[00117] In another embodiment, the invention comprises a topical dosage form. Topical administration includes, for example, dermal and transdermal administration, such as by means of transdermal patches or iontophoresis devices, intraocular administration, or intranasal administration or by inhalation. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are delivered by a transdermal device, administration will be carried out using a reservoir-membrane type patch. Petition 870250087244, dated 09 / 26 / 2025, p. 59 / 190 47 / 160 porous or solid matrix. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin adhesives, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated—see, for example, BC Finnin and TM Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

[00118] Suitable formulations for topical ocular administration include, for example, eye drops in which the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or auditory administration may be in the form of drops of a micronized suspension or solution in sterile isotonic saline solution with adjusted pH. Other formulations suitable for ocular and auditory administration include ointments, biodegradable implants (i.e., absorbable gel sponges, collagen) and non-biodegradable implants (i.e., silicone), wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative such as benzalkonium chloride.These formulations can also be administered by iontophoresis.

[00119] For intranasal administration, the compounds of the invention are conveniently administered in the form of a solution or suspension from a pump-operated spray canister, which is compressed or pumped by the patient, or as an aerosol presentation from a pressurized canister or nebulizer. Petition 870250087244, dated 09 / 26 / 2025, page 60 / 190 48 / 160 pain, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered as a dry powder (alone, as a mixture, for example, in a dry mixture with lactose, or as a mixed-component particle, for example, mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electro-hydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[00120] In another embodiment, the invention comprises a rectal pharmaceutical form. Such a rectal pharmaceutical form may be in the form of, for example, a suppository. Cocoa butter is a traditional base for suppositories, but various alternatives may be used as appropriate.

[00121] Other excipients and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations regarding formulations and effective administration procedures are well known in the art and described in standard textbooks. Drug formulation is discussed, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Petition 870250087244, dated 09 / 26 / 2025, page 61 / 190 49 / 160 Press, 2005; Stahl, P. Heinrich e Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use. Nova Iorque: Wiley VCH, 2011; e Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. Nova Iorque: Informa Healthcare USA, Inc., 2016.

[00122] Acceptable excipients are non-toxic to individuals at the dosages and concentrations used and may comprise one or more of the following: 1) buffers, such as phosphate, citrate or other organic acids; 2) salts, such as sodium chloride; 3) antioxidants, such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkylparabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol or m-cresol; 6) low molecular weight polypeptides (less than about 10 residues); 7) proteins such as serum albumin, gelatin or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates, including glucose, mannose, or dextrins; 11) chelating agents such as EDTA;12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counterions, such as sodium, metal complexes (e.g., Zn-protein complexes) or 14) nonionic surfactants, such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[00123] The compounds of the invention containing liposomes can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK; Clinical development of liposome-based drugs: formulation, characterization and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and phosphatidylcholine. Petition 870250087244, dated 09 / 26 / 2025, page 62 / 190 50 / 160 PEG-derived thidylethanolamine (PEG-PE). Liposomes are extruded through filters with defined pore sizes to produce liposomes with the desired diameter.

[00124] The compounds of the invention can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are described in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[00125] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of the invention, matrices which are presented in the form of molded articles, for example, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, L-glutamic acid and 7-ethyl-L-glutamate copolymers, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[00126] The formulations to be used for intravenous administration must be sterile. This is easily achieved, for example, by filtration through sterile filtration membranes. The compounds of the invention are generally placed in a container with a Petition 870250087244, dated 09 / 26 / 2025, page 63 / 190 51 / 160 sterile access port, for example, a bag or bottle for intravenous solution with a stopper that can be pierced by a hypodermic injection needle.

[00127] Suitable emulsions can be prepared using commercially available fat emulsions, such as lipid emulsions comprising soybean oil, a lipid emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and cottonseed oil lipid emulsions. The active ingredient can be dissolved in a premixed emulsion composition or, alternatively, it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed by mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soy lecithin) and water. It should be noted that other ingredients may be added, for example, glycerol or glucose, to adjust the tonicity of the emulsion.Suitable emulsions typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

[00128] For example, emulsion compositions may be those prepared by mixing a compound of the invention with lipid emulsions comprising soybean oil or components thereof (soybean oil, egg phospholipids, glycerol and water).

[00129] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof and powders. Liquid or solid compositions may contain pharmaceutically acceptable excipients. Petition 870250087244, dated 09 / 26 / 2025, page 64 / 190 52 / 160 suitable components, as established above. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions in pharmaceutically acceptable solvents, preferably sterile, may be nebulized using gases. Nebulized solutions may be inhaled directly from the nebulizer device, or the nebulizer device may be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. Compositions in solution, suspension, or powder may be administered, preferably orally or nasally, from devices that release the formulation in an appropriate manner.

[00130] A drug product intermediate (DPI) is a partially processed material that must undergo further processing steps before becoming a bulk drug product. The compounds of the invention can be formulated into a drug product intermediate (DPI) containing the active ingredient in a higher free energy form than the crystalline form. One reason for using a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, enhanced bulk transport through the mucus layer adjacent to epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include enhanced solid-state stability and downstream manufacturing capabilities. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (e.g., amorphous solid dispersions (ASDs)).There are many known techniques in the art for manufacturing ASDs that produce material suitable for integration into a bulk drug product, for example, spray-dried dispersions (SDDs), melt extrudates (often called HMEs), coprecipitate. Petition 870250087244, dated 09 / 26 / 2025, page 65 / 190 53 / 160 of the amorphous drug nanoparticles and nanoadsorbates. In one embodiment, the amorphous solid dispersions comprise a compound of the invention and a polymeric excipient. Other excipients, as well as the concentrations of said excipients and the compound of the invention, are well known in the art and described in standard textbooks. See, for example, Amorphous solid dispersions theory and practice by Navnit Shah et al. Administration and Dosage

[00131] A compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as the compound per se or, alternatively, as a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. For administration and dosage purposes, the compound itself, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer thereof shall simply be referred to as the compounds of the invention.

[00132] The compounds of the invention are administered by any suitable route, in the form of a pharmaceutical composition adapted to that route and in a dose effective for the intended treatment. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[00133] In a preferred embodiment, the compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the bloodstream directly from the mouth.

[00134] In another embodiment, the compounds of the invention can also be administered parenterally, for example, directly into the bloodstream, muscle or an internal organ. The means Petition 870250087244, dated 09 / 26 / 2025, page 66 / 190 Suitable routes of administration for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous routes. Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors, and infusion techniques.

[00135] In another embodiment, the compounds of the invention can also be administered topically to the skin or mucous membranes, i.e., dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention can be administered rectally or vaginally. In another embodiment, the compounds of the invention can also be administered directly into the eye or ear.

[00136] The dosage regimen for the compounds of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound employed. Thus, the dosage regimen can vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg / kg (i.e., mg of the compound of the invention per kg of body weight) for the treatment of the conditions indicated and discussed herein. In another embodiment, the total daily dose of the compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg. It is not uncommon for the administration of the compounds of the invention to be repeated several times a day (typically, no more than 4 times). Multiple doses per day may be used to increase the total daily dose, if desired.In some forms, the compound, a pharmaceutically acceptable salt, Petition 870250087244, dated 09 / 26 / 2025, page 67 / 190 55 / 160 The tautomer or a pharmaceutically acceptable salt of the tautomer thereof is administered once daily, twice daily, or three times daily. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer thereof is administered once daily. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer thereof is administered twice daily. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer thereof is administered three times daily.

[00137] In one embodiment, a compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer thereof or a pharmaceutically acceptable salt of the tautomer thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, a tautomer thereof or a pharmaceutically acceptable salt of the tautomer thereof, may be administered orally in the form of a tablet or capsule. The dosage of the compound, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer may be adjusted based on the patient's response and symptoms.In some embodiments, the compound or pharmaceutical composition may provide the compound in an amount of about 0.01 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 750 mg, from about 750 mg to about 1000 mg, from about 1250 mg to about 1500 mg, from about 1500 mg to about 1750 mg, from about 1750 mg to about 2000 mg, from about 2000 mg to about 2250 mg, from about 2250 mg to about 2500 mg, from about 2500 mg to about 2750 mg, from about 2750 mg to about 3000 mg, from about 3000 mg. Petition 870250087244, dated 09 / 26 / 2025, page 68 / 190 56 / 160 mg to about 3250 mg, from about 3250 mg to about 3500 mg, from about 3500 mg to about 3750 mg, from about 3750 mg to about 4000 mg, from about 4000 mg to about 4250 mg, from about 4250 mg to about 4500 mg, from about 4500 mg to about 4750 mg, or from about 4750 mg to about 5000 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer thereof may be supplied in an amount of about 1 mg to about 2500 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 1 mg to about 100 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 1 mg to about 50 mg.In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 1 mg to about 25 mg. In some embodiments, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 150 mg to about 2500 mg. In some embodiments, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 150 mg to about 500 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 100 mg to about 1000 mg.In some embodiments, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 500 mg to about 1500 mg. In al. Petition 870250087244, dated 09 / 26 / 2025, page 69 / 190 57 / 160 In some embodiments, the compound, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer may be supplied in an amount of about 1500 mg to about 2500 mg. In some embodiments, the compound, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer thereof may be supplied in an amount of about 2500 mg to about 5000 mg.

[00138] A compound, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 0.01 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 250 mg, about 300 mg, about 350 mg, about of 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg,about 1900 mg, about 2000 mg, about, 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 3400 mg, about 3600 mg, about 3800 mg, about 4000 mg, approximately 4200 mg, approximately 4400 mg, approximately 4600 mg, approximately 4800 mg, or approximately 5000 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or salt. Petition 870250087244, dated 09 / 26 / 2025, page 70 / 190 A pharmaceutically acceptable 58 / 160 dose of the tautomer described herein can be supplied in an amount of about 5 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein can be supplied in an amount of about 10 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein can be supplied in an amount of about 15 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein can be supplied in an amount of about 25 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein can be supplied in an amount of about 50 mg.In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 75 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 100 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 250 mg. In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 500 mg.In a preferred embodiment, the compound, pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer described herein may be supplied in an amount of about 1000 mg. Petition 870250087244, dated 09 / 26 / 2025, page 71 / 190 59 / 160 Therapeutic Methods and Uses

[00139] The compounds described can activate AMPK and may be useful in treating a condition associated with AMPK. In a preferred embodiment, the compounds of the invention may be a pan-AMPK activator and may be useful in treating a condition associated with AMPK. In some embodiments, the condition or disorder is a metabolic disorder, an inflammatory disorder, an autoimmune disorder, a gastrointestinal barrier dysfunction disorder, a functional gastrointestinal disorder, an eating disorder, a nutritional disorder, an allergy, or a central nervous system (CNS) disorder. In a preferred embodiment, the AMPK-activating compounds of the invention may be administered to an individual in need thereof to treat a metabolic disorder. In a preferred embodiment, the AMPK-activating compounds of the invention may be administered to an individual in need thereof to treat an inflammatory or autoimmune disorder.In a preferred embodiment, the AMPK-activating compounds of the invention can be administered to an individual in need thereof to treat a gastrointestinal barrier dysfunction disorder or a functional gastrointestinal disorder.

[00140] In some embodiments, the AMPK-activating compounds described herein may treat a metabolic disorder or a complication resulting from a selected metabolic condition from the group consisting of type 2 diabetes, gestational diabetes, insulin resistance, hyperglycemia, hypercholesterolemia, hypertriglyceridemia (elevated levels of triglyceride-rich lipoproteins), obesity, abdominal obesity, vascular restenosis, hyperinsulinemia, glucose intolerance, atherosclerosis, metabolic syndrome, hypertension, high hepatic glucose production, high blood glucose concentrations, non-alcoholic steatohepatitis (NASH), dyslipidemia, dyslipidemia Petition 870250087244, dated 09 / 26 / 2025, page 72 / 19060 / 160 mixed, diabetic dyslipidemia, protection against ischemia and reperfusion damage, a lipid disorder, elevated plasma triglyceride levels, elevated free fatty acid levels, elevated cholesterol levels, high low-density lipoprotein (LDL) levels, low high-density lipoprotein (HDL) levels, chronic kidney disease, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, hypoxia, cancer, non-alcoholic fatty liver disease (NAFLD), glucocorticoid-induced apoptosis, skeletal muscle wasting, sarcopenia, high levels of circulating free fatty acids (FFAs), heart attack, cardiomyopathy, heart failure, and atherosclerosis.In a preferred embodiment, the AMPK-activating compounds of the present invention can treat a selected metabolic disorder from the group consisting of type 2 diabetes, gestational diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or hypertension.

[00141] In some embodiments, the AMPK-activating compounds described herein can treat a selected inflammatory or autoimmune disorder from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, graft-versus-host disease (GVHD), radiation-induced enteritis, chemotherapy-induced enteritis, and necrotizing enterocolitis. In some embodiments, the AMPK-activating compounds described herein can treat gastrointestinal lesions resulting from toxic assaults such as radiation or chemotherapy. In a preferred embodiment, the AMPK-activating compounds of the present invention can treat a selected inflammatory or autoimmune disorder from the group consisting of inflammatory bowel disease, colitis, ulcerative colitis, and Crohn's disease. In a preferred embodiment, the AMPK-activating compounds of the present invention Petition 870250087244, dated 09 / 26 / 2025, p. 73 / 190 61 / 160 can treat inflammatory bowel disease. In a preferred embodiment, the AMPK-activating compounds of the present invention can treat colitis. In a preferred embodiment, the AMPK-activating compounds of the present invention can treat ulcerative colitis. In a preferred embodiment, the AMPK-activating compounds of the present invention can treat Crohn's disease.

[00142] In some embodiments, the AMPK-activating compounds described herein may treat a gastrointestinal barrier dysfunction disorder, such as environmental enteric dysfunction or spontaneous bacterial peritonitis. In some embodiments, the AMPK-activating compounds described herein may treat ischemic colitis or sclerosing cholangitis.

[00143] In some embodiments, the AMPK-activating compounds described herein can treat a selected functional gastrointestinal disorder from the group consisting of irritable bowel syndrome, functional dyspepsia, functional abdominal distension, functional diarrhea, functional constipation, gastroparesis, microbiome dysbiosis-related disorders, and opioid-induced constipation. In a preferred embodiment, the AMPK-activating compounds of the invention can treat a selected functional gastrointestinal disorder from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, and functional constipation.

[00144] In some embodiments, the AMPK-activating compounds described herein may treat an eating disorder or a selected nutritional disorder from the group consisting of hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, and intestinal insufficiency. In some embodiments, the AMPK-activating compounds described herein may treat complications associated with an eating or nutritional disorder, such as left ventricular hypertrophy. Petition 870250087244, dated 09 / 26 / 2025, page 74 / 190 62 / 160

[00145] In some embodiments, the AMPK-activating compounds described herein may treat an allergy, such as food allergies and celiac disease. In some embodiments, the AMPK-activating compounds described herein may treat nausea and vomiting.

[00146] In some embodiments, the AMPK-activating compounds described herein may treat a selected central nervous system disorder from the group consisting of mood disorder, anxiety, depression, affective disorder, schizophrenia, malaise, cognitive disorder, chemical dependency, autism, epilepsy, a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, Lewy body dementia, episodic cluster headaches, migraines and pain.

[00147] In some modalities, the AMPK-activating compounds described herein may decrease fatty acid synthesis; increase fatty acid oxidation; increase ketogenesis; decrease cholesterol synthesis, lipogenesis and / or triglyceride synthesis; decrease blood glucose levels and / or concentrations; improve glucose homeostasis; normalize glucose metabolism; decrease blood pressure; increase HDL levels; decrease LDL levels; decrease plasma triglyceride levels; decrease fatty acid levels; decrease hepatic glucose production; improve insulin action; decrease blood pressure; improve insulin sensitivity; suppress hepatic glucose production; inhibit de novo lipogenesis; simulate muscle glucose uptake; modulate insulin secretion by pancreatic β cells; decrease body weight; increase skeletal muscle mass; or prevent skeletal muscle mass loss.In a preferred embodiment, the AMPK-activating compounds described herein may treat or reduce systemic infection or systemic inflammation caused by a permeable intestinal barrier. In a preferred embodiment, the compounds... Petition 870250087244, dated 09 / 26 / 2025, page 75 / 190 The 63 / 160 AMPK activators described here are pan-AMPK activators. Co-administration

[00148] The compounds of the invention can be used alone or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein, wherein the compound of the invention, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer thereof, is used in combination with one or more other therapeutic agents discussed herein.

[00149] The administration of two or more compounds in combination means that all compounds are administered in a timely manner sufficient to affect the individual's treatment. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, in the same or different administration schedules, and with or without specific time limits, depending on the treatment regimen. Furthermore, simultaneous administration may be achieved by mixing the compounds before administration or by administering them at the same time but as separate pharmaceutical forms, at the same or different administration sites. Examples of combination include, but are not limited to, concomitant administration, co-administration, simultaneous administration, sequential administration, and administered simultaneously.

[00150] A compound of the invention and one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term fixed combination means that a compound of the invention, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, and one or more therapeutic agents are both administered to an individual simultaneously in a single composition or dose. Petition 870250087244, dated 09 / 26 / 2025, page 76 / 190 64 / 160 gem. The term non-fixed combination means that a compound of the invention, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, and one or more therapeutic agents are formulated as separate compositions or dosages, so that they can be administered to an individual in need of them simultaneously or at different times, with varying time limits between them, wherein such administration provides effective levels of the two or more compounds in the individual's body.

[00151] In one embodiment, the compounds of this invention are administered in combination with the specifically named agents, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[00152] The present invention also provides any of the uses, methods or compositions as defined above, wherein the compound of Formula I, Ia, II, III, IVa-c and V, pharmaceutically acceptable salt, tautomer or pharmaceutically acceptable salt of the tautomer thereof, is used in combination with another pharmacologically active compound, particularly one of the functionally defined classes or specific compounds listed below. These agents may be administered as part of the same pharmaceutical form or of separate pharmaceutical forms, by the same route of administration or by different routes, and in the same or different administration schedules, according to standard pharmaceutical practice known to one skilled in the art.

[00153] Agents suitable for use in combination therapy with a compound of Formula I, Ia, II, III, IVa-c and V, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof, include: sulfasalazine, mesalazine, prednisone, azathioprine Petition 870250087244, dated 09 / 26 / 2025, page 77 / 190 65 / 160 prine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporine, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, antihistamines, rifampicin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, mycophenolate sodium, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxacin, NSAIDs, solumedrol, depomedrol and dexamethasone.

[00154] Other agents suitable for use in combination therapy with a compound of Formula I, Ia, II, III, IVa-c and V, a pharmaceutically acceptable salt, tautomer or a pharmaceutically acceptable salt of the tautomer thereof, include: a 5-lipoxygenase activator protein (FLAP) antagonist; a leukotriene antagonist (LTRA), such as an LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2 antagonist, for example, montelukast or zafirlukast; a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine type 2 receptor antagonist, for example, loratadine, fexofenadine, desloratadine, levocetirizine, metapyrylene or cetirizine; an α1-adrenergic receptor agonist or an α2-adrenergic receptor agonist, for example, phenylephrine, methoxamine, oxymetazoline or methylnorephrine; an M3 muscarinic receptor antagonist, for example, tiotropium or ipratropium; a dual M3 muscarinic receptor antagonist / β2 agonist;a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, for example, theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or nedocromil sodium; a cyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (for example, aspirin or ibuprofen) or a selective inhibitor (for example, celecoxib or valdecoxib); a glucocorticosteroid, for example, fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide; Petition 870250087244, dated 09 / 26 / 2025, page 78 / 190 66 / 160 or beclametasone; an anti-inflammatory monoclonal antibody, for example, infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; a β2 agonist, for example, salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a long-acting β2 agonist; an integrin antagonist, for example, natalizumab; an adhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B1 or B2 receptor antagonist; an immunosuppressive agent, such as an IgE pathway inhibitor (e.g., omalizumab) or cyclosporine; a matrix metalloproteinase (MMP) inhibitor, such as an MMP-9 or MMP-12 inhibitor; a tachykinin NK1, NK2 or NK3 receptor antagonist; a protease inhibitor, such as an elastase, chymase, or catheopsin G inhibitor; an adenosine A2a receptor agonist; an adenosine A2b receptor antagonist; a urokinase inhibitor;a dopamine receptor agonist (e.g., ropinirole), particularly a dopamine D2 receptor agonist (e.g., bromocriptine); an NFkB pathway modulator, such as an IKK inhibitor; an additional cytokine signaling pathway modulator, such as a syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R, or MK-2 inhibitor; a mucolytic, mucokinetic, or antitussive agent; an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelial sodium channel blocker (ENaC) or epithelial sodium channel inhibitor (EnaC); a nucleotide receptor agonist, such as a P2Y2 agonist; a thromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g., Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2 receptor antagonist (DP2); a prostaglandin D2 receptor antagonist (DP1); a hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor; interferon-β; a soluble human TNF receptor, for example, Etanercept;an HDAC inhibitor; a phosphoinositide 3-kinase gamma (PI3Ky) inhibitor; Petition 870250087244, dated 09 / 26 / 2025, page 79 / 190 67 / 160 a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor; a CXCR-1 or CXCR-2 receptor antagonist; an IRAK-4 inhibitor; and a TLR-4 or TLR-9 inhibitor, including pharmaceutically acceptable salts of the specifically named compounds. The agents may be administered with another active agent, the second active agent being administered orally or topically.

[00155] These agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles, such as saline solution, Ringer's solution, dextrose solution and the like. The specific dosage regimen, i.e., dose, time and repetition, will depend on the individual in question and their medical history. Kits

[00156] Another aspect of the invention provides kits comprising the compound of the invention or pharmaceutical compositions comprising the compound of the invention. A kit may include, in addition to the compound of the invention or a pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as the therapeutic agents for co-administration described herein.

[00157] In another embodiment, the invention comprises kits suitable for use in carrying out the treatment methods described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in sufficient quantities to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds of the invention in sufficient quantities to carry out the methods of the invention. Petition 870250087244, dated 09 / 26 / 2025, page 80 / 190 68 / 160 and a container for dosing. Synthetic Methods

[00158] The compounds of the present invention can be synthesized by synthetic routines that include processes analogous to those well known in the chemical art, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or can be prepared using methods well known to those skilled in the art. Many of the compounds used herein are related to, or can be derived from, compounds in which one or more scientific interests or commercial needs have arisen. Consequently, such compounds may be one or more of the following: 1) commercially available; 2) reported in the literature; or 3) prepared from other commonly available substances by someone skilled in the art, using materials that have been reported in the literature.

[00159] Detailed descriptions of the individual reaction steps are detailed in the EXAMPLES section below. Those skilled in the art will understand that other synthetic routines can be used to synthesize the compounds of the invention. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be substituted to provide one or more of a variety of derivatives or reaction conditions. Furthermore, many of the compounds prepared by the methods described below can be modified in light of this invention using conventional chemistry well known to those skilled in the art.

[00160] Those skilled in the art will understand that the experimental conditions set forth in the following Preparations and Examples are illustrative of suitable conditions for effecting the transformations shown and that it may be necessary or desirable to vary the conditions. Petition 870250087244, dated 09 / 26 / 2025, page 81 / 190 69 / 160 precise actions employed for the preparation of the compounds of the invention. It will further be understood that it may be necessary or desirable to carry out the transformations in a different order from that described in the Preparations and Examples, or to modify one or more of the transformations, to provide the desired compound of the invention.

[00161] In preparing the compounds of the invention, it is observed that some of the preparation methods useful for preparing the compounds described herein may require protection of the remote functionality (e.g., a primary amine, secondary amine, carboxyl group, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is easily determined by one skilled in the art. The use of such protection / deprotection methods is also within the scope of skill in the art. For a general description of protecting groups and their use, see the book Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 8th edition, March.

[00162] For example, if a compound contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites in the molecule if left unprotected. Consequently, such functionalities may be protected by an appropriate protecting group (PG), which may be removed in a subsequent step. Suitable protecting groups for protecting amines and carboxylic acids include those protecting groups commonly used in peptide synthesis (such as N-tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the reaction conditions described and may be removed without chemically altering other functionalities in a compound of the invention. Petition 870250087244, dated 09 / 26 / 2025, page 82 / 190 70 / 160 General Experimental Details

[00163] In the non-limiting Examples and Preparations illustrating the invention and presented in the description and diagrams below, the following abbreviations, definitions, and analytical procedures may be mentioned. Other abbreviations common in the art may also be used. The compounds of the present invention have been named using ChemDraw Professional™ version 20 (Perkin Elmer) or have been given names consistent with IUPAC nomenclature.

[00164] The 1H nuclear magnetic resonance (NMR) spectra were consistent in all cases with the proposed structures. The characteristic chemical shifts (δ) are given in parts per million from tetramethylsilane, using conventional abbreviations for designating the main peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; quintet; m, multiplet; br, broad. The following abbreviations were used for common NMR solvents: CD3CN, deuteroacetonitrile; CDCh, deuterochloroform; DMSO-d6, deuterodimethyl sulfoxide; and MeOD, deuteromethanol. Where appropriate, tautomers may be recorded in the NMR data; and some exchangeable protons may not be visible. Some resonances in the NMR spectrum appear as complex multiplets because the isolate is a mixture of two conformers.

[00165] Mass spectra were recorded by electron impact ionization (EI), electrovaporization ionization (ESI), or atmospheric pressure chemical ionization (APCI). The observed ions are reported as EM m / ze and may be positive ions of the compound [M]+, compound plus a proton [M+H]+, or compound plus a sodium ion [M+Na]+. In some cases, the only ions observed may be fragment ions reported as [M+H-(lost fragment)]+. When relevant, the reported ions are assigned to isotopes of chlorine (35Cl and / or37Cl), bromine (79Br and / or81Br), and tin (120Sn). Petition 870250087244, dated 09 / 26 / 2025, page 83 / 190 71 / 160

[00166] When TLC, chromatography, or HPLC were used to purify compounds, someone skilled in the art could choose any appropriate solvent or combination of solvents to purify the desired compound. Chromatographic separations (excluding HPLC) were performed using silica gel adsorbent unless otherwise indicated.

[00167] All reactions were carried out under continuous stirring under an atmosphere of nitrogen or argon gas, unless otherwise indicated. In some cases, the reactions were purged with nitrogen or argon gas before the start of the reaction. In these cases, the nitrogen or argon gas was bubbled through the liquid phase of the mixture for approximately the specified time. The solvents used were commercial anhydrous grades. All starting materials were commercially available products. In some cases, the starting materials were prepared according to procedures described in the literature. It will be evident to one skilled in the art that the term concentrate, as used herein, generally refers to the practice of evaporating the solvent under reduced pressure, typically carried out using a rotary evaporator. Abbreviations Ac2O is acetic anhydride; B2(Pin)2 is bis(pinacolato)diboron; br is broad; tBu is tert-butyl; °C stands for degrees Celsius; CDCl3 is deuterochloroform; δ is chemical shift; d is a doublet; dd is a doublet of doublets; ddd is a doublet of a doublet of doublets; Petition 870250087244, dated 09 / 26 / 2025, page 84 / 190 72 / 160 dt is a doublet of triplets; DCM stands for dichloromethane; methylene chloride; DMF is N,N-dimethylformamide; DMSO-d6 is deuterodimethyl sulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; g is gram; HPLC stands for high-performance liquid chromatography; h is time(s); KOAc is potassium acetate; L stands for liter; LC stands for liquid chromatography; m is a multiplet; M is molar; (MH)- is the negative ion of the compound with the least proton; MeOD is deuterated methanol; MeOH is methanol; mg stands for milligram; MHz stands for megahertz; min(s) means minute(s); mL stands for milliliter; mm stands for millimeters; mM is millimolar; mmol is millimole; EM stands for mass spectrometry; (M+H)+ is the positive ion of the compound with the proton; NMR stands for nuclear magnetic resonance; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II); Petition 870250087244, dated 09 / 26 / 2025, page 85 / 190 73 / 160 Pd(dppf)Cl2-CH2Cl2 is dichloromethane [1,1'bis(diphenylphosphine)ferrocene]dichloropalladium(II) complex; Pd(OAc)2 is palladium(II) acetate; Pd(PPh3)4 is tetracis(triphenylphosphine)palladium(0); PPh3 is triphenylphosphine; ppm stands for parts per million; psi stands for pounds per square inch; q is a quartet; tr is retention time; s is a singleton; SFC stands for supercritical fluid chromatography; t is a triplet; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; TLC stands for thin-layer chromatography; μ is micron; pL stands for microliters; UPLC stands for high-performance liquid chromatography; and Xantfos is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

[00168] The Schemes described below aim to provide a general description of the methodology employed in the preparation of the compounds of the present invention. In the following Schemes, the general methods for the preparation of the compounds are shown in racemic or enantioenriched form. It will be evident to one skilled in the art that all synthetic transformations can be conducted in a precisely similar manner, regardless of whether the materials are enantioenriched or racemic. Furthermore, resolution to the desired optically active material can occur at any desired point in the sequence, using well-known methods such as those described herein and in the chemical literature. Petition 870250087244, dated 09 / 26 / 2025, page 86 / 190 74 / 160

[00169] Reaction Scheme IA describes general procedures for the synthesis of compounds of Formula (I). In Reaction Scheme IA, the chemical groups are as defined in the descriptive report; additionally, in Reaction Scheme IA: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromine, or chlorine; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group, where -C(O)OR is a chemically inert ester to the described cross-coupling reactions, but where -C(O)OR can be easily converted to -C(O)OR1 to provide compounds of Formula (I), preferably R = methyl, ethyl, benzyl, or tert-butyl; -BY2 = a boronic acid or boronate ester suitable for transition metal-catalyzed cross-coupling reactions, preferably boronic acid or pinacolboronate.

[00170] Heteroaryl halide intermediates (1a) can be prepared based on methods known in the literature (Tetrahedron Letters 2007, 48, 2457; WO2011008572; Bioorganic & Medicinal Chemistry 2014, 22, 1156; Journal of Organic Chemistry 2023, 88, 13049) in combination with standard functional group interconversions described in Reaction Scheme II, Reaction Scheme II, Reaction Scheme III and Reaction Scheme IV. Boronate intermediates (1b) can be prepared as described in WO2011061168 or WO2014140078. The conversion of heteroaryl halide intermediates (1a) into boronate intermediates (1d) can be easily achieved when A1= CR8 by methods known in the literature (WO2018229543; WO2022221526; WO2012119046). Halide intermediates (1e) can be prepared by methods widely reported in the literature. Intermediates (1c) can be prepared by transition metal-catalyzed cross-coupling of halide and boronate intermediates (1a) and (1b), or (1e) and (1d), using procedures analogous to ACS Medicinal Chemistry Letters 2020, 11, Petition 870250087244, dated 09 / 26 / 2025, page 87 / 190 75 / 160 825; Journal of Medicinal Chemistry 2021, 64, 4498; WO 2019201297; WO 2016164285; Journal of Medicinal Chemistry 2014, 57, 5129; WO2019213570. Compounds of Formula (I) can be prepared by transesterification or hydrolysis of Intermediates (1c) based on procedures well known in the literature (WO2012137089; Tetrahedron Letters 2018, 59, 2917; WO2022150574; WO 2022229341).

[00171] The borylation of Intermediate (1a) to give Intermediate (1d) can be carried out under standard palladium-catalyzed reaction conditions, using a catalyst such as [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base such as potassium acetate and a borylation reagent such as bis(pinacolato)diboron, in a suitable solvent such as dioxane, at a temperature preferably between 80 and 110 °C. The cross-coupling between the halide intermediate (1a) and the boronate intermediate (1b), or between the halide intermediate (1e) and the boronate intermediate (1d), to provide the intermediate (1c), can be effected using a catalyst such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'bis(diphenylphosphine)ferrocene]dichloro-palladium(II) and a base such as potassium fluoride, potassium carbonate or sodium bicarbonate, in a suitable solvent such as aqueous dioxane or aqueous 1,2-dimethoxyethane, at an appropriate temperature, preferably between 80 and 110 °C.The conversion of the ester intermediate (1c) into a compound of Formula (I) can be carried out under standard conditions for cleavage of the -C(O)OR ester. For R = small alkyl, such as methyl or ethyl, hydrolysis to give carboxylic acid of Formula (I) can be carried out with a suitable metal hydroxide, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in a solvent such as water or a mixed aqueous-organic solvent, such as aqueous methanol, ethanol and / or tetrahydrofuran, at an appropriate temperature, preferably between 0 and 110 °C. For R = tert-butyl, the cleavage of the tert-butyl ester... Petition 870250087244, dated 09 / 26 / 2025, p. 88 / 190 76 / 160 butyl, promoted by acid, to provide carboxylic acid of Formula (I), can be carried out with a suitable combination of acid and solvent, such as trifluoroacetic acid in dichloromethane or hydrogen chloride in dioxane, at an appropriate temperature, preferably between 0 and 30°C. Reaction Scheme IA (1d) Formula (I)

[00172] In Reaction Scheme IB, the chemical groups are as defined in the descriptive report; additionally, in Reaction Scheme IB: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromine, or chlorine; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group, where -C(O)OR is a chemically inert ester to the described cross-coupling reactions, but where -C(O)OR can be easily converted to -C(O)OR1 to provide compounds of Formula (I), preferably R = methyl, ethyl, benzyl, or tert-butyl; -BY2 = a boronic acid or boronate ester suitable for transition metal-catalyzed cross-coupling reactions, preferably Petition 870250087244, dated 09 / 26 / 2025, page 89 / 190 77 / 160 boronic acid or pinacolboronate.

[00173] Reaction Scheme IB describes an alternative routine for Intermediates (1c) by introducing an alternative R4 group. Although Reaction Scheme IB represents variants of the R4 group, one skilled in the art will recognize that analogous procedures can be applied to prepare analogous derivatives at any of the substituents R2 to R6. Bis(boronate) intermediates (1f) can be prepared according to bibliographic references (Chemistry - An Asian Journal 2013, 8, 1368; Organometallics 2002, 21, 4886; Organometallics 2014, 33, 1291). Monoboronate intermediates (1g) can be prepared by selective cross-coupling of bis(boronate) intermediates (1f) with heteroaryl halide intermediates (1a) (ACS Macro Letters 2012, 1, 392; WO2016115360; US20160072072; ACS Catalysis 2021, 11, 5968).Intermediates (1c) can be prepared by transition metal-catalyzed cross-coupling of boronate intermediates (1g) with appropriate (heteroaryl)halide intermediates (1h) using procedures analogous to those in ACS Medicinal Chemistry Letters 2020, 11, 825; Journal of Medicinal Chemistry 2021, 64, 4498; WO 2019201297; WO 2016164285; Journal of Medicinal Chemistry 2014, 57, 5129; WO 2019213570.

[00174] The cross-coupling between the halide intermediate (1a) and the (bis)boronate intermediate (1f) can be carried out using a catalyst such as tetracis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) dichloride and a base such as potassium carbonate or sodium carbonate, in a suitable solvent such as aqueous dioxane or aqueous tetrahydrofuran, at an appropriate temperature, preferably between 80 and 120 °C. The cross-coupling between the boronate intermediate (1g) and the halide intermediate (1h), to provide the intermediate (1c), can be carried out using a catalyst such as dichloride Petition 870250087244, dated 09 / 26 / 2025, pp. 90 / 190 78 / 160 of bis(triphenylphosphine)palladium(II) or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as potassium fluoride, potassium carbonate or sodium bicarbonate, in a suitable solvent such as aqueous dioxane or aqueous 1,2-dimethoxyethane, at an appropriate temperature, preferably between 80 and 110 °C. IB reaction scheme

[00175] Reaction Scheme II describes the general procedures for the synthesis of Intermediates (2d). In Reaction Scheme II, the chemical groups are as defined in the descriptive report; additionally, in Reaction Scheme II: X = a halide suitable for cross-coupling reactions catalyzed by transition metals, preferably iodine, bromine or chlorine; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group, where -C(O)OR is a chemically inert ester to the cross-coupling reactions described, but where -C(O)OR Petition 870250087244, dated 09 / 26 / 2025, pp. 91 / 190 79 / 160 can be easily converted to -C(O)OR1 to give compounds of Formula (I), preferably R = methyl, ethyl, benzyl or tert-butyl.

[00176] Substituted (aza)indole intermediates (2a) can be prepared based on methods reported in the literature (RSC Advances 2014, 4, 4672; WO2014049133; European Journal of Organic Chemistry 2008, 5, 783; WO2019236957; Journal of Medicinal Chemistry 2021, 64, 14968; RSC Advances 2017, 7, 52852; US20190185469; WO2013010880). Intermediates (2b) can be synthesized from (aza)indole intermediates (2a) based on procedures from the literature (RSC Advances 2018, 8, 13121; WO2011123946; WO 2020173400). Unsaturated intermediates (2c) can be prepared by olefination of aldehyde intermediates (2b) under standard conditions (WO 200979767; Chemical Reviews 1989, 89, 863; Organic Letters 2017, 19, 1500; European Journal of Medicinal Chemistry 2022, 234, 114248; European Journal of Medicinal Chemistry 2010, 45, 298; WO2016102633). Intermediates (2d) can be prepared by reducing unsaturated intermediates (2c) with appropriate choice of reaction conditions to avoid unwanted reduction of other functional groups; Hydrogenation with a platinum catalyst can promote the selective reduction of olefins in the presence of halides (Journal of the American Chemical Society 1922, 44, 1397; Journal of the American Chemical Society 1960, 82, 6090; WO 200876805; US 2020247768). Alternatively, Intermediates (2d) can be prepared directly from Intermediates (2b) by reaction with malonate derivatives (Synthetic Communications 25, 3067; US5350872; EP3275867; WO201535223; Bioorganic & Medicinal Chemistry 2017, 25, 2995).

[00177] The aldehyde intermediate (2b) can be prepared from the fused pyrrole intermediate (2a) by reaction with sodium nitrite and an acid, preferably hydrochloric acid, in a suitable solvent such as aqueous N,N-dimethylformamide, aqueous dioxane, aqueous acetone. Petition 870250087244, dated 09 / 26 / 2025, p. 92 / 190 80 / 160 or water, at an appropriate temperature, preferably between 0 and 30 °C. The olefinic intermediate (2c) can be synthesized from the aldehyde intermediate (2b) by reaction with a suitable olefining reagent, preferably (carbetoxymethylene)triphenylphosphorane or (tert-butoxycarbonylmethylene)triphenylphosphorane, in a suitable solvent, such as tetrahydrofuran, dichloromethane or ethanol, at an appropriate temperature, preferably between 20 and 70 °C. The reduction of the olefin intermediate (2c) to the intermediate (2d) can be achieved by catalytic hydrogenation, preferably using platinum oxide as a catalyst and hydrogen gas as a reducing agent, in a suitable solvent, such as ethanol or ethyl acetate, at an appropriate temperature, preferably between 20 and 40 °C.Alternatively, the Intermediate (2d) can be prepared directly from the aldehyde Intermediate (2b) by reaction with a malonate derivative, preferably 2,2-dimethyl-1,3-dioxane4,6-dione, and a base and a reducing agent, preferably triethylamine and formic acid, in a suitable solvent, preferably dioxane, at a suitable temperature, preferably between 50 and 100 °C. Reaction scheme II (2d)

[00178] Reaction Scheme II Reaction Scheme III describes general procedures for the synthesis of Intermediates (3g) by Petition 870250087244, dated 09 / 26 / 2025, p. 93 / 190 81 / 160 means of standard interconversions of protective groups and functional groups, well known to those skilled in the art.In Reaction Scheme II, Reaction Scheme III, the chemical groups are as defined in the descriptive report; except that, in Reaction Scheme II, Reaction Scheme III, A2 is limited to CH2, CHD, CD2; additionally, in Reaction Scheme II: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromine or chlorine; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group, where C(O)OR is a chemically inert ester to the cross-coupling reactions described, but where -C(O)OR can be easily converted to -C(O)OR1 to provide compounds of Formula (I), preferably R = methyl, ethyl, benzyl or tert-butyl; PG = a suitable protecting group for the reactions described, preferably 2-tetrahydropyranyl or (2-(trimethylsilyl)ethoxy)methyl; X1 = a suitable leaving group for the reactions described, preferably mesylate, tosylate, chloride or bromide; m = 0 or 1.

[00179] The N-protected Intermediates (3b) can be prepared from Intermediates (3a) using standard protecting group strategies, as described in PGM Wuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014. General approaches for homologation of carboxylic acid derivatives are described in Synthesis 1979, 1979, 633. The carboxylic acid intermediate (3c) can be synthesized by hydrolysis or deprotection of the ester intermediate (3b) (WO2012137089; Tetrahedron Letters 2018, 59, 2917; WO2022150574; WO2022229341). The alcohol intermediate (3d) can be prepared by reducing the carboxylic acid intermediate (3c) using hydride sources, as described in Advanced Synthesis & Catalysis 2021, 363, 4867; Journal of Medicinal Chemistry 2011, 54, 1333. The alcohol intermediate (3d) can be Petition 870250087244, dated 09 / 26 / 2025, page 94 / 190 82 / 160 converted into the Leaving Group Intermediate (3e), as described in Synthesis 2006, 10, 1635; Journal of the American Chemical Society 2020, 142, 2766; Chemical Communications 2018, 54, 1877. The Nitrile Intermediate (3f) can be prepared from the Intermediate (3e) by reaction with a cyanide source (Organic Letters 2017, 19, 4742; WO2022204150). Alternatively, the Nitrile Intermediate (3f) can be prepared directly from the Alcohol Intermediate (3d) (Tetrahedron Letters 1999, 40, 7355). Ester intermediate (3g) can be synthesized from nitrile intermediate (3f) by treatment with alcoholic acid, both to convert the nitrile and to cleave an acid-labile N protecting group (Synthetic Communications 2003, 33, 3271; European Journal of Organic Chemistry 2000, 21, 3575).

[00180] The N-Protected Intermediate (3b) can be prepared from the Intermediate (3a) by reaction with an appropriate protecting group reagent and an acid or base, as appropriate. Preferably, the 2-tetrahydropyranyl protecting group can be introduced using 3,4-dihydro-2H-pyran and p-toluenesulfonic acid in a solvent such as THF, at an appropriate temperature, preferably between 20 and 50 °C. Alternatively, the (2(trimethylsilyl)ethoxy)methyl protecting group can be introduced using (2(trimethylsilyl)ethoxy)methyl chloride and an appropriate base, such as sodium hydride, potassium tert-butoxide or N,N-diisopropylethylamine, in a solvent such as tetrahydrofuran or N,N-dimethylformamide, at an appropriate temperature, preferably between 0 and 30 °C. The conversion of the ester intermediate (3b) into an acid intermediate (3c) can be carried out under standard conditions for cleavage of the -C(O)OR ester.For R = small alkyl, such as methyl or ethyl, hydrolysis to provide carboxylic acid intermediate (3c) can be carried out with a suitable metal hydroxide, such as sodium hydroxide, hydroxide. Petition 870250087244, dated 09 / 26 / 2025, p. 95 / 190 83 / 160 potassium or lithium hydroxide, in a solvent such as water or a mixed organic-aqueous solvent, such as aqueous methanol, ethanol and / or tetrahydrofuran at an appropriate temperature, preferably between 20 and 60 °C. For R = tert-butyl, the acid-promoted cleavage of the tert-butyl ester to provide a carboxylic acid intermediate (3c) can be carried out with a suitable combination of acid and solvent, such as trifluoroacetic acid in dichloromethane or hydrogen chloride in dioxane, at an appropriate temperature, preferably between 0 and 30 °C.

[00181] The reduction of the acid intermediate (3c) to the alcoholic intermediate (3d) can be carried out with a suitable hydride source, preferably borane, borane tetrahydrofuran complex or lithium aluminum hydride in a solvent such as tetrahydrofuran or diethyl ether, at a suitable temperature, preferably between 0 and 60 °C. The leaving group intermediate (3e) can be prepared from the alcoholic intermediate (3d) by reaction with an activating reagent and a base, preferably methanesulfonic anhydride or methanesulfonyl chloride and triethylamine or pyridine, in a suitable solvent such as dichloromethane, at a suitable temperature, preferably between 0 and 30 °C.The nitrile intermediate (3f) can be prepared from the leaving group intermediate (3e) by reaction with a cyanide source in a suitable solvent, such as trimethylsilyl cyanide and potassium fluoride in N,N-dimethylformamide, or sodium cyanide in dimethyl sulfoxide, at a suitable temperature, preferably between 25 and 90 °C. The ester intermediate (3g) can be synthesized by treating the nitrile intermediate (3f) with an alcoholic acid, preferably sulfuric acid or hydrogen chloride in methanol or ethanol; the acidic reaction conditions also cleave the labile acid protecting group N. Petition 870250087244, dated 09 / 26 / 2025, page 96 / 190 84 / 160 Reaction scheme III (3f) (3g)

[00182] Reaction Scheme IV describes the general procedures for the synthesis of compounds of Formula (I). In Reaction Scheme IV, the chemical groups are as defined in the descriptive report; except that in Reaction Scheme IV, A2 is limited to S, O, NH; additionally in Reaction Scheme IV: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably bromine or chlorine; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group, where -C(O)OR is a chemically inert ester to the described cross-coupling reactions, but where -C(O)OR can be easily converted to -C(O)OR1 to provide compounds of Formula (I), preferably R = methyl, ethyl, benzyl or tert-butyl; -BY2 = a boronic acid or boronate ester Petition 870250087244, dated 09 / 26 / 2025, p. 97 / 190 85 / 160 suitable for cross-coupling reactions catalyzed by transition metals, preferably boronic acid or pinacolboronate; PG = a protecting group suitable for the reactions described, preferably 2-tetrahydropyranyl.

[00183] Substituted (aza)indazole intermediates (4a) are commercially available and well known in the literature, as is their conversion to 3-iodine intermediates (4b) and then to N-protected intermediates (4c) (European Journal of Medicinal Chemistry 2020, 203, 11255; Synlett 2009, 615-619; Journal of Organic Chemistry 2009, 74, 6331; WO2023196720; WO2023091707; WO2022133037; WO2013030138; WO2018011628; Journal of Medicinal Chemistry 2017, 60, 2361; PGM Wuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014). Intermediates (4e) can be prepared by transition metal-catalyzed cross-coupling of iodide intermediates (4c) and thiol intermediates (4d) (A2 = S; WO2009149837; WO2011138265), or alcohol intermediates (4d) (A2 = O; WO2009089359; WO2016004272; WO2009149837), or amine intermediates (4d) (A2 = NH; European Journal of Medicinal Chemistry 2021, 213, 113192; Synthesis 2011, 16, 2651).Cross-coupling product intermediates (4f) can be prepared from halide (4e) and boronate (1b) intermediates by methods analogous to those described in Reaction Scheme IA for the conversion of intermediates (1a) into intermediates (1c). Compounds of Formula (I) can be prepared from intermediates (4f) by sequential cleavage of the N protecting group in intermediate (4g), followed by ester hydrolysis, or by sequential ester hydrolysis in intermediate (4h), followed by cleavage of the N protecting group. Hydrolysis of intermediates (4f) or intermediates (4g) can be conducted based on procedures well known in the literature (WO2012137089; Tetra. Petition 870250087244, dated 09 / 26 / 2025, pp. 98 / 190 86 / 160 hedron Letters 2018, 59, 2917; WO2022150574; WO2022229341). Cleavage of N protective groups of Intermediates (4f) or Intermediates (4h) can be conducted based on PGM Wuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014.

[00184] Intermediate (4b) can be prepared by iodination of Intermediate (4a) by reaction with a suitable iodinating reagent, such as iodine or N-iodosuccinimide, in the presence of a base, such as potassium hydroxide or potassium tert-butoxide, in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, at a suitable temperature, preferably between 0 and 30 °C. The protecting Intermediate N (4c) can be prepared from Intermediate (4b) by reaction with a suitable protecting group reagent and an acid or base, as appropriate. Preferably, the 2-tetrahydropyranyl protecting group can be introduced using 3,4-dihydro-2Hpyran and p-toluenesulfonic acid in a solvent such as tetrahydrofuran, at a suitable temperature, preferably between 20 and 50 °C.Alternatively, the (2-(trimethylsilyl)ethoxy)methyl protecting group can be introduced using 2-(trimethylsilyl)ethoxymethyl chloride and a suitable base, such as sodium hydride, potassium tert-butoxide or N,N-diisopropylethylamine, in a solvent such as tetrahydrofuran or N,N-dimethylformamide at a suitable temperature, preferably between 0 and 30 °C. The intermediate (4e) can be prepared by transition metal-catalyzed cross-coupling of the iodide intermediate (4c) and the thiol intermediate (4d) (A2 = S) using a transition metal catalyst and a ligand, preferably Pd2(dba)3 and Xantfos, in a suitable solvent such as toluene, with a suitable base, preferably N,N-diisopropylethylamine, at a suitable temperature, preferably between 40 and 70 °C.

[00185] The intermediates (4e) can be prepared by coupling Petition 870250087244, dated 09 / 26 / 2025, page 99 / 190 87 / 160 Transition metal-catalyzed crosslinking of iodide (4c) and alcohol (4d) intermediates (A2 = O) using a transition metal catalyst and a ligand, preferably copper(I) iodide and 1,10-phenanthroline, in a suitable solvent, such as toluene or ethanol, with a suitable base, preferably potassium fluoride or cesium carbonate, at a suitable temperature, preferably between 100 and 120 °C. The intermediate (4e) can be prepared by transition metal-catalyzed cross-coupling of the iodide intermediate (4c) and the amine intermediate (4d) (A2 = NH) using a transition metal catalyst and a ligand, preferably copper(I) iodide and N-(2,6-difluorophenyl)-6-hydroxypicolinamide, in a suitable solvent, such as dioxane or toluene, with a suitable base and additive, preferably potassium carbonate and sodium ascorbate, at a suitable temperature, preferably between 90 and 110 °C.The cross-coupling between the halide intermediate (4e) and the boronate intermediate (1b) can be carried out using a catalyst such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as potassium fluoride, potassium carbonate or sodium bicarbonate, in a suitable solvent such as aqueous dioxane or aqueous 1,2-dimethoxyethane, at an appropriate temperature, preferably between 80 and 110 °C.

[00186] The conversion of the ester intermediate (4f) to intermediate (4h), or of the ester intermediate (4g) to a compound of formula (I), can be carried out under standard conditions for cleavage of the -C(O)OR ester. For R = small alkyl, such as methyl or ethyl, hydrolysis to give a carboxylic acid can be carried out with a suitable metal hydroxide, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in a solvent such as water or a mixed organic-aqueous solvent, such as aqueous methanol, ethanol and / or tetrahydrofuran Petition 870250087244, dated 09 / 26 / 2025, pp. 100 / 190 88 / 160 no, at an appropriate temperature, preferably between 0 and 110 °C. For R = tert-butyl, the acid-promoted cleavage of the tert-butyl ester to provide a carboxylic acid can be carried out with a suitable combination of acid and solvent, such as trifluoroacetic acid in dichloromethane or hydrogen chloride in dioxane, at an appropriate temperature, preferably between 0 and 30 °C. The 2-tetrahydropyranyl protecting group can be removed by treating Intermediate (4f) or Intermediate (4h) with an appropriate acid, preferably trifluoroacetic acid, in an appropriate solvent, such as dichloromethane, at an appropriate temperature, preferably between 10 and 30 °C.The (2-(trimethylsilyl)ethoxy)methyl protecting group can be removed by treating Intermediate (4f) or Intermediate (4h) with an appropriate acid-solvent combination, such as trifluoroacetic acid-dichloromethane, or hydrochloric acid-methanol, at an appropriate temperature, preferably between 10 and 50 °C. Alternatively, the (2-(trimethylsilyl)ethoxy)methyl protecting group can be removed by treating Intermediate (4f) or Intermediate (4h) with an appropriate fluorine source, such as tetra-N-butylammonium fluoride, in an appropriate solvent, such as tetrahydrofuran, at an appropriate temperature, preferably between 20 and 60 °C. Petition 870250087244, dated 09 / 26 / 2025, pp. 101 / 190 89 / 160 Reaction scheme IV Rb1 Formula (I) EXAMPLES

[00187] For a better understanding of this invention, the following examples are presented. These examples are merely illustrative and should not be interpreted as limiting the scope of the invention. Liquid Chromatography Analytical Methods LC Method A: Acquity UPLC BEH C18 2.1 mm χ 50 mm, 1.7 μm; A: 10 mM ammonium acetate in 95:5 H2O:CHaCN, B: 10 mM ammonium acetate in 5:95 H2O:CH3CN, Gradient from 5% to Petition 870250087244, dated 09 / 26 / 2025, p. 102 / 190 90 / 160 100% of B for 1 min, then 100% of B for 0.2 min; 1.0 mL / min. LC B method: Xbridge C18 2.1 mm x 50 mm, 5 μm; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, Gradient from 1% to 5% B for 0.6 min, then to 100% B for 3.4 min; 0.8 mL / min; 40 °C. LC Method C: Xbridge C18 2.1mm x 50mm, 5μ; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, Gradient from 10% B for 0.5 min, then to 100% B for 3.5 min; 0.8 mL / min, 40 °C. LC D Method: Xbridge C18 2.1mm x 50mm, 5μ; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, Gradient from 25% B for 0.5 min, then to 100% B for 3.0 min; 0.8 mL / min, 40 °C. LC E method: Xbridge C18 2.1 mm x 50 mm, 5 μm; A: 0.05% NH4OH in H2O, B: CH3CN, Gradient from 5% B for 0.5 min, then to 100% B for 2.9 min; 0.8 mL / min, 40 °C. LC F method: Xbridge C18 2.1 mm x 50 mm, 5 μm; A: 0.05% NH4OH in H2O, B: CH3CN, Gradient from 5% B for 0.5 min, then to 100% B for 2.9 min; 0.8 mL / min, 60 °C. LC Method G: Waters Atlantis C18 4.6 x 50mm, 5 μ; A: 0.05% TFA in H2O, B: 0.05% TFA in CH3CN, Gradient from 5 to 95% B for 4 min; 2 mL / min. Preparation 1. Ethyl (E)-3-(5-bromo-6-chloro-1H-indazol-3-yl)acrylate.

[00188] (Carbetoxymethylene)triphenylphosphorane (50.3 g, 145 mmol) was added to a solution of 5-bromo-6-chloro-1H-indazol-3 Petition 870250087244, dated 09 / 26 / 2025, p. 103 / 190 91 / 160 carbaldehyde (25.0 g, 96.0 mol) in THF (500 mL). The resulting mixture was heated to 50 °C for 16 hours, then concentrated. The residue was purified by silica gel chromatography (0 to 20% THF: petroleum ether) to give ethyl (E)-3-(5-bromo-6-chloro-1-hindazol-3-yl)acrylate as a yellow solid (23 g). 1H NMR (400 MHz, DMSO-d6) δ 13.86 (br s, 1 H), 8.64 (s, 1 H), 7.92 (s, 1 H), 7.87 (d, 1 H), 6.82 (d, 1 H), 4.22 (q, 2 H), 1.28 (t, 3 H); EM (M + H)+330.9. Preparation 2. Ethyl 3-(5-bromo-6-chloro-1H-indazol-3-yl)propanoate.

[00189] PtO2 (3.17 g, 14.0 mmol) was added to a solution of ethyl (E)-3-(5-bromo-6-chloro-1H-indazol-3-yl)acrylate (23 g, 70 mmol) in EtOH (1.0 L) and EtOAc (0.30 L). The mixture was stirred at 25 °C under a H2 gas atmosphere (flask) for 16 hours. Filtration and concentration yielded the crude product which was purified by silica gel chromatography (0 to 20% THF: petroleum ether) to give ethyl 3(5-bromo-6-chloro-1H-indazol-3-yl)propanoate as a white solid (16 g). 1H NMR (DMSO-d6) δ 12.99 (s, 1 H), 8.25 (s, 1 H), 7.77 (s, 1 H), 4.03 (q, 2 H), 3.16 (t, 2 H), 2.78 (t, 2 H), 1.14 (t, 3 H); EM (M + H)+332.9. Preparation 2, Alternate Procedure. Ethyl 3-(5-bromo-6-chloro-1-hindazol-3-yl)propanoate. Petition 870250087244, dated 09 / 26 / 2025, page 104 / 190 92 / 160

[00190] 2,2-Dimethyl-1,3-dioxane-4,6-dione (183 g, 1.27 mmol), EtaN (322 mL, 2.31 mol) and formic acid (214 mL, 5.67 mol) were sequentially added to a solution of 5-bromo-6-chloro-1-hindazol-3-carbaldehyde (300 g, 1.16 mol) in dioxane (3.0 L). The resulting mixture was heated to 100 °C for 16 hours, then cooled to room temperature and H2O (200 mL) was added. Aqueous HCl solution (3 M) was added to adjust the pH to ~2 to 3, then the solution was extracted with EtOAc (2 χ 100 mL). The combined organics were washed with saturated aqueous NaCl solution (3 χ 100 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0 to 5% THF : DCM) to give ethyl 3-(5-bromo-6-chloro-1H-indazol-3-yl)propanoate as a yellow solid. Two reactions on this same scale yielded a combined total of 469 g of ethyl 3-(5-bromo-6-chloro-1H-indazol-3-yl)propanoate. 1H NMR (DMSO-d6) δ 12.99 (s, 1 H), 8.25 (s, 1 H), 7.77 (s, 1 H), 4.03 (q, 2 H), 3.16 (t, 2 H), 2.78 (t, 2 H), 1.14 (t, 3 H); EM (M + H)+332.9. Preparation 3. Ethyl 3-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)-1H-indazol-3-yl)propanoate.

[00191] 1,4-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (35.8 g, 109 mmol), Pd(PPh3)4 (2.51 g, 2.17 mmol) and an aqueous solution of K2CO3 (0.2 M, 72.4 mL, 145 mmol) were sequentially added to a solution of ethyl 3-(5-bromo-6-chloro-1H-indazol-3yl)propanoate (12 g, 36 mmol) in dioxane (150 mL). The resulting mixture was stirred under N2 gas at 120 °C for 5 hours, then Petition 870250087244, dated 09 / 26 / 2025, pp. 105 / 190 93 / 160 was cooled and diluted with H2O (50 mL). The volatile organics were evaporated under reduced pressure, then the residue was extracted with EtOAc (2 χ 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0 to 20% THF: petroleum ether) to provide a solid that was suspended in petroleum ether (50 mL). Filtration and drying yielded ethyl 3-(6-chloro-5-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazol-3yl)propanoate as a yellow solid (7.0 g). 1H NMR (400 MHz, DMSO-d) H), 1.12 (t, 3 H); EM (M + H)+455.1. Preparation 4. 4'-Bromo-[1,1'-biphenyl]-2-ol.

[00192] (2-hydroxyphenyl)boronic acid (536 g, 1.17 mol), Pd(PPh3)4 (102 g, 26.5 mmol) and K3PO4 (1125 g, 1.59 mol) were sequentially added to a solution of 1-bromo-4-iodobenzene (1000 g, 1.06 mol) in H2O (2.5 L) and dioxane (7.5 L). The mixture was stirred over N2 gas at 80 °C for 17 hours, then cooled and divided between H2O (1.0 L) and EtOAc (3 χ 1.0 L). The combined organics were washed with saturated aqueous NaCl solution (1.0 L), dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0 to 7% EtOAc: petroleum ether) to give 4'-bromo-[1,1'-biphenyl]-2-ol as a yellow oil (625 g). 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1 H), 7.58 (d, 2 H), 7.50 (d, 2 H), 7.25 (d, 1 H), 7.17 (m, 1 H), 6.95 (dd, 1 H), 6.87 (m, 1 H). Petition 870250087244, dated 09 / 26 / 2025, pp. 106 / 190 94 / 160 Preparation 5. 4'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol.

[00193] B2Pin2 (808 g, 1.16 mol), Pd(dppf)Cl2 (91.8 g, 48.1 mmol) and KOAc (369 g, 1.45 mol) were sequentially added to a solution of 4'-bromo-[1,1'-biphenyl]-2-ol (625 g, 963 mmol) in dioxane (6.5 L), and the resulting mixture was stirred over N2 gas at 100 °C for 16 hours, then cooled and divided between H2O (1.5 L) and EtOAc (3 χ 1.5 L). The combined organics were washed with saturated aqueous NaCl solution (1.0 L), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0 to 3% EtOAc: petroleum ether) to give 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol as a white solid (500 g). 1H NMR (400 MHz, CDCh) δ 7.86 (d, 2 H), 7.41 (d, 2 H), 7.18 (m, 2 H), 6.91 (m, 2 H), 5.16 (s, 1 H), 1.29 (s, 12 H). Preparation 6. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoate.

[00194] A solution of ethyl 3-(5-bromo-6-chloro-1H-indazol-3-yl)propanoate (5.00 g, 15.0 mmol), 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol (5.36 g, 18.1 mmol) and KF (2.68 g, 45.2 mmol) in dioxane (75 mL) and H2O (25 mL) was sprayed with N2 gas for 20 minutes. Pd(dppf)Cb (1.10 g, 1.51 mmol) was added Petition 870250087244, dated 09 / 26 / 2025, p. 107 / 190 95 / 160 saturates and the mixture was heated to 80 °C for 17 hours, then cooled to room temperature. The mixture was divided between EtOAc (2χ) and H2O, and the combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20 to 50% EtOAc : heptane) to provide a solid that was suspended in EtOH. Filtration and drying yielded ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)propanoate as a white solid (2.6 g). 1H NMR (400 MHz, DMSO-d) H), 6.97 (d, 1 H), 6.91 (m, 1 H), 4.03 (q, 2 H), 3.19 (t, 2 H), 2.79 (t, 2 H), 1.13 (t, 3 H); EM (M + H)+421.2. Preparation 7. Ethyl 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1Hindazol-3-yl)propanoate.

[00195] Pd(dppf)Cl2-CH2Cl2 (19 mg, 0.026 mmol) was added to a mixture of 4-bromobenzamide (58 mg, 0.29 mmol), ethyl 3-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazol-3-yl)propanoate (120 mg, 0.26 mmol) and K2CO3 (109 mg, 0.79 mmol) in dioxane (5 mL) and H2O (1 mL) and the resulting mixture was heated to 80 °C for 2 hours. The mixture was cooled to room temperature and then extracted with EtOAc (2 χ 20 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The resulting solid was purified by silica gel chromatography (50 to 100% petroleum ether: EtOAc, then 10:1 of Petition 870250087244, dated 09 / 26 / 2025, pp. 108 / 190 96 / 160 EtOAc : MeOH) to give ethyl 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)6-chloro-1H-indazol-3-yl)propanoate as a yellow solid (95 mg). EM (M + H)+448.1. Preparation 8. 5-Bromo-3-formyl-1H-indazol-6-carbonitrile.

[00196] A solution of NaNO2 (521 mg, 7.6 mmol) in H2O (3.8 mL) was added to a solution of 5-bromo-1H-indol-6-carbonitrile (167 mg, 0.76 mmol) in acetone (7.6 mL). The mixture was sprayed with N2 for 0.5 minutes, then cooled to 0 °C. Hydrochloric acid (2 M, 3.8 mL, 7.6 mmol) was added and the resulting mixture was stirred at 0 °C for 1.5 hours, then at room temperature for 3.5 hours. The resulting solids (120 mg), a mixture of 5-bromo-3-formyl-1H-indazol-6-carbonitrile and unreacted 5-bromo-1H-indol-6-carbonitrile, were collected and used in the next step without further purification. EM (MH)-248,1. Preparation 9. Ethyl (E)-3-(5-bromo-6-cyano-1H-indazol-3-yl)acrylate.

[00197] (Carbetoxymethylene)triphenylphosphorane (209 mg, 0.60 mmol) was added to a solution of 5-bromo-3-formyl-1H-indol-6-carbonitrile (100 mg, 0.40 mmol) in THF (1.5 mL) and the resulting mixture was heated at 50 °C for 5 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (5 to 65% EtOAc:heptane) to give ethyl (E)-3-(5-bromo-6-cyano-1Hindazol-3-yl)acrylate, contaminated with 5-bromo-1H-indol-6-carbonitrile. The material was used in the subsequent reaction without further purification. EM Petition 870250087244, dated 09 / 26 / 2025, pp. 109 / 190 97 / 160 (MH)-318.1. Preparation 10. Ethyl 3-(5-bromo-6-cyano-1H-indazol-3-yl)propanoate.

[00198] A suspension of ethyl 3-(5-bromo-6-cyano-1H-indazol-3yl)acrylate (47 mg, 0.15 mmol) in EtOH (15 mL) was added to PtO2 (13 mg, 0.057 mmol) and EtOH (2 mL) in a Paar reactor. The reactor was purged sequentially with N2 (3.51 kg / cm2 (50 psi), 3χ) and with H2 (2.10 kg / cm2 (30 psi), 3χ) and then maintained under H2 for 13 hours. The resulting mixture was filtered through Celite, rinsed with EtOH, and the filtrate was concentrated. Silica gel chromatography (0 to 70% EtOAc: heptane) yielded ethyl 3-(5-bromo-6-cyano-1-hindazol-3-yl)propanoate (18 mg). ME (MH) -320.1. Preparation 11. Ethyl 3-(5-bromo-6-fluoro-1H-indazol-3-yl)propanoate.

[00199] Ethyl 3-(5-bromo-6-fluoro-1H-indazol-3-yl)propanoate was prepared from 5-bromo-6-fluoro-1H-indazol-3-carbaldehyde by methods analogous to Preparations 9 and 10. EM (MH)-313.2. ci Cl N NH Preparation 12. 5,6-Dichloro-1H-pyrazolo[4,3-b]pyridine.

[00200] KOAc (2.36 g, 24 mmol) and Ac2O (7.56 mL, 80 mmol) were sequentially added to a solution of 5,6-dichloro-2-methylpyridin-3-amine (3.5 g, 20 mmol) in CHCh (10 mL). The resulting mixture was heated to 60 °C for 2 hours, then dicyclo Petition 870250087244, dated 09 / 26 / 2025, pp. 110 / 190 98 / 160 hexane-18-crown-6 (745 mg, 2.0 mmol) and a solution of isoamyl nitrite (6.45 mL, 47 mmol) in CHCh (5 mL) were added and heating at 60 °C was continued for 21 hours. The mixture was cooled and concentrated. The resulting residue was dissolved in MeOH (50 mL) and H2O (11 mL), then solid K2CO3 was added at 0 °C, and the mixture was stirred for 10 minutes at 0 °C, then for 1.5 hours at room temperature. The resulting solids were collected by filtration to provide 5,6-dichloro-1Hpyrazolo[4,3-b]pyridine (1.9 g). EM (MH)-186.1. Preparation 13. 5,6-Dichloro-3-iodo-1H-pyrazolo[4,3-b]pyridine.

[00201] Solid KOH (673 mg, 12 mmol) and I2 (1.83 g, 7.2 mmol) were sequentially added to a solution of 5,6-dichloro-1Hpyrazolo[4,3-b]pyridine (752 mg, 4.0 mmol) in DMF (15 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes, then at room temperature for 18 hours. Excess I2 was abruptly stopped by the addition of saturated aqueous Na2S2O3 solution, then the mixture was diluted with H2O (30 mL) and acidified to pH 3 to 4 by the addition of aqueous HCl solution (1 M, 6 mL). The mixture was extracted with 10% MeOH:DCM (3 x 60 mL). The combined organics were washed sequentially with saturated aqueous NaHCO3 solution and with H2O (2x), then dried over MgSO4. The concentration yielded a yellow solid which was triturated with 10% EtOAc:heptane to give 5,6-dichloro-3iodo-1H-pyrazolo[4,3-b]pyridine as a yellow solid (1.25 g). EM (MH) -312.0. Petition 870250087244, dated 09 / 26 / 2025, pp. 111 / 190 99 / 160 Preparation 14. 5,6-Dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazolo[4,3-b]pyridine.

[00202] 3,4-Dihydro-2H-pyran (0.82 mL, 9.0 mmol) and p-toluenesulfonic acid monohydrate (103 mg, 0.60 mmol) were sequentially added to a solution of 5,6-dichloro-3-iodo-1H-pyrazolo[4,3b]pyridine (991 mg, 3.0 mmol) in THF (15 mL). The resulting mixture was heated to 50 °C for 9 hours, then at room temperature for 12 hours. The mixture was divided between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to provide a solid which was triturated with heptane to provide 5,6-dichloro-3-iodo1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine as a beige solid (1.1 g). Preparation 15. Ethyl (E)-3-(5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazolo[4,3-b]pyridin-3-yl)acrylate.

[00203] A solution of 5,6-dichloro-3-iodo-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazolo[4,3-b]pyridine (597 mg, 1.5 mmol), tri(o-tolyl)phosphine (120 mg, 0.37 mmol) and Pd(OAc)2 (43 mg, 0.19 mmol) in DMF (7.5 mL) was sprayed with N2 for 5 minutes. Triethylamine (0.60 mL, 4.3 mmol) and ethyl acrylate (0.18 mL, 1.7 mmol) were added and the resulting mixture was heated to 80 °C for 4 hours. An additional portion of Petition 870250087244, dated 09 / 26 / 2025, p. 112 / 190 100 / 160 ethyl acrylate (0.18 mL, 1.7 mmol) was added and heating at 80 °C was continued for a further 19 hours. The mixture was cooled and combined with an analogous mixture from a reaction that was run on a scale of 80 mg (0.20 mmol) of 5,6-dichloro-3-iodo-1(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine. The combined materials were concentrated to remove DMF, and the resulting residue was divided between EtOAc and H2O. The organic layer was sequentially washed with saturated aqueous NaHCO3 solution, H2O, and brine, then concentrated. Silica gel chromatography (0 to 100% EtOAc: heptane) provided ethyl (E)-3-(5,6-dichloro-1-(tetrahydro-2H-pyran2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate (483 mg). EM (M + H)+370.2. Preparation 16. Ethyl (E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate.

[00204] A mixture of 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-[1,1'-biphenyl]-2-ol (59 mg, 0.20 mmol), ethyl (E)-3-(5,6-dichloro-1(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate (74 mg, 0.20 mmol), saturated aqueous NaHCO3 solution (0.5 mL) and 1,2-dimethoxyethane (1 mL) was sprayed with N2 for 5 minutes. Pd(dppf)Cl2 (8.2 mg, 0.010 mmol) was added and the mixture was heated to 60 °C for 22 hours. The mixture was cooled and combined with an analogous mixture from a reaction carried out on an identical scale. The combined mixtures were divided between EtOAc and H2O. The organic layer was washed with saturated aqueous NaHCO3 solution, then concentrated. Silica gel chromatography (0 to 100% EtOAc : heptane) yielded ethyl (E)-3-(6-chloro-5-(2'-hydroxy)Petição 870250087244, dated 09 / 26 / 2025, page 113 / 190 101 / 160 [1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3yl)acrylate (102 mg). EM (M + H)+504.3. Preparation 17. Ethyl (E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate.

[00205] TFA (0.30 mL, 4.0 mmol) was added to a solution of ethyl (E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate (99 mg, 0.20 mmol) in DCM (2 mL). After 2.5 hours, an additional portion of TFA (0.30 mL, 4.0 mmol) was added. After another 2.5 days, the mixture was concentrated and the resulting residue was divided between EtOAc and H2O. The organic was sequentially washed with saturated aqueous NaHCO3 solution and with brine, then concentrated. Silicagel chromatography (0 to 100% EtOAc : heptane) provided ethyl (E)-3-(6-chloro-5-(2'hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate (58 mg). Preparation 18. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)propanoate.

[00206] Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3b]pyridin-3-yl)propanoate was prepared from ethyl (E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)acrylate by a procedure analogous to Preparation 10. Ethyl 3-(6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)propanoate was purified by silica gel chromatography (0 to 100% EtOAc: heptane). EM (M Petition 870250087244, dated 09 / 26 / 2025, pp. 114 / 190 102 / 160 + H)+422.4. Preparation 19. 5-Bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1Hindazole.

[00207] 3,4-Dihydro-2H-pyran (7.5 mL, 82 mmol) and p-toluenesulfonic acid monohydrate (520 mg, 2.7 mmol) were sequentially added to a solution of 5-bromo-6-chloro-3-iodo-1H-indazole (9.76 g, 27.3 mmol) in DCM (50 mL). The resulting mixture was stirred for 16 hours, then concentrated. The resulting residue was treated with aqueous NaOH solution (1 M) to dissolve p-toluenesulfonic acid, and the remaining solids were collected by filtration to provide 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1Hindazole (3.58 g). Preparation 20. Methyl (5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1Hindazol-3-yl)glycinate.

[00208] A mixture of 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2Hpyran-2-yl)-1H-indazole (200 mg, 0.45 mmol), glycine methyl ester hydrochloride (63 mg, 0.50 mmol), CuI (8.6 mg, 0.045 mmol), N-(2,6-difluorophenyl)-6-hydroxypicolinamide (34 mg, 0.14 mmol), K2CO3 (250 mg, 1.8 mmol) and sodium ascorbate (9.0 mg, 0.045 mmol) in a sealed microwave flask was purged with N2 (3 *), then dioxane (2.27 mL) was added and the resulting mixture was heated to Petition 870250087244, dated 09 / 26 / 2025, pp. 115 / 190 103 / 160 100 °C for 18 hours. The resulting mixture was cooled, diluted with EtOAc and filtered through Celite. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (0 to 100% EtOAc : heptane) to give methyl (5-bromo-6-chloro-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)glycinate as a solid (115 mg). EM (M + H)+404.1. Preparation 21. Methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)glycinate.

[00209] A mixture of 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-[1,1'-biphenyl]-2-ol (110 mg, 0.37 mmol), K2CO3 (118 mg, 0.86 mmol) and Pd(dppf)Cl2-CH2Cl2 (23 mg, 0.029 mmol) in a sealed microwave flask was purged with N2 (3χ). A solution of methyl (5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)glycinate (115 mg, 0.029 mmol) in dioxane (2.0 mL) and then H2O (0.5 mL) were sequentially added and the resulting mixture was heated at 90 °C for 1.75 hours. The mixture was cooled and filtered through Celite, rinsing with EtOAc, and the filtrate was concentrated to remove organic solvents. The resulting mixture was extracted with DCM (3χ). The combined organics were dried over MgSO4 and concentrated. Silica gel chromatography (0 to 100% EtOAc : heptane) yielded methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)glycinate (83 mg). MS (M + H)+492.3. Petition 870250087244, dated 09 / 26 / 2025, pp. 116 / 190 104 / 160 Preparation 22. (6-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2Hpyran-2-yl)-1H-indazol-3-yl)glycine.

[00210] Aqueous NaOH solution (1 M, 0.50 mL, 0.50 mmol) was added to a mixture of methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)glycinate (20 mg, 0.041 mmol) and MeOH (0.5 mL). The mixture was heated to 50 °C for 1 hour, then cooled and diluted with aqueous HCl solution (1 M) until a precipitate formed. The mixture was extracted with 20% MeOH:DCM (2 mL), and the organic layer was concentrated to give (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)1H-indazol-3-yl)glycine (22 mg) which was used without further purification. EM (M + H)+478.2. Preparation 23. Methyl 2-((5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)1H-indazol-3-yl)thio)acetate.

[00211] To a sealed microwave flask containing Pd2(dba)3 (41 mg, 0.044 mmol) and Xantphos (51 mg, 0.088 mmol) under a N2 atmosphere, a solution of 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (196 mg, 0.44 mmol) in toluene (2 mL), N,N-diisopropylethylamine (78 µL, 0.44 mmol) and me Petition 870250087244, dated 09 / 26 / 2025, pp. 117 / 190 105 / 160 til 2-mercaptoacetate (40 pL, 0.44 mmol). The resulting mixture was heated to 45 °C for 1.5 hours, then cooled and diluted with H2O. The organic layer was collected, and the aqueous layer was extracted with EtOAc (2χ). The combined organics were washed with brine, dried over MgSO4, and concentrated. Silica gel chromatography (0 to 100% EtOAc : heptane) yielded methyl 2-((5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)thio)acetate as a solid (114 mg). EM (M + H)+421.2. Preparation 24. Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)thio)acetate.

[00212] Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-3-yl)thio)acetate was prepared from methyl 2-((5bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)thio)acetate by a method analogous to Preparation 21. MS (M + H) + 509.4. Preparation 25. Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H indazol-3-yl)thio)acetate.

[00213] TFA (0.30 mL, 3.9 mmol) was added to a mixture of methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2yl)-1H-indazol-3-yl)thio)acetate (16 mg, 0.031 mmol) and DCM (0.5 mL). After 2.5 hours, the mixture was concentrated to provide methyl 2-((6Petition 870250087244, dated 09 / 26 / 2025, page 118 / 190 106 / 160 chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)thio)acetate which was used without further purification. EM (M + H)+425.3. Preparation 26. Ethyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1Hindazol-3-yl)propanoate.

[00214] 3,4-Dihydro-2H-pyran (8.77 mL, 96.5 mmol) and p-toluenesulfonic acid monohydrate (1.66 g, 9.65 mmol) were sequentially added to a solution of ethyl 3-(5-bromo-6-chloro-1H-indazol-3-yl)propanoate (16.0 g, 48.3 mmol) in THF (100 mL). The resulting mixture was heated to 50 °C for 4 hours, then cooled. The mixture was divided between saturated aqueous NaHCO3 solution (30 mL) and EtOAc (3 χ 100 mL). The combined organics were dried over Na2SO4 and concentrated. Silica gel chromatography (0 to 80% EtOAc: petroleum ether) yielded ethyl 3-(5-bromo-6-chloro-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)propanoate as a solid (16.5 g). EM (M + H)+417.1. Preparation 27. 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)1H-indazol-3-yl)propanoic acid.

[00215] LiOH-H2O (303 mg, 7.2 mmol) was added to a solution of ethyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3yl)propanoate (1.0 g, 2.4 mmol) in THF (10 mL), MeOH (10 mL) and Petition 870250087244, dated 09 / 26 / 2025, pp. 119 / 190 107 / 160 H2O (10 mL) at 15 °C. After 3 hours, the mixture was concentrated to remove organic solvents, then the pH was adjusted to ~3 by adding aqueous HCl solution. The resulting white solids were collected and dried to give 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)propanoic acid (0.90 g). EM (M + H)+388.9. Preparation 28. 3-(5-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H indazol-3-yl)propan-1-ol.

[00216] Borane tetrahydrofuran complex (1 M solution in THF (6.96 mL, 6.96 mmol) was added dropwise to a solution of 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3yl)propanoic acid (0.90 g, 2.32 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred for 16 hours at 15 °C. MeOH was added and the mixture was concentrated. The resulting residue was divided between H2O (30 mL) and EtOAc (100 mL, then 60 mL). The combined organics were washed with brine (2 χ 30 mL) and concentrated to give 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)1H-indazol-3-yl)propan-1-ol (0.80 g) as a solid which was used without further purification. EM (M + H)+375.0. Preparation 29. 3-(5-bromo-6-chloro-1-(tetrahydro methanesulfonate) 2H-pyran-2-yl)-1H-indazol-3-yl)propyl. Petition 870250087244, dated 09 / 26 / 2025, pp. 120 / 190 108 / 160

[00217] Triethylamine (1.49 mL, 10.7 mmol) and methanesulfonic anhydride (1.49 g, 8.56 mmol) were sequentially added to a solution of 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3yl)propan-1-ol (0.80 g, 2.1 mmol) in DCM (45 mL) at 0 °C. The resulting mixture was stirred for 18 hours at 10 °C, then divided between DCM (30 mL) and H2O (2 x 20 mL). The combined organics were washed sequentially with aqueous citric acid solution (0.5 M, 20 mL) and with brine (20 mL), then dried over Na2SO4 and concentrated to give 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)propyl methanesulfonate (0.96 g) as an oil which was used without further purification. EM (M + H)+452.9. Preparation 30. 4-(5-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1Hindazol-3-yl)butanenitrile.

[00218] Trimethylsilyl cyanide (425 mg, 4.28 mmol) and KF (249 mg, 4.28 mmol) were sequentially added to a solution of 3(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)propyl methanesulfonate (0.96 g, 2.1 mmol) in DMF (20 mL). The resulting mixture was heated for 16 hours at 90 °C, then cooled and partitioned between EtOAc and H2O. The organic layer was washed with brine, then dried over Na2SO4 and concentrated. Silica gel chromatography (15% EtOAc: petroleum ether) yielded 4-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3yl)butanenitrile (0.30 g) as an oil. EM (M + H) +381.9. Petition 870250087244, dated 09 / 26 / 2025, pp. 121 / 190 109 / 160 Preparation 31. Ethyl 4-(5-bromo-6-chloro-1H-indazol-3-yl)butanoate.

[00219] Sulfuric acid (1 mL) was added dropwise to a solution of 4-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3yl)butanenitrile (0.30 g, 0.78 mmol) in EtOH (5 mL), and the resulting mixture was heated to 100 °C for 16 hours, then cooled and concentrated. Saturated aqueous NaHCO3 solution (30 mL) was added, and the mixture was extracted with EtOAc (3 χ 100 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated. Silica gel chromatography (0 to 50% EtOAc: petroleum ether) yielded ethyl 4-(5-bromo-6-chloro-1H-indazol-3-yl)butanoate (150 mg) as an oil. EM (M + H) +346.9. Preparation 32. Ethyl 3-(5-(4'-(((tert-butoxycarbonyl)amino)methyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoate.

[00220] Ethyl 3-(5-(4'-(((tert-butoxycarbonyl)amino)methyl)-2'-hydroxy[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoate was prepared from tert-butyl (4-bromo-3-hydroxybenzyl)carbamate by a procedure analogous to Preparation 7. EM (M + H)+550.1. Petition 870250087244, dated 09 / 26 / 2025, pp. 122 / 190 110 / 160 Preparation 33. Methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)6-chloro-1H-indazol-3-yl)propanoate.

[00221] A solution of HCl in dioxane (4 M, 2.0 mL, 8.0 mmol) was added to a solution of ethyl 3-(5-(4'-((((tert-butoxycarbonyl)amino)methyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoate (55 mg, 0.10 mmol) in MeOH (4 mL). After 3 hours at 20 °C, the resulting mixture was concentrated to give methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3yl)propanoate (44 mg) which was used without further purification. EM (M + H)+ 437.3. Preparation 34. tert-Butyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2yl)-1H-indazol-3-yl)propanoate.

[00222] tert-Butyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1Hindazol-3-yl)propanoate was prepared from 5-bromo-6-chloro-1H-indazol-3-carbaldehyde and (tert-butoxycarbonylmethylene)triphenylphosphorane by procedures analogous to Preparations 9, 10, and 26. EM (M + H)+445.1. Preparation 35. Methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6-chloro-1(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-hydroxy-[1,1'-biphenyl]-4 Petition 870250087244, dated 09 / 26 / 2025, pp. 123 / 190 111 / 160 carboxylate.

[00223] Methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-hydroxy-[1,1'-biphenyl]-4-carboxylate was prepared from tert-butyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)1H-indazol-3-yl)propanoate, 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene and methyl 4-bromo-3-hydroxybenzoate by procedures analogous to Preparations 3 and 7. EM (M + H)+591.5. Example 1. 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid.

[00224] Aqueous NaOH solution (1.0 M, 26.0 mL, 26.0 mmol) was added to a solution of ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4yl)-1H-indazol-3-yl)propanoate (2.14 g, 5.08 mmol) in inhibitor-free THF (12.5 mL) and EtOH (12.5 mL). After 4 hours, the mixture was concentrated to remove organics, then the aqueous residue was diluted with H2O (25 mL). The resulting solution was heated to 100 °C and held at that temperature for 15 minutes. An aqueous HCl solution (1.0 M, 27 mL, 27 mmol) was added dropwise to the heated solution, resulting in the formation of a precipitate. The mixture was heated under reflux for 16 hours, then cooled to room temperature and stirred for a further 4 hours. The solids were collected by filtration and dried under a stream of N2 gas to give 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid as a white crystalline solid (1.6 g). 1H NMR (400 MHz, DMSO-d) H), 7.18 (m, 1 H), 6.97 (d, 1 H), 6.91 (t, 1 H), 3.16 (t, 2 H), 2.72 (t, 2 H); Petition 870250087244, dated 09 / 26 / 2025, pp. 124 / 190 112 / 160 EM (M + H)+393,1.

[00225] The following examples were synthesized by analogous methods and starting materials as described for 3-(6-chloro-5(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid. Example 2. 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid.

[00226] Synthesized from 1,4-dibromobenzene, (2-hydroxy-3-methoxyphenyl)boronic acid and 1,4-bis(5,5-dimethyl-1,3,2-dioxaborinan-2yl)benzene by methods analogous to those described for 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid. 1H NMR (400 MHz, DMSO-d) H), 6.88 (m, 1 H), 3.86 (s, 3 H), 3.16 (t, 2 H), 2.72 (t, 2 H); EM (M + H)+423.3. Example 3. 3-(6-chloro-5-(3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)propanoic acid.

[00227] Synthesized 1-bromo-2-fluoro-4-iodobenzene by analogous methods as described for 3-(6-chloro-5-(2'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid. 1H NMR (400 MHz, MeOD) δ 7.76 (s, 1 H), 7.62 (s, 1 H), 7.43 (m, 2 H), 7.36 (m, 2 H), 7.17 (m, 1 H), 6.91 (m, 2 H), 3.25 (t, 2 H), 2.79 (t, 2 H); EM (M + H)+411.2. Petition 870250087244, dated 09 / 26 / 2025, pp. 125 / 190 113 / 160 Example 4. 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indol-3yl)propanoic acid.

[00228] Synthesized from 5-bromo-6-chloro-1H-indole-3-carbaldehyde by methods analogous to those described for 3-(6-chloro-5-(2'hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1 H), 9.63 (s, 1 H), 8.32 (s, 1 H), 7.56 (m, 6H), 7.32 (m, 1 H), 7.20 (m, 2 H), 6.93 (m, 2 H), 2.93 (t, 2 H), 2.56 (t, 2 H); MS (M + H)+392.0. Example 5. 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1Hindazol-3-yl)propanoic acid.

[00229] LiOH-H2O (27 mg, 0.64 mmol) was added to a mixture of ethyl 3-(5-(4'-carbamoyl-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1Hindazol-3-yl)propanoate (95 mg, 0.21 mmol) in MeOH (3 mL) and H2O (1 mL), and the resulting mixture was stirred for 16 hours. The mixture was concentrated to remove organics, then the aqueous residue was acidified to pH ~3 by the addition of aqueous HCl solution (1 M). The resulting solid was collected, rinsed with H2O, and dried to give 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1Hindazol-3-yl)propanoic acid as a solid (72 mg). 1H NMR (400 MHz, MeOD) δ 7.99 (d, 2 H), 7.85 (s, 1 H), 7.82 (d, 2 H), 7.77 (d, 2 H), 7.64 (s, 1 H), 7.58 (d, 2 H), 3.27 (m, 2 H), 2.70 (m, 2 H); Petition 870250087244, dated 09 / 26 / 2025, pp. 126 / 190 114 / 160 EM (M + H)+420,1.

[00230] The following examples were synthesized by analogous methods and starting materials as described for 3-(5-(4'carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoic acid. Example 6. 3-(5-(4'-carbamoyl-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoic acid.

[00231] Synthesized 4-bromo-3-hydroxybenzamide by analogous methods as described for 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4yl)-6-chloro-1H-indazol-3-yl)propanoic acid. 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1 H), 7.68 (m, 2 H), 7.63 (s, 1 H), 7.50 (m, 2 H), 7.43 (m, 3 H), 3.27 (m, 2 H), 2.71 (m, 2 H); EM (M + H)+436.1. Example 7. 3-(6-Chloro-5-(4-(3-hydroxypyridin-4-yl)phenyl)-1H-indazol3-yl)propanoic acid.

[00232] Synthesized 4-bromopyridin-3-ol by analogous methods as described for 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro1H-indazol-3-yl)propanoic acid. 1H NMR (400 MHz, MeOD) δ 8.19 (s, 1 H), 8.10 (d, 1 H), 7.82 (s, 1 H), 7.78 (d, 2 H), 7.65 (s, 1 H), 7.56 (d, 2 H), 7.46 (d, 1 H), 3.27 (m, 2 H), 2.78 (m, 2H); EM (M + H)+394.2. Petition 870250087244, dated 09 / 26 / 2025, pp. 127 / 190 115 / 160 Example 8. 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoic acid.

[00233] NaOH (20 mg, 0.51 mmol) was added to methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoate (44 mg, 0.10 mmol), MeOH (4 mL) and H2O (2 mL) at 20 °C. After 3 hours, the pH was adjusted to ~4 with 2 M hydrochloric acid. The mixture was concentrated, and the residue was purified by reverse-phase HPLC to give 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazol-3-yl)propanoic acid. EM (M + H)+422.1. LC A method, tr 0.60 min. Example 19. (6-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)glycine.

[00234] TFA (0.20 mL, 2.6 mmol) was added to a mixture of (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1-hindazol-3-yl)glycine (22 mg, 0.046 mmol) and DCM (1.0 mL). After 3.5 hours, the mixture was concentrated and the resulting residue was purified by reverse-phase HPLC to give (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)glycine (3.4 mg). EM (M + H)+394.3. Method LC G, tr 2.60 min. Petition 870250087244, dated 09 / 26 / 2025, pp. 128 / 190 116 / 160 Example 31. 3-(6-Chloro-5-(2'-hydroxy-4'-(methoxycarbonyl)-[1,1'biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid.

[00235] A mixture of methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-hydroxy-[1,1'-biphenyl]4-carboxylate (40 mg, 0.068 mmol) and a solution of HCl in dioxane (4 M, 5.0 mL, 20 mmol) was stirred at 25 °C for 16 hours. The mixture was concentrated and the resulting residue was purified by reversed-phase HPLC to give 3-(6-chloro-5-(2'-hydroxy-4'(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid (17 mg).1H NMR (400 MHz, MeOD) δ 7.82 (s, 1 H), 7.69 (d, 2 H), 7.65-7.55 (m, 3 H), 7.51 (d, 2 H), 7.46 (d, 1 H), 3.91 (s, 3 H), 3.26 (t, 2 H), 2.76 (t, 2 H); MS (M + H)+451.3.

[00236] The examples in Table 1 were prepared using methods analogous to the methods described above. Table 1. AMPK activation compounds Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 9 H2Ns / 0 LJ] HO HO í j) ( ZN NH 3-(6-chloro-5-(2'-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 472.2 Method A 0.661 min Petition 870250087244, dated 09 / 26 / 2025, pp. 129 / 190 117 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 10 h3c 0 jl HO / 0 HO í jj ( ZN NH 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 437.3 Method A 0.813 min 11 IN^OH CI^^N 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)thio)acetic acid P25 411.1 Method G 2.92 min 12 0 H3Cx JJ h3C Γ HO / ^t^XH CI \ ZN NH acid 3-(6-chloro-5-(4'(dimethylcarbamoyl)-2'hydroxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic P7 464.3 Method A 0.702 min 13 I IO Z m ° Vv ' QO / O z \ / XX o acid 3-(5-(4'-(1-amino2,2,2-trifluoroethyl)-2'hydroxy-[1,1'-biphenyl]-4-yl)-6chloro-1H-indazol-3yl)propanoic P7 490.2 Method A 0.75 min 14 / ^ci H°Vo Π Γ θι^τΠι / CH3 OH 'WV / TxJ Ύ X> acid 3-(6-chloro-5-(6'chloro-2'-hydroxy-3'-methoxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic P7 457.2 Method A 0.829 min Petition 870250087244, dated 09 / 26 / 2025, pp. 130 / 190 118 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 15 ^XCH3 Cl II %^OH OH JL Λ j[ ^05 Ci>XH 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 407 Method C 2.938 min 16 r HO. ° iYi S CH3 OH __( 3-(6-chloro-5-(4'fl uoro-2'-hydroxy-3'-m ethoxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 441.3 Method A 0.855 min 17 U)—V ___ / \—z / --\ / / X / \ owo __ / j V / / Π / ZN NH 3-(6-chloro-5-(2'hydroxy-4',6'-dimethyl-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 421 Method C 3.076 min 20 / ΓΛ^0Η3 / / HO )=O ho / J η / CI-^X-^Á. ZN NH 3-(6-Chloro-5-(3'fluoro-2'-hydroxy-6'-methyl[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 425 Method C 3 min Petition 870250087244, dated 09 / 26 / 2025, pp. 131 / 190 119 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 21 HCH Ίθΐ %-OH OH Ls JL 3-(6-chloro-5-(2'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 423 Method C 2.795 min 22 %^OH F 3-(6-chloro-5-(3'fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 411 Method C 2.893 min 23 0 H3Cx J] h L JI HO / ° HO Í jl ( jTYx NH acid 3-(6-chloro-5-(2'hydroxy-4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic P7 450.1 Method A 0.72 min 24 I ω o \ ω=ο / \\ ocy / \ / ° ΙΖχ zo acid 3-(6-chloro-5-(4'-(Smethylsulfonimidoyl)-[1,1' biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 454.2 Method A 0.66 min 25 _ HO„ / X, \=sO JO Γ ? ΐ[Ίι / J oh 3-(6-chloro-5-(3'ethoxy-2'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic P7 437 Method A 0.909 min Petition 870250087244, dated 09 / 26 / 2025, pp. 132 / 190 120 / 160 Example: Structure IUPAC Name Analogous Synthesis LC Method EM (M + H)+ tr 26 IT %-OH H,C. δ 7.85 (s, 1 H), 7.62 (s, 1 H), 7.49 (s, 4 H), 6.91 (dd, 1 H), 6.64 (t, 1 H), 3.90 (s, 3 H), 3.26 (t, 2 H), 2.70 (t, 2 H); EM (M + H)+ 441.0. 27 τ Ο Ο / Ζχ ΛΑ 0 Petition 870250087244, dated 09 / 26 / 2025, pp. 133 / 190 121 / 160 Ex# Structure IUPAC name Analog synthesis LC method EM (M + H)+ tr 28 TH V-0H H3C. Jk / 0 r OH Jk J CI'^^'N acid 3-(6-chloro-5-(4'chloro-2'-hydroxy-3'-methoxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 1H NMR (400 MHz, MeO H), 7.63 (m, 3 H), 7.49 (d, 2 H), 7.10 (d, 1 H), 6.95 (d, 1 H), 3.88 (s, 3 H), 3.27 (t, 2 H), 2.73 (t, 2 H); EM (M + H)+ 457.0. 29 X o 0 ZI os O—\ « zo / on X acid 3-(6-chloro-5-(4'(dimethylcarbamoyl)-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 448 Method C 2,608 min 30 x XO ° z O / z <XI X ácido 3-(5-(4'-(2-amino-2oxoetil)-[1,1'-bifenil]-4-il)-6cloro-1H-indazol-3il)propanoico P7 434 Método C 2,405 min 32 X Ο Λ o o O O ΙΖ^\γ° O X ácido 3-(6-cloro-5-(4'(metilsulfonamido)-[1,1'bifenil]-4-il)-1H-indazol-3il)propanoico P7 470 Método C 2,604 min Petition 870250087244, of 26 / 09 / 2025, p. 134 / 190 122 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 33 o, li T ^-OH j FN r H 3-(6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid P6, P11 377.4 Method G 1.96 min 34 H3C^x^ / OH η TT OH 3-(6-chloro-5-(2'-hydroxy-4'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 407 Method C 2.746 min 35 rTV°H 1 1 %— OH H 3-(6-cyano-5-(2'-hydroxy-[1,1 '-biphenyl]-4-yl)1H-indazol-3-yl)propanoic P6, P10 384.2 Method G 2.52 min. 36 O XL M H0 líi V°H λ CI-^^N 4'-(3-(2-carboxyethyl)6-chloro-1H-indazol-5-yl)-2-hydroxy-[1,1'-biphenyl]-4-carboxylic acid P7 437.3 Method A 0.556 min 37 I o Xs owo— o C_7 ozo X 3-(6-chloro-5-(2'-hydroxy-3'-isopropoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 451.4 Method A 0.913 min 38 0 o OOO o OI 3-(6-chloro-5-(4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 506 Method B 2,496 min Petition 870250087244, dated 09 / 26 / 2025, pp. 135 / 190 123 / 160 Ex# Structure IUPAC Name Similar Synthesis Method LC EM (M + H)+ tr 39 I ο A ζ-ο ___ / ω Ω Ο Ο ιζ Ο I acidic 3-(6-chloro-5-(4'-(Nmethylacetamido)-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic P7 448 Method C 2,625 min 40 I Ο 'ζι \7 Ο 0 ΖΑ / ζ / -ο CM Τ ácido 3-(6-chloro-5-(4'sulfamoyl-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid P7 456 Method C 2,465 min 41 Τ Ο ^ΖΖ \7 Ο ζζ Ή ο τ' 3-(5-(4'(acetamidomethyl)-[1,1'biphenyl]-4-yl)-6-chloro-1Hindazol-3-yl)propanoic acid P7 448 Method C 2,494 min 42 F ίΓΐ °·^-ΟΗ OH J CI-^^N 3-(6-chloro-5-(5'fl uoro-2'-hidróxi-3'-m ethóxi[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 441.1 Method A 0.821 min 43 QA Λο« L'jfV> ácido 4-(6-cloro-5-(2'hidróxi-[1,1 '-bifenil]-4-yl)1H-indazol-3-yl)butanoico P31, P6 407.3 Método A 0.905 min 44 h3c. / ° οζ %-οη ^jTT> CI-^^N ácido 3-(6-cloro-5-(4'(metilsulfonyl)-[1,1 '-bifenil]4-yl)-1H-indazol-3yl)propanoico P7 455.3 Método A 0.735 min Petition 870250087244, 09 / 26 / 2025, pág. 136 / 190 124 / 160 Ex# Structure IUPAC name Analogous synthesis Method LC EM (M + H)+ tr 45 °·^οη ci / OH ks, Jk J 3-(6-chloro-5-(3'chloro-2'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 427 Method C 3.071 min 46 nr °y°H 33-n CI^^N 3-(6-chloro-5-(2'chloro-6'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 427 Method C 2.928 min 47 F^OH ox Il T ^OH acid 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid P7 411 Method C 2.907 min 48 <^CH3 Ok li T ^--OH ^Oón 3-(6-chloro-5-(2'-methyl-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 391 Method D 2.739 min 49 T o 'os O \- / \7 izs zr / 5 o I 3-(6-chloro-5-(2'chloro-6'-hydroxy-4'-methoxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 457 Method C 2.932 min 50 OQ °y°H íOx^u nO3 C'X^'h 3-(6-chloro-5-(2'fluoro-6'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 411 Method C 2.807 min Petition 870250087244, dated 09 / 26 / 2025, pp. 137 / 190 125 / 160 Example: Structure IUPAC Name Analogous Synthesis LC Method EM (M + H)+ tr 51 °y°HCI^H 3-(5-([1,1'-biphenyl]-4yl)-6-chloro-1H-indazol-3yl)propanoic acid P7 377.3 Method A 0.895 min 52 H3C'°V1 V°hr OH J 3-(6-chloro-5-(2'-hydroxy-3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 453 Method C 2.887 min 53 I o I t X ω zAz,o OOO o I acid 3-(6-chloro-5-(4-(2hydroxy-1-methyl-1Hbenzo[d]imidazol-5yl)phenyl)-1H-indazol-3yl)propanoic P7 447 Method C 2.506 min 54 T o O õ / / \\ oo acid 3-(6-chloro-5-(4-(2,2dioxide-1,3-dihydrobenzo[c]thiophen-5yl)phenyl)-1H-indazol-3yl)propanoic P7 467 Method B 2.844 min 55 r^>\ OK I II %^OH acid 3-(6-chloro-5-(3'cyano-2'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic P7 418 Method C 2.842 min 56 h, fall °y ohs ιΓχ λ7 3-(6-chloro-5-(4-(5-methylthiophen-2-yl)phenyl)-1-hindazol-3-yl)propanoic acid P7 397 Method D 2.745 min Petition 870250087244, dated 09 / 26 / 2025, pp. 138 / 190 126 / 160 Ex# Estrutura Nome de IUPAC Síntese análoga Método LC EM (M + H)+ tr 57 XE O o / ==\ θ θ-δ _ ácido 3-(6-cloro-5-(3'(difluorometóxi)-2'-hidróxi[1,1'-bifenil]-4-yl)-1Hindazol-3-yl)propanoico P7 459.1 Metodo A 0.841 min 58 t o C / tx H Y / 3 o X ácido 3-(6-cloro-5-(4-(5(hydroxymetil)thiofen-3yl)fenil)-1H-indazol-3yl)propanoico P7 413 Método C 2,581 min 59 I Jo o o O o o t ácido 3-(6-cloro-5-(4-(2methoxythiazol-4-yl)fenil)-1Hindazol-3-yl)propanoico P7 414 Method C 3.051 min 60 ω __ / ο / =\ 1 / \ ω ο _y Ζ V^zP Ο I 3-(6-chloro-5-(4-(4methylthiophen-3-yl)phenyl)-1Hindazol-3-yl)propanoic acid P7 397 Method D 2.656 min 61 [<η>Ι1 θ^-OH Ι Ί j 3-(6-chloro-5-(3'(hydroxymethyl)-[1,1'-biphenyl]4-yl)-1H-indazol-3yl)propanoic acid P7 407 Method E 2.1 min 62 X Ο 'ζι £ Ο 0 Ο / ==' s ο / ο M τ 3-(6-chloro-5-(2'hydroxy-3'-methoxy-6'-methyl[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 437 Method A 0.865 min 63 xS.χΟΗ _ h3c YjJ yoH j CI-^^N 3-(6-chloro-5-(2'hydroxy-4'-(methylthio)-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 439.2 Method A 0.871 min. Petition 870250087244, dated 09 / 26 / 2025, pp. 139 / 190 127 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 64 II T 3-(6-chloro-5-(4'chloro-2'-hydroxy-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 427 Method D 2.508 min 65 Z^ S / ω 0 O o X 3-(6-chloro-5-(4-(isothiazol-4-yl)phenyl)-1hindazol-3-yl)propanoic acid P7 384 Method C 2.739 min 66 HO O, \___ / |l CI-'^^'N 3-(6-chloro-5-(4-(2(hydroxymethyl)thiazol-4yl)phenyl)-1H-indazol-3yl)propanoic acid P7 414 Method B 2.614 min 67 jCCx Voh aOCn 3-(6-chloro-5-(6'chloro-3'-fluoro-2'-hydroxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 455.2 Method A 0.833 min 68 0%—OH OH IL acid 3-(6-chloro-5-(4-(7hydroxy-2,3-dihydrobenzofuran-6-yl)phenyl)1H-indazol-3-yl)propanoic P7 435.3 Method A 0.793 min 69 c> O \- / \7 OX acid 3-(6-chloro-5-(4'(difluoromethoxy)-2'-hydroxy[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic P7 459.1 Method A 0.85 min 70% Petition 870250087244, dated 09 / 26 / 2025, pp. 140 / 190 128 / 160 Example: Structure IUPAC Name Analogous Synthesis LC Method EM (M + H)+ tr 71 FT 1 '\^OH CI^^N 3-(6-chloro-5-(3',4'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 429.1 Method A 0.836 min 72 T o xzr O õ O zm Z 3-(5-(4'-(2-amino-2oxoethoxy)-[1,1'-biphenyl]-4-yl)6-chloro-1H-indazol-3yl)propanoic acid P7 450 Method C 2.46 min 73 TO ° \S r O Õ O / =^ 3-(6-chloro-5-(2'-hydroxy-[1,1 '-biphenyl]-4-yl)1H-pyrazolo[4,3-b]pyridin-3yl)propanoic acid P31, P6 437.3 Method A 0.941 min 75 zí?\XCH3 / 0H ΎΥΊ OH JL ^05 4-(6-chloro-5-(2'hydroxy-6'-methyl-[1,1'biphenyl]-4-yl)-1H-indazol-3yl)butanoic acid P31, P6 421.2 Method A 0.899 min 76 0 JI HOV HN-'^ι^ \=° CH3 Ü 3-(6-chloro-5-(4'(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid P7 434 Method F 1.96 min Petition 870250087244, dated 09 / 26 / 2025, pp. 141 / 190 129 / 160 Example: Structure IUPAC Name Analogous Synthesis Method LC EM (M + H)+ tr 77 I o zz OO \- / / \ ,o H o τ 3-(6-chloro-5-(4'-((3-hydroxypropyl)carbamoyl)[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid P7 478 Method C 2.368 min 78 OH £ T / ? Tfll / ch3 oh 1 j3n 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)butanoic acid P31, P6 451.2 Method A 0.952 min Biosynthesis of glucuronide metabolic compounds

[00237] The compound from Example 1 (50 μM) was incubated with mouse liver microsomes (2 mg / mL) containing 10 μg / mL of alamethicin, 3.3 mM of MgCb, and 5 mM of uridine diphosphate glucuronic acid, in a total volume of 40 mL of KH2PO4 (100 mM, pH 7.4). Incubation was conducted in a 250 mL Erlenmeyer flask in a water bath with agitation, maintained at 37 °C for 60 hours. At the end of the incubation, the incubate was divided into n = 2 aliquots of 20 mL, and 20 mL of CH3CN were added to each sample, and the mixture was transferred to two 50 mL conical polypropylene tubes and vigorously mixed in a vortex mixer. The tubes were centrifuged in a Beckman centrifuge at 1800 g for 10 minutes, and the supernatant was transferred to new 50 mL conical polypropylene tubes. The tubes were then subjected to vacuum centrifugation in a Genevac evaporator, set to the mixing configuration for HPLC, for approximately 4 hours to remove the CH3CN.To the remaining solution, 10 mL of 0.1% formic acid in water:acetonitrile (95:5% v:v) were added, and the resulting mixture was centrifuged in a Beckmann centrifuge at 40,000 g for 30 min. Petition 870250087244, dated 09 / 26 / 2025, pp. 142 / 190 130 / 160 to clarify the supernatant.

[00238] The supernatants were combined and transferred to a 50 mL conical polypropylene tube and applied directly to a Varian Polaris C18 column (4.6 x 250 mm; 5 mm particle size) via a Jasco HPLC pump at a flow rate of 0.8 mL / min. After the application of 20 mL, another 5 mL of 0.1% formic acid in water:acetonitrile (95:5, % v:v) was pumped onto the column to ensure the HPLC lines were free of supernatant. The HPLC column was then transferred to an Agilent 1200 HPLC-UV system. The effluent was collected directly into the PAS HTS-xt fraction collector. The mobile phase used consisted of 0.1% formic acid (mobile phase A) and CH3CN (mobile phase B) at a flow rate of 0.5 mL / min. The mobile phase composition started with 95% A / 5% B, was maintained at this composition for 5 minutes, followed by a linear gradient to 5% A / 95% B at 45 minutes and maintained until 48 minutes, returning to the initial conditions at 60 minutes.The mobile phase program and data collection were initiated with a dummy injection of water from the autosampler. Fractions were collected every 7 seconds onto a wide-well polypropylene microtiter plate. Fractions collected in the region of interest (i.e., where the UV detector showed the presence of significant absorbance) were injected (5 mL) into a second HPLC gradient method using the same mobile phases with a Phenomenex XB-C18 column, 2.1 x 100 mm, 1.7 ua at a flow rate of 0.4 mL / min to test purity. The mobile phase composition started at 95% A / 5% B, was held at this composition for 0.5 minutes, followed by a linear gradient to 5% A / 95% B at 3.75 minutes, held for up to 4 minutes, and returned to initial conditions at 5 minutes. The fractions containing the product of interest were combined in a 15 mL conical glass tube, and the solvent was... Petition 870250087244, dated 09 / 26 / 2025, pp. 143 / 190 131 / 160 evaporated by vacuum centrifugation in a Genevac evaporator. After drying, they were prepared for NMR analysis. For structural characterization, the samples were dissolved in 0.045 mL of deuterated methanol - MeOD 100% (Cambridge Isotope Laboratories, Andover, MA) and placed in a 1.7 mm NMR tube in a dry argon atmosphere. For quantitative NMR, after structural characterization, the samples were dried and reconstituted in 0.045 mL of dimethyl sulfoxide - DMSO 100% (Cambridge Isotope Laboratories, Andover, MA) and placed in a 1.7 mm NMR tube in a dry argon atmosphere. The spectra of 1H and 13C were referenced using the residual solvent (DMSO-d6 -1H δ = 2.50 ppm relative to TMS δ = 0.00,13C δ = 39.50 ppm relative to TMS, δ = 0.00, MeODd4 -1H δ = 3.35 ppm relative to TMS, δ = 0.00,13C δ = 49.3 ppm relative to TMS, δ = 0.00).NMR spectra were recorded on a Bruker Avance 600 MHz (Bruker BioSpin Corporation, Billerica, MA) controlled by Topspin V4.0 and equipped with a 1.7 mm Cryo TCI probe. 1D spectra were recorded using an approximate scan width of 8400 Hz and a total recycle time of approximately 7 s. The resulting mean free induction decays were transformed using a 1.0 Hz exponential line broadening to improve the signal-to-noise ratio. 2D data were recorded using standard pulse sequences provided by Bruker. At a minimum, a 1K x 128 data matrix was acquired using a minimum of 2 scans and 16 dummy scans with a spectral width of 10000 Hz in the f2 dimension. The 2D datasets were zero-loaded up to at least 1k data point. Post-acquisition data processing was performed using MestReNova V12.1. All conditions for acquiring this data are contained in the raw file.Quantification was performed using a 5 mM external standard of benzoic acid. Petition 870250087244, dated 09 / 26 / 2025, pp. 144 / 190 132 / 160 (Cambridge Isotope Laboratories, Andover, MA) and the quantification plugin of the Mnova software. 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Example 79) 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazol-5-yl)-[1,1'-biphenyl]-2yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Example 80) Expression and purification of AMPK111

[00239] A tricistronic AMPK expression construct was prepared, which included open reading frames encoding the full-length α1, β1, and δ1 subunits of human AMPK, with a ribosome binding site (RBS) upstream of each coding region. The construct was subcloned into the pET-14b expression vector (Novagen, Madison, Wisconsin) using standard molecular biology techniques. The tricistronic AMPK construct was transformed into the E. coli BL21-CodonPlus™ (DE3)-RIPL strain (Stratagene), and transformants were screened on LB agar plates (Luria-Bertani) containing ampicillin (100 pg / mL). Ten liters of LB medium (MP Biomedical LB broth no. 11-3002-032) containing 100 pg / mL of carbenicillin were inoculated with 100 mL of shaken flask E. coli culture (BL-21, pET-14b, AMPK 111) in a 10 L working volume BF4 bioreactor (New Brunswick Scientific Co.) at 37 °C, 600 rpm and 6 L / minute. Petition 870250087244, dated 09 / 26 / 2025, pages 145 / 190 133 / 160 aeration. Optical density measurements of the samples were performed on an UltroSpec 2000 spectrophotometer (Pharmacia Biotech) at 600 nm.

[00240] When cell density reached ~0.9 OD, the temperature was reduced to 18 °C and the culture was induced at 18 °C with 0.1 mM isopropyl thiogalactoside (IPTG). The cell pellet was collected approximately 18 hours after induction by refrigerated continuous flow centrifugation (Heraeus, rotor no. 8575) at 15,000 rpm at 4 °C. The cell pellets were aliquoted into four portions, flash-frozen in liquid nitrogen, and stored at -80 °C until purification. For purification, the frozen cell paste was thawed and resuspended in 50 mL of lysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM Tris-2-carboxyethyl phosphine (TCEP), 20 mM imidazole, and 0.001% Triton X-100).After sonication, the insoluble material was removed by centrifugation at 15,000 rpm in a Sorvall® RC5 plus centrifuge for 30 minutes at 4 °C, and the supernatant was loaded onto a 5 mL HisTrap™ HP column (GE Healthcare, Piscataway, NJ) and washed with five column volumes of lysis buffer. Bound proteins were eluted using an elution buffer containing 300 mM imidazole. Fractions containing AMPK subunits were pooled based on 10% SDS-PAGE analysis and dialyzed overnight in dialysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100). Purified AMPK was phosphorylated at its Thr 172 activation loop by incubating 1.0 pM of the AMPK complex in the presence of 200 nM of CaMKKB (calmodulin-dependent protein kinase B, obtained from the University of Dundee) in phosphorylation buffer for 30 minutes at 30 °C.The phosphorylated AMPK complex was re-purified on a HisTrap™ HP column as before, and dialyzed overnight in dialysis buffer. The complex of... Petition 870250087244, dated 09 / 26 / 2025, pp. 146 / 190 134 / 160 Phosphorylated AMPK was subsequently purified by gel filtration chromatography using a Superdex 200 HiLoad 16 / 60 column (GE Healthcare) in SEC buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100). The final samples were stored at -20 °C with 25% glycerol. Expression and purification of AMPK221

[00241] A tricistronic AMPK expression construct was developed, including open reading frames encoding the full-length α2, β2, and δ1 subunits of human AMPK, with a ribosome binding site (RBS) upstream of each coding region. The construct was subcloned into the pET-14b expression vector (Novagen, Madison, Wisconsin) using standard molecular biology techniques. The tricistronic AMPK construct was transformed into the E. coli BL21-CodonPlus™ (DE3)-RIPL strain (Stratagene), and transformants were screened on LB agar plates (Luria-Bertani) containing ampicillin (100 pg / mL). Ten liters of LB medium (MP Biomedical LB broth n° 11-3002-032) containing 100 pg / mL of carbenicillin were inoculated with 100 mL of shaken flask E. coli culture (BL-21, pET-14b, AMPK 221) in a 10 L working volume BF4 bioreactor (New Brunswick Scientific Co.) at 37 °C, 600 rpm and 6 L / minute aeration.Optical density measurements of the samples were performed using an UltroSpec 2000 spectrophotometer (Pharmacia Biotech) at 600 nm.

[00242] When the cell density reached ~0.9 OD, the temperature was reduced to 18 °C and the culture was induced at 18 °C with 0.1 mM isopropyl thiogalactoside (IPTG). The cell pellet was collected ~18 hours after induction by refrigerated continuous flow centrifugation (Heraeus, rotor no. 8575) at 15,000 rpm at 4 °C. The cell pellets were aliquoted into four portions, flash-frozen in liquid nitrogen, and stored at -80 °C until purification. For the Petition 870250087244, dated 09 / 26 / 2025, pp. 147 / 190 135 / 160 purification, the frozen cell paste was thawed and resuspended in 50 mL of lysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM Tris-2-carboxyethyl phosphine (TCEP), 20 mM imidazole, and 0.001% Triton X-100). After sonication, insoluble material was removed by centrifugation at 15,000 rpm in a Sorvall® RC5 plus centrifuge for 30 minutes at 4 °C, and the supernatant was loaded onto a 5 mL HisTrap™ HP column (GE Healthcare, Piscataway, NJ) and washed with five column volumes of lysis buffer. Bound proteins were eluted using an elution buffer containing 300 mM imidazole. Fractions containing AMPK subunits were pooled based on 10% SDS-PAGE analysis and dialyzed overnight in dialysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100).Purified AMPK was phosphorylated at its activation loop Thr 172 by incubating 1.0 pM of the AMPK complex in the presence of 200 nM CaMKKB (calmodulin-dependent protein kinase B) obtained from the University of Dundee in phosphorylation buffer for 30 minutes at 30 °C. The phosphorylated AMPK complex was repurified on a HisTrap™ HP column as before, dialyzed overnight in dialysis buffer. The phosphorylated AMPK complex was subsequently purified by gel filtration chromatography with a Superdex 200 HiLoad 16 / 60 column (GE Healthcare) in SEC buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100). The final samples were stored at -20 °C with 25% glycerol. Expression and purification of PP2A

[00243] The coding sequence of the catalytic subunit of recombinant human Protein Phosphatase 2A (PPP2CA; 308 aa, P67775, AA2-309) with an N-terminal FLAG 2X label and a TEV protease site was synthesized and subcloned into the expression vector. Petition 870250087244, dated 09 / 26 / 2025, pp. 148 / 190 136 / 160 pFastBac Dual (Thermo Fisher, 10712024) under the PolH promoter and the regulatory subunit of Protein Phosphatase 2A (PPP2R1A; 508 aa, P30153, AA2-589) with an N-terminal His label. A TEV protease site was synthesized and subcloned into the same vector under the p10 promoter. The vector was used to produce baculoviruses using the Bac-to-Bac System (Thermo Fisher), which was subsequently used to express the protein in Sf9 cells (Expression Systems, 94001F). Sf9 cells were cultured in ESF 921 medium (Expression Systems, 96-001-01) at a volume of 3 L in a sterile 5 L Thomson Optimum growth flask with a vent cap (Thomson Instrument Company, 931116) at 27 °C, under agitation at 115 rpm and with a 2-inch agitation diameter. P0 virus was used at 10 ml / L to infect cells at a density of ~2.5 x 10⁶ cells / ml with viability >95%.The collection time (71 hours after infection) was indicated by the percentage of cell viability (~80%) and the increase in cell diameter (>3 microns). The cell paste was collected by centrifugation in a Thermo Sorvall RC 3BP+ centrifuge at 5000 x e frozen at -80 °C.

[00244] For purification, the 3 L of cell paste culture were again suspended in 175 mL of lysis / wash buffer (50 mM Tris pH 8.0, 300 mM NaCl, 10% glycerol, 1 mM TCEP). The cells were lysed by microfluidization at 1,054.60 kg / cm2 (15,000 psi) for 3 passes and clarified by centrifugation at 30,000 x g. 5 mL of FLAG resin were equilibrated with lysis buffer. The equilibrated FLAG resin was added to the supernatant and left to stand for 6 hours. The protein was then washed with 20 volumes of lysis buffer and eluted from the resin with 7 mL of elution buffer (50 mM Tris pH 8.0, 300 mM NaCl, 10% glycerol, 0.25 mg / mL FLAG peptide). The eluted fractions were analyzed by SDS-PAGE, mass spectrometry, and PP2a activity. The total concentration Petition 870250087244, dated 09 / 26 / 2025, pp. 149 / 190 Protein content was determined using Superdex 200 16-60, with a concentration of 0.149 mg / mL. Biochemical profile of AMPK activators by AMPK111

[00245] The biochemical EC50 (half the maximum concentration required for complete activation) of the compounds for AMPK activation was evaluated by the HTRF assay using the LANCE Ultra ULight-Acetyl-CoA Carboxylase (SAMS) peptide (commercially available, Perkin Elmer catalog TRF0133-M). 5 μL of 0.3 nM phosphorylated AMPK 111 (isolation detailed above) diluted in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.25 mM DTT, 0.01% Tween-20, 0.01% BSA (pH 7.5)) were added to 384-well blank plates (Corning catalog code 3824) containing 0.075 μL of the test compound (solubilized and serially diluted in DMSO, in a series of 11-point, ½ log dilutions, tested in duplicate).

[00246] The plates were centrifuged at 1000 RPM for 10 seconds. After a fifteen-minute incubation at room temperature, 5 μL of 30 nM PP2A protein phosphatase (isolation detailed above) diluted in assay buffer were added to the plate to dephosphorylate pThr172 from AMPK. The plates were centrifuged at 1000 RPM for 10 seconds. After 120 minutes of incubation, 5 μL of a substrate mixture containing 60 nM okadaic acid (Tocris catalog number 1136), 150 nM SAMS peptide (Perkin Elmer catalog TRF0133-M), and 60 μM ATP (Teknova catalog number A1204) diluted in assay buffer were added to the plate. The plates were centrifuged at 1000 RPM for 10 seconds. The reaction was stopped after 60 minutes of incubation at room temperature by adding 5 μL of a stop and detection cocktail, which consisted of Perkin Elmer Lance 1X buffer (Perkin Elmer catalog number CR97-100), 40 mM EDTA (Ther catalog number Petition 870250087244, dated 09 / 26 / 2025, pages 150 / 190 138 / 160 µM Fisher BP2482-100) and 2 nM Eu-anti-Acetyl-CoA Carboxylase antibody [pSer70] (Perkin Elmer, TRF0208-M). Plates were centrifuged at 1000 RPM for 10 seconds. Plates were incubated for 1 hour and then read on an Envision reader with a setting for TR-FRET ratio = 10,000X (fluorescence intensity 665 nM / fluorescence intensity 615 nM). EC50 values ​​were determined from these data using a 4-parameter fitting algorithm and are presented in Table 2. Biochemical profile of AMPK activators by AMPK221

[00247] The biochemical EC50 (half the maximum concentration required for complete activation) of compounds for AMPK activation was evaluated by HTRF assay using the LANCE Ultra ULight-Acetyl-CoA Carboxylase (SAMS) peptide (commercially available, Perkin Elmer Catalog TRF0133-M). 5 μL of 0.3 nM phosphorylated AMPK 221 (isolation detailed above) diluted in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCb, 0.25 mM DTT, 0.01% Tween-20, 0.01% BSA (pH 7.5)) were added to 384-well blank plates (Corning catalog code 3824) containing 0.075 μL of the test compound (solubilized and serially diluted in DMSO, in an 11-point, ½ logarithmic series, and tested in duplicate).

[00248] The plates were centrifuged at 1000 RPM for 10 seconds. After a fifteen-minute incubation at room temperature, 5 μL of 15 nM PP2A protein phosphatase (isolation detailed above) diluted in assay buffer were added to the plate to dephosphorylate pThr172 from AMPK. The plates were centrifuged at 1000 RPM for 10 seconds. After incubation for 120 minutes, 5 μL of substrate mixture containing 30 nM okadaic acid (Tocris catalog number 1136), 150 nM SAMS peptide (Perkin Elmer catalog TRF0133-M), and 240 μM ATP (Teknova catalog number A1204), Petition 870250087244, dated 09 / 26 / 2025, pp. 151 / 190 139 / 160 diluted in assay buffer were added to the plate. The plates were centrifuged at 1000 RPM for 10 seconds. The reaction was stopped after 60 minutes of incubation at room temperature by the addition of 5 μL of stop and detection cocktail, which consisted of Perkin Elmer Lance 1X buffer (Perkin Elmer catalog number CR97-100), 40 mM EDTA (Thermo Fisher catalog number BP2482-100), and 2 nM Eu-anti-Acetyl CoA Carboxylase antibody [pSer70] (Perkin Elmer, TRF0208-M). The plates were centrifuged at 1000 RPM for 10 seconds. The plates were incubated for 1 hour and then read on an Envision reader with a setting for TR-FRET ratio = 10,000 X (fluorescence intensity 665 nM / fluorescence intensity 615 nM). EC50 values ​​were determined from these data using a 4-parameter fitting algorithm and are presented in Table 2. Table 2: Biochemical profile of AMPK activators by AMPK 111 and AMPK221 Example AMPK 111 EC50 AMPK 221 nM eMax (%) nM eMax (%) 1 47 75 88 57 2 29 80 34 66 3 189 83 528 61 4 62 74 665 34 5 89 59 37 62 6 6 64 4 53 7 90 71 359 57 8 26 75 38 56 9 11 90 41 68 10 29 76 48 55 11 53 62 60 44 12 16 72 62 56 Petition 870250087244, dated 09 / 26 / 2025, pp. 152 / 190 140 / 160 Example AMPK 111 EC50 AMPK 221 nM eMax (%) nM eMax (%) 13 21 86 69 67 14 45 74 72 65 15 35 75 76 52 16 37 86 81 64 17 34 80 83 49 18 12 84 96 64 19 54 79 144 34 20 16 82 97 61 21 151 65 97 56 22 111 74 100 59 23 2 71 5 56 24 19 86 106 48 25 144 71 107 61 26 107 77 114 66 27 7 87 125 62 28 277 73 136 63 29 46 72 162 63 30 36 80 173 65 31 57 84 190 61 32 136 71 198 41 33 301 57 196 57 34 228 68 197 50 35 137 67 198 47 36 45 68 200 49 37 464 70 205 52 38 95 67 209 64 39 109 69 218 59 Petition 870250087244, dated 09 / 26 / 2025, pp. 153 / 190 141 / 160 Example AMPK 111 EC50 AMPK 221 nM eMax (%) nM eMax (%) 40 92 85 306 68 41 70 66 235 65 42 291 68 244 64 43 51 80 248 62 44 85 79 204 52 45 123 82 263 66 46 20 82 267 59 47 113 83 282 59 48 365 43 367 9 49 96 74 325 61 50 153 76 337 55 51 312 71 355 22 52 6 85 19 65 53 218 69 644 55 54 217 61 1006 64 55 208 45 389 38 56 363 48 477 18 57 103 75 426 63 58 215 76 573 57 59 609 30 546 13 60 241 53 532 21 61 692 55 645 34 62 25 72 14 57 63 281 56 565 64 64 203 76 617 48 65 263 79 795 58 66 365 74 1087 63 Petition 870250087244, dated 09 / 26 / 2025, pages 154 / 190 142 / 160 Example AMPK 111 EC50 AMPK 221 nM eMax (%) nM eMax (%) 67 69 85 953 63 68 29 71 19 69 69 480 73 1151 58 70 285 74 1086 49 71 279 73 994 60 72 99 103 1831 114 73 26 86 2115 30 74 92 80 66 69 75 74 75 229 63 76 6 67 13 53 77 70 66 82 58 78 93 78 87 66 79 39 67 29 27 80 >21100 >21100 Crystal shape analysis (Example Compound 1, Shape 1)

[00249] Powder X-ray diffraction (PXRD) analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set for continuous illumination of 15 mm. The diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD aperture set to 4.111 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. In addition, the energy-dispersive detector used a nickel filter to filter out unwanted wavelengths. Data were collected on the Theta-Theta goniometer at Cu wavelengths from 3.0 to 40.0 degrees 2-Theta using a step size of 0.0160 degrees and a step time of 1.0 second. The anti-scatter screen was set to a fixed distance of 1.5 mm. Samples were rotated at 15 / min. Petition 870250087244, dated 09 / 26 / 2025, pages 155 / 190 143 / 160 during collection. Samples were prepared by placing them in a low-noise silicon sample holder and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software, and analysis was performed using EVA diffract plus software. The sample holder used in a specific experiment is given by a codename within the filename: SD = small divot holder.

[00250] Samples were prepared by placing them in a low-noise silicon sample holder and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software, and analysis was performed using EVA diffract plus software. The PXRD diffractogram is shown in Figure 1. Using the peak search algorithm in EVA software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were made manually; the output of the automated assignments was visually verified, and peak positions were adjusted to the maximum peak. Peaks with relative intensity > 3% were generally chosen. Peaks that were not resolved or that were consistent with noise were not selected. A typical error associated with the PXRD peak position, as stated in the USP, is up to + / - 0.2° 2-Theta (USP941). The list of peaks is presented in Table 3.The characteristic peaks of Form 1 are presented in Table 4. Figure 1 shows the PXRD of the compound from Example 1, Form 1. Table 3. List of peaks for Form 1, Example 1, using a threshold >3%. Angle (°2-theta) Relative Intensity (%) 6.3 15 7.9 3 Petition 870250087244, dated 09 / 26 / 2025, pp. 156 / 190 144 / 160 Angle (°2-theta) Relative Intensity (%) 12.6 64 14.5 7 15.8 5 17.5 3 18.0 5 18.3 18 18.8 61 19.3 15 19.7 34 22.0 12 22.5 16 23.4 22 23.7 18 24.4 100 25.3 3 26.6 13 27.0 3 27.1 3 27.5 13 29.1 8 29.5 8 29.8 6 30.6 3 31.1 3 31.3 6 31.5 19 32.1 13 Petition 870250087244, dated 09 / 26 / 2025, pp. 157 / 190 145 / 160 Angle (°2-theta) Relative Intensity (%) 34.0 4 34.8 6 35.9 3 Table 4. Characteristic Peaks of Shape 1, example 1 Angle (°2-theta) Relative Intensity (%) 12.6 64 18.8 61 19.7 34 24.4 100 Deuterated Analogues of the Compounds of the Invention

[00251] Métodos gerais / revisões de obtenção de perfil de metabólitos e identificação de metabólitos de um composto são descritos em: Dalvie, et al., Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites, Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., Biotransformations in Drug Metabolism, cap. 3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10,1002 / 9781119851042.ch3; Wu, Y., et al, Metabolite Identification in the Preclinical and Clinical Phase of Drug Development, Current Drug Metabolish, 2021, 22, 11, 838-857, 10,2174 / 1389200222666211006104502; Godzien, J., et al, Chapter Fifteen - Metabolite Annotation and Identification.

[00252] Several publicly and commercially available software tools are available to assist in predicting metabolic pathways and metabolites of compounds. Examples of these tools include BioTransformer 3.0 (biotransformer.ca / new), which predicts the metabolic biotransformations of small molecules using a Petition 870250087244, dated 09 / 26 / 2025, pp. 158 / 190 146 / 160 database of known metabolic reactions; MetaSite (moldiscovery.com / software / metasite / ), which predicts metabolic transformations related to cytochrome P450-mediated reactions and flavin-containing monooxygenase in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolic structures using a range of machine learning models, covering phase I and phase II biotransformations of small molecules.

[00253] The metabolic profile of Example 1 is evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey, and human), recombinant human cytochrome P450 enzymes, recombinant human UGT enzymes, and animal plasma (mouse, rat, and dog). The metabolic profile of Example 1 consists of oxidation and glucuronidation. MetaSite (moldiscovery.com / software / metasite / ) was used to predict cytochrome P450-related metabolic transformations and flavin-containing monooxygenase-mediated reactions in the phase I metabolism of Example 1-D. Examples 1-D1 to 1-D24 in Table 5 may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosing requirements, reduced CYP450 inhibition (competitive or time-dependent), or an improvement in the therapeutic index or tolerability.

[00254] A person skilled in the art can produce additional deuterated analogs of Example 1 with different combinations of Y1-Y5, as shown in Table 5. These additional deuterated analogs can provide therapeutic advantages similar to those that can be achieved by the deuterated analogs. The compounds shown in Table 5 are predictive deuterated analogs (PDAs) of Example 1. The PDAs are predicted based on the metabolic profile of Example 1. Petition 870250087244, dated 09 / 26 / 2025, pages 159 / 190 147 / 160 Table 5. Deuterated prophetic compounds of Example 1 Sample Number Y1 Y2 Y3 y4a. y4b Y5 1-D1 DHHHH 1-D2 HDHHH 1-D3 HHDHH 1-D4 HHHDH 1-D5 HHHHD 1-D6 DDHHH 1-D7 DHDHH 1-D8 DHHDH 1-D9 DHHHD 1-D10 HD1DHHH 1-DDHD-12-DHDHD-12 1-D13 HHDDH 1-D14 HHDHD 1-D15 HHHDD 1-D16 DDDHH 1-D17 DDHDH 1-D18 DDHHD 1-D19 HDDDH 1-D20 HDDHD 1-D21 HHDDD 1-D22 DDDDH 1-DDH3 DDDHD 1-D2D-DDHD Petition 870250087244, of 26 / 09 / 2025, p. 160 / 190 148 / 160 MODALITY

[00255] The following non-limiting modalities provide illustrative examples of the invention, but do not limit the scope of the invention.

[00256] Modality 1. A compound of Formula (I): Rb1 Formula (I) a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein: - A1st CR8, or N; - A2é CH2, CHD, CD2, S, O, or NH; - A3 is CH, CD, or N; - R1 is H, D, C1-8 alkyl, C3-6 cycloalkyl or 4 to 6 membered heterocycloalkyl; - R2, R3, R5, and R6 are each independently H, D, OH, or halogen; - R4 is a monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with R9, R10, R11, R12, or R13, wherein R9, R10, R11, R12, and R13 are each independently H, D, halogen, CN, oxo, C1-8 alkyl, C3-6 cycloalkyl, C0-6 alkylene ORx, C1-6 haloalkylene ORx, C0-6 alkylene (C0-6haloalkyl) NRxRy, C1-6 alkylene (C1-6haloalkyl) NRxRy, 4- to 6-membered heterocycloalkyl, C(O)ORx, C0-6 alkylene-C(O) NRxRy, OC1-3 alkylene heterocycloalkyl, OC1-3 alkylene-C(O)NRxRy, O(Ci-6 alkyl)SO2NRxNRy, NRxRy, NHSO2Rx, SRx, S-C1-6 alkylene-C(O)NRxRy, S(O)RxRy, SO2Rx, Petition 870250087244, dated 09 / 26 / 2025, pp. 161 / 190 149 / 160 SO2NRxRy, S(O)(NRx)Ry, S(O)(NRx)Ry, or SÜ2Rx; wherein each Rxe Ry is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C36 cycloalkyl, C1-6 alkylene-amide, OC0-2 alkylene-heterocycloalkyl, 4- to 6-membered heterocycloalkyl, C(O)C1-6 alkyl, imino, or C1-6 alkylsulfonyl; or Rxe Ry together with the atoms to which Rxe Ry are attached may form an optionally substituted ring; - R7 is C1-3 alkyl, C3-6 cycloalkyl, cyano or halogen; - Rb1, Rb2, and Rb3 are each independently H or D; - R8 is H, D, or halogen; and - n is 0, 1, or 2

[00257] Embodiment 2. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein A1 is CH or CF.

[00258] Embodiment 3. The compound of embodiment 1 or 2, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein A2 is CH2 or S.

[00259] Embodiment 4. The compound of any of embodiments 1 to 3, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein A3 is N.

[00260] Embodiment 5. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein A1 is N and A3 is N.

[00261] Embodiment 6. The compound of any of embodiments 1 to 5, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R1 is H.

[00262] Embodiment 7. The compound of any of the embodiments 1 to 6, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R2 is a halogen; and R3, R5, and R6 are each independently H.

[00263] Modality 8. The compound of any of the modalities Petition 870250087244, dated 09 / 26 / 2025, pp. 162 / 190 150 / 160 dates 1 to 5, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R2, R3, R5, and R6 are each independently H.

[00264] Embodiment 9. The compound of any of embodiments 1 to 8, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, where R7 is Cl.

[00265] Embodiment 10. The compound of any of the embodiments 1 to 9, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R4 is phenyl, wherein R9, R10, R11, R12, and R13 are each independently H, D, Cl, F, CN, C1-3 alkyl, C1-6 alkylene-OH, C1-6 alkylene-OC1-6 alkyl, OH, OC1-6 alkyl, OC1-6 haloalkyl, O(C1-3 alkylene)heterocycloalkyl, O(C1-3 alkylene)-C(O)NRxRy, C1-3 alkyleneNRxRy, C(O)OH, C(O)OC1-3 alkyl, C0-2 alkylene-C(O)NRxRy, SO2NRxRy, S(O)(NRx)Ry, NRxRy, SRx, or SO2Rx.

[00266] Embodiment 11. The compound of any of embodiments 1 to 10, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R4 is a 6-membered monocyclic heteroaryl compound, wherein at least one of R9, R10, R11, R12 and R13 is C1-3 alkoxy, halogen, hydroxy or C(O)NH2.

[00267] Embodiment 12. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the compound has the structure Formula (II): Formula (II), Petition 870250087244, dated 09 / 26 / 2025, pp. 163 / 190 151 / 160 where: - R2 is H, D, or halogen; R7 is Cl or CN; - A2 is CH2, CHD, CD2, S, or NH; - A4 is CR9 or N; - R9 is H, F, Cl, C1-3 alkyl, C1-3 alkylene-O-C1-3 alkyl, C1-3 alkylene-NH2, COOH, C(O)OC1-3 alkyl, C1-3 alkylene-C(O)NH2, C(O)NHC1-3 alkyl, C(O)N(C1-3 alkyl)2, C1-6 alkylene(C1- 6haloalkyl)NH2, C0-2 alkylene-NH(C(O)C1-3 alkyl), OC1-3 alkyl, OCi3haloalkyl, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkyleneC(O)NH2, NHSO2C1-3 alkyl, N(Ci-3 alkyl)(C(O)C1-3 alkyl), SC1-3 alkyl, S-C1-3 alkylene-C(O)NH2, SO(NH)C1-3 alkyl, SO2NH2, or SO2C1-3 alkyl; - R10 is H, D, or OH; - R11 is H, D, halogen, CN, O(C1-3 alkyl), or O(C1-3 haloalkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring; - R12 is H, OC1-3 alkyl, or C1-3 alkylene-OH; - R13 is H, F, Cl, or C1-3 alkyl; and - n is either 1 or 2.

[00268] Embodiment 13. The compound of embodiment 12, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R10 is OH.

[00269] Embodiment 14. The compound of embodiment 12 or 13, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, where R7 is Cl.

[00270] Embodiment 15. The compound of any of embodiments 12 to 14, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein A2 is CH2 or S. Petition 870250087244, dated 09 / 26 / 2025, pp. 164 / 190 152 / 160

[00271] Embodiment 16. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the compound has the structure Formula (III): in which: - R9 is H, D, halogen, C1-3 alkyl, C(O)NH2, C1-3 alkyleneNH2, C1-3 alkylene-O-C1-3 alkyl, C(O)OC1-3 alkyl, C(O)OH, OC1-3 alkyl, OC1-3 haloalkyl, -O(C1-3 alkyl)SO2NH2, C1-6 alkylene(C16 haloalkyl)NH2, SC1-3 alkyl, or -C(O)NRxRy, where each Rx and Ry are independently H or C1-6 alkyl; and - R11 is H, D, halogen, CN, or -O(C1-3 alkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring.

[00272] Embodiment 17. The compound of embodiment 16, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein: - R9 is H or -C(O)NRxRy, where each Rx and Ry is independently H, D, or C1-6 alkyl; and - R11 is H or -O(C1-3 alkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring.

[00273] Embodiment 18. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the compound has the structure Petition 870250087244, dated 09 / 26 / 2025, pp. 165 / 190 153 / 160 Formula (IVa), Formula (IVb), or (IVc): Formula (IVa) Formula (IVb) Formula (IVc) wherein each R9, R10, and R11 are independently H, C1-3 alkyl, C1-3 alkylene-OH, or OC1-3 alkyl.

[00274] Embodiment 19. The compound of embodiment 18, or the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R9, R10, and R11 are each independently H.

[00275] Embodiment 20. The compound of embodiment 18, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein R10 is C1-3 alkyl, C1-3 alkylene-OH or OC1-3 alkyl.

[00276] Embodiment 21. The compound of embodiment 1, or the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the compound has the structure Formula (V): Petition 870250087244, dated 09 / 26 / 2025, pp. 166 / 190 154 / 160 where: - R10 is H, D, or OH; - R9 and R11 together with the carbon atom to which R9 and R11 are attached form a ring, wherein the ring is a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the ring is optionally substituted with C1-3 alkyl, OH or oxo.

[00277] Embodiment 22. The compound of embodiment 21, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the ring is a 5-membered heterocycloalkyl.

[00278] Embodiment 23. The compound of embodiment 21, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the ring is a 5-membered heteroaryl.

[00279] Embodiment 24. The compound of any of the embodiments 21 to 23, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, wherein the ring is substituted with C1-3 alkyl, OH, or oxo.

[00280] Modality 25. The compound of embodiment 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, selected from the group consisting of: 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; Petition 870250087244, dated 09 / 26 / 2025, pp. 167 / 190 155 / 160 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran-6yl)phenyl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1-hindazol-3-yl)butanoic acid; 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoyl)oxy)-3,4,5-tri-hydroxytetrahydro-2H-pyran-2carboxylic acid; e 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazol-5-yl)-[1,1'biphenyl]-2-yl)oxy)-3,4,5-tri-hydroxytetrahydro-2H-pyran-2-carboxylic acid.

[00281] Modality 26. 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

[00282] Modality 27. 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4yl)-1H-indazol-3-yl]propanoic acid.

[00283] Modality 28. A compound of the structure: Petition 870250087244, dated 09 / 26 / 2025, pages 168 / 190 156 / 160

[00284] Embodiment 29. A pharmaceutical composition comprising the compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof and a pharmaceutically acceptable excipient.

[00285] Modality 30. A method for treating a condition, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any of the modalities 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[00286] Modality 31. The modality 30 method, in which the inflammatory condition or autoimmune condition is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, celiac disease, atopic dermatitis, psoriasis, rheumatoid arthritis, and lupus.

[00287] Modality 32. The modality 30 method, in which the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, functional constipation.

[00288] Modality 33. The method of any of the modalities 30 to 32, in which the administration is oral.

[00289] Modality 34. The method of any of the modalities 30 to 33, in which the therapeutically effective amount is from about 1 mg to about 2500 mg. Petition 870250087244, dated 09 / 26 / 2025, pp. 169 / 190 157 / 160

[00290] Modality 35. The method of any of the modalities 30 to 34, in which administration is once a day.

[00291] Modality 36. The method of any of the modalities 30 to 34, where administration is twice a day.

[00292] Modality 37. A method for treating a condition, comprising: a) administering to an individual in need thereof a therapeutically effective amount of the compound of any of the embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof; and b) administer a therapeutically effective amount of an additional therapeutic agent.

[00293] Modality 38. The modality 37 method, in which the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[00294] Modality 39. The modality 38 method, in which the inflammatory condition or autoimmune condition is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, colitis, and Crohn's disease.

[00295] Modality 40. The modality 38 or 39 method, in which the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, functional constipation.

[00296] Modality 41. The method of any of the modalities 37 to 40, in which the administration of the compound, or a pharmaceutically acceptable salt thereof, is oral.

[00297] Modality 42. The method of any of the modalities 37 to 41, in which the therapeutically effective amount of the compound, a pharmaceutically acceptable salt, a tautomer, or a salt Petition 870250087244, dated 09 / 26 / 2025, pp. 170 / 190 The pharmaceutically acceptable concentration of the tautomer of the same, 158 / 160, is from about 1 mg to about 2500 mg.

[00298] Embodiment 43. The method of any of the embodiments 37 to 42, in which the therapeutically effective amount of the compound, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, is from about 1 mg to about 100 mg.

[00299] Embodiment 44. A compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, for use as a medicament.

[00300] Embodiment 45. A compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, for use in the treatment of an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[00301] Embodiment 46. Use of a compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, in the manufacture of a medicament for the treatment of an inflammatory condition, an autoimmune condition or a functional gastrointestinal disorder.

[00302] Embodiment 47. Use of a compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, as a medicament.

[00303] Modality 48. Use of a compound according to any of embodiments 1 to 28, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, in the treatment of an inflammatory condition, a Petition 870250087244, dated 09 / 26 / 2025, pp. 171 / 190 159 / 160 autoimmune condition or a functional gastrointestinal disorder.

[00304] Modality 49. Crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4yl)-1H-indazol-3-yl]propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

[00305] Modality 50. The crystalline compound of modality 49 having a powder X-ray diffraction pattern comprising diffraction peaks of 12.6 ± 0.2, 18.8 ± 0.2, 19.7 ± 0.2 and 24.4 ± 0.2 degrees two theta.

[00306] Each of the embodiments described herein may be combined with any other embodiment(s) described herein, provided that it / they are not inconsistent with the embodiment(s) with which it / they are combined. Furthermore, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped with one or more other compounds from the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiments described herein. In addition, each of the embodiments described herein includes within its scope the pharmaceutically acceptable salts of the compounds described herein.

[00307] It will be evident to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be evident to those skilled in the art from consideration of the descriptive report and practice of the invention described herein. The descriptive report and examples are intended to be considered only as exemplary, with the true scope and spirit of the invention being indicated by the following claims.

[00308] All references cited herein, including patents, patent applications, articles, textbooks and the like, and the references Petition 870250087244, dated 09 / 26 / 2025, pp. 172 / 190 The literature and similar materials cited herein, to the extent that they are not already included, are incorporated herein by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differ from or contradict this application, including but not limited to defined terms, usage of the term, described techniques and the like, this application shall prevail. Petition 870250087244, dated 09 / 26 / 2025, pp. 173 / 190

Claims

1 / 8 CLAIMS 1. Compound, characterized in that it has Formula (I): Formula (I) a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein: - A1 is CR8, or N; - A2 is CH2, CHD, CD2, S, O, or NH; - A3 is CH, CD, or N; - R1 is H, D, C1-8 alkyl, C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted; - R2, R3, R5, and R6 are each independently H, D, OH, or halogen;- R4 is a monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with R9, R10, R11, R12, or R13, wherein R9, R10, R11, R12, and R13 are each independently H, D, halogen, CN, oxo, C1-8 alkyl, C3-6 cycloalkyl, C0-6 alkylene-ORx, C1-6 haloalkylene-ORx, C0-6 alkylene(C06haloalkyl)NRxRy, C1-6 alkylene(C1-6haloalkyl)NRxRy, 4- to 6-membered heterocycloalkyl, C(O)ORx, C0-6 alkylene-C(O)NRxRy, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkylene-C(O)NRxRy, O(C1-6 alkyl)SO2NRxNRy, NRxRy, NHSO2Rx, SRx, S-C1-6 alkylene-C(O)NRxRy, S(O)RxRy, SO2Rx, SO2NRxRy, S(O)(NRx)Ry, S(O)(NRx)Ry, or SO2Rx; Petition 870250087244, dated 09 / 26 / 2025, page. 174 / 190 2 / 8 wherein each Rx and Ry is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 alkylene-amide, OC0-2 alkylene-heterocycloalkyl, 4- to 6-membered heterocycloalkyl, C(O)Ci-6 alkyl, imino or C1-6 alkylsulfonyl;or Rx and Ry together with the atoms to which Rx and Ry are attached may form an optionally substituted ring; - R7 is C1-3 alkyl, C3-6 cycloalkyl, cyano or halogen; - Rb1, Rb2 and Rb3 are each independently H or D; - R8 is H, D or halogen; and - n is 0, 1 or 2.

2. Compound according to claim 1, the pharmaceutically acceptable salt, the tautomer or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that A1 is CH or CF.

3. Compound according to claim 1 or 2, the pharmaceutically acceptable salt, the tautomer or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that A2 is CH2 or S.

4. Compound according to any one of claims 1 to 3, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that A3 is N.

5. A compound according to any one of claims 1 to 4, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that R1 is H.

6. Compound according to any one of claims 1 to 5, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized by the fact that R2, R3, R5, and R6 are each independently H.

7. Compound according to any one of claims 1 to 6, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that R7 is Cl.

8. Compound according to any one of claims 1 to 7, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that R4 is phenyl, wherein R9, R10, R11, R12 and R13 are each independently H, D, Cl, F, CN, C1-3 alkyl, C1-6 alkylene-OH, C16 alkylene-OC1-6 alkyl, OH, OC1-6 alkyl, OC1-6 haloalkyl, O(C1-3 alkylene)heterocycloalkyl, O(C1-3 alkylene)-C(O)NRxRy, C1-3 alkylene-NRxRy, C(O)OH, C(O)OC1-3 alkyl, CO-2 alkylene-C(O)NRxRy, SO2NRxRy, S(O)(NRx)Ry, NRxRy, SRx, or SO2Rx.

9. Compound according to claim 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that the compound has the structure of Formula (II): R11 Formula (II), wherein: - R2 is H, D, or halogen; - R7 is Cl or CN; - A2 is CH2, CHD, CD2, S, or NH; - A4 is CR9 or N; - R9 is H, D, F, Cl, C1-3 alkyl, C1-3 alkylene-O-C1-3 al Petition 870250087244, dated 09 / 26 / 2025, p.176 / 190 4 / 8 kyl, C1-3 alkylene-NH2, COOH, C(O)OCi-3 alkyl, C1-3 alkyleneC(O)NH2, C(O)NHCi-3 alkyl, C(O)N(Ci-3 alkyl)2, C1-6 alkylene(C1-6 haloalkyl)NH2, C0-2 alkylene-NH(C(O)C1-3 alkyl), OC1-3 alkyl, OC1-3 haloalkyl, OC1-3 alkylene-heterocycloalkyl, OC1-3 alkyleneC(O)NH2, NHSO2C1-3 alkyl, N(Ci-3 alkyl)(C(O)C1-3 alkyl), SC1-3 alkyl, S-C1-3 alkylene-C(O)NH2, SO(NH)C1-3 alkyl, SO2NH2, or SO2C1-3 alkyl; - R10 is H, D, or OH; - R11 is H, D, halogen, CN, O(C1-3 alkyl) or O(C1-3 haloalkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring; - R12 is H, D, OC1-3 alkyl, or C1-3 alkylene-OH; - R13 is H, D, F, Cl, or C1-3 alkyl; and - n is 1 or 2.

10. Compound according to claim 9, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that R10 is OH.

11. Compound according to claim 9 or 10, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that R7 is Cl.

12. Compound according to any one of claims 9 to 11, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that A2 is CH2 or S.

13. Compound according to claim 9, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that: - R9 is H or -C(O)NRxRy, wherein each Rx and Ry are independently H or C1-6 alkyl; and - R11 is H or -O(C1-3 alkyl); or R9 and R11 together with the carbon atom to which R9 and R11 are attached form an optionally substituted ring.

14. Compound according to claim 1, the pharmaceutically acceptable salt, the tautomer, or the pharmaceutically acceptable salt of the tautomer thereof, characterized in that it is selected from the group consisting of: 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran6-yl)phenyl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid;3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4yl)-1H-indazol-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)butanoic acid; Petition 870250087244, dated 09 / 26 / 2025, page. 178 / 190 6 / 8 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)1H-indazol-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1Hindazol-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2carboxylic acid; and 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazol-5-yl)[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; 15. Compound according to claim 1, characterized in that the compound is 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof.

16. Compound according to claim 1, characterized in that the compound is 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

17. Compound according to claim 1, characterized in that the compound is 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)butanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

18. Compound according to claim 1, characterized in that the compound is 3-(6-chloro-5-(2'-hydroxy-4'(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoic acid, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof.

19. Compound according to claim 1, characterized in that the compound is 6-((3-(6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazol-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro Petition 870250087244, dated 09 / 26 / 2025, page 179 / 190 7 / 8 2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt, a tautomer or a pharmaceutically acceptable salt of the tautomer thereof.

20. Pharmaceutical composition, characterized in that it comprises the compound, as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, and a pharmaceutically acceptable excipient.

21. A method for treating a condition, characterized in that it comprises administering to an individual in need thereof a therapeutically effective amount of the compound, as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, wherein the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

22. Method according to claim 21, characterized in that the inflammatory condition or autoimmune condition is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, celiac disease, atopic dermatitis, psoriasis, rheumatoid arthritis and lupus.

23. Method according to claim 21, characterized in that the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, functional constipation.

24. Method according to claim 21, characterized in that the administration is oral.

25. Method according to claim 21, characterized in that the therapeutically effective amount is from about 1 mg to about 2500 mg. Petition 870250087244, dated 09 / 26 / 2025, pp. 180 / 190 8 / 8 26. Use of a compound, as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of the tautomer thereof, characterized in that it is for the manufacture of a medicament for the treatment of an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder. Petition 870250087244, dated 09 / 26 / 2025, pp. 181 / 190

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