Substituted indazolepropionic acid derivative compounds and their use as AMPK activators

Abstract

The present invention relates to a substituted indazolepropionic acid derivative of formula (I) capable of activating adenosine 5'-monophosphate activated protein kinase (AMPK), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. The present invention further relates to a pharmaceutical composition comprising an AMPK-activating substituted indazolepropionic acid derivative of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, and at least one pharmaceutically acceptable additive, and a method for treating a condition comprising administering an AMPK-activating substituted indazolepropionic acid derivative of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. [Formula 1] TIFF2026515644000097.tif6292

Description

[Technical Field]

[0001] [Background technology]

[0002] Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a highly conserved serine / threonine kinase that functions as a central regulator of energy homeostasis. AMPK has been demonstrated to mediate multiple pathways within intestinal epithelial cells, including direct regulation 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-related diseases associated with intestinal permeability or "leaky gut." [Overview of the project] [Problems that the invention aims to solve]

[0003] Given the functional properties of AMPK in energy and tissue homeostasis, a potent and direct intestinal targeting activator of AMPK is needed to address conditions associated with AMPK activation. [Means for solving the problem]

[0004] In part, this invention relates to a compound of formula (I):

[0005] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - A 1 CR 8 , or N, - A 2 These are CH2, CHD, CD2, S, O, or NH. - A 3 is CH, CD, or N, - R 1is H, D, C which may each be substituted 1~8 alkyl, C 3~6 cycloalkyl, or 4-6 member heterocycloalkyl, and - R 2 , R 3 , R 5 , and R 6 are each independently H, D, OH, or halogen, and - R 4 are each R 9 , R 10 , R 11 , R 12 , or R 13 which may be substituted with monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl, and R 9 , R 10 , R 11 , R 12 , and R 13 are each independently H, D, halogen, CN, oxo, C 1~8 alkyl, C 3~6 cycloalkyl, C 0~6 alkylene-OR x , C 1~6 haloalkylene-OR x , C 0~6 alkylene(C 0~6 haloalkyl)NR x R y , C 1~6 alkylene(C 1~6 haloalkyl)NR x R y , 4-6 member heterocycloalkyl, C(O)OR x , C 0~6 alkylene-C(O)NR x R y , OC 1~3 alkylene-heterocycloalkyl, OC 1~3 alkylene-C(O)NR x R y , O(C 1~6 alkyl)SO2NR x NR y , NR x R y , NHSO2Rx , SR x SC 1~6 Alkylene-C(O)NR x R y S(O)R x R y SO2R x SO2NR x R y , S(O)(NR x )R y , S(O)(NR x )R y , or SO2R x And R x and R y These are H, D, and C, respectively, independently. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 1~6 Alkylene amide, OC 0~2 Alkylene-heterocycloalkyl, 4-6 membered heterocycloalkyl, C(O)C 1~6 Alkyl, imino, or C 1~6 It is an alkylsulfonyl or R x and R y R x and R y Together with the atom to which it is bonded, it may form a ring that may be substituted. - R 7 C 1~3 Alkyl, C 3~6 It is a cycloalkyl, cyano, or halogen, - R b1 , R b2 , and R b3 Each is independently either H or D, - R 8 These are H, D, or halogens. - n is 0, 1, or 2.

[0006] 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers are further disclosed herein. The present invention further provides 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid. Structure:

[0007] [ka] Compounds of the above are disclosed herein.

[0008] The present invention provides a method for treating a condition comprising administering to a subject in need of the treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of

[0009] The present invention further provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer for use as a medicament. The present invention also provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer 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 thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer in the manufacture of a medicament for treating 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 thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer as a medicament. The present invention further provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer in the treatment of an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[0010] 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 thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0011] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as set forth in the claims.

Brief Description of the Drawings

[0012] [Figure 1] Example 1 shows the PXRD of the compound of Form 1.

Modes for Carrying Out the Invention

[0013] The present invention can be more readily understood by referring to the following detailed description of embodiments and examples of the invention included in this specification. It should be understood that the present invention is not limited to the specific synthesis methods to be produced, and of course the synthesis methods can vary. It should also be understood that the technical terms used in this specification are only intended to describe specific embodiments and are not intended to be limiting.

[0014] 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 as a heterotrimeric protein complex consisting of a catalytic α-subunit, a scaffold β-subunit, and a regulatory γ-subunit. Multiple isoforms encoded by different genes (e.g., two α, two β, three γ) enable up to 12 possible AMPK heterotrimeric complexes, each with distinct cellular and tissue expression profiles. AMPK is activated by upstream kinases, including liver kinase β1 (LKB1) and calcium / calmodulin-dependent protein kinase β (CamKKβ), which phosphorylate the Thr172 active site residue within the α-subunit of AMPK. AMPK is also activated when the intracellular adenosine monophosphate (AMP):adenosine triphosphate (ATP) ratio, or on a smaller scale, the adenosine diphosphate (ADP):ATP ratio, increases under energy stress conditions such as nutrient starvation, inflammation, and hypoxia (Xiao, B. et al., Nature 449:496~500 (2007)). When activated, AMPK restores energy equilibrium by phosphorylating 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). Furthermore, AMPK can regulate and reprogram metabolism through transcriptional changes by phosphorylation factors that induce or repress gene transcription.

[0015] Multiple approaches exist, both direct and indirect, for pharmacologically activating AMPK (Kim, J. et al., Exp Mol Med 48:e224 (2016)). 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (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 allosterically activate AMPK by binding to the γ-subunit of AMPK. In contrast, direct AMPK agonists can activate AMPK and protect it from dephosphorylation by binding to the metabolic (ADaM) site between the α and β subunits of AMPK and to allosteric drugs. Both pan-β and β1 selective AMPK agonists have been described.

[0016] AMPK activity can be altered due to metabolic and inflammatory diseases, including conditions such as obesity, diabetes, cardiovascular disease, and cancer. In addition, 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 regulation 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., Int J Mol Sci 20:6012 (2018)). Strengthening the intestinal barrier may have therapeutic potential for metabolic and inflammatory diseases associated with intestinal permeability or "leaky gut" (Odenwald, MA. et al., Clin Gastrenterol Hepatol 11:1075~1083 (2013)). AMPK activators are being developed for systemic administration. Given the functional properties of AMPK in energy and tissue homeostasis, a potent and direct intestinal targeting activator of AMPK is needed to address conditions associated with AMPK activation.

[0017] AMPK activating compounds, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers are disclosed herein. AMPK activating pharmaceutical compositions comprising an AMPK activating compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, and at least one pharmaceutically acceptable additive are also disclosed herein. Methods for synthesizing an AMPK activating compound or a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, and methods for administering an AMPK activating compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer to a subject requiring such treatment are further disclosed herein. In some embodiments, the AMPK-activating compounds disclosed herein, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers can be used to treat metabolic disorders, inflammatory disorders, autoimmune disorders, gastrointestinal barrier dysfunction, functional gastrointestinal disorders, central nervous system disorders, feeding disorders, nutritional disorders, or allergies. In a preferred embodiment, the AMPK-activating compounds disclosed herein, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers can be used to treat metabolic disorders, inflammatory disorders, autoimmune disorders, gastrointestinal barrier dysfunction, or functional gastrointestinal disorders.

[0018] definition Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have meanings commonly understood by those skilled in the art. The present invention as described herein can be properly carried out in the absence of any element not specifically disclosed herein.

[0019] "The compounds of the present invention" or "the compounds of the present disclosure" include compounds of formulas I, Ia, II, III, IVa-c, and V, as well as novel intermediates used in their preparation. Those skilled in the art will recognize that the compounds of the present invention include, where possible, conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereoisomers), racemates of such isomers, diastereoisomers and other mixtures, and their tautomers. Those skilled in the art will also recognize that the compounds of the present invention include, where possible, solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labeled versions thereof.

[0020] As used herein, the singular forms "a," "an," and "the" also include plural references unless otherwise indicated. For example, "a" substituents include one or more substituents.

[0021] Where used herein, the term "about" means that, when used to modify a numerically defined parameter (e.g., a dose of an AMPK-activating compound, its pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer), the parameter may vary by 10% above or below the numerical value described 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.

[0022] The term "and / or" means one or more. For example, "X and / or Y" is understood to mean either "X and Y" or "X or Y," and is interpreted as providing clear support for both meanings or for either meaning. Similarly, when more than two indications are listed, such as in "X, Y and / or Z," this is understood to mean either i) "X and Y," "X, Y and Z," "X and Z," or "Y and Z," or ii) "X or Y or Z," and is interpreted as providing clear support for all meanings.

[0023] Any open valencies appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures disclosed herein indicate the presence of hydrogen, unless otherwise indicated.

[0024] When it is stated that substituents are "independently selected" from the group, each substituent is selected independently of the others. Therefore, each substituent may be identical or different from the others.

[0025] "Optional" or "optional" means that the event or situation described later may or may not occur, and that the description includes both instances in which the event or situation occurs and instances in which it does not.

[0026] The terms “may be substituted” and “substituted or unsubstituted” are used interchangeably to indicate that a particular group described may not have non-hydrogen substituents (i.e., is unsubstituted) or that the group may have one or more non-hydrogen substituents (i.e., is substituted). Unless otherwise specified, the total number of possible substituents is equal to the number of H atoms present on the unsubstituted form of the group described. If an optional substituent, such as an oxo (=O) substituent, is bonded via a double bond, the group occupies two available valencies, and therefore the total number of other substituents involved is reduced by two. If optional substituents are selected independently from a list of options, the selected groups may be the same or different. Throughout this disclosure, it will be understood that the number and nature of optional substituents will be limited insofar as such substitutions have chemical significance to those skilled in the art.

[0027] "Halogen" or "halo" refers to fluoro, chloro, bromo, and iodine (F, Cl, Br, I). In a preferred embodiment, "halo" refers to fluoro. In a preferred embodiment, "halo" refers to chloro.

[0028] "Cyano" refers to a substituent that has a carbon atom bonded to a nitrogen atom by a triple bond, i.e., -C≡N.

[0029] "Hydroxy" refers to the -OH group.

[0030] "Oxo" refers to oxygen (=O) that is double-bonded.

[0031] C1~C x The terms C1-C2, C1-C3...C1-C xIt includes. By way of example only, the groups shown as "C1~C4" indicate that 1 to 4 carbon atoms are present in that part, that is, a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. For example, "C1~C4 alkyl" indicates that 1 to 4 carbon atoms are present in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0032] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which all the atoms forming the ring skeleton are carbon atoms. This term is distinguished from a "heterocyclic" ring or "heterocycle" in which the ring skeleton contains at least one atom different from carbon. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. For example, carbocycles include cycloalkyl and aryl.

[0033] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical having the specified number of carbon atoms, including straight-chain or branched-chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms ("C1~C 12 alkyl"), 1 to 8 carbon atoms ("C1~C8 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 3 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. Alkyl groups may be optionally substituted, unsubstituted, or substituted as further defined herein.

[0034] The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by at least one same or different halogen atom. For example, "fluoroalkyl" means an alkyl as defined herein substituted with 1, 2, or 3 fluoro atoms. Exemplary (C1) fluoroalkyl compounds include fluoromethyl, difluoromethyl, and trifluoromethyl; exemplary (C2) fluoroalkyl 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 referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0035] "Alkoxy" refers to an alkyl group as defined herein that is singly bonded to an oxygen atom. The point of attachment of the alkoxy radical to the molecule is via the oxygen atom. An alkoxy radical may also be represented as alkyl-O- or O(C 1~x alkyl). The alkoxy group may contain, but is 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.

[0036] "Alkoxyalkyl" refers to an alkyl group as defined herein that is substituted by an alkoxy group as defined herein. "Alkoxyalkyl" may also be represented as C 1~x alkylene-O-C 1~y alkyl. Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-.

[0037] "Cycloalkyl" refers to a fully saturated hydrocarbon ring system having a specified number of carbon atoms, which may be a monocyclic bridge, condensed bicyclic, or polycyclic ring system linked to the base molecule via the carbon atoms of the cycloalkyl ring. Cycloalkyls are not limited to those having 3 to 12 carbon atoms ("C3-C3"). 12 The cycloalkyl group may contain 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"). Typical cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantanyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraenyl, dekalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. The cycloalkyl group may be optionally substituted, unsubstituted, or substituted as further defined herein.

[0038] "Cycloalkoxy" refers to a cycloalkyl group, as defined herein, that is single-bonded to an oxygen atom. The bonding site of a cycloalkoxy radical to a molecule is via the oxygen atom. Cycloalkoxy radicals are cycloalkyl-O- or OC. 1~xThese are sometimes referred to as cycloalkyl groups. 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"). Typical cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantanyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraenyl, dekalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl.

[0039] A "heterocycloalkyl" contains a specified number of ring atoms, and contains at least one heteroatom selected from N, O, and S as a ring member, and the ring S atom may be substituted with one or two oxo groups (i.e., S(O) q A heterocycloalkyl ring (where q is 0, 1, or 2) refers to a fully saturated ring system in which a heterocycloalkyl ring is linked to a base molecule via a ring atom that may be C or N. A heterocycloalkyl ring may be spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, and such spirocyclic, bridged, or fused rings themselves may be saturated, unsaturated, partially unsaturated to the extent that aromaticity has chemical significance, or aromatic, provided that the bonding site to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may have N, O, and S(O) as ring members. qThe heterocycloalkyl ring may contain 1 to 4 heteroatoms or 1 to 2 cyclic heteroatoms selected from the above, provided that such heterocycloalkyl rings do not contain two adjacent oxygen or sulfur atoms. The heterocycloalkyl ring may be substituted, unsubstituted, or otherwise substituted, as further defined herein. Such substituents may be located on a heterocyclic ring bonded to the base molecule, or on a spirocyclic, bridging, or fused ring bonded thereto. The heterocycloalkyl ring may include, but is not limited to, 3 to 8-membered heterocycloalkyl groups, e.g., 4 to 7 or 4 to 6-membered heterocycloalkyl groups, according to the definition herein. Examples of heterocycloalkyl rings include, but are not limited to, oxiran (oxiranil), thiran (thiranil), aziridine (aziridinil), oxetane (oxetanil), thietan (thietanil), azetidine (azetidinil), tetrahydrofuran (tetrahydrofuranil), tetrahydrothiophene (tetrahydrothiophenyl), pyrrolidine (pyrrolidinil), tetrahydropyran (tetrahydropyranil), tetrahydrothiopyran (tetrahydrothiopyranil), piperidine (piperidinil), 1,4-dioxane (1,4-dioxanil), 1,4-oxathialan (1, This includes monovalent radicals of 4-oxatiaranil, morpholine (morpholinyl), 1,4-dithiane (1,4-dithianyl), piperazine (piperazinyl), thiomorpholine (thiomorpholinyl), oxepane (oxepanyl), thiepan (thiepanyl), azepan (azepanyl), 1,4-dioxepane (1,4-dioxepaneyl), 1,4-oxathepanane (1,4-oxathepanyl), 1,4-oxazepanane (1,4-oxazepanyl), 1,4-thiazepanane (1,4-thiazapanyl), 1,4-diazepanane (1,4-diazepanyl), or 1,4-ditepane (1,4-dithiepanyl).Exemplary examples of bridged and fused heterocycloalkyl groups include, but are not limited to, monovalent radicals 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.

[0040] "Aryl" contains the specified number of ring atoms, and all carbon atoms in the ring are sp 2 Hybridized and the pi electrons are conjugated, referring to a monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring system. Aryl groups include, but are not limited to, 6 to 20 carbon atoms ("C6~C 20 Aryl"), 6 to 14 carbon atoms ("C6~C 14 Aryl"), 6 to 12 carbon atoms ("C6~C 12 Aryl"), or 6 to 10 carbon atoms ("C6~C 10 Aryl") and may contain. A fused aryl group 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. An aryl group may be optionally substituted, unsubstituted, or optionally substituted as further defined herein.

[0041] Similarly, "heteroaryl" or "heteroaromatic" contains the specified number of ring atoms, includes at least one heteroatom selected from N, O, and S as a ring member in the ring, and all carbon atoms in the ring are sp [[ID=佃]] 2This refers to a hybridized, pi-conjugated, monocyclic, bicyclic (e.g., heterobiaryl, condensed), or polycyclic ring system. The heteroaryl group may contain, but is not limited to, 5 to 20 ring atoms ("5-20 membered heteroaryl"), 5 to 14 ring atoms ("5-14 membered heteroaryl"), 5 to 12 ring atoms ("5-12 membered heteroaryl"), 5 to 10 ring atoms ("5-10 membered heteroaryl"), 5 to 9 ring atoms ("5-9 membered heteroaryl"), or 5 to 6 ring atoms ("5-6 membered heteroaryl"). The heteroaryl ring is bonded to the base molecule via the ring atoms of the heteroaromatic ring. Therefore, either a 5- or 6-membered heteroaryl ring may be bonded to the base molecule alone or in a condensed structure via ring C or N atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanil, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrididinyl, pyrimidinyl, pyrazinyl, benzofuranil, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthilidinyl, sinnolinyl, quinazolinyl, quinoxalinyl, and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanil, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings. The heteroaryl group may be optionally substituted, unsubstituted, or substituted, as further defined herein.Exemplary examples of monocyclic heteroaryl groups include, but are not limited to, pyrrole (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-oxa-2,3-diazolyl), and 1-oxa-2,4-diazole (1-oxa-2,4-diazolyl This includes monovalent radicals of 1-oxa-2,5-diazole (1-oxa-2,5-diazolyl), 1-oxa-3,4-diazole (1-oxa-3,4-diazolyl), 1-thia-2,3-diazole (1-thia-2,3-diazolyl), 1-thia-2,4-diazole (1-thia-2,4-diazolyl), 1-thia-2,5-diazole (1-thia-2,5-diazolyl), 1-thia-3,4-diazole (1-thia-3,4-diazolyl), tetrazole (tetrazolyl), pyridine (pyridinyl), pyridazine (pyridadinyl), pyrimidine (pyrimidinyl), or pyrazine (pyradinyl).

[0042] Exemplary examples of fused ring heteroaryl groups include, but are not limited to, benzofuran (benzofuranyl), benzothiophene (benzothiophenyl), indole (indolyl), benzimidazole (benzimidazolyl), indazole (indazolyl), benzotriazole (benzotriazolyl), pyrrolo[2,3-b]pyridine (pyrrolo[2,3-b]pyridinyl), pyrrolo[2,3-c]pyridine (pyrrolo[2,3-c]pyridinyl), pyrrolo[3,2-c]pyridine (pyrrolo[3,2-c]pyridinyl), and pyrrolo[3,2-b]pyrid Pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridine (imidazo[4,5-b]pyridinyl), imidazo[4,5-c]pyridine (imidazo[4,5-c]pyridinyl), pyrazolo[4,3-d]pyridine (pyrazolo[4,3-d]pyridinyl), 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), Indoridine (Indolidinyl), Imidazol[1,2-a]pyridine (Imidazol[1,2-a]pyridinyl), Imidazol[1,5-a]pyridine (Imidazol[1,5-a]pyridinyl), Pyrazol[1,5-a]pyridine (Pyrazol[1,5-a]pyridinyl), Pyrrolo[1,2-b]pyridazine (Pyrrolo[1,2-b]pyridadinyl), Imidazol[1,2-c]pyrimidine (Imidazol[1,2-c]pyrimidinyl), Quinoline (Quinolinyl), Isoquinoline (Isoquinolinyl), Sinnoline (Sinnolinyl) ), quinazoline (azaquinazoline), quinoxaline (quinoxalinyl), phthalazine (phthalazinyl), 1,6-naphthiridine (1,6-naphthyridinyl), 1,7-naphthiridine (1,7-naphthyridinyl), 1,8-naphthiridine (1,8-naphthyridinyl), 1,5-naphthiridine (1,5-naphthyridinyl), 2,6-naphthiridine (2,6-naphthyridinyl), 2,7-naphthiridine (2,7-naphthyridinyl), pyrido[3,2-d]pyrimidine (pyrimido[3,2-d]pyrimidine), pyrido[4,3-d]pyrimidine (pyrimido[4,This includes [3-d]pyrimidinyl), pyrido[3,4-d]pyrimidine (pyrimido[3,4-d]pyrimidinyl), pyrido[2,3-d]pyrimidine (pyrimido[2,3-d]pyrimidinyl), pyrido[2,3-b]pyrazine (pyrimido[2,3-b]pyrazine), pyrido[3,4-b]pyrazine (pyrimido[3,4-b]pyrazine), pyrid[5,4-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl), pyrazino[2,3-b]pyrazine (pyrazino[2,3-b]pyrazine), or pyrid[4,5-d]pyrimidine (pyrimido[4,5-d]pyrimidinyl).

[0043] "Amino" refers to an unsubstituted -NH2 group. When it is stated that amino is substituted or may be substituted, the term is -NR. x R y It includes the morphological base, where R x and R y Each of these is independently defined as further described herein. For example, “alkylamino” is R x and R y -NR is a compound where one side is an alkyl group and the other side is H. x R y It refers to the base, and "dialkylamino" is R x and R y Both are alkyl moieties, and the alkyl moieties have a specified number of carbon atoms -NR x R y This refers to (for example, -NH(C1~C4 alkyl) or -N(C1~C4 alkyl)2).

[0044] The terms "alkylamino" or "aminoalkyl" are R x and R y Each of these is independently an H, alkyl group, or alkylene group in the formula -NHR x or -NR x R y It refers to the radical of R. For example, "alkylamino" is R x and R y The group -NR is a group in which one side is an alkyl moiety and the other side is H. x Ry It can refer to; "dialkylamino" is R x and R y Both are alkyl parts -NR x R y It can refer to an alkyl group, where the alkyl portion has a specified number of carbon atoms (e.g., -NH(C1~C4 alkyl) or -N(C1~C4 alkyl)2). In some embodiments, aminoalkyl refers to an -NH-alkylene or alkylene-NH-alkylene, where each alkylene is independently substituted or unsubstituted.

[0045] The term "pharmaceutically acceptable" means that a substance (e.g., a compound described herein) or any salt thereof, or a composition containing the substance or salt of the present invention, is suitable for administration to a subject or patient.

[0046] As used herein, the term "deuterium enrichment factor" refers to the ratio of the amount of deuterium to the amount of hydrogen and the natural abundance of deuterium, respectively. Atomic arrangements indicated as having deuterium typically have, in certain embodiments, deuterium enrichment factors of at least 1000 (15% deuterium), at least 2000 (30% deuterium), at least 3000 (45% deuterium), at least 3500 (52.5% deuterium), at least 3500 (52.5% deuterium with each indicated deuterium atom), at least 4000 (60% deuterium), at least 4500 (67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium), at least 6000 (90% deuterium), at least 6333.3 (95% deuterium), at least 6466.7 (97% deuterium), at least 6600 (99% deuterium), or at least 6633.3 (99.5% deuterium).

[0047] As used herein, the terms “to treat,” “to treat,” or “treatment” encompass both preventive, protective, and palliative treatments, i.e., reducing, mitigating, or slowing the progression of any tissue damage to a patient’s disease (or condition) or disease-related thereto.

[0048] As used herein, the terms “subject,” “individual,” or “patient,” used interchangeably, refer to any animal, including mammals. Mammals according to the present invention include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, humans, and similar animals, and encompass mammals in utero. In one embodiment, humans are preferred subjects. Human subjects may be of any sex and at any developmental stage.

[0049] As used herein, the term “therapeutic dose” means the amount of an active compound or medicinal substance that elicits a biological or medical response in a tissue, system, animal, individual, or human, as determined 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 disease, pathology, or disorder in individuals who are susceptible to disease, pathology, or disorder but have not yet experienced or presented the pathology or overall symptoms of the disease; (2) inhibiting the disease; for example, inhibiting the disease, condition, or disorder in an individual experiencing or presenting the pathology or overall symptoms of the disease, condition, or disorder (i.e., preventing (or slowing) the further development of the pathology or overall symptoms or both); and (3) Remission of a disease; for example, in an individual experiencing or presenting with the pathology or overall symptoms of a disease, condition, or disorder, remission of the disease, condition, or disorder (i.e., reversal of the pathology or overall symptoms or both).

[0050] Compound of the present invention AMPK-activating compounds are disclosed herein. In some embodiments, the compounds disclosed herein are pan-AMPK-activating compounds.

[0051] This disclosure relates to compounds of formula (I):

[0052] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - A 1 CR 8 , or N, - A 2 These are CH2, CHD, CD2, S, O, or NH. - A 3 is CH, CD, or N, - R 1 H, D, and C may be substituted respectively. 1~8 Alkyl, C 3~6 They are cycloalkyl or 4-6 member heterocycloalkyl groups. - R 2 , R 3 , R 5 , and R 6 Each of these is independently H, D, OH, or a halogen. - R 4 These are R, respectively. 9 , R 10 , R 11 , R 12 , or R 13 A monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl which may be substituted with R 9 , R 10 , R 11 , R 12 , and R 13 These are H, D, halogen, CN, oxo, and C, respectively, independently. 1~8 Alkyl, C 3~6 Cycloalkyl, C 0~6 Alkilen-ORx , C 1~6 Haloalkilene-OR x , C 0~6 Alkylene (C 0~6 (Haloalkyl) NR x R y , C 1~6 Alkylene (C 1~6 (Haloalkyl) NR x R y , 4-6 member heterocycloalkyl, C(O)OR x , C 0~6 Alkylene-C(O)NR x R y , OC 1~3 Alkylene-heterocycloalkyl, OC 1~3 Alkylene-C(O)NR x R y , O(C 1~6 Alkyl)SO2NR x NR y , NR x R y NHSO2R x , SR x SC 1~6 Alkylene-C(O)NR x R y S(O)R x R y SO2R x SO2NR x R y , S(O)(NR x )R y , S(O)(NR x )R y , or SO2R x And R x and R y These are H, D, and C, respectively, independently. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 1~6 Alkylene amide, OC 0~2 Alkylene-heterocycloalkyl, 4-6 membered heterocycloalkyl, C(O)C 1~6 Alkyl, imino, or C 1~6 It is an alkylsulfonyl or R xand R y R x and R y Together with the atom to which it is bonded, it may form a ring that may be substituted. - R 7 C 1~3 Alkyl, C 3~6 It is a cycloalkyl, cyano, or halogen, - R b1 , R b2 , and R b3 Each is independently either H or D, - R 8 These are H, D, or halogens. - n is 0, 1, or 2.

[0053] In some embodiments, the compound is the compound of formula (Ia):

[0054] [ka] or a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0055] In some embodiments, A 1 CR 8 In some embodiments, A 1 is N. In some embodiments, R 8 H is H. In some embodiments, R 8 is a halogen. In a preferred embodiment, A 1 It is either CH or CF.

[0056] In some embodiments, A 2 is O or NH. In a preferred embodiment, A 2 is CH2 or S. In a preferred embodiment, A 2 is CH2. In a preferred embodiment, A 2 S is.

[0057] In some embodiments, A 3is CH. In a preferred embodiment, A 3 In one preferred embodiment, A 1 N is A 3 It is N.

[0058] In some embodiments, R 1 is H, D, or C 1~8 It is alkyl. In some embodiments, R 1 C 3~6 It is a cycloalkyl or a 4-6 member heterocycloalkyl. In some embodiments, R 1 is -6-O-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. In a preferred embodiment, R 1 H is H.

[0059] In some embodiments, R 2 H is H. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 3 H is H. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 5 H is H. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 6 H is H. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is OH. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In a preferred embodiment, R 2 It is a halogen, and R 3 , R5 , and R 6 Each of these is independently H. In one preferred embodiment, R 2 , R 3 , R 5 , and R 6 Each of these is independently H.

[0060] In some embodiments, R 4 It is a 6-membered monoring aryl. In some embodiments, R 4 This is 1, 2, or 3 R a It is a six-membered monocyclic aryl that is replaced by R. In some embodiments, 4 is 1, 2, or 3 R a It is a 5 or 6-membered monocyclic heteroaryl substituted with R. In one preferred embodiment, R 4 It is phenyl, and R 9 , R 10 , R 11 , R 12 , and R 13 These are H, D, Cl, F, CN, and C, respectively, independently. 1~3 Alkyl, C 1~6 Alkylene-OH, C 1~6 Alkylene-OC 1~6 alkyl, OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, O(C) 1~3 Alkylene) Heterocycloalkyl, O(C) 1~3 Alkylene)-C(O)NR x R y , C 1~3 Alkilen-NR x R y C(O)OH, C(O)OC 1~3 Alkyl, C 0~2 Alkylene-C(O)NR x R y SO2NR x R y , S(O)(NR x )R y , NR x R y , SR x , or SO2R x In a preferred embodiment, R4 It is a 6-membered monocyclic heteroaryl, and R 9 , R 10 , R 11 , R 12 , and R 13 At least one of them is C 1~3 It is an alkoxy, halogen, hydroxyl, or C(O)NH2.

[0061] In some embodiments, R 7 C 1~3 It is alkyl. In some embodiments, R 7 C 3~6 It is cycloalkyl. In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is cyano. In some embodiments, R 7 is a halogen. In one preferred embodiment, R 7 is Cl. In a preferred embodiment, R 7 It is F.

[0062] This disclosure also relates to compounds of formula (II):

[0063] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - R 2 These are H, D, or halogens. - R 7 is Cl or CN, - A 2 These are CH2, CHD, CD2, S, or NH. - A 4 CR 9 or N, - R 9 These are H, F, Cl, C 1~3 Alkyl, C 1~3 Alkylene-OC 1~3 Alkyl, C 1~3Alkylene-NH2, COOH, C(O)OC 1~3 Alkyl, C 1~3 Alkylene-C(O)NH2, C(O)NHC 1~3 Alkyl, C(O)N(C 1~3 Alkyl)2, C 1~6 Alkylene (C 1~6 Haloalkyl)NH2,C 0~2 Alkylene-NH(C(O)C) 1~3 Alkyl), OC 1~3 Alkyl, OC 1~3 Haloalkyl, OC 1~3 Alkylene-heterocycloalkyl, OC 1~3 Alkylene-C(O)NH2, NHSO2C 1~3 Alkyl, N(C 1~3 Alkyl)(C(O)C 1~3 Alkyl), SC 1~3 Alkyl, SC 1~3 Alkylene-C(O)NH2, SO(NH)C 1~3 Alkyl, SO2NH2, or SO2C 1~3 It is alkyl, - R 10 is H, D, or OH, - R 11 H, D, halogen, CN, O(C 1~3 Alkyl), or O(C 1~3 (haloalkyl) or R 9 and R 11 R 9 and R 11 Together with the carbon atom to which it is bonded, it forms a ring that may be substituted. - R 12 H, OC 1~3 Alkyl, or C 1~3 It is alkylene-OH, - R 13 is H, F, Cl, or C 1~3 It is alkyl, - n is either 1 or 2.

[0064] In some embodiments, R 7 is CN. In a preferred embodiment, R7 It is Cl.

[0065] In some embodiments, R 9 These are H, F, Cl, C 1~3 Alkyl, C 1~3 Alkylene-OC 1~3 Alkyl, C 1~3 Alkylene-NH2, COOH, C(O)OC 1~3 Alkyl, C 1~3 Alkylene-C(O)NH2, C(O)NHC 1~3 Alkyl, C(O)N(C 1~3 Alkyl)2, C 1~3 Haloalkylene-NH2, C 0~2 Alkylene-NH(C(O)C) 1~3 Alkyl), OC 1~3 Alkyl, OC 1~3 Haloalkyl, OC 1~3 Alkylene-heterocycloalkyl, OC 1~3 Alkylene-C(O)NH2, NHSO2C 1~3 Alkyl, N(C 1~3 Alkyl)(C(O)C 1~3 Alkyl), SC 1~3 Alkyl, SC 1~3 Alkylene-C(O)NH2, SO(NH)C 1~3 Alkyl, SO2NH2, or SO2C 1~3 It is alkyl. In some embodiments, R 9 H, C 1~3 Alkylene-OC 1~3 Alkyl, C 1~3 Alkylene-NH2, C 1~3 Alkylene-C(O)NH2, C 1~3 Alkylene (C 1~3 (Haloalkyl)NH2, or C 0~2 Alkylene-NH(C(O)C) 1~3 It is alkyl. In some embodiments, R 9 NHSO2C 1~3 Alkyl or N(C) 1~3 Alkyl)(C(O)C 1~3 It is alkyl. In some embodiments, R 9 SC 1~3Alkyl, SC 1~3 Alkylene-C(O)NH2, SO(NH)C 1~3 Alkyl, SO2NH2, or SO2C 1~3 It is alkyl. In a preferred embodiment, R 9 is H. In a preferred embodiment, R 9 is C(O)NH2. In a preferred embodiment, R 9 C 1~3 It is alkylene-NH2.

[0066] In some embodiments, R 10 is H or D. In a preferred embodiment, R 10 It is OH.

[0067] In some embodiments, R 11 is H, F, Cl, or CN. In some embodiments, R 11 O(C) 1~3 Alkyl) or O(C 1~3 It is a haloalkyl. In one preferred embodiment, R 11 H is H.

[0068] This disclosure further relates to compounds of formula (III):

[0069] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - R 9 H, D, halogen, C 1~3 Alkyl, C(O)NH2, C 1~3 Alkylene-NH2, C 1~3 Alkylene-OC 1~3 Alkyl, C(O)OC 1~3 Alkyl, C(O)OH, OC 1~3 Alkyl, OC 1~3 Haloalkyl, -O(C) 1~3 Alkyl)SO2NH2, C 1~6 Alkylene (C 1~6Haloalkyl)NH2, SC 1~3 Alkyl, or -C(O)NR x R y And R x and R y Each of these is independently H or C 1~6 It is alkyl, R 11 H, D, halogen, CN, or -O(C 1~3 Alkyl) or R 9 and R 11 R 9 and R 11 [It forms a ring, which may be substituted, together with the carbon atom to which it is bonded.]

[0070] In one preferred embodiment, R 9 is H or -C(O)NR x R y And R x and R y Each of these is independently H or C 1~6 It is alkyl, R 11 is H or -O(C 1~3 Alkyl) or R 9 and R 11 R 9 and R 11 Together with the bonded carbon atom, it forms a ring that may be substituted.

[0071] This disclosure also relates to compounds of formula (IVa), formula (IVb), or formula (IVc):

[0072] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, R 9 , R 10 , and R 11 H and C are independent of each other. 1~3 Alkyl, C 1~3 Alkylene-OH, or OC 1~3 It is alkyl.

[0073] In one preferred embodiment, R 9 , R 10 , and R 11 Each of these is independently H. In one preferred embodiment, R 10 C 1~3 Alkyl, C 1~3 Alkylene-OH or OC 1~3 It is alkyl.

[0074] This disclosure also relates to compounds of formula (V):

[0075] [ka] The present invention provides a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - R 10 is H, D, or OH, - R 9 and R 11 R 9 and R 11 Together with the bonded carbon atom, it forms an optionally substituted ring, the ring being a 5 or 6-membered heterocycloalkyl or 5 or 6-membered heteroaryl, and the ring is C 1~3 [May be substituted with alkyl, OH, or oxo.]

[0076] In some embodiments, the ring is a 6-membered heterocycloalkyl. In one preferred embodiment, the ring is a 5-membered heterocycloalkyl. In some embodiments, the ring is a 6-membered heteroaryl. In one preferred embodiment, the ring is a 5-membered heteroaryl.

[0077] In one preferred embodiment, the ring is C 1~3 It is substituted with alkyl. In a preferred embodiment, the ring is substituted with OH. In a preferred embodiment, the ring is substituted with oxo.

[0078] In some embodiments, the compounds of the Disclosure, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers are, 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran-6-yl)phenyl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)butanoic acid; 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; and Selected from the group consisting of 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazole-5-yl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

[0079] In a preferred embodiment, the compound is 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In a preferred embodiment, the compound is 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid. In a preferred embodiment, the compound has the structure:

[0080] [ka] It holds.

[0081] Any compound in this specification can be purified. The compounds in this specification can be purified to a purity of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, and at least 2%. 2%, at least 23% purity, at least 24% purity, at least 25% purity, at least 26% purity, at least 27% purity, at least 28% purity, at least 29% purity, at least 30% purity, at least 31% purity, at least 32% purity, at least 33% purity, at least 34% purity, at least 35% purity, at least 36% purity, at least 37% purity, at least 38% purity, at least 39% purity, at least 40% purity, at least 41% purity, at least 42% purity, at least 43% purity, at least 44% purity %, at least 45% purity, at least 46% purity, at least 47% purity, at least 48% purity, at least 49% purity, at least 50% purity, at least 51% purity, at least 52% purity, at least 53% purity, at least 54% purity, at least 55% purity, at least 56% purity, at least 57% purity, at least 58% purity, at least 59% purity, at least 60% purity, at least 61% purity, at least 62% purity, at least 63% purity, at least 64% purity, at least 65% purity, at least 66% purity , at least 67% purity, at least 68% purity, at least 69% purity, at least 70% purity, at least 71% purity, at least 72% purity, at least 73% purity, at least 74% purity, at least 75% purity, at least 76% purity, at least 77% purity, at least 78% purity, at least 79% purity, at least 80% purity, at least 81% purity, at least 82% purity, at least 83% purity, at least 84% purity, at least 85% purity, at least 86% purity, at least 87% purity, at least 88% purity,It may be 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% pure, at least 99.1% pure, at least 99.2% pure, at least 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.

[0082] Pharmaceutically acceptable salts The term "pharmaceutically acceptable salt" generally refers to a salt of the present invention prepared by reacting a free base or a free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to obtain a salt of the present invention that is suitable for administration to a subject or patient. For an overview 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.

[0083] In addition, the compounds of this disclosure may also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, that may be useful as intermediates for one or more of the following: 1) preparing the compounds of formulas I, Ia, II, III, IVa-c, and V; 2) purifying the compounds of formulas I, Ia, II, III, IVa-c, and V; 3) separating enantiomers of the compounds of formulas I, Ia, II, III, IVa-c, and V; or 4) separating diastereoisomers of the compounds of formulas I, Ia, II, III, IVa-c, and V.

[0084] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetates, adipines, aspartates, benzoates, besilates, bicarbonates / carbonates, bisulfates / sulfates, borates, cansilates, citrates, cyclamates, edisylates, esylates, formates, fumarates, gluceptates, glucons, glucurons, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrobromites / bromids, hydroiodides / iodides, isethionates, This includes lactates, malates, maleates, malons, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, 1,5-naphthalenedisulfonic acid, and xinafoates.

[0085] Suitable base 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.

[0086] Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, may also be formed.

[0087] A pharmaceutically acceptable salt of the compound of the present invention may be prepared by a method well known to those skilled in the art, including, but not limited to, the following procedure: (i) A procedure involving reacting the compound of the present invention with a desired acid or base; (ii) a procedure by removing an acid or base instability protecting group from a suitable precursor of the compound of the present invention, or by opening the ring of a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) A procedure for converting one salt of the compound of the present invention to another salt. This can be achieved by reacting it with a suitable acid or salt, or by using a suitable ion exchange procedure.

[0088] These procedures are typically carried out in solution. The resulting salt can be precipitated and filtered off, or recovered by evaporation of the solvent.

[0089] solvate The compounds of the present invention and their pharmaceutically acceptable salts may exist in non-solvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the present invention, its pharmaceutically acceptable salt, its tautomer, or a pharmaceutically acceptable salt of its tautomer, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

[0090] In addition, the compounds of formulas 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: 1) preparing the compounds of formulas I, Ia, II, III, IVa-c, and V; 2) purifying the compounds of formulas I, Ia, II, III, IVa-c, and V; 3) separating enantiomers of the compounds of formulas I, Ia, II, III, IVa-c, and V; or 4) separating diastereoisomers of the compounds of formulas I, Ia, II, III, IVa-c, and V.

[0091] The currently accepted classification system for organic hydrates defines them as isolated site, channel, or metal ion-coordinated hydrates. See KRMorris's *Polymorphism in Pharmaceutical Solids* (HGBrittain, Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are isolated from direct contact with each other by the interposition of organic molecules. In channel hydrates, water molecules exist within lattice channels, where they are adjacent to other water molecules. In metal ion-coordinated hydrates, water molecules are bound to metal ions.

[0092] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry, independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and dry conditions. In such cases, non-stoichiometry is the norm.

[0093] complex Multicomponent complexes (other than salts and solvates) in which a drug and at least one other component exist in stoichiometric or non-stoichiometric amounts are also included within the scope of the present invention. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bonded together by non-covalent interactions; for example, hydrogen-bonded complexes (cocrystals) can be formed with neutral molecules or salts. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or physical grinding of the components. See Chem Commun, 17;1889–1896 by O. Almarsson and MJ Zaworotko (2004). For a general overview of multicomponent complexes, see J Pharm Sci, 64(8), 1269–1288 by Haleblian (August 1975).

[0094] solid form The compounds of the present invention can exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on the temperature. Typically, such materials do not exhibit a characteristic X-ray diffraction pattern and are more formally described as liquids, although they exhibit solid properties. Upon heating, a change occurs from solid to liquid properties, which is typically characterized by a second-order phase transition ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an internal structure with regularly arranged molecules and exhibits a characteristic X-ray diffraction pattern with specified peaks. Such materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is typically characterized by a first-order phase transition ("melting point").

[0095] The compounds of the present invention may also exist in intermediate states (intermediate phases or liquid crystals) under suitable conditions. These intermediate states are between the true crystalline state and the true liquid state (either molten or in solution), and consist of a two-dimensional order at the molecular level. Intermediate states resulting from temperature changes are described as "thermotropic," while those resulting from the addition of a second component, such as water or another solvent, are described as "lyotropic." Compounds capable of forming a lyotropic intermediate phase are described as "amphiphilic" and ionic (-COO - Na + , -COO - K + , or -SO3 - Na + (etc.) or nonionic (-N - N + It consists of molecules with polar head groups (such as (CH3)3). For further information, see Crystals and the Polarizing Microscope, NH. Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970).

[0096] In a preferred embodiment, the compound of the present disclosure is a crystalline compound. In a preferred embodiment, the compound is crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In a preferred embodiment, the compound is crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer having an X-ray powder diffraction pattern including 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 2-theta.

[0097] stereoisomer The compounds of the present invention may exist as two or more stereoisomers. Stereoiomers of a compound may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereoisomers, rotational isomers, atropisomers, and conformational isomers. For example, a compound of the present invention containing one or more chiral carbon atoms may exist as two or more stereoisomers. Cis / trans isomers may also exist in saturated rings. Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0098] A pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer of the compound of the present invention may also contain counterions that are optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0099] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of the present invention contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereoisomers can be separated by chromatography, fractional crystallization, or by using both of the above techniques, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. Using chromatography, the chiral compound of the present invention (and its chiral precursor) can be obtained in an enantiomerically concentrated form, and typically, the concentrated mixture is obtained by HPLC concentration of the eluent. Chiral chromatography using subcritical and supercritical fluids can be used. 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 the references cited therein).

[0100] When any racemic mixture crystallizes, two different types of crystals can occur. The first type is the racemic compound (true racemic compound) mentioned above, which produces a single, uniform crystal form containing equimolar amounts of both enantiomers. The second type is a racemic mixture or aggregate in which equimolar amounts of two crystalline forms, each containing a single enantiomer, are produced. Both crystalline forms present in a racemic mixture have the same physical properties, although they may have different physical properties compared to a true racemic mixture. Racemic mixtures can be separated by prior art known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds by ELEEliel and SHWilen (Wiley, 1994).

[0101] Tautomerism When structural isomers are interconvertible across low-energy barriers, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism in the compounds of the present invention containing imino / amino, keto / enol, or oxime / nitroso groups, or lactam / lactim, or so-called valence tautomerism in compounds containing aromatic moieties. This means that a single compound may exhibit more than one type of isomer.

[0102] For the sake of brevity, the compounds of the present invention are illustrated herein in a single tautomer, but it should be emphasized that all possible tautomers are included within the scope of the present invention.

[0103] Isotopes The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of the present invention, in which one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number that is dominant in nature.

[0104] Examples of isotopes suitable for inclusion in the compound of the present invention include: 2H(D, Deuterium) and 3 Hydrogen such as H(T, tritium), 11 C, 13 C and 14 Carbon such as C, 36 Chlorine such as Cl 18 Fluorine such as F 123 I and 125 Iodine such as I 13 N and 15 Nitrogen such as N, 15 O, 17 O and 18 Oxygen such as O, 32 Phosphorus such as P, and 35 It may contain sulfur isotopes such as S.

[0105] Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes, are useful in either or both drug or substrate tissue distribution studies. Radioactive isotopes, for example, tritium and 14 C is particularly useful for this purpose, considering the ease of their incorporation and the rapid means of detection. Positron-emitting isotopes, for example 11 C, 18 F, 15 O and 13 Substitution with N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Substitution with deuterium may result in certain therapeutic benefits stemming from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, decreased CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerance.

[0106] In some embodiments, this disclosure provides deuterium-labeled (or deuterated) compounds and salts, the formulas and variants of such compounds and salts being as described herein, respectively, and independently. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance higher than the natural abundance of deuterium (typically about 0.015%). Experienced practitioners have recognized that in chemical compounds containing hydrogen atoms, the hydrogen atoms actually exist as 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 present invention may be defined by the deuterium concentration factor. It is understood that one or more deuterium atoms may be exchanged for hydrogen under physiological conditions.

[0107] In some embodiments, the deuterium compound is selected from one of the compounds described in Table 5 shown in the Examples section. In some embodiments, one or more hydrogen atoms on a specific metabolic site on the compound of the present invention are deuterated. In some embodiments, the deuterium compound is

[0108] [ka] It is selected from the group consisting of the following.

[0109] The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the attached examples and preparation examples, using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0110] The pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent may be isotope-substituted, for example, D2O, d6-acetone, or d6-DMSO.

[0111] Prodrug The compounds of the present invention can be administered in the form of prodrugs. Therefore, certain derivatives of the compounds of the present invention that themselves have little or no pharmacological activity may, when administered intracellularly or onto the body, be converted to compounds of the present invention having desired activity, for example, by hydrolytic cleavage, particularly catalyzed by esterase or peptidase enzymes. Such derivatives are referred to as “prodrugs.” Further information on the use of prodrugs 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.).

[0112] The prodrugs according to the present invention can be produced, for example, by replacing a suitable functional group present in the compound of the present invention with a specific part known to those skilled in the art, as a "pro-mole," as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0113] Therefore, the prodrug according to the present invention may be (a) an ester or amide derivative of a carboxylic acid when present in the compound of the present invention; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in the compound of the present invention; (c) an amide, imine, carbamate or amine derivative of an amino group when present in the compound of the present invention; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivative of a thiol group when present in the compound of the present invention; or an oxime or imine derivative of a carbonyl group when present in the compound of the present invention.

[0114] Some specific examples of prodrugs according to the present invention include: (I) When the compound of the present invention contains a carboxylic acid functional group (-COOH), its ester, for example, the hydrogen of the carboxylic acid functional group of the compound is C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g., t Compounds that are replaced by BuC(=O)OCH2-); (ii) When the compound of the present invention contains an alcohol functional group (-OH), an ester thereof, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by -CO(C1~C8 alkyl) (e.g., methyl carbonyl), or in which the alcohol is esterified with an amino acid; (iii) If the compound of the present invention contains an alcohol functional group (-OH), then an ether thereof, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by (C1~C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2; (iv) If the compound of the present invention contains an alcohol functional group (-OH), then the phosphate, for example, the hydrogen of the alcohol functional group of the compound is -P(=O)(OH)2 or -P(=O)(O - Na + )2 or -P(=O)(O - )2Ca 2+ Compounds that have been replaced by; (v) If the compound of the present invention contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), then the amide, for example, optionally, one or both of the hydrogen atoms of the amino functional group of the compound are (C1~C 10 ) Compounds in which the amino group is replaced by an alkanoyl group, -COCH2NH2, or the amino group is derivatized with an amino acid; (vi) If the compound of the present invention contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), then the amine, for example, a compound in which one or both hydrogens of the amino functional group of the compound are replaced by -CH2OP(=O)(OH)2. It includes.

[0115] Certain compounds of the present invention can act as prodrugs of other compounds of the present invention. It is also possible for two compounds of the present invention to act together as a prodrug. In certain circumstances, a prodrug of a compound of the present invention can be made by internally linking two functional groups in the compound of the present invention, for example, to form a lactone.

[0116] metabolites The active metabolites of the compounds of the present invention, i.e., compounds that are often formed in vivo by oxidation or dealkylation upon administration of a drug, are also included within the scope of the present invention. Some examples of metabolites according to the present invention, but are not limited to these, (I) If the compound of the present invention contains an alkyl group, its hydroxyalkyl derivative (-CH > -COH): (ii) If the compound of the present invention contains an alkoxy group, its hydroxy derivative (-OR → -OH); (iii) If the compound of the present invention contains a tertiary amino group, its secondary amino derivative (-NRR' → -NHR or -NHR'); (iv) If the compound of the present invention contains a secondary amino group, its primary derivative (-NHR → -NH2); (v) If the compound of the present invention contains a phenyl moiety, its phenol derivative (-Ph → -PhOH); (vi) If the compound of the present invention contains an amide group, its carboxylic acid derivative (-CONH2 → COOH); and (vii) If the compound contains a hydroxyl or carboxylic acid group, the compound may be metabolized, for example, by conjugation with glucuronic acid to form a glucuronide. Other conjugation metabolic pathways exist. These pathways are often known as phase II metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also be conjugated.

[0117] In one preferred embodiment, the metabolites of the compounds disclosed herein may include the O-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid moiety. In one preferred embodiment, the metabolite is 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In one preferred embodiment, the metabolite has the structure:

[0118] [ka] It has a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer.

[0119] In one preferred embodiment, the metabolite is 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazole-5-yl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In one preferred embodiment, the metabolite has the structure:

[0120] [ka] It has a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer.

[0121] In one preferred embodiment, the metabolite is 3-(6-chloro-5-(2'-(sulfoxy)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In some embodiments, the metabolite is 3-(6-chloro-5-(2'-(sulfoxy)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid further containing a hydroxyl group, or a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. In some embodiments, the metabolite has the structure:

[0122] [ka] It has a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer.

[0123] Pharmaceutical composition In another embodiment, the present invention includes pharmaceutical compositions. For the purposes of pharmaceutical compositions, the compound itself, its pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers are simply referred to as the compound of the present invention. A "pharmaceutical composition" means a mixture of one or more of the compound of the present invention as an active ingredient, or its pharmaceutically acceptable salts, tautomers, solvates, hydrates, or prodrugs, and at least one pharmaceutically acceptable additive.

[0124] The term "additive" is used herein to describe any component other than the compounds of the present invention. The selection of an additive will depend largely on factors such as the mode of administration, the effect of the additive on solubility and stability, and the properties of the dosage form.

[0125] As used herein, “additives” include all physiologically compatible solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, carriers, diluents, and the like. Examples of additives include one or more of water, saline, phosphate buffer solution, dextrose, glycerol, ethanol, and the like, or combinations thereof, and may also include isotonic agents, such as sugars, sodium chloride, or polyalcohols, such as mannitol or sorbitol, in the composition. Examples of additives also include various organic solvents (such as hydrates and solvates). Pharmaceutical compositions may optionally contain additional additives, such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavorings, colorants or pigments, and the like. For example, for oral administration, tablets containing various additives such as citric acid can be used with various disintegrants such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and gum arabic. Examples of additives, though not limited to them, include calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions can also be used in filled soft and hard gelatin capsules. Therefore, non-limiting examples of additives also include lactose and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are preferred for oral administration, the active compounds therein can be combined with various sweeteners or flavorings, colorants or pigments, and, if desired, emulsifiers or suspending agents, along with additional additives such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0126] Examples of additives include pharmaceutically acceptable substances that enhance the shelf life or efficacy of a compound, such as humectants or small amounts of auxiliary substances, such as humectants or emulsifiers, preservatives, or buffers.

[0127] The compositions of the present invention may take various forms. These include, for example, liquid formulations (e.g., formulations for injection and infusion), dispersants or suspensions, and liquid, semi-solid, and solid dosage forms such as tablets, capsules, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0128] Typical compositions are in the form of injectable or infusion solutions, such as compositions similar to those generally used for passive immunization of humans with antibodies. 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.

[0129] Oral administration of solid dosage forms can be provided in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the compounds of the present invention. In another embodiment, the oral administration may be in powder or granular form. In another embodiment, the oral dosage form is sublingual, such as lozenges. In such solid dosage forms, the compounds of the present invention are typically combined with one or more adjuvants. Such capsules or tablets may include controlled-release formulations. In the case of capsules, tablets, and pills, the dosage forms may include buffers or may be prepared with enteric coatings. In one preferred embodiment, the compounds of the present disclosure are administered orally. In one preferred embodiment, the compounds of the present disclosure are administered orally as soft capsules, pills, or tablets. In one preferred embodiment, the compounds of the present disclosure are administered orally in an immediate-release form. In one preferred embodiment, the compounds of the present disclosure are administered orally in a sustained-release form.

[0130] In another embodiment, oral administration may be in liquid form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, liquids, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (e.g., water). Such compositions may contain auxiliary agents such as one or more wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or fragrances.

[0131] In another embodiment, the present invention includes parenteral dosage forms. "Pareral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal and intramuscular injections, intrasternal injections, and injectable preparations. Preparations for injection (i.e., sterile aqueous or oily suspensions for injection) can be formulated using one or more suitable dispersants, wetting agents, or suspending agents according to known techniques.

[0132] In another embodiment, the present invention includes topical dosage forms. "Topical administration" includes, for example, transdermal and transdermal administration such as transdermal patches or ion electrophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered by a transdermal device, administration will be achieved using patches of either reservoir and porous membrane type or solid matrix variants. Typical formulations for this purpose include gels, hydrogels, lotions, liquids, creams, ointments, sprays, bandages, foams, films, skin patches, wafers, implants, sponges, fibers, adhesive bandages, and microemulsions. Liposomes may also be used. Typical additives include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. A permeation enhancer can be incorporated. For example, see BCFinnin and TMMorgan, J.Pharm.Sci., vol.88, pp. 955-958, 1999.

[0133] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present invention are dissolved or suspended in suitable additives. Typical formulations suitable for ocular or ocular administration may be in the form of ultrafine-ground suspensions or solution drops in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and ocular administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and microparticles or vesicles such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as geran gum can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by ion electrophoresis.

[0134] For intranasal administration, the compounds of the present invention are conveniently delivered in the form of a solution or suspension from a pump-type spray container squeezed or pumped by the patient, or as an aerosol spray dispensing from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder from a dry powder inhaler (either alone or as a mixture, e.g., a dry blend with lactose, or as mixed component particles, e.g., mixed with phospholipids such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or from a nebulizer with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, e.g., chitosan or cyclodextrin.

[0135] In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form may be, for example, a suppository. Cocoa butter is the conventional suppository base, but various alternatives can be used if appropriate.

[0136] Other known additives and administration methods in the pharmaceutical field may also be used. The pharmaceutical compositions of the present invention can be prepared by any well-known pharmaceutical technique, such as effective formulations and administration procedures. The above-mentioned studies on effective formulations and administration procedures are well-known in the art and are described in standard textbooks. Drug formulations are 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 Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds., Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Britain, Harry G., Ed., Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0137] Acceptable additives are nontoxic to the subject at the dosage and concentration used and may include one or more of the following: 1) buffering agents such as phosphates, citrates, and other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid and methionine; 4) preservatives such as octadecyldimethylbenzylammonium 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 (less than approximately 10 residues) polypeptides; 7) serum albumin, 1) Proteins such as gelatin or immunoglobulins; 8) Hydrophilic polymers such as polyvinylpyrrolidone; 9) Amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) Monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; 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), poloxamer, or polyethylene glycol (PEG).

[0138] Liposomes containing the compounds of the present invention 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 produced by reverse-phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a specified pore size to obtain liposomes with a desired diameter.

[0139] The compounds of the present invention can also be encapsulated in microcapsules prepared, for example, by coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, using colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0140] Sustained-release preparations can be used. A preferred example of a sustained-release preparation comprises a semipermeable matrix of a solid hydrophobic polymer containing the compound of the present invention, the matrix being in the form of a molded article, e.g., a film, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate), such as those used in leuprolide acetate for depot suspensions, sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0141] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the present invention are generally placed in containers having a sterile access port, such as intravenous fluid bags or vials with a stopper that can be pierced by a subcutaneous injection needle.

[0142] Suitable emulsions can be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, egg phospholipids, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient can be dissolved in a pre-mixed emulsion composition, or, by other means, in an emulsion formed by mixing oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or tonsil oil) and phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) with water. It will be found that other components, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. A suitable emulsion should typically contain up to 20% oil, for example, between 5 and 20%. The lipid emulsion contains lipid droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[0143] For example, an emulsion composition may be prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, egg phospholipids, glycerol, and water).

[0144] Compositions for inhalation or inhalation include liquid and suspension formulations in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as presented above. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic action. Compositions in preferably sterile, pharmaceutically acceptable solvents can be atomized using gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be attached to a face mask, tent, or intermittent positive pressure ventilator. Solutions, suspensions, or powder compositions can be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0145] A formulation intermediate (DPI) is a partially processed substance that requires further processing steps before becoming a bulk formulation. The compounds of the present invention can be formulated into formulation intermediate DPIs containing the active ingredient in a form with a higher free energy than the crystalline form. One reason for using DPIs is to improve oral absorption characteristics due to low solubility, slow dissolution, improved material transport via the mucin layer adjacent to epithelial cells, and, in some cases, to overcome limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the formulation intermediate contains the compound of the present invention (e.g., an amorphous solid dispersion (ASD)) isolated and stabilized in an amorphous state. Many techniques exist known in the art to produce ASDs that produce substances suitable for incorporation into bulk formulations, e.g., spray-dried dispersions (SDDs), melt extrudes (often referred to as HMEs), coprecipitations, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion contains the compound of the present invention and polymer additives. Other additives, as well as the concentrations of the aforementioned additives and the compounds disclosed herein, are well known in the art and are described in standard textbooks. For example, see "Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0146] Administration and medication The compound of the present invention is administered in an amount effective to treat the pathological conditions described herein. The compound of the present invention may be administered as the compound itself, or, by other means, as a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer. For the purposes of administration and drug delivery, the compound itself, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer will simply be referred to as the compound of the present invention.

[0147] The compounds of the present invention are administered by any preferred 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 present invention can be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0148] In one preferred embodiment, the compound of the present invention can be administered orally. Oral administration may involve swallowing, which allows the compound to enter the gastrointestinal tract, or it may involve buccal or sublingual administration, which allows the compound to enter the bloodstream directly from the mouth.

[0149] In another embodiment, the compounds of the present invention may be administered parenterally, for example, directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

[0150] In another embodiment, the compounds of the present invention may be administered topically to the skin or mucous membrane, i.e., cutaneously or transdermally. In another embodiment, the compounds of the present invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may be administered directly to the eyes or ears.

[0151] The administration regimen for the compound of the present invention or a composition containing the compound is based on various factors, including the patient's species, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the administration regimen can vary widely. In one embodiment, the total daily dose of the compound of the present invention is typically about 0.01 to about 100 mg / kg (i.e., mg of the compound of the present invention per kg of body weight) for the treatment of the indications discussed herein. In another embodiment, the total daily dose of the compound of the present invention is about 0.1 to about 50 mg / kg, and in yet another embodiment, about 0.5 to about 30 mg / kg. It is not uncommon to repeat the administration of the compound of the present invention multiple times a day (typically no more than four times). If desired, multiple doses per day can typically be used to increase the total daily dose. In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer is administered once, twice, or three times a day. In one preferred embodiment, the compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer is administered once daily. In one preferred embodiment, the compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer is administered twice daily. In one preferred embodiment, the compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer is administered three times daily.

[0152] In one embodiment, a pharmaceutical composition comprising the compound of the Disclosure, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof, or the compound, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a tautomer thereof, can be administered orally in the form of a tablet or capsule. The dosage of the compound, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof can be adjusted based on the patient's response and symptoms. In some embodiments, the compound or pharmaceutical composition contains the compound in amounts of approximately 0.01 mg to approximately 150 mg, approximately 150 mg to approximately 250 mg, approximately 250 mg to approximately 500 mg, approximately 500 mg to approximately 750 mg, approximately 750 mg to approximately 1000 mg, approximately 1250 mg to approximately 1500 mg, approximately 1500 mg to approximately 1750 mg, approximately 1750 mg to approximately 2000 mg, approximately 2000 mg to approximately 2250 mg, and approximately 2250 mg to approximately 2500 mg. The compound can be provided in amounts of approximately 2500mg to 2750mg, approximately 2750mg to 3000mg, approximately 3000mg to 3250mg, approximately 3250mg to 3500mg, approximately 3500mg to 3750mg, approximately 3750mg to 4000mg, approximately 4000mg to 4250mg, approximately 4250mg to 4500mg, approximately 4500mg to 4750mg, or approximately 4750mg to 5000mg. In a preferred embodiment, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer can be provided in amounts of approximately 1mg to 2500mg. In a preferred embodiment, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer can be provided in amounts of approximately 1mg to 100mg. In one preferred embodiment, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 1 mg to about 50 mg. In another preferred embodiment, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 1 mg to about 25 mg. In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 150 mg to about 2500 mg.In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 150 mg to about 500 mg. In a preferred embodiment, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 100 mg to about 1000 mg. In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 500 mg to about 1500 mg. In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 1500 mg to about 2500 mg. In some embodiments, the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 2500 mg to about 5000 mg.

[0153] Compounds disclosed herein, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers, in amounts of approximately 0.01 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 8 It can be supplied in amounts of 00 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2100 mg, approximately 2200 mg, approximately 2300 mg, approximately 2400 mg, approximately 2500 mg, approximately 2600 mg, approximately 2700 mg, approximately 2800 mg, approximately 2900 mg, approximately 3000 mg, approximately 3200 mg, approximately 3400 mg, approximately 3600 mg, approximately 3800 mg, approximately 4000 mg, approximately 4200 mg, approximately 4400 mg, approximately 4600 mg, approximately 4800 mg, or approximately 5000 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 5 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 10 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 15 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 25 mg.In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 50 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 75 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 100 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 250 mg. In one preferred embodiment, the compound disclosed herein, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer can be provided in an amount of about 500 mg. In one preferred embodiment, the compounds disclosed herein, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers can be provided in an amount of about 1000 mg.

[0154] Treatment methods and use The compounds of this disclosure can activate AMPK and may be useful in treating AMPK-related conditions. In one preferred embodiment, the compounds of this disclosure may be pan-AMPK activators and may be useful in treating AMPK-related conditions. In some embodiments, the condition or disorder may be 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 one preferred embodiment, the AMPK activating compound of this disclosure may be administered to a subject in need to treat a metabolic disorder. In one preferred embodiment, the AMPK activating compound of this disclosure may be administered to a subject in need to treat an inflammatory or autoimmune disorder. In one preferred embodiment, the AMPK activating compound of this disclosure may be administered to a subject in need to treat a gastrointestinal barrier dysfunction disorder or a functional gastrointestinal disorder.

[0155] In some embodiments, the AMPK-activating compounds disclosed herein are used to treat type 2 diabetes, gestational diabetes, insulin resistance, hyperglycemia, hypercholesterolemia, hypertriglyceridemia (high levels of triglyceride-rich lipoprotein), obesity, abdominal obesity, vascular restenosis, hyperinsulinemia, glucose intolerance, atherosclerosis, metabolic syndromes, hypertension, hyperhepatic glucose release, hyperglycemia, non-alcoholic steatohepatitis (NASH), dyslipidemia, mixed dyslipidemia, diabetic dyslipidemia, protection against ischemia and reperfusion injury, lipid disorders, and high levels of plasma triglycerides. Metabolic disorders or complications arising from metabolic conditions selected from the group consisting of cerides, high levels of free fatty acids, high levels of cholesterol, high levels of low-density lipoprotein (LDL), low levels of high-density lipoprotein (HDL), chronic kidney disease, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, hypoxia, cancer, non-alcoholic fatty liver disease (NAFLD), glucocorticoid-induced apoptosis, decreased skeletal muscle mass, sarcopenia, high circulating free fatty acids (FFA), heart attack, cardiomyopathy, heart failure, and atherosclerosis can be treated. In a preferred embodiment, the AMPK-activating compounds of this disclosure can treat metabolic disorders selected from the group consisting of type 2 diabetes mellitus, gestational diabetes mellitus, hyperglycemia, metabolic syndromes, obesity, hypercholesterolemia, or hypertension.

[0156] In some embodiments, the AMPK-activating compounds disclosed herein can treat inflammatory or autoimmune disorders selected 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 colitis, chemotherapy-induced colitis, and necrotizing pancolitis. In some embodiments, the AMPK-activating compounds disclosed herein can treat gastrointestinal injuries resulting from toxic injuries such as radiation or chemotherapy. In one preferred embodiment, the AMPK-activating compounds of this disclosure can treat inflammatory or autoimmune disorders selected from the group consisting of inflammatory bowel disease, colitis, ulcerative colitis, and Crohn's disease. In one preferred embodiment, the AMPK-activating compounds of this disclosure can treat inflammatory bowel disease. In one preferred embodiment, the AMPK-activating compounds of this disclosure can treat colitis. In one preferred embodiment, the AMPK-activating compounds of this disclosure can treat ulcerative colitis. In one preferred embodiment, the AMPK-activating compound of the present disclosure can treat Crohn's disease.

[0157] In some embodiments, the AMPK-activating compounds disclosed herein can treat gastrointestinal barrier dysfunction, such as environmental intestinal dysfunction or spontaneous bacterial peritonitis. In some embodiments, the AMPK-activating compounds disclosed herein can treat ischemic colitis or sclerosing cholangitis.

[0158] In some embodiments, the AMPK-activating compounds disclosed herein can treat functional gastrointestinal disorders selected from the group consisting of irritable bowel syndrome, functional dyspepsia, functional abdominal distension, functional abdominal bloating, functional diarrhea, functional constipation, gastroparesis, disorders associated with endogenous microbiome dysbiosis, and opioid-induced constipation. In a preferred embodiment, the AMPK-activating compounds of this disclosure can treat functional gastrointestinal disorders selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, and functional constipation.

[0159] In some embodiments, the AMPK-activating compounds disclosed herein can treat eating disorders or nutritional deficiencies selected from the group consisting of bulimia nervosa, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, and intestinal insufficiency. In some embodiments, the AMPK-activating compounds disclosed herein can treat complications associated with eating disorders or nutritional deficiencies, such as left ventricular hypertrophy.

[0160] In some embodiments, the AMPK-activating compounds disclosed herein can treat allergies, such as food allergies and celiac sprouts. In some embodiments, the AMPK-activating compounds disclosed herein can treat nausea and vomiting.

[0161] In some embodiments, the AMPK-activating compounds disclosed herein can treat central nervous system disorders selected from the group consisting of mood disorders, anxiety, depression, affective disorders, schizophrenia, fatigue, cognitive impairment, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Lewy body dementia, recurrent cluster headaches, migraines, and pain.

[0162] In some embodiments, the AMPK-activating compounds of this disclosure can reduce fatty acid synthesis; increase fatty acid oxidation; increase ketone production; reduce cholesterol synthesis, lipid synthesis, and / or triglyceride synthesis; lower blood glucose levels and / or concentrations; improve glucose homeostasis; normalize glucose metabolism; lower blood pressure; increase HDL levels; lower LDL levels; lower plasma triglyceride levels; lower fatty acid levels; reduce hepatic glucose release; improve insulin action; lower blood pressure; improve insulin sensitivity; suppress hepatic glucose release; inhibit liponeogenesis; stimulate muscle glucose uptake; modulate insulin secretion by pancreatic β-cells; reduce body weight; increase skeletal muscle mass; or prevent a decrease in skeletal muscle mass. In one preferred embodiment, the AMPK-activating compounds disclosed herein have a leaky gut barrier and can therefore treat or alleviate systemic infections or systemic inflammation. In one preferred embodiment, the AMPK-activating compounds disclosed herein are pan-AMPK activators.

[0163] Co-administration The compounds of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides any use, method or composition as defined herein, in which the compounds of the present invention, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer is used in combination with one or more other therapeutic agents discussed herein.

[0164] The administration of two or more compounds "in combination" means that all compounds are administered in sufficient time proximity to affect the treatment in question. Two or more compounds may be administered synchronously or sequentially, with or without specific time intervals, via the same or different routes of administration, on the same or different administration schedules, depending on the treatment regimen. In addition, synchronous administration can be achieved by mixing the compounds before administration, or by administering the compounds at the same time, but at the same or different administration sites, in separate dosage forms. Examples of "in combination" include, but are not limited to, "simultaneous administration," "co-administration," "synchronous administration," "sequential administration," and "administered synchronously."

[0165] The compounds of the present invention and one or more other therapeutic agents can be administered as fixed or unfixed combinations of active ingredients. The term "fixed combination" means that both the compound of the present invention, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer, and one or more therapeutic agents are administered to a subject synchronously in a single composition or dosage. The term "unfixed combination" means that the compound of the present invention, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer, and one or more therapeutic agents are formulated as separate compositions or dosages so that they can be administered synchronously to a subject in need, or at different times with varying intervening timeframes that result in effective levels of two or more compounds in the subject's body.

[0166] In one embodiment, the compound of the present invention is administered in combination with a pharmaceutically acceptable salt of a pharmaceutically acceptable drug, as well as a pharmaceutically acceptable solvate of the drug and its salt, which are pharmaceutically acceptable drugs.

[0167] The present invention also provides any use, method or composition as defined above, in which compounds of formulas I, Ia, II, III, IVa-c, and V, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers are used in combination with other pharmacologically active compounds, in particular one of the functionally defined classes or specific compounds listed below. These agents can be administered as part of the same or separate dosage forms, by the same or different routes of administration, and in the same or different schedules of administration, in accordance with standard pharmacologic practices known to those skilled in the art.

[0168] Suitable agents for use in combination therapy with compounds of formulas I, Ia, II, III, IVa-c, and V, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers include sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporine, and tacrolimus. This includes fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, antihistamines, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, sodium mycophenolate, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxan, NSAIDs, solu-medrol, depo-medrol, and dexamethasone.

[0169] Other suitable agents for use in combination therapy with compounds of formulas I, Ia, II, III, IVa-c, and V, their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable salts of tautomers include: 5-lipoxygenase-activated protein (FLAP) antagonists; leukotriene antagonists (LTRAs), e.g., LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2 antagonists, e.g., montelukast or zafirlukast; histamine receptor antagonists, e.g., histamine Type 1 receptor antagonists or histamine type 2 receptor antagonists, e.g., loratidine, fexofenadine, desloratidine, levocetirizine, metapyrylene, or cetirizine; α1-adrenergic receptor agonists or α2-adrenergic receptor agonists, e.g., phenylephrine, methoxamine, oxymetazoline, or methylnorephedrine; muscarinic M3 receptor antagonists, e.g., tiotropium or ipratropium; dual muscarinic M3 receptor antagonists / β 2. Agonists; PDE inhibitors, e.g., PDE3 inhibitors, PDE4 inhibitors or PDE5 inhibitors, e.g., theophylline, sildenafil, vardenafil, tadalafil, ibudilast, siromilast or roflumilast; sodium cromoglycate or nedocromil sodium; cyclooxygenase (COX) inhibitors, e.g., non-selective inhibitors (e.g., aspirin or ibuprofen) or selective inhibitors (e.g., celecoxib or vardecoxib); glucocorticosteroids, e.g., fluticasone, mometasone, denatura Xamethasone, prednisolone, budesonide, ciclesonide, or beclomethasone; anti-inflammatory monoclonal antibodies, e.g., infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab, or mepolizumab; β2 agonists, e.g., salmeterol, albuterol, salbutamol, fenoterol, or formoterol, especially long-acting β2 agonists; integrin antagonists, e.g., natalizumab; adhesion molecule inhibitors, e.g., VLA-4 antagonists; kinin B1 or B2 receptor antagonists;Immunosuppressants, e.g., IgE pathway inhibitors (e.g., omalizumab) or cyclosporine; matrix metalloproteinase (MMP) inhibitors, e.g., MMP-9 or MMP-12 inhibitors; tachykinin NK1, NK2 or NK3 receptor antagonists; protease inhibitors, e.g., elastase, chymase or catheopsin G inhibitors; adenosine A; 2a Receptor agonist; adenosine A 2b Receptor antagonists; urokinase inhibitors; dopamine receptor agonists (e.g., ropinirole), especially dopamine D2 receptor agonists (e.g., bromocriptine); modulators of the NFκB pathway, e.g., IKK inhibitors; further modulators of cytokine signaling pathways, e.g., inhibitors of syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; mucolytics, mucokinetics or antitussives; antibiotics; antiviral drugs; vaccines; chemokines; epithelial sodium channel (ENaC) blockers or inhibitors; nucleotide receptor agonists, e.g., P2Y2 agonists; thromboxane inhibitors; nayl Asin; 5-lipoxygenase (5-LO) inhibitors, e.g., dileuton; adhesion molecules, e.g., VLAM, ICAM, or ELAM; CRTH2 receptor (DP2) antagonists; prostaglandin D2 receptor (DP1) antagonists; hematopoietic prostaglandin D2 synthase (HPGDS) inhibitors; interferon-β; soluble human TNF receptors, e.g., etanercept; HDAC inhibitors; phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors; phosphoinositide 3-kinase delta (PI3Kδ) inhibitors; CXCR-1 or CXCR-2 receptor antagonists; IRAK-4 inhibitors; and TLR-4 or TLR-9 inhibitors, including pharmaceutically acceptable salts of the compounds specifically named. The agents may be administered together with another active agent, the second active agent may be administered either orally or topically.

[0170] These drugs and the compounds of the present invention can be combined with pharmaceutically acceptable vehicles such as physiological saline, Ringer's solution, dextrose solution, and the like. Specific dosing regimens, i.e., dosage, timing, and repetitions, will depend on the specific individual and their medical history.

[0171] kit Another aspect of the present invention provides a kit comprising the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention. The kit may include, in addition to the compound of the present invention or its pharmaceutical composition, a diagnostic or therapeutic agent. The kit may include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit comprises the compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit comprises the compound or its pharmaceutical composition and one or more therapeutic agents, for example, therapeutic agents for simultaneous administration as described herein.

[0172] In another embodiment, the present invention includes a kit 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 compounds of the present invention in sufficient quantities to carry out the method of the present invention. In another embodiment, the kit comprises one or more compounds of the present invention in sufficient quantities to carry out the method of the present invention, and a container for dosage and a container for dosage.

[0173] Synthesis method The compounds of the present invention can be synthesized by synthetic routes involving processes similar to those well known in the chemical field, particularly in light of the description contained herein. Starting materials are generally available from commercial suppliers 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 from which one or more scientific importance or commercial needs arise. Thus, such compounds may be one or more of the following: 1) commercially available; 2) reported in the literature; or 3) prepared by those skilled in the art from other commercially available substances using materials reported in the literature.

[0174] A more detailed description of each reaction step is provided in the Examples section below. Those skilled in the art will see that the compounds of the present invention can be synthesized using other synthetic routes. While specific starting materials and reagents are discussed below, they can be substituted with other starting materials and reagents to obtain one or more derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified using conventional chemical actions well known to those skilled in the art in light of this disclosure.

[0175] Those skilled in the art will recognize that the experimental conditions described in the following preparation examples and examples are illustrative of suitable conditions for performing the transformations shown, and that it may be necessary or desirable to change the exact conditions used to prepare the compounds of the present invention. Furthermore, it will be recognized that it may be necessary or desirable to perform the transformations in a different order than those described in the preparation examples and examples, or to modify one or more of the transformations to obtain the desired compounds of the present invention.

[0176] In preparing the compounds of the present invention, it should be noted that some of the preparation methods useful for preparing the compounds described herein may require the protection of distant functional groups (e.g., primary amines, secondary amines, carboxyls, etc., in the precursors of the compounds of the present invention). The need for such protection should vary depending on the properties of the distant functional groups and the conditions of the preparation method. Those skilled in the art will readily determine the need for such protection. The use of such protection / deprotection methods is also within the scope of skill in the art. For an overview of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th edition.

[0177] For example, if a compound contains an amine or carboxylic acid functional group, such a functional group, if left unprotected, may interfere with reactions at other parts of the molecule. Therefore, such functional groups can be protected with a suitable protecting group (PG) that can be removed in a later step. Suitable protecting groups for amine and carboxylic acid protection include protecting groups commonly used in peptide synthesis (such as Nt-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 can typically be removed without chemically altering other functional groups in the compounds of the present invention.

[0178] General experimental details In illustrating the present invention and in the non-limiting examples and preparations described in the following scheme, the following abbreviations, definitions, and analytical procedures may be referenced. Other abbreviations common in the art may also be used. The compounds of the present invention were named using ChemDraw Professional® version 20 (Perkin Elmer) or given names consistent with IUPAC nomenclature.

[0179] 1 The 1H nuclear magnetic resonance (NMR) spectra were consistent in all cases with the proposed structure. Characteristic chemical shifts (δ) are shown in parts per million from tetramethylsilane to low magnetic field, using conventional abbreviations to specify the major peaks: e.g., s, singleline; d, doubleline; t, tripleline; q, quadrupleline; quin, quinupline; m, multiline; br, broad. The following abbreviations are used for common NMR solvents: CD3CN, juteroacetonitrile; CDCl3, deuterated chloroform; DMSO-d6, juterodimethylsulfoxide; and MeOD, juteromethanol. Where appropriate, tautomers may be recorded in the NMR data; some interchangeable protons may be invisible. Some resonances in the NMR spectrum appear as complex multilines because the isolate is a mixture of two conformational isomers.

[0180] Mass spectra were recorded using electron impulse ionization (EI), electrospray ionization (ESI), or atmospheric pressure chemical ionization (APCI). The observed ions were reported as MS m / z, and the compound [M] + , compound + proton [M + H] + , or compound + sodium ion [M + Na] + It can be a cation. In some cases, the only ion observed is [M+H-(lost fragment)]. + It may also be reported as a fragment ion. If relevant, the reported ion is chlorine ( 35 Cl and / or 37 Cl), bromine ( 79 Br and / or 81 Br) and tin ( 120 This designates an isotope of Sn.

[0181] When TLC, chromatography, or HPLC is used to purify a compound, a person skilled in the art can select any suitable solvent or combination of solvents to purify the desired compound. Chromatographic separation (except HPLC) was carried out using silica gel adsorbents unless otherwise specified.

[0182] All reactions were carried out under a nitrogen or argon atmosphere using continuous stirring, unless otherwise specified. In some cases, the reactants were purged with nitrogen or argon gas before the start of the reaction. In these cases, nitrogen or argon gas was blown into the liquid phase of the mixture for approximately the specified time. The solvents used were commercially available anhydrous grade. All starting materials were commercially available products. In some cases, the starting materials were prepared according to reported literature procedures. It will be apparent to those skilled in the art that the term “concentration” as used herein generally refers to the carrying out of evaporation of the solvent under reduced pressure, typically achieved by the use of a rotary evaporator.

[0183] Abbreviation Ac2O is acetic anhydride; B2(Pin)2 is bis(pinacorato)diborone; br is broad; tBu is tert-butyl; °C is the unit of temperature in Celsius; CDCl3 is deuterated chloroform; δ is a chemical shift; d is a double line; dd is a double double line; ddd is a double dt is a double line with a triple line; DCM is dichloromethane; it is methylene chloride; DMF is N,N-dimethylformamide; DMSO-d6 is deuterated dimethyl sulfoxide;  is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; g stands for grams; HPLC is high-pressure liquid chromatography; h is time; KOAc is potassium acetate; L stands for liter; LC stands for liquid chromatography; m is a multiline; M is a mole; (MH) - It is a compound-proton anion; MeOD is deuterated methanol; MeOH is methanol; mg stands for milligram; MHz stands for megahertz; min is minutes; mL stands for milliliter; mm stands for millimeter; mM is millimoles; An mmol is a millimolecule; MS stands for Mass Spectrometry; (M+H) + It is a compound + proton cation; NMR is nuclear magnetic resonance; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II); Pd(dppf)Cl2-CH2Cl2 is a [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) dichloromethane complex; Pd(OAc)2 is palladium(II) acetate; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0); PPh3 is triphenylphosphine; ppm is parts per million; psi is pounds per square inch; q is a quadruple line; rt is the retention time; s is a single line; SFC is supercritical fluid chromatography; t is a triple line; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin-layer chromatography; μ is a micron; μL is a microliter; UPLC is ultra-high-performance liquid chromatography; Xantphos is 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0184] The scheme described below is intended to provide an overview of the methods used in the preparation of the compounds of the present invention. In the following scheme, the general methods for preparing the compounds are shown in either racemic or enantioenriched forms. It will be apparent to those skilled in the art that all synthetic transformations can be carried out in exactly the same manner, regardless of whether the substance is enantioenriched or racemic. Furthermore, the resolution into the desired optically active substance can be carried out at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[0185] Reaction scheme IA outlines a general procedure for synthesizing the compound of formula (I). In reaction scheme IA, the chemical groups are as defined herein; in addition, in reaction scheme IA: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromo, or chloro; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group (where -C(O)OR is an ester that is chemically inert to the described cross-coupling reaction, but -C(O)OR is -C(O)OR 1 R is readily convertible to yield the compound of formula (I), preferably R = methyl, ethyl, benzyl, or tert-butyl; -BY2 = a boronic acid or boronic acid ester suitable for transition metal-catalyzed cross-coupling reactions, preferably a boronic acid or pinacol boronic acid ester.

[0186] The heteroaryl halide intermediate (1a) can be prepared by combining standard functional group interconversions described in reaction schemes II, III, and IV, 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). The boronic acid ester intermediate (1b) can be prepared as described in WO2011061168 or WO2014140078. The conversion from heteroaryl halide intermediate (1a) to boronic acid ester intermediate (1d) is performed by A 1 =CR 8If so, this can be readily achieved by methods known in the literature (WO2018229543;WO2022221526;WO2012119046). The halide intermediate (1e) can be prepared by methods widely reported in the literature. Intermediate (1c) can be prepared by transition metal-catalyzed cross-coupling of the halide and boronic acid ester intermediates (1a) and (1b), or (1e) and (1d), using procedures similar to those in ACS Medicinal Chemistry Letters 2020, 11, 825; Journal of Medicinal Chemistry 2021, 64, 4498;WO2019201297;WO2016164285;Journal of Medicinal Chemistry 2014, 57, 5129;WO2019213570. The compound of formula (I) can be prepared by transesterification or hydrolysis of intermediate (1c) according to procedures well known in the literature (WO2012137089; Tetrahedron Letters 2018, 59, 2917; WO2022150574; WO2022229341).

[0187] Boration of intermediate (1a) to obtain intermediate (1d) can be carried out under standard palladium-catalyzed reaction conditions by 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, preferably at a temperature between 80 and 110°C. Cross-coupling between the halide intermediate (1a) and the boronic acid ester intermediate (1b), or between the halide intermediate (1e) and the boronic acid ester intermediate (1d), to obtain intermediate (1c) can be carried out using a catalyst, such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium fluoride, potassium carbonate, or sodium bicarbonate, in a suitable solvent, such as an aqueous solution of dioxane or 1,2-dimethoxyethane, at a suitable temperature preferably between 80 and 110°C. The conversion from ester intermediate (1c) to the compound of formula (I) can be carried out under standard conditions for cleaving the -C(O)OR ester. When R = small alkyl, such as methyl or ethyl, hydrolysis to obtain the carboxylic acid of formula (I) can be carried out using a suitable metal hydroxide, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, in a solvent, such as water, or a mixed water-organic solvent, such as methanol, ethanol, and / or aqueous tetrahydrofuran solution, at a suitable temperature preferably between 0 and 110°C. When R = tert-butyl, acid-acidified cleavage of the tert-butyl ester to obtain the carboxylic acid of formula (I) can be carried out using a suitable combination of acid and solvent, such as trifluoroacetic acid in dichloromethane, or hydrogen chloride in dioxane, at a suitable temperature preferably between 0 and 30°C.

[0188] [ka]

[0189] In reaction scheme IB, the chemical groups are as defined herein; in addition, in reaction scheme IB: X = a halide suitable for transition metal catalyzed cross-coupling reactions, preferably iodine, bromo, or chloro; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group (where -C(O)OR is an ester that is chemically inert to the described cross-coupling reaction, but -C(O)OR is -C(O)OR 1 R is readily convertible to yield compounds of the compound of formula (I), preferably R = methyl, ethyl, benzyl, or tert-butyl; -BY2 = boronic acid or boronic acid ester suitable for transition metal-catalyzed cross-coupling reactions, preferably boronic acid or pinacol boronic acid ester.

[0190] Reaction scheme IB is alternative R 4 An alternative route to intermediate (1c) via the introduction of a group is illustrated. Reaction scheme IB is R 4 The original variant is illustrated, but those skilled in the art can apply a similar procedure to R 2 ~R 6It will be acknowledged that similar derivatives can be prepared with any of the substituents. The bis(boronic acid ester) intermediate (1f) can be prepared according to the references (Chemistry - An Asian Journal 2013, 8, 1368; Organometallics 2002, 21, 4886; Organometallics 2014, 33, 1291). The mono-boronic acid ester intermediate (1g) can be prepared by selective monocoscoping of the bis(boronic acid ester) intermediate (1f) with the heteroaryl halide intermediate (1a) (ACS Macro Letters 2012, 1, 392; WO2016115360; US20160072072; ACS Catalysis 2021, 11, 5968). Intermediate (1c) can be prepared by transition metal-catalyzed cross-coupling of a boronic acid ester intermediate (1g) with a suitable (heteroaryl)halide intermediate (1h) using a procedure similar to that described in ACS Medicinal Chemistry Letters 2020, 11, 825; Journal of Medicinal Chemistry 2021, 64, 4498; WO2019201297; WO2016164285; Journal of Medicinal Chemistry 2014, 57, 5129; WO2019213570.

[0191] The cross-coupling between the halide intermediate (1a) and the (bis)boronic acid ester intermediate (1f) can be carried out using a catalyst, such as tetrakis(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 an aqueous solution of dioxane or tetrahydrofuran, preferably at a suitable temperature between 80 and 120°C. The cross-coupling between the boronic acid ester intermediate (1g) and the halide intermediate (1h) to obtain intermediate (1c) can be carried out using a catalyst, such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium fluoride, potassium carbonate, or sodium bicarbonate, in a suitable solvent, such as an aqueous solution of dioxane or 1,2-dimethoxyethane, preferably at a suitable temperature between 80 and 110°C.

[0192] [ka]

[0193] Reaction scheme II outlines the general procedure for synthesizing intermediate (2d). In reaction scheme II, the chemical groups are as defined herein; in addition, in reaction scheme II: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromo, or chloro; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group (where -C(O)OR is an ester that is chemically inert to the described cross-coupling reaction, but -C(O)OR is -C(O)OR 1 It can be easily converted to a compound of formula (I), preferably R = methyl, ethyl, benzyl, or tert-butyl.

[0194] The substituted (aza)indole intermediate (2a) can be prepared based on the 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). Intermediate (2b) can be synthesized from (aza)indole intermediate (2a) based on the literature procedure (RSC Advances 2018, 8, 13121; WO2011123946; WO2020173400). The unsaturated intermediate (2c) can be prepared by olefination of the aldehyde intermediate (2b) under standard conditions (WO200979767; 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). Intermediate (2d) can be prepared by reducing the unsaturated intermediate (2c) by appropriately selecting reaction conditions to avoid the undesirable reduction of other functional groups; hydrogenation with a platinum catalyst may promote selective olefin reduction in the presence of a halide (Journal of the American Chemical Society 1922, 44, 1397; Journal of the American Chemical Society 1960, 82, 6090; WO200876805; US2020247768).Alternatively, intermediate (2d) can be prepared directly from intermediate (2b) by reaction with a malonic acid ester derivative (Synthetic Communications 25, 3067; US5350872; EP3275867; WO201535223; Bioorganic & Medicinal Chemistry 2017, 25, 2995).

[0195] The aldehyde intermediate (2b) can be prepared from the condensed pyrrole intermediate (2a) by reacting it with sodium nitrite and an acid, preferably hydrochloric acid, in a suitable solvent, such as an aqueous solution of N,N-dimethylformamide, an aqueous solution of dioxane, an aqueous solution of acetone, or water, at a suitable temperature preferably between 0 and 30°C. The olefin intermediate (2c) can be synthesized from the aldehyde intermediate (2b) by reacting it with a suitable olefinating reagent, preferably (carboethoxymethylene)triphenylphosphorane or (tert-butoxycarbonylmethylene)triphenylphosphorane, in a suitable solvent, such as tetrahydrofuran, dichloromethane, or ethanol, at a suitable temperature preferably between 20 and 70°C. Reduction from the olefin intermediate (2c) to intermediate (2d) can be achieved by catalytic hydrogenation, preferably in a suitable solvent, such as ethanol or ethyl acetate, at a suitable temperature preferably between 20 and 40°C, using platinum oxide as a catalyst and hydrogen gas as a reducing agent. Alternatively, intermediate (2d) can be prepared by directly reacting aldehyde intermediate (2b) with a malonic acid ester derivative, preferably 2,2-dimethyl-1,3-dioxane-4,6-dione, and a base and reducing agent, preferably triethylamine and formic acid, in a suitable solvent, preferably dioxane, at a suitable temperature between 50 and 100°C.

[0196] [ka]

[0197] Reaction Scheme III outlines a general procedure for synthesizing the intermediate (3g) via the interconversion of standard protecting and functional groups, which is well known to those skilled in the art. In Reaction Scheme III, the chemical groups are as defined herein; however, in Reaction Scheme III, A 2 Except that is limited to CH2, CHD, and CD2; in addition, in reaction scheme III: X = a halide suitable for transition metal-catalyzed cross-coupling reactions, preferably iodine, bromo, or chloro; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group (where -C(O)OR is an ester that is chemically inert to the described cross-coupling reaction, but -C(O)OR is -C(O)OR 1 X 1 = A leaving group suitable for the described reaction, preferably a mesylate, tosylate, chloride, or bromide; m = 0 or 1.

[0198] The N-protected intermediate (3b) can be prepared from intermediate (3a) using a standard protecting group strategy as described in PGMWuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014. A general approach for homologizing carboxylic acid derivatives is 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 a hydride source, as described in Advanced Synthesis & Catalysis 2021, 363, 4867; Journal of Medicinal Chemistry 2011, 54, 1333. The alcohol intermediate (3d) can be converted to 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 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).The ester intermediate (3g) can be synthesized from the nitrile intermediate (3f) by treatment with an alcoholic acid for both nitrile conversion and cleavage of the acid-unstable N-protecting group (Synthetic Communications 2003, 33, 3271; European Journal of Organic Chemistry 2000, 21, 3575).

[0199] The N-protected intermediate (3b) can be prepared from intermediate (3a) by reaction with a suitable protecting reagent and a suitable acid or base. Preferably, the 2-tetrahydropyranyl protecting group can be introduced using 3,4-dihydro-2H-pyran and p-toluenesulfonic acid in a solvent, e.g., THF, at a suitable 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 a suitable base, e.g., sodium hydride, potassium tert-butoxide, or N,N-diisopropylethylamine in a solvent, e.g., tetrahydrofuran or N,N-dimethylformamide, at a suitable temperature preferably between 0 and 30°C. The conversion from ester intermediate (3b) to acid intermediate (3c) can be carried out under standard conditions for cleaving the -C(O)OR ester. For R = small alkyl, such as methyl or ethyl, hydrolysis to obtain the carboxylic acid intermediate (3c) can be carried out using a suitable metal hydroxide, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, in a solvent, such as water, or a mixed water-organic solvent, such as methanol, ethanol, and / or aqueous tetrahydrofuran solution, at a suitable temperature, preferably between 20 and 60°C. For R = tert-butyl, acid-acidified cleavage of the tert-butyl ester to obtain the carboxylic acid intermediate (3c) can be carried out using a suitable combination of acid and solvent, such as trifluoroacetic acid in dichloromethane or hydrogen chloride in dioxane, at a suitable temperature, preferably between 0 and 30°C.

[0200] The reduction from the acid intermediate (3c) to the alcohol intermediate (3d) can be carried out in a solvent, such as tetrahydrofuran or diethyl ether, at a suitable temperature preferably between 0 and 60°C, using a suitable hydride source, preferably borane, a boranetetrahydrofuran complex, or lithium aluminum hydride. The leaving group intermediate (3e) can be prepared from the alcohol 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 in N,N-dimethylformamide and potassium fluoride, 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 sulfuric acid or hydrogen chloride in an alcoholic acid, preferably methanol or ethanol; acidic reaction conditions also cleave acid-unstable N-protecting groups.

[0201] [ka]

[0202] Reaction Scheme IV outlines the general procedure for synthesizing the compound of formula (I). In Reaction Scheme IV, the chemical groups are as defined herein; however, in Reaction Scheme IV, A 2 Except that is limited to S, O, and NH; in addition, in reaction scheme IV: X = a halide suitable for transition metal catalyzed cross-coupling reactions, preferably bromo or chloro; R = a carbon-bonded (hetero)alkyl or (hetero)aryl group (where -C(O)OR is an ester that is chemically inert to the described cross-coupling reaction, but -C(O)OR is -C(O)OR 1R is preferably methyl, ethyl, benzyl, or tert-butyl, which can be easily converted to yield the compound of formula (I); -BY2 is a boronic acid or boronic acid ester suitable for transition metal-catalyzed cross-coupling reactions, preferably a boronic acid or pinacol boronic acid ester; PG is a protecting group suitable for the described reaction, preferably 2-tetrahydropyranyl.

[0203] Substitutive (aza)indazole intermediates (4a) are commercially available and well-known in the literature, and their conversion to the 3-iodine intermediate (4b) and then to the N-protected intermediate (4c) is also common (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; PGMWuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014). Intermediate (4e) is the iodide intermediate (4c) and thiol intermediate (4d) (A 2 =S;WO2009149837;WO2011138265), or alcohol intermediate (4d)(A 2 =O;WO2009089359;WO2016004272;WO2009149837), or amine intermediate (4d) (A 2The compounds can be prepared by transition metal-catalyzed cross-coupling (=NH; European Journal of Medicinal Chemistry 2021, 213, 113192; Synthesis 2011, 16, 2651). The cross-coupling product intermediate (4f) can be prepared from the halide intermediate (4e) and the boronic acid ester intermediate (1b) by a method similar to that described in reaction scheme IA for converting intermediate (1a) to intermediate (1c). The compounds of formula (I) can be prepared from intermediate (4f) by sequential cleavage of the N-protecting group to intermediate (4g), followed by ester hydrolysis, or by sequential ester hydrolysis to intermediate (4h), followed by cleavage of the N-protecting group. Hydrolysis of intermediate (4f) or intermediate (4g) can be carried out according to the well-known procedure described in the literature (WO2012137089; Tetrahedron Letters 2018, 59, 2917; WO2022150574; WO2022229341). Cleavage of the N-protecting group from intermediate (4f) or intermediate (4h) can be carried out according to PGMWuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2014.

[0204] Intermediate (4b) can be prepared by iodinating intermediate (4a) in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, in the presence of a base, such as potassium hydroxide or potassium tert-butoxide, at a suitable temperature preferably between 0 and 30°C, by reacting it with a suitable iodinating reagent, such as iodine or N-iodosuccinimide. N-protected intermediate (4c) can be prepared from intermediate (4b) by reaction with a suitable protecting group reagent and a suitable acid or base. Preferably, the 2-tetrahydropyranyl protecting group can be introduced using 3,4-dihydro-2H-pyran 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. Intermediate (4e) is introduced using a transition metal catalyst and ligand, preferably Pd2(dba)3 and xanthophos, together with a suitable base, preferably N,N-diisopropylethylamine, in a suitable solvent, such as toluene, at a suitable temperature preferably between 40 and 70°C. Iodide intermediate (4c) and thiol intermediate (4d) (A 2 It can be prepared by a transition metal-catalyzed cross-coupling of (=S).

[0205] Intermediate (4e) is prepared in a suitable solvent, such as toluene or ethanol, together with a suitable base, preferably potassium fluoride or cesium carbonate, at a suitable temperature preferably between 100 and 120°C, using a transition metal catalyst and ligand, preferably copper(I) iodide and 1,10-phenanthroline, to produce iodide intermediate (4c) and alcohol intermediate (4d) (A 2The intermediate (4e) can be prepared by transition metal catalysis cross-coupling of (=O). The intermediate (4e) is prepared in a suitable solvent, such as dioxane or toluene, together with a suitable base and additives, preferably potassium carbonate and sodium ascorbate, at a suitable temperature preferably between 90 and 110°C, using a transition metal catalyst and ligand, preferably copper(I) iodide and N-(2,6-difluorophenyl)-6-hydroxypicolinamide, to produce the iodide intermediate (4c) and amine intermediate (4d) (A 2 It can be prepared by a transition metal-catalyzed cross-coupling of (=NH). The cross-coupling between the halide intermediate (4e) and the boronic acid ester intermediate (1b) can be carried out in a suitable solvent, such as an aqueous solution of dioxane or 1,2-dimethoxyethane, at a suitable temperature preferably between 80 and 110°C, using a catalyst, such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium fluoride, potassium carbonate, or sodium bicarbonate.

[0206] The conversion from ester intermediate (4f) to intermediate (4h), or from ester intermediate (4g) to the compound of formula (I), can be carried out under standard conditions for cleaving the -C(O)OR ester. For R = small alkyl, e.g., methyl or ethyl, hydrolysis to obtain the carboxylic acid can be carried out with a suitable metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably at a suitable temperature between 0 and 110°C, in a solvent, e.g., water, or a mixed water-organic solvent, e.g., methanol, ethanol, and / or aqueous tetrahydrofuran solution. For R = tert-butyl, acid-acidified cleavage of the tert-butyl ester to obtain the carboxylic acid can be carried out with a suitable acid-solvent combination, e.g., trifluoroacetic acid in dichloromethane, or hydrogen chloride in dioxane, preferably at a suitable temperature between 0 and 30°C. The 2-tetrahydropyranyl protecting group can be removed by treating intermediate (4f) or intermediate (4h) with a suitable acid, preferably trifluoroacetic acid, preferably in a suitable solvent, e.g., dichloromethane, at a suitable temperature between 10 and 30°C. The (2-(trimethylsilyl)ethoxy)methyl protecting group can be removed by treating intermediate (4f) or intermediate (4h) with a suitable acid-solvent combination, such as trifluoroacetic acid-dichloromethane or hydrochloric acid-methanol, preferably at a suitable temperature between 10 and 50°C. Alternatively, the (2-(trimethylsilyl)ethoxy)methyl protecting group can be removed by treating intermediate (4f) or intermediate (4h) with a suitable fluoride source, such as tetra-N-butylammonium fluoride, in a suitable solvent, such as tetrahydrofuran, preferably at a suitable temperature between 20 and 60°C.

[0207] [ka] [Examples]

[0208] The following embodiments are provided to allow for a better understanding of the present invention. These embodiments are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0209] Liquid chromatography analysis method LC method A: Acquity UPLC BEH C18 2.1 mm × 50 mm, 1.7 μm; A: 10 mM ammonium acetate in 95:5 H2O:CH3CN, B: 10 mM ammonium acetate in 5:95 H2O:CH3CN, gradient 5% to 100% B over 1 minute, then 100% B over 0.2 minutes; 1.0 mL / min. LC method B: Xbridge C18 2.1 mm × 50 mm, 5 μm; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, gradient from 1% to 5% B over 0.6 min, then to 100% B over 3.4 min; 0.8 mL / min; 40°C. LC method C: Xbridge C18 2.1 mm × 50 mm, 5 μm; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, gradient to 10% B over 0.5 minutes, then to 100% B over 3.5 minutes; 0.8 mL / min, 40°C. LC method D: Xbridge C18 2.1 mm × 50 mm, 5 μm; A: 0.0375% TFA in H2O, B: 0.01875% TFA in CH3CN, gradient to 25% B over 0.5 minutes, then to 100% B over 3.0 minutes; 0.8 mL / min, 40°C. LC method E: Xbridge C18 2.1 mm × 50 mm, 5 μm; A: 0.05% NH4OH in H2O, B: CH3CN, gradient to 5% B over 0.5 minutes, then to 100% B over 2.9 minutes; 0.8 mL / min, 40°C. LC method F: Xbridge C18 2.1 mm × 50 mm, 5 μm; A: 0.05% NH4OH in H2O, B: CH3CN, gradient to 5% B over 0.5 minutes, then to 100% B over 2.9 minutes; 0.8 mL / min, 60°C. LC method G: Waters Atlantis C18 4.6×50mm, 5μ; A: 0.05% TFA in H2O, B: 0.05% TFA in CH3CN, gradient over 4 minutes from 5 to 95%; 2mL / min.

[0210] [ka] Preparation Example 1. Ethyl (E)-3-(5-bromo-6-chloro-1H-indazole-3-yl)acrylate. (Carboethoxymethylene)triphenylphosphoran (50.3 g, 145 mmol) was added to a solution of 5-bromo-6-chloro-1H-indazole-3-carboaldehyde (25.0 g, 96.0 mol) in THF (500 mL). The resulting mixture was heated at 50°C for 16 hours and then concentrated. The residue was purified by silica gel chromatography (0-20% THF: petroleum ether) to obtain ethyl(E)-3-(5-bromo-6-chloro-1H-indazole-3-yl)acrylate as a yellow solid (23 g). 1 1H NMR (400 MHz, DMSO-d6) δ 13.86 (br s, 1H), 8.64 (s, 1H), 7.92 (s, 1H), 7.87 (d, 1H), 6.82 (d, 1H), 4.22 (q, 2H), 1.28 (t, 3H); MS (M+H) + 330.9.

[0211] [ka] Preparation example 2. Ethyl 3-(5-bromo-6-chloro-1H-indazole-3-yl)propanoate. PtO2 (3.17 g, 14.0 mmol) was added to a solution of ethyl(E)-3-(5-bromo-6-chloro-1H-indazole-3-yl)acrylate (23 g, 70 mmol) in EtOH (1.0 L) and siRNA (0.30 L). The mixture was stirred at 25°C for 16 hours under an atmosphere of H2 gas (balloon). The mixture was filtered and concentrated to obtain the crude product, which was purified by silica gel chromatography (0-20% THF: petroleum ether) to obtain ethyl 3-(5-bromo-6-chloro-1H-indazole-3-yl)propanoate as a white solid (16 g). 1 1H NMR (DMSO-d6) δ 12.99 (s, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 4.03 (q, 2H), 3.16 (t, 2H), 2.78 (t, 2H), 1.14 (t, 3H); MS (M+H) + 332.9.

[0212] [ka] Preparation Example 2, Alternative Procedure: Ethyl 3-(5-bromo-6-chloro-1H-indazole-3-yl)propanoate. 2,2-dimethyl-1,3-dioxane-4,6-dione (183 g, 1.27 mmol), Et3N (322 mL, 2.31 mol), and formic acid (214 mL, 5.67 mol) were sequentially added to a solution of 5-bromo-6-chloro-1H-indazole-3-carboaldehyde (300 g, 1.16 mol) in dioxane (3.0 L). The resulting mixture was heated at 100°C for 16 hours, then cooled to ambient temperature, and H2O (200 mL) was added. The pH was adjusted to approximately 2-3 by adding aqueous HCl (3 M), and the solution was then extracted with siRNA (2 × 100 mL). The combined organic matter was washed with saturated aqueous NaCl (3 × 100 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-5% THF:DCM) to obtain ethyl 3-(5-bromo-6-chloro-1H-indazole-3-yl)propanoate as a yellow solid. These two reactions on the same scale yielded a total of 469 g of ethyl 3-(5-bromo-6-chloro-1H-indazole-3-yl)propanoate. 1 1H NMR (DMSO-d6) δ 12.99 (s, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 4.03 (q, 2H), 3.16 (t, 2H), 2.78 (t, 2H), 1.14 (t, 3H); MS (M+H) + 332.9.

[0213] [ka] Preparation Example 3. Ethyl 3-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-yl)propanoate. 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-indazole-3-yl)propanoate (12 g, 36 mmol) in dioxane (150 mL). The resulting mixture was stirred at 120 °C for 5 hours under N2 gas, then cooled and diluted with H2O (50 mL). The volatile organic compounds were evaporated under reduced pressure, and the residue was extracted with ELISA (2 × 100 mL). The combined organic compounds were dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by silica gel chromatography (0-20% THF: petroleum ether) to obtain a solid, which was then slurryed in petroleum ether (50 mL). After filtration and drying, ethyl 3-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-yl)propanoate was obtained as a yellow solid (7.0 g). 1 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.76 (m, 3H), 7.68 (s, 1H), 7.47 (d, 2H), 4.03 (q, 2H), 3.18 (t, 2H), 2.79 (t, 2H), 1.33 (s, 12H), 1.12 (t, 3H); MS (M+H) + 455.1.

[0214] [ka] Preparation example 4. 4'-bromo-[1,1'-biphenyl]-2-ol. (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 at 80°C for 17 hours under N2 gas, then cooled and partitioned between H2O (1.0 L) and SiO (3 × 1.0 L). The combined organic matter was washed with saturated aqueous NaCl (1.0 L), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-7% SiO: petroleum ether) to obtain 4'-bromo-[1,1'-biphenyl]-2-ol as a yellow oil (625 g). 1 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.58 (d, 2H), 7.50 (d, 2H), 7.25 (d, 1H), 7.17 (m, 1H), 6.95 (dd, 1H), 6.87 (m, 1H).

[0215] [ka] Preparation Example 5. 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol. 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). The resulting mixture was stirred at 100°C for 16 hours under N2 gas, then cooled and partitioned between H2O (1.5 L) and SiO2 (3 × 1.5 L). The combined organic matter was washed with saturated NaCl aqueous solution (1.0 L), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-3% siRNA: petroleum ether) to obtain 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol as a white solid (500 g). 1 1H NMR (400 MHz, CDCl3) δ 7.86 (d, 2H), 7.41 (d, 2H), 7.18 (m, 2H), 6.91 (m, 2H), 5.16 (s, 1H), 1.29 (s, 12H).

[0216] [ka] Preparation Example 6. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoate. N2 gas was sprayed over 20 minutes onto a solution of ethyl 3-(5-bromo-6-chloro-1H-indazole-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). Pd(dppf)Cl2 (1.10 g, 1.51 mmol) was added, and the mixture was heated to 80°C for 17 hours, then cooled to ambient temperature. The mixture was partitioned between siRNA(2×) and H2O, and the combined organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-50% siRNA:heptane) to obtain a solid, which was then slurryed in EtOH. After filtration and drying, ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoate was obtained as a white solid (2.6 g). 1 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.58 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.64 (d, 2H), 7.48 (d, 2H), 7.33 (dd, 1H), 7.18 (m, 1H), 6.97 (d, 1H), 6.91 (m, 1H), 4.03 (q, 2H), 3.19 (t, 2H), 2.79 (t, 2H), 1.13 (t, 3H); MS (M+H) + 421.2.

[0217] [ka] Preparation Example 7. Ethyl 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate. Pd(dppf)Cl2-CH2Cl2 (19 mg, 0.026 mmol) was added to a mixture of dioxane (5 mL), 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-indazole-3-yl)propanoate (120 mg, 0.26 mmol), and K2CO3 (109 mg, 0.79 mmol) in H2O (1 mL). The resulting mixture was heated at 80°C for 2 hours. The mixture was cooled to ambient temperature and then extracted with siRNA (2 × 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated. The obtained solid was purified by silica gel chromatography (50-100% petroleum ether: Â, then 10:1 Â:MeOH) to obtain ethyl 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate as a yellow solid (95 mg). MS(M+H) + 448.1.

[0218] [ka] Preparation example 8. 5-bromo-3-formyl-1H-indazole-6-carbonitride. A solution of NaNO2 (521 mg, 7.6 mmol) in H2O (3.8 mL) was added to a solution of 5-bromo-1H-indole-6-carbonitrile (167 mg, 0.76 mmol) in acetone (7.6 mL). N2 was sprinkled over the mixture for 0.5 minutes, and 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, and then at ambient temperature for 3.5 hours. The resulting solid (120 mg), a mixture of 5-bromo-3-formyl-1H-indazole-6-carbonitrile and unreacted 5-bromo-1H-indole-6-carbonitrile was collected and used in the next step without further purification. MS(MH) - 248.1.

[0219] [ka] Preparation example 9. Ethyl (E)-3-(5-bromo-6-cyano-1H-indazole-3-yl)acrylate. (Carboethoxymethylene)triphenylphosphorane (209 mg, 0.60 mmol) was added to a solution of 5-bromo-3-formyl-1H-indazole-6-carbonitride (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 (5-65% Â:heptane) to obtain ethyl(E)-3-(5-bromo-6-cyano-1H-indazole-3-yl)acrylate containing 5-bromo-1H-indole-6-carbonitride. The substance was used in the next reaction without further purification. MS(MH) - 318.1.

[0220] [ka] Preparation Example 10. Ethyl 3-(5-bromo-6-cyano-1H-indazole-3-yl)propanoate. A suspension of ethyl 3-(5-bromo-6-cyano-1H-indazole-3-yl)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 sequentially purged with N2 (50 psi, 3 ×) and H2 (30 psi, 3 ×), and then held under H2 for 13 hours. The resulting mixture was filtered through Celite, rinsed with EtOH, and the filtrate was concentrated. Ethyl 3-(5-bromo-6-cyano-1H-indazole-3-yl)propanoate (18 mg) was obtained by silica gel chromatography (0-70% HCl:heptane). MS (MH) - 320.1.

[0221] [ka] Preparation Example 11. Ethyl 3-(5-bromo-6-fluoro-1H-indazole-3-yl)propanoate. Ethyl 3-(5-bromo-6-fluoro-1H-indazole-3-yl)propanoate was prepared from 5-bromo-6-fluoro-1H-indazole-3-carboaldehyde by a method similar to that used in Preparation Examples 9 and 10. MS(MH) - 313.2.

[0222] [ka] Preparation example 12. 5,6-Dichloro-1H-pyrazolo[4,3-b]pyridine. KOAc (2.36 g, 24 mmol) and Ac2O (7.56 mL, 80 mmol) were sequentially added to a solution of 5,6-dichloro-2-methylpyridine-3-amine (3.5 g, 20 mmol) in CHCl3 (10 mL). The resulting mixture was heated at 60°C for 2 hours, then dicyclohexano-18-crown-6 (745 mg, 2.0 mmol) and a solution of isoamyl nitrite (6.45 mL, 47 mmol) in CHCl3 (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 at 0°C for 10 minutes, and then at ambient temperature for 1.5 hours. The obtained solid was filtered to obtain 5,6-dichloro-1H-pyrazolo[4,3-b]pyridine (1.9 g). MS(MH) - 186.1.

[0223] [ka] Preparation example 13. 5,6-Dichloro-3-iodo-1H-pyrazolo[4,3-b]pyridine. Solid KOH (673 mg, 12 mmol) and I2 (1.83 g, 7.2 mmol) were sequentially added at 0°C to a solution of 5,6-dichloro-1H-pyrazolo[4,3-b]pyridine (752 mg, 4.0 mmol) in DMF (15 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then at ambient temperature for 18 hours. The excess I2 was quenched by adding saturated Na2S2O3 aqueous solution, and the mixture was then diluted with H2O (30 mL) and acidified to pH 3-4 by adding HCl aqueous solution (1 M, 6 mL). The mixture was extracted with 10% MeOH:DCM (3 × 60 mL). The combined organic matter was sequentially washed with saturated NaHCO3 aqueous solution and H2O (2 ×), and then dried on MgSO4. The solution was concentrated to obtain a yellow solid, which was then ground with 10% siRNA:heptane to obtain 5,6-dichloro-3-iodo-1H-pyrazolo[4,3-b]pyridine as a yellow solid (1.25 g). MS(MH) - 312.0.

[0224] [ka] Preparation Example 14. 5,6-Dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine. 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[4,3-b]pyridine (991 mg, 3.0 mmol) in THF (15 mL). The resulting mixture was heated at 50°C for 9 hours, then at ambient temperature for 12 hours. The mixture was partitioned between saturated aqueous NaHCO3 and ELISA. The organic layer was washed with brine, dried over MgSO4, concentrated, and the solid was ground with heptane to obtain 5,6-dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine as a beige solid (1.1 g).

[0225] [ka] Preparation Example 15. Ethyl(E)-3-(5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)acrylate. A solution of 5,6-dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-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 at 80°C for 4 hours. An additional portion of 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 a similar mixture from a reaction carried out 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 substance was concentrated to remove DMF, and the resulting residue was partitioned between HCl and H2O. The organic layer was washed sequentially with saturated NaHCO3 aqueous solution, H2O, and brine, and then concentrated. Ethyl(E)-3-(5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)acrylate (483 mg) was obtained by silica gel chromatography (0-100% HCl:heptane). MS(M+H) + 370.2.

[0226] [ka] Preparation Example 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]pyridine-3-yl) acrylate. A mixture of 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[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]pyridine-3-yl) acrylate (74 mg, 0.20 mmol), saturated NaHCO3 aqueous 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 at 60°C for 22 hours. The mixture was cooled and combined with a similar mixture from a reaction carried out on the same scale. The combined mixture was partitioned between ELISA and H2O. The organic layer was washed with saturated NaHCO3 aqueous solution and then concentrated. Ethyl(E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl) acrylate (102 mg) was obtained by silica gel chromatography (0-100% HCl:heptane). MS(M+H) + 504.3.

[0227] [ka] Preparation Example 17. Ethyl(E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl) acrylate. 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-2-yl)-1H-pyrazolo[4,3-b]pyridine-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 partitioned between ethyl and H2O. The organic matter was washed sequentially with saturated NaHCO3 aqueous solution and brine, and then concentrated. Ethyl (E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl) acrylate (58 mg) was obtained by silica gel chromatography (0-100% HCl:heptane).

[0228] [ka] Preparation Example 18. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)propanoate. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)propanoate was prepared from ethyl(E)-3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)acrylate using a procedure similar to that of Preparation Example 10. Ethyl 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)propanoate was purified by silica gel chromatography (0-100% HCl:heptane). MS(M+H) + 422.4.

[0229] [ka] Preparation example 19. 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. 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 and then concentrated. The resulting residue was treated with an aqueous solution of NaOH (1 M) to dissolve the p-toluenesulfonic acid, and the remaining solid was filtered to obtain 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.58 g).

[0230] [ka] Preparation Example 20. Methyl (5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate. A mixture of 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 0.45 mmol), glycine methyl 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 vial was purged with N2 (3×), then dioxane (2.27 mL) was added, and the resulting mixture was heated at 100°C for 18 hours. The resulting mixture was cooled, diluted with ethyl acetate, and filtered through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel chromatography (0-100% Â:heptane) to obtain methyl (5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate as a solid (115 mg). MS(M+H) +404.1.

[0231] [ka] Preparation Example 21. Methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate. A mixture of 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[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 vial was purged with N2 (3×). A solution of methyl(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate (115 mg, 0.029 mmol) in dioxane (2.0 mL), followed by H2O (0.5 mL), was added sequentially, and the resulting mixture was heated at 90°C for 1.75 hours. The mixture was cooled, filtered through Celite while rinsing with ethyl acetate, and the filtrate was concentrated to remove the organic solvent. The resulting mixture was extracted with DCM (3×). The combined organic matter was dried over MgSO4 and concentrated. Methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate (83 mg) was obtained by silica gel chromatography (0-100% ethyl acetate:heptane). MS(M+H) + 492.3.

[0232] [ka] Preparation Example 22. (6-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycine. An aqueous solution of NaOH (1 M, 0.50 mL, 0.50 mmol) was added to a mixture of methyl (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycinate (20 mg, 0.041 mmol) and MeOH (0.5 mL). The mixture was heated at 50°C for 1 hour, then cooled and diluted with aqueous HCl (1 M) until a precipitate formed. The mixture was extracted with 20% MeOH:DCM (2 mL), and the organic layer was concentrated to obtain (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)glycine (22 mg), which was used without further purification. MS(M+H) + 478.2.

[0233] [ka] Preparation Example 23. Methyl 2-((5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)thio)acetate. To a sealed microwave vial containing Pd2(dba)3 (41 mg, 0.044 mmol) and xanthophos (51 mg, 0.088 mmol) under an 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 2-mercaptoacetate methyl (40 μL, 0.44 mmol) were sequentially added. The resulting mixture was heated at 45°C for 1.5 hours, then cooled and diluted with H2O. The organic layer was collected, and the aqueous layer was extracted with ELISA (2×). The combined organic matter was washed with brine, dried over MgSO4, and concentrated. Methyl 2-((5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)thio)acetate was obtained as a solid (114 mg) by silica gel chromatography (0-100% siRNA:heptane). MS(M+H) + 421.2.

[0234] [ka] Preparation Example 24. Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)thio)acetate. Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)thio)acetate was prepared from methyl 2-((5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)thio)acetate by a method similar to that of Preparation Example 21. MS(M+H) + 509.4.

[0235] [ka] Preparation Example 25. Methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)thio)acetate. 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-2-yl)-1H-indazole-3-yl)thio)acetate (16 mg, 0.031 mmol) and DCM (0.5 mL). After 2.5 hours, the mixture was concentrated to obtain methyl 2-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)thio)acetate, which was used without further purification. MS(M+H) + 425.3.

[0236] [ka] Preparation Example 26. Ethyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoate. 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-indazole-3-yl)propanoate (16.0 g, 48.3 mmol) in THF (100 mL). The resulting mixture was heated at 50°C for 4 hours and then cooled. The mixture was partitioned between saturated NaHCO3 aqueous solution (30 mL) and siRNA (3 × 100 mL). The combined organic matter was dried over Na2SO4 and concentrated. Ethyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoate was obtained as a solid (16.5 g) by silica gel chromatography (0-80% ethyl: petroleum ether). MS(M+H) + 417.1.

[0237] [ka] Preparation Example 27. 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoic acid. LiOH-H2O (303 mg, 7.2 mmol) was added at 15°C to a solution of ethyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoate (1.0 g, 2.4 mmol) in THF (10 mL), MeOH (10 mL), and H2O (10 mL). After 3 hours, the mixture was concentrated to remove the organic solvent, and then the pH was adjusted to approximately 3 by adding aqueous HCl. The resulting white solid was collected and dried to obtain 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoic acid (0.90 g). MS(M+H) + 388.9.

[0238] [ka] Preparation example 28. 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propan-1-ol. Boranetetrahydrofuran complex (1M solution in THF, 6.96 mL, 6.96 mmol) was added dropwise at 0°C to a solution of 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoic acid (0.90 g, 2.32 mmol) in THF (20 mL). The resulting mixture was stirred at 15°C for 16 hours. MeOH was added, and the mixture was concentrated. The resulting residue was partitioned between H2O (30 mL) and  (100 mL, then 60 mL). The combined organic matter was washed with brine (2 × 30 mL), concentrated, and 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propan-1-ol (0.80 g) was obtained as a solid and used without further purification. MS(M+H) + 375.0.

[0239] [ka] Preparation Example 29. 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propylmethanesulfonate. Triethylamine (1.49 mL, 10.7 mmol) and methanesulfonic anhydride (1.49 g, 8.56 mmol) were sequentially added at 0°C to a solution of 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propan-1-ol (0.80 g, 2.1 mmol) in DCM (45 mL). The resulting mixture was stirred at 10°C for 18 hours and then partitioned between DCM (30 mL) and H2O (2 × 20 mL). The combined organic materials were sequentially washed with citric acid aqueous solution (0.5 M, 20 mL) and brine (20 mL), then dried on Na2SO4 and concentrated to obtain 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propylmethanesulfonate (0.96 g) as an oily substance, which was used without further purification. MS(M+H) + 452.9.

[0240] [ka] Preparation example 30. 4-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)butanenitrile. 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-indazole-3-yl)propylmethanesulfonate (0.96 g, 2.1 mmol) in DMF (20 mL). The resulting mixture was heated at 90°C for 16 hours, then cooled and partitioned between siRNA and H2O. The organic layer was washed with brine, then dried over Na2SO4 and concentrated. Silica gel chromatography (15% siRNA: petroleum ether) yielded 4-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)butanenitrile (0.30 g) as an oil. MS(M+H) + 381.9.

[0241] [ka] Preparation Example 31. Ethyl 4-(5-bromo-6-chloro-1H-indazole-3-yl)butanoate. Sulfuric acid (1 mL) was added dropwise to a solution of 4-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)butanenitrile (0.30 g, 0.78 mmol) in EtOH (5 mL). The resulting mixture was heated at 100 °C for 16 hours, then cooled and concentrated. Saturated NaHCO3 aqueous solution (30 mL) was added, and the mixture was extracted with HCl (3 × 100 mL). The combined organic matter was washed with brine, dried on Na2SO4, and concentrated. Ethyl 4-(5-bromo-6-chloro-1H-indazole-3-yl)butanoate (150 mg) was obtained as an oil by silica gel chromatography (0-50% HCl: petroleum ether). MS(M+H) + 346.9.

[0242] [ka] Preparation Example 32. Ethyl 3-(5-(4'-(((tert-butoxycarbonyl)amino)methyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate. Ethyl 3-(5-(4'-(((tert-butoxycarbonyl)amino)methyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate was prepared from tert-butyl(4-bromo-3-hydroxybenzyl)carbamate using a procedure similar to that of Preparation Example 7. MS(M+H) + 550.1.

[0243] [ka] Preparation Example 33. Methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate. A solution of HCl in dioxane (4M, 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-indazole-3-yl)propanoate (55 mg, 0.10 mmol) in MeOH (4 mL). After 3 hours at 20°C, the resulting mixture was concentrated to obtain methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoate (44 mg), which was used without further purification. MS(M+H) + 437.3.

[0244] [ka] Preparation example 34. tert-butyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoate. tert-butyl 3-(5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)propanoate was prepared from 5-bromo-6-chloro-1H-indazole-3-carboaldehyde and (tert-butoxycarbonylmethylene)triphenylphosphoran by a procedure similar to that of Preparation Examples 9, 10, and 26. MS(M+H) + 445.1.

[0245] [ka] Preparation Example 35. Methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)-2-hydroxy-[1,1'-biphenyl]-4-carboxylate. Methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-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-indazole-3-yl)propanoate, 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, and methyl 4-bromo-3-hydroxybenzoate using a procedure similar to that of Preparation Examples 3 and 7. MS(M+H) + 591.5.

[0246] [ka] (Example 1) 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. An aqueous solution of NaOH (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]-4-yl)-1H-indazole-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 organic matter, and the aqueous residue was then diluted with H2O (25 mL). The resulting solution was heated to 100°C and held at that temperature for 15 minutes. An aqueous solution of HCl (1.0 M, 27 mL, 27 mmol) was added dropwise to the heated solution, and a precipitate formed. The mixture was heated under reflux for 16 hours, then cooled to ambient temperature and stirred for a further 4 hours. The solid was filtered and dried under a stream of N2 gas to obtain 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid as a crystalline white solid (1.6 g). 1 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 12.11 (s, 1H), 9.58 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.33 (dd, 1H), 7.18 (m, 1H), 6.97 (d, 1H), 6.91 (t, 1H), 3.16 (t, 2H), 2.72 (t, 2H); MS (M+H) + 393.1.

[0247] The following examples were synthesized using a method and starting materials similar to those described for 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid.

[0248] [ka] (Example 2) 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. It was synthesized from 1,4-dibromobenzene, (2-hydroxy-3-methoxyphenyl)boronic acid, and 1,4-bis(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzene by a method similar to that described for 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. 1 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 12.12 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.62 (d, 2H), 7.48 (d, 2H), 6.97 (m, 2H), 6.88 (m, 1H), 3.86 (s, 3H), 3.16 (t, 2H), 2.72 (t, 2H); MS (M+H) + 423.3.

[0249] [ka] (Example 3) 3-(6-chloro-5-(3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. It was synthesized from 1-bromo-2-fluoro-4-iodobenzene by a method similar to that described for 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. 1 1H NMR (400MHz, MeOD) δ 7.76 (s, 1H), 7.62 (s, 1H), 7.43 (m, 2H), 7.36 (m, 2H), 7.17 (m, 1H), 6.91 (m, 2H), 3.25 (t, 2H), 2.79 (t, 2H); MS (M+H) + 411.2.

[0250] [ka] (Example 4) 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indole-3-yl)propanoic acid. It was synthesized from 5-bromo-6-chloro-1H-indole-3-carboaldehyde by a method similar to that described for 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. 1 1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 9.63 (s, 1H), 8.32 (s, 1H), 7.56 (m, 6H), 7.32 (m, 1H), 7.20 (m, 2H), 6.93 (m, 2H), 2.93 (t, 2H), 2.56 (t, 2H); MS (M+H) + 392.0.

[0251] [ka] (Example 5) 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. 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-1H-indazole-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 organic matter, and the aqueous residue was then acidified to approximately pH 3 by adding aqueous HCl (1 M). The resulting solid was collected, rinsed with H2O, and dried to obtain 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid as a solid (72 mg). 1 1H NMR (400 MHz, MeOD) δ 7.99 (d, 2H), 7.85 (s, 1H), 7.82 (d, 2H), 7.77 (d, 2H), 7.64 (s, 1H), 7.58 (d, 2H), 3.27 (m, 2H), 2.70 (m, 2H); MS (M+H) + 420.1.

[0252] The following examples were synthesized using a method and starting materials similar to those described for 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid.

[0253] [ka] (Example 6) 3-(5-(4'-carbamoyl-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. It was synthesized from 4-bromo-3-hydroxybenzamide by a method similar to that described for 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. 1 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (m, 2H), 7.63 (s, 1H), 7.50 (m, 2H), 7.43 (m, 3H), 3.27 (m, 2H), 2.71 (m, 2H); MS (M+H) + 436.1.

[0254] [ka] (Example 7) 3-(6-chloro-5-(4-(3-hydroxypyridine-4-yl)phenyl)-1H-indazole-3-yl)propanoic acid. It was synthesized from 4-bromopyridine-3-ol by a method similar to that described for 3-(5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. 1 1H NMR (400 MHz, MeOD) δ 8.19 (s, 1H), 8.10 (d, 1H), 7.82 (s, 1H), 7.78 (d, 2H), 7.65 (s, 1H), 7.56 (d, 2H), 7.46 (d, 1H), 3.27 (m, 2H), 2.78 (m, 2H); MS (M+H) + 394.2.

[0255] [ka] (Example 8) 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. NaOH (20 mg, 0.51 mmol) was added to methyl 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-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 approximately 4 with 2 M hydrochloric acid. The mixture was concentrated, and the residue was purified by reverse-phase HPLC to obtain 3-(5-(4'-(aminomethyl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-6-chloro-1H-indazole-3-yl)propanoic acid. MS(M+H) + 422.1. LC method A, room temperature, 0.60 min.

[0256] [ka] (Example 19) (6-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)glycine. 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)-1H-indazole-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 obtain (6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)glycine (3.4 mg). MS(M+H) + 394.3. LC method G, room temperature, 2.60 minutes.

[0257] [ka] (Example 31) 3-(6-chloro-5-(2'-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid. A mixture of methyl 4'-(3-(3-(tert-butoxy)-3-oxopropyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-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 reverse-phase HPLC to obtain 3-(6-chloro-5-(2'-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid (17 mg). 1 H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.69 (d, 2H), 7.65-7.55 (m, 3H), 7.51 (d, 2H), 7.46 (d, 1H), 3.91 (s, 3H), 3.26 (t, 2H), 2.76 (t, 2H); MS (M+H) + 451.3.

[0258] The examples in Table 1 were prepared using methods similar to those described above.

[0259] [Table 1-1]

[0260] [Table 1-2]

[0261] [Table 1-3]

[0262] [Table 1-4]

[0263] [Table 1-5]

[0264] [Table 1-6]

[0265] [Table 1-7]

[0266] [Table 1-8]

[0267] [Table 1-9]

[0268] [Table 1-10]

[0269] [Table 1-11]

[0270] [Table 1-12]

[0271] [Table 1-13]

[0272] [Table 1-14]

[0273] Biosynthesis of Glucuronide Metabolite Compounds The compound from Example 1 (50 μM) was incubated with mouse liver microsomes (2 mg / mL) containing 10 μg / mL aramethicine, 3.3 mM MgCl2, and 5 mM uridine diphosphate glucuronic acid in 40 mL of KH2PO4 (100 mM, pH 7.4). Incubation was carried out in a 250 mL Erlenmeyer flask in a shaking water bath maintained at 37 °C for 60 hours. At the end of incubation, the incubation was divided into n=2, 20 mL alicots, 20 mL of CH3CN was added to each sample, and the mixtures were transferred to two 50 mL polypropylene conical tubes and vigorously mixed with a vortex mixer. The tubes were rotated in a Beckman centrifuge at 1800 g for 10 minutes, and the supernatant was transferred to a new 50 mL polypropylene conical tube. The tube was subjected to vacuum centrifugation for approximately 4 hours in a Genevac evaporator set to HPLC mixture settings to remove CH3CN. To the remaining solution, 10 mL of 0.1% formic acid:acetonitrile (95:5, % v:v) in water was added, and the resulting mixture was centrifuged in a Beckmann centrifuge at 40,000 g for 30 minutes to clarify the supernatant.

[0274] The supernatant was combined and transferred to a 50 mL polypropylene conical tube, and then applied directly to a Varian Polaris C18 column (4.6 × 250 mm; 5 mm particle size) via a Jasco HPLC pump at a flow rate of 0.8 mL / min. After applying 20 mL, an additional 5 mL of 0.1% formic acid:acetonitrile (95:5, %v:v) in water was pumped into the column to ensure that the supernatant was removed from the HPLC line. The HPLC column was then transferred to an Agilent 1200 HPLC-UV system. The effluent was collected directly in a PAS HTS-xt fraction collector. The mobile phases used were 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 was started at 95%A / 5%B and held for 5 minutes, followed by a linear gradient to 5%A / 95%B at 45 minutes, held until 48 minutes, and returned to the original conditions at 60 minutes. Mobile phase programming and data acquisition were initiated by dummy water injection from the autosampler. Fractions were collected every 7 seconds into a wide-well polypropylene microtiter plate. Fractions collected in the relevant region (i.e., the region where the UV detector showed significant absorbance) were tested for purity by injecting 5 mL at a flow rate of 0.4 mL / min using a second HPLC gradient method with the same mobile phase using a Phenomenex XB-C18, 2.1 × 100 mm, 1.7 u column. The mobile phase composition was started at 95%A / 5%B and held for 0.5 minutes, followed by a linear gradient to 5%A / 95%B at 3.75 minutes, held until 4 minutes, and returned to the original conditions at 5 minutes. The products were combined in 15 mL conical glass tubes, and the solvent was evaporated by vacuum centrifugation in a Genevac evaporator. After drying, the samples were prepared for NMR analysis.

[0275] For structural characterization purposes, the sample was dissolved in 0.045 mL of 100% deuterated methanol-MeOD (Cambridge Isotope Laboratories, Andover, MA) and placed in a 1.7 mm NMR tube under a dry argon atmosphere. For quantitative NMR, after structural characterization was complete, the sample was dried, reconstituted in 0.045 mL of 100% dimethyl sulfoxide-DMSO (Cambridge Isotope Laboratories, Andover, MA), and placed in a 1.7 mm NMR tube under a dry argon atmosphere. Using the residual solvent, 1 H and 13 The C spectrum was referenced (DMSO-d6-TMS δ=0.00). 1 For H δ = 2.50 ppm and TMS δ = 0.00 13C δ=39.50 ppm, MeOD-d4-TMS δ=0.00 vs. 1H δ=3.35 ppm, TMS δ=0.00 vs. 13C δ=49.3 ppm). NMR spectra were recorded using a Bruker Avance 600 MHz (Bruker BioSpin Corporation, Billerica, MA) controlled by Topspin V4.0 and equipped with a 1.7 mm TCI Cryo probe. 1D spectra were recorded using an approximate sweep width of 8400 Hz and a total recycle time of approximately 7 seconds. The resulting time-averaged free induction decay was transformed using exponential line broadening at 1.0 Hz to improve the signal-to-noise ratio. 2D data were recorded using a standard pulse sequence provided by Bruker. A data matrix of at least 1K×128 was acquired using at least two scans and 16 dummy scans with a spectral width of 10,000 Hz in f² dimension. The 2D dataset was zero-filled to at least 1k data points. Post-acquisition data processing was performed using MestReNova V12.1. All conditions for data acquisition are included in the raw files. Quantification was achieved using the external standard of 5 mM benzoic acid (Cambridge Isotope Laboratories, Andover, MA) and the quantification plugin for Mnova software.

[0276] [ka] 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Example 79)

[0277] [ka] 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazole-5-yl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Example 80)

[0278] AMPK111 expression and purification A tricistronic AMPK expression construct was prepared, which contained an open reading frame encoding the full-length α1, β1, and δ1 subunits of human AMPK, along with the ribosome-binding sites (RBS) preceding each coding region. This construct was subcloned into the pET-14b expression vector (Novagen, Madison, Wisconsin) using standard molecular biology techniques. The AMPK tricistronic construct was transformed into *E. coli* BL21-CodonPlus®(DE3)-RIPL strain (Stratagene), and the transformants were selected on LB (Luria-Bertani) agar plates containing ampicillin (100 μg / mL). 100 mL of Escherichia coli (E. coli) shaken flask culture (BL-21, pET-14b, AMPK 111) was inoculated into 10 liters of LB medium containing 100 μg / mL carbenicillin (MP Biomedical LB broth #11-3002-032) in a BF4 10 L working volume bioreactor (New Brunswick Scientific Co.) at 37°C, 600 rpm, and 6 L / min aeration. Optical density measurements were performed on the sample using an UltraSpec 2000 spectrophotometer (Pharmacia Biotech) at 600 nm.

[0279] When the cell density reached approximately OD 0.9, the temperature was reduced to 18°C, and the culture was induced with 0.1 mM isopropylthiogalactoside (IPTG) at 18°C. The cell paste was collected approximately 18 hours after induction by continuous flow centrifugation at 15,000 rpm at 4°C (Heraeus, rotor #8575). The cell pellet was divided into four portions, rapidly 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-carboxyethylphosphine (TCEP), 20 mM imidazole, and 0.001% Triton X-100). After ultrasonic treatment, insoluble substances were removed by centrifugation at 15,000 rpm for 30 minutes at 4°C using a Sorvall® RC5 plus centrifuge. The supernatant was loaded into a 5 mL HisTrap® HP column (GE Healthcare, Piscataway, NJ) and washed with 5 column volumes of lysis buffer. The bound proteins were eluted using an elution buffer containing 300 mM imidazole. The fraction containing the AMPK subunit was collected based on SDS-10% 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). The purified AMPK complex was phosphorylated at its activation loop Thr 172 by incubation at 30°C for 30 minutes in the presence of 200 nM CaMKKB (calmodulin-dependent protein kinase B obtained from Dundee University) in phosphorylation buffer. The phosphorylated AMPK complex was re-purified using a HisTrap® HP column as before and dialyzed overnight in dialysate buffer.The phosphorylated AMPK complex was further purified in SEC buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100) by gel filtration chromatography using a Superdex 200 HiLoad 16 / 60 column (GE Healthcare). The final sample was stored at -20°C with 25% glycerol.

[0280] AMPK221 expression and purification A tricistronic AMPK expression construct was designed containing an open reading frame encoding the full-length α2, β2, and δ1 subunits of human AMPK, along with the ribosome-binding site (RBS) preceding each coding region. The construct was subcloned into the pET-14b expression vector (Novagen, Madison, Wisconsin) using standard molecular biology techniques. The AMPK tricistronic construct was transformed into *E. coli* BL21-CodonPlus™ (DE3)-RIPL strain (Stratagene), and the transformants were selected on LB (Luria-Bertani) agar plates containing ampicillin (100 μg / mL). 100 mL of Escherichia coli (E. coli) shaken flask culture (BL-21, pET-14b, AMPK 221) was inoculated into 10 liters of LB medium containing 100 μg / mL carbenicillin (MP Biomedical LB broth #11-3002-032) in a BF4 10 L working volume bioreactor (New Brunswick Scientific Co.) at 37°C, 600 rpm, and aeration at 6 L / min. Optical density of the sample was measured at 600 nm using an UltraSpec 2000 spectrophotometer (Pharmacia Biotech).

[0281] When the cell density reached approximately OD 0.9, the temperature was reduced to 18°C, and the culture was induced with 0.1 mM isopropylthiogalactoside (IPTG) at 18°C. The cell paste was collected approximately 18 hours after induction by continuous flow centrifugation at 15,000 rpm at 4°C (Heraeus, rotor #8575). The cell pellet was divided into four portions, rapidly 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-carboxyethylphosphine (TCEP), 20 mM imidazole, and 0.001% Triton X-100). After ultrasonic treatment, insoluble substances were removed by centrifugation at 15,000 rpm for 30 minutes at 4°C using a Sorvall® RC5 plus centrifuge. The supernatant was loaded into a 5 mL HisTrap® HP column (GE Healthcare, Piscataway, NJ) and washed with 5 column volumes of lysis buffer. The bound proteins were eluted using an elution buffer containing 300 mM imidazole. The fraction containing the AMPK subunit was collected based on SDS-10% 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). The purified AMPK complex was phosphorylated at its activation loop Thr 172 by incubation at 30°C for 30 minutes in the presence of 200 nM CaMKKB (calmodulin-dependent protein kinase B obtained from Dundee University) in phosphorylation buffer. The phosphorylated AMPK complex was re-purified using a HisTrap® HP column as before and dialyzed overnight in dialysate buffer.The phosphorylated AMPK complex was further purified in SEC buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and 0.001% Triton X-100) by gel filtration chromatography using a Superdex 200 HiLoad 16 / 60 column (GE Healthcare). The final sample was stored at -20°C with 25% glycerol.

[0282] Expression and purification of PP2A The coding sequence for the human recombinant protein phosphatase 2A catalytic subunit (PPP2CA; 308 aa, P67775, AA2-309), including the N-terminal 2X FLAG tag and TEV protease moiety, was synthesized and subcloned into the pFastBac Dual expression vector (Thermo Fisher, 10712024) under the PolH promoter and N-terminal His tag-containing protein phosphatase 2A regulatory subunit (PPP2R1A; 508 aa, P30153, AA2-589). The TEV protease moiety was synthesized and subcloned into the same vector under the p10 promoter. Baculoviruses were generated using the vectors via the Bac-to-Bac System (Thermo Fisher), and the proteins were expressed in Sf9 cells (Expression Systems, 94-001F) using the Bac-to-Bac System (Thermo Fisher) in succession. Sf9 cells were cultured in ESF 921 medium (Expression Systems, 96-001-01) at 3 L volume in a sterile 5 L Thomson Optimum Growth Flask (Thomson Instrument Company, 931116) with a vent cap at 27°C with shaking at 115 rpm over a 2-inch shaking diameter. Cells were infected with 10 ml / L of P0 virus at a density of approximately 2.5 × 10⁶ vc / ml with a viability of >95%. At harvest time (71 hours post-infection), cell viability percentage (approximately 80%) and cell diameter increase (>3 microns) were indicated. Cell paste was collected by centrifugation in a Thermo Sorvall RC 3BP + 5000 × g centrifuge and frozen at -80°C.

[0283] For purification, 3 L of culture equivalent to cell paste was resuspended in 175 mL of lysis / wash buffer (50 mM Tris pH 8.0, 300 mM NaCl, 10% glycerol, 1 mM TCEP). Cells were lysed in three passes by microfluidization at 15,000 PSI and clarified by centrifugation at 30,000 × g. 5 mL of FLAG resin was equilibrated with lysis buffer. The equilibrated FLAG resin was added to the supernatant and batch-bound 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 fraction was analyzed by SDS-PAGE, Mass Spec, and PP2a activity. The total protein concentration was determined to be 0.149 mg / mL using Superdex 200 16-60.

[0284] Biochemical profiling of AMPK activators using AMPK111 The HTRF assay using LANCE Ultra ULight-Acetyl-CoA Carboxylase (SAMS) peptide (commercially available, Perkin Elmer catalog TRF0133-M) revealed the biochemical EC of compounds that activate AMPK. 50 The 50% concentration required for complete activation was evaluated. 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)), was added to a white 384-well plate (Corning catalog number 3824) containing 0.075 μL of the test compound (solubilized and serially diluted in DMSO at 11 points in a 1 / 2 log dilution series, tested in two sets).

[0285] The plate was rotated at 1000 RPM for 10 seconds. After 15 minutes of incubation at room temperature, 5 μL of 30 nM protein phosphatase PP2A (isolation detailed above) diluted in assay buffer was added to the plate to dephosphorylate pThr172 of AMPK. The plate was rotated at 1000 RPM for 10 seconds. After 120 minutes of incubation, 5 μL of a substrate mixture containing 60 nM okadaic acid (Tocris catalog no. 1136), 150 nM SAMS peptide (Perkin Elmer catalog no. TRF0133-M), and 60 μM ATP (Teknova catalog no. A1204) diluted in assay buffer was added to the plate. The plate was rotated at 1000 RPM for 10 seconds. After incubation at room temperature for 60 minutes, the reaction was stopped by adding 5 μL of a stop and detection cocktail consisting of 1 × Perkin Elmer Lance buffer (Perkin Elmer catalog no. CR97-100), 40 mM EDTA (Thermo Fisher catalog no. BP2482-100), and 2 nM Eu-anti-Acetyl CoA Carboxylase [pSer70] antibody (Perkin Elmer, TRF0208-M). The plate was rotated at 1000 RPM for 10 seconds. The plate was incubated for 1 hour, and then read using an Envision reader with a TR-FRET ratio of 10,000X (fluorescence intensity 665 nM / fluorescence intensity 615 nM). 50 The values ​​are determined from this data using a 4-parameter fitting algorithm and are shown in Table 2.

[0286] Biochemical profiling of AMPK activators using AMPK221 The HTRF assay using LANCE Ultra ULight-Acetyl-CoA Carboxylase (SAMS) peptide (commercially available, Perkin Elmer catalog TRF0133-M) revealed the biochemical EC of compounds that activate AMPK. 50The 50% concentration required for complete activation was evaluated. 5 μL of 0.3 nM phosphorylated AMPK 221 (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)), was added to a white 384-well plate (Corning catalog number 3824) containing 0.075 μL of the test compound (solubilized, serially diluted 11 points in DMSO using a 1 / 2 log series, and tested in two sets).

[0287] The plate was rotated at 1000 RPM for 10 seconds. After 15 minutes of incubation at room temperature, 5 μL of 15 nM protein phosphatase PP2A (isolation detailed above) diluted in assay buffer was added to the plate to dephosphorylate pThr172 of AMPK. The plate was rotated at 1000 RPM for 10 seconds. After 120 minutes of incubation, 5 μL of a substrate mixture containing 30 nM okadaic acid (Tocris catalog no. 1136), 150 nM SAMS peptide (Perkin Elmer catalog no. TRF0133-M), and 240 μM ATP (Teknova catalog no. A1204) diluted in assay buffer was added to the plate. The plate was rotated at 1000 RPM for 10 seconds. After incubation at room temperature for 60 minutes, the reaction was stopped by adding 5 μL of a stop and detection cocktail consisting of 1 × Perkin Elmer Lance buffer (Perkin Elmer catalog no. CR97-100), 40 mM EDTA (Thermo Fisher catalog no. BP2482-100), and 2 nM Eu-anti-Acetyl CoA Carboxylase [pSer70] antibody (Perkin Elmer, TRF0208-M). The plate was rotated at 1000 RPM for 10 seconds. The plate was incubated for 1 hour, and then read using an Envision reader with a TR-FRET ratio of 10,000X (fluorescence intensity 665 nM / fluorescence intensity 615 nM). 50The values ​​are determined from this data using a 4-parameter fitting algorithm and are shown in Table 2.

[0288] [Table 2-1]

[0289] [Table 2-2]

[0290] [Table 2-3]

[0291] Crystal morphology analysis (Example 1, compound of morphology 1) Powder X-ray diffraction (PXRD) analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a copper (Cu) radiation source. The diffusion slit was set to 15 mm continuous illumination. Diffraction radiation was detected by a PSD-Lynx Eye detector with a 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, an energy-dispersive detector and nickel filter were used to remove unwanted wavelengths. Data were acquired using a theta-theta goniometer at Cu wavelengths from 3.0 to 40.0 degrees (2 theta), with a step size of 0.0160 degrees and a step time of 1.0 second. A scattering prevention screen was set to a fixed distance of 1.5 mm. During acquisition, the sample was rotated at 15 / min. The sample was prepared by placing it in a silicon low-background sample holder and rotated during acquisition. Data were acquired using Bruker DIFFRAC Plus software, and analysis was performed using EVA diffract plus software. The sample holder used in a specific experiment is indicated by a codename within the filename: SD = small divot holder.

[0292] Samples were prepared by placing them in a silicon low-background sample holder and rotating them during acquisition. Data were acquired using Bruker DIFFRAC Plus software, and analysis was performed using EVA diffract plus software. The PXRD diffractogram is shown in Figure 1. Preliminary peak assignment was performed using the peak search algorithm in the EVA software, with selected peaks having a threshold of 1. To ensure validity, adjustments were made manually; the output of the auto-assignment was visually verified, and peak positions were adjusted to the maximum peak values. Peaks with a relative intensity of 3% or more were generally selected. Peaks that were not separated or matched noise were not selected. The typical error associated with peak position from the PXRD, as stated in the USP, is a maximum of + / -0.2°² theta (USP-941). The peak list is shown in Table 3. Characteristic peaks for Form 1 are presented in Table 4. Figure 1 shows the PXRD of the compound of Example 1, Form 1.

[0293] [Table 3]

[0294] [Table 4]

[0295] Deuterated analogs of the compounds disclosed herein For general methods / overviews of obtaining a compound metabolite profile and identifying metabolites, see 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," Ch.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; described in Godzien, J. et al., "Chapter Fifteen - Metabolite Annotation and Identification".

[0296] Numerous publicly available commercial software tools are available to help predict the metabolic pathways and metabolites of compounds. Examples of such tools include BioTransformer 3.0 (biotransformer.ca / new) (predicts the biometabolic transformations of small molecules using a database of known metabolic reactions); MetaSite (moldiscovery.com / software / metasite / ) (predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase-mediated reactions in phase I metabolism); and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) (proposes predictions of metabolic pathways and metabolite structures using extensive machine learning models, covering phase I and II biomechanical transformations of small molecules).

[0297] The metabolite profiles of Example 1 were evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey, and human), recombinant human cytochrome P450 enzyme, recombinant human UGT enzyme, and plasma from animals (mouse, rat, and dog). The metabolite profiles of Example 1 consist of oxidation and glucuronidation. MetaSite (moldiscovery.com / software / metasite / ) was used to predict metabolic conversions related to cytochrome P450 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 result in certain therapeutic benefits arising from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, decreased CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0298] A person skilled in the art would know Y as shown in Table 5. 1 ~Y 5Additional deuterated analogs of Example 1 can be prepared with different combinations of these compounds. Such additional deuterated analogs may offer similar therapeutic benefits 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.

[0299] [ka]

[0300] [Table 5]

[0301] Embodiment The following non-limiting embodiments illustrate examples of the present invention, but do not limit the scope of the invention.

[0302] Embodiment 1. Compound of formula (I):

[0303] [ka] The pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - A 1 CR 8 , or N, - A 2 These are CH2, CHD, CD2, S, O, or NH. - A 3 is CH, CD, or N, - R 1 H, D, C 1~8 Alkyl, C 3~6 They are cycloalkyl or 4-6 member heterocycloalkyl groups. - R 2 , R 3 , R 5 , and R 6Each of these is independently H, D, OH, or a halogen. - R 4 These are R, respectively. 9 , R 10 , R 11 , R 12 , or R 13 A monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl which may be substituted with R 9 , R 10 , R 11 , R 12 , and R 13 These are H, D, halogen, CN, oxo, and C, respectively, independently. 1~8 Alkyl, C 3~6 Cycloalkyl, C 0~6 Alkilen-OR x , C 1~6 Haloalkilene-OR x , C 0~6 Alkylene (C 0~6 (Haloalkyl) NR x R y , C 1~6 Alkylene (C 1~6 (Haloalkyl) NR x R y , 4-6 member heterocycloalkyl, C(O)OR x , C 0~6 Alkylene-C(O)NR x R y , OC 1~3 Alkylene-heterocycloalkyl, OC 1~3 Alkylene-C(O)NR x R y , O(C 1~6 Alkyl)SO2NR x NR y , NR x R y NHSO2R x , SR x SC 1~6 Alkylene-C(O)NR x R y S(O)R x R y SO2R x SO2NR x R y, S(O)(NR x )R y , S(O)(NR x )R y , or SO2R x And R x and R y These are H, D, and C, respectively, independently. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 1~6 Alkylene amide, OC 0~2 Alkylene-heterocycloalkyl, 4-6 membered heterocycloalkyl, C(O)C 1~6 Alkyl, imino, or C 1~6 It is an alkylsulfonyl or R x and R y R x and R y Together with the atom to which it is bonded, it may form a ring that may be substituted. - R 7 C 1~3 Alkyl, C 3~6 It is a cycloalkyl, cyano, or halogen, - R b1 , R b2 , and R b3 Each is independently either H or D, - R 8 These are H, D, or halogens. - n is 0, 1, or 2.

[0304] Embodiment 2. A 1 The compound of Embodiment 1, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein the compound is CH or CF.

[0305] Embodiment 3. A 2 The compound of Embodiment 1 or 2, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein the compound is CH2 or S.

[0306] Embodiment 4. A 3 A compound from any one of Embodiments 1 to 3, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein N is present.

[0307] Embodiment 5. A 1 However, N is A 3 The compound of Embodiment 1, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein N is present.

[0308] Embodiment 6. R 1 A compound from any one of Embodiments 1 to 5, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein H is present.

[0309] Embodiment 7. R 2 However, it is halogen, R 3 , R 5 , and R 6 A compound from any one of Embodiments 1 to 6, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein each of the elements is independently H.

[0310] Embodiment 8. R 2 , R 3 , R 5 , and R 6 A compound from any one of Embodiments 1 to 5, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein each of the elements is independently H.

[0311] Embodiment 9. R 7 However, the compound is Cl, one of the compounds from Embodiments 1 to 8, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0312] Embodiment 10. R4 However, it is phenyl, and R 9 , R 10 , R 11 , R 12 , and R 13 Each of these independently comprises H, D, Cl, F, CN, and C. 1~3 Alkyl, C 1~6 Alkylene-OH, C 1~6 Alkylene-OC 1~6 alkyl, OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, O(C) 1~3 Alkylene) Heterocycloalkyl, O(C) 1~3 Alkylene)-C(O)NR x R y , C 1~3 Alkilen-NR x R y C(O)OH, C(O)OC 1~3 Alkyl, C 0~2 Alkylene-C(O)NR x R y SO2NR x R y , S(O)(NR x )R y , NR x R y , SR x , or SO2R x A compound from any one of Embodiments 1 to 9, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0313] Embodiment 11. R 4 However, it is a 6-membered monocyclic heteroaryl, and R 9 , R 10 , R 11 , R 12 , and R 13 At least one of them is C 1~3 A compound from any one of Embodiments 1 to 10, which is an alkoxy, halogen, hydroxyl, or C(O)NH2, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0314] Embodiment 12. Structural formula (II):

[0315] [ka] A compound of Embodiment 1 having, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. [In the formula, - R 2 These are H, D, or halogens. - R 7 is Cl or CN, - A 2 These are CH2, CHD, CD2, S, or NH. - A 4 CR 9 or N, - R 9 These are H, F, Cl, C 1~3 Alkyl, C 1~3 Alkylene-OC 1~3 Alkyl, C 1~3 Alkylene-NH2, COOH, C(O)OC 1~3 Alkyl, C 1~3 Alkylene-C(O)NH2, C(O)NHC 1~3 Alkyl, C(O)N(C 1~3 Alkyl)2, C 1~6 Alkylene (C 1~6 Haloalkyl)NH2,C 0~2 Alkylene-NH(C(O)C) 1~3 Alkyl), OC 1~3 Alkyl, OC 1~3 Haloalkyl, OC 1~3 Alkylene-heterocycloalkyl, OC 1~3 Alkylene-C(O)NH2, NHSO2C 1~3 Alkyl, N(C 1~3 Alkyl)(C(O)C 1~3 Alkyl), SC 1~3 Alkyl, SC 1~3 Alkylene-C(O)NH2, SO(NH)C 1~3 Alkyl, SO2NH2, or SO2C 1~3 It is alkyl, - R10 is H, D, or OH, - R 11 H, D, halogen, CN, O(C 1~3 Alkyl), or O(C 1~3 (haloalkyl) or R 9 and R 11 R 9 and R 11 Together with the carbon atom to which it is bonded, it forms a ring that may be substituted. - R 12 H, OC 1~3 Alkyl, or C 1~3 It is alkylene-OH, - R 13 is H, F, Cl, or C 1~3 It is alkyl, - n is either 1 or 2.

[0316] Embodiment 13. R 10 The compound of Embodiment 12, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein the compound is OH.

[0317] Embodiment 14. R 7 The compound of Embodiment 12 or 13, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein the compound is Cl.

[0318] Embodiment 15. A 2 However, any one of the compounds from Embodiments 12 to 14, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein the compound is CH2 or S.

[0319] Embodiment 16. Structural formula (III):

[0320] [ka] A compound of Embodiment 1 having, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. [In the formula, - R 9 H, D, halogen, C 1~3 Alkyl, C(O)NH2, C 1~3 Alkylene-NH2, C 1~3 Alkylene-OC 1~3 Alkyl, C(O)OC 1~3 Alkyl, C(O)OH, OC 1~3 Alkyl, OC 1~3 Haloalkyl, -O(C) 1~3 Alkyl)SO2NH2, C 1~6 Alkylene (C 1~6 Haloalkyl)NH2, SC 1~3 Alkyl, or -C(O)NR x R y And R x and R y Each of these is independently H or C 1~6 It is alkyl, R 11 H, D, halogen, CN, or -O(C 1~3 Alkyl) or R 9 and R 11 R 9 and R 11 [It forms a ring, which may be substituted, together with the carbon atom to which it is bonded.]

[0321] Embodiment 17. - R 9 However, H or -C(O)NR x R y And R x and R y Each of these independently corresponds to H, D, or C 1~6 It is alkyl, - R 11 However, H or -O(C 1~3 Alkyl) or R 9 and R 11 However, R 9 and R 11Together with the carbon atom to which it is bonded, it forms a ring that may be substituted. The compound of Embodiment 16, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof.

[0322] Embodiment 18. Structural formula (IVa), formula (IVb), or formula (IVc):

[0323] [ka] A compound of Embodiment 1 having, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer. [In the formula, R 9 , R 10 , and R 11 H and C are independent of each other. 1~3 Alkyl, C 1~3 Alkylene-OH, or OC 1~3 It is alkyl.

[0324] Embodiment 19. R 9 , R 10 , and R 11 A compound of Embodiment 18, or a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, wherein each of the elements is independently H.

[0325] Embodiment 20. R 10 However, C 1~3 Alkyl, C 1~3 Alkylene-OH or OC 1~3 A compound of Embodiment 18, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof, which is alkyl.

[0326] Embodiment 21. Structural formula (V):

[0327] [ka] A compound of Embodiment 1 having, or a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof. [In the formula, - R 10 is H, D, or OH, - R 9 and R 11 R 9 and R 11 Together with the bonded carbon atom, it forms a ring, and the ring is a 5 or 6-membered heterocycloalkyl or 5 or 6-membered heteroaryl, and the ring is C 1~3 [May be substituted with alkyl, OH, or oxo.]

[0328] Embodiment 22. The compound of Embodiment 21, wherein the ring is a five-membered heterocycloalkyl group, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0329] Embodiment 23. A compound of Embodiment 21, wherein the ring is a five-membered heteroaryl compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0330] Embodiment 24. The ring is C 1~3 A compound from any one of embodiments 21 to 23, substituted with alkyl, OH, or oxo, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0331] Embodiment 25. 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran-6-yl)phenyl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)butanoic acid; 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; and A compound of Embodiment 1, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer, selected from the group consisting of 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazole-5-yl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

[0332] Embodiment 26. 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0333] Embodiment 27. 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid.

[0334] Embodiment 28. structure:

[0335] [ka] A compound of [this].

[0336] Embodiment 29. A pharmaceutical composition comprising a compound according to any of Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof, and a pharmaceutically acceptable additive.

[0337] Embodiment 30. A method for treating a condition, comprising administering to a subject in need of such treatment a therapeutically effective amount of any compound from Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[0338] Embodiment 31. The method of Embodiment 30, wherein the inflammatory 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.

[0339] Embodiment 32. The method of Embodiment 30, wherein the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, and functional constipation.

[0340] Embodiment 33. A method of administration by oral administration, as described in any one of embodiments 30 to 32.

[0341] Embodiment 34. One of the methods of Embodiments 30 to 33, wherein the therapeutically effective dose is approximately 1 mg to approximately 2500 mg.

[0342] Embodiment 35. Any one of embodiments 30 to 34, wherein the drug is administered once daily.

[0343] Embodiment 36. One of the embodiments 30 to 34, wherein the drug is administered twice a day.

[0344] Embodiment 37. A method for treating a condition, a) administering to a subject in need a therapeutically effective dose of one of the compounds from Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer; b) A method comprising administering an additional therapeutically effective dose of a therapeutic agent.

[0345] Embodiment 38. The method of Embodiment 37, wherein the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[0346] Embodiment 39. The method of Embodiment 38, wherein the inflammatory or autoimmune condition is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, colitis, and Crohn's disease.

[0347] Embodiment 40. The method of embodiment 38 or 39, wherein the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, and functional constipation.

[0348] Embodiment 41. A method according to any one of embodiments 37 to 40, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

[0349] Embodiment 42. A method according to any one of Embodiments 37 to 41, wherein the therapeutically effective dose of the compound, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer is approximately 1 mg to approximately 2500 mg.

[0350] Embodiment 43. A method according to any one of Embodiments 37 to 42, wherein the therapeutically effective dose of the compound, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer is about 1 mg to about 100 mg.

[0351] Embodiment 44. Compounds according to any of Embodiments 1 to 28, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers, for use as pharmaceuticals.

[0352] Embodiment 45. Compounds according to any one of Embodiments 1 to 28, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers, for use in the treatment of inflammatory conditions, autoimmune conditions, or functional gastrointestinal disorders.

[0353] Embodiment 46. Use of a compound according to any of Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof in the manufacture of a pharmaceutical for treating an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

[0354] Embodiment 47. Use as a pharmaceutical product of a compound according to any one of Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer.

[0355] Embodiment 48. Use of a compound according to any one of Embodiments 1 to 28, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof, for the treatment of inflammatory conditions, autoimmune conditions, or functional gastrointestinal disorders.

[0356] Embodiment 49. Crystalline 3-[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl]propanoic acid, pharmaceutically acceptable salts thereof, tautomers, or pharmaceutically acceptable salts of tautomers.

[0357] Embodiment 50. A crystalline compound of Embodiment 49 having an X-ray powder diffraction pattern including diffraction peaks at 12.6±0.2, 18.8±0.2, 19.7±0.2, and 24.4±0.2 degrees 2-theta.

[0358] Each of the embodiments described herein may be combined with any other embodiment described herein that is not inconsistent with the combined embodiment. In addition, any of the compounds described in the Examples, or a pharmaceutically acceptable salt thereof, may be claimed individually or as a group with one or more other compounds from the Examples, or a pharmaceutically acceptable salt thereof, for any of the embodiments described herein. Furthermore, each of the embodiments described herein intends, within its scope, a pharmaceutically acceptable salt of the compound described herein.

[0359] It will be apparent to those skilled in the art that the present invention can be modified and altered in various ways without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art by examining the details and practices of the invention disclosed herein. This specification and the examples are for illustrative purposes only, and the true scope and spirit of the invention are intended to be shown by the following claims.

[0360] All references cited herein, including patents, patent applications, documents, textbooks, and similar materials, and references cited herein, are incorporated herein by reference in their entirety unless they have not yet been incorporated. If any of the incorporated documents and similar materials differ from or conflict with this application, including, but not limited to, defined terms, usage of terms, described technology, or similar materials, this application shall prevail.

Claims

1. Compound of formula (I): 【Chemistry 1】 A pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of the tautomer. [In the formula, - A １ CR ８ , or N, - A ２ CH ２ , CHD, CD ２ , S, O, or NH, - A ３ is CH, CD, or N, -R １ is each independently optionally substituted H, D, C １～８ alkyl, C ３～６ cycloalkyl, or 4- to 6-membered heterocycloalkyl, and - R ２ , R ３ , R ５ , and R ６ Each of these is independently H, D, OH, or a halogen. - R ４ These are R ９ , R １０ , R １１ , R １２ , or R １３ A monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl which may be substituted with R ９ , R １０ , R １１ , R １２ , and R １３ These are H, D, halogen, CN, oxo, and C, respectively, independently. １～８ Alkyl, C ３～６ Cycloalkyl, C ０～６ Alkylene-OR ｘ , C １～６ Haloalkilenes OR ｘ , C ０～６ Alkylene (C ０～６ (Haloalkyl) NR ｘ R ｙ , C １～６ Alkylene (C １～６ (Haloalkyl) NR ｘ R ｙ , 4-6 member heterocycloalkyl, C(O)OR ｘ , C ０～６ Alkylene-C(O)NR ｘ R ｙ , OC １～３ Alkylene-heterocycloalkyl, OC １～３ Alkylene-C(O)NR ｘ R ｙ , O(C １～６ Alkyl)SO ２ NR ｘ NR ｙ , NR ｘ R ｙ NHSO ２ R ｘ , SR ｘ S-C １～６ Alkylene-C(O)NR ｘ R ｙ S(O)R ｘ R ｙ SO ２ R ｘ SO ２ NR ｘ R ｙ , S(O)(NR ｘ ) R ｙ , S(O)(NR ｘ ) R ｙ , or SO ２ R ｘ And R ｘ and R ｙ These are H, D, and C, respectively, independently. １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C １～６ Alkylene amide, OC ０～２ Alkylene-heterocycloalkyl, 4-6 membered heterocycloalkyl, C(O)C １～６ Alkyl, imino, or C １～６ It is an alkylsulfonyl or R ｘ and R ｙ R ｘ and R ｙ Together with the atom to which it is bonded, it may form a ring that may be substituted. - R ７ C １～３ Alkyl, C ３～６ It is a cycloalkyl, cyano, or halogen, -R ｂ１ 、R ｂ２ 、and R ｂ３ are each independently H or D, - R ８ These are H, D, or halogen, - n is 0, 1, or 2.

2. A １ The compound according to claim 1, wherein the compound is CH or CF, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

3. A ２ However, CH ２ A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof, wherein the compound is S.

4. A ３ A compound according to any one of claims 1 to 3, wherein N is present, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

5. R １ The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of said tautomer, wherein R is H.

6. R ２ , R ３ , R ５ , and R ６ A compound according to any one of claims 1 to 5, wherein each of the elements is independently H, a pharmaceutically acceptable salt thereof, a tautomer, or a pharmaceutically acceptable salt of the tautomer.

7. R ７ A compound according to any one of claims 1 to 6, wherein the compound is Cl, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

8. R ４ However, it is phenyl, and R ９ , R １０ , R １１ , R １２ , and R １３ Each of these independently comprises H, D, Cl, F, CN, and C. １～３ Alkyl, C １～６ Alkylene-OH, C １～６ Alkylene-OC １～６ Alkyl, OH, OC １～６ Alkyl, OC １～６ Haloalkyl, O(C) １～３ Alkylene) Heterocycloalkyl, O(C) １～３ Alkylene)-C(O)NR ｘ R ｙ , C １～３ Alkylene-NR ｘ R ｙ , C(O)OH, C(O)OC １～３ Alkyl, C ０～２ Alkylene-C(O)NR ｘ R ｙ SO ２ NR ｘ R ｙ , S(O)(NR ｘ ) R ｙ , NR ｘ R ｙ , SR ｘ , or SO ２ R ｘ A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

9. Structural formula (II): 【Chemistry 2】 A compound according to claim 1, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof, having the above. [In the formula, - R ２ These are H, D, or halogen, - R ７ is Cl or CN, - A ２ CH ２ , CHD, CD ２ , S, or NH, - A ４ CR ９ or N, - R ９ H, D, F, Cl, C １～３ Alkyl, C １～３ Alkylene-OC １～３ Alkyl, C １～３ Alkylene-NH ２ , COOH, C(O)OC １～３ Alkyl, C １～３ Alkylene-C(O)NH ２ C(O)NHC １～３ Alkyl, C(O)N(C １～３ Alkyl) ２ , C １～６ Alkylene (C １～６ Haloalkyl) NH ２ , C ０～２ Alkylene-NH(C(O)C) １～３ Alkyl), OC １～３ Alkyl, OC １～３ Haloalkyl, OC １～３ Alkylene-heterocycloalkyl, OC １～３ Alkylene-C(O)NH ２ NHSO ２ C １～３ Alkyl, N(C) １～３ Alkyl) (C(O)C １～３ Alkyl), SC １～３ Alkyl, S-C １～３ Alkylene-C(O)NH ２ SO(NH)C １～３ Alkyl, SO ２ NH ２ , or SO ２ C １～３ It is alkyl, - R １０ is H, D, or OH, - R １１ H, D, halogen, CN, O(C) １～３ Alkyl), or O(C) １～３ (Haloalkyl) or R ９ and R １１ R ９ and R １１ Together with the carbon atom to which it is bonded, it forms a ring that may be substituted. - R １２ H, D, OC １～３ Alkyl, or C １～３ It is an alkylene-OH group. - R １３ is H, D, F, Cl, or C １～３ It is alkyl, - n is either 1 or 2.

10. R １０ The compound according to claim 9, wherein the compound is OH, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

11. R ７ The compound according to claim 9 or 10, wherein the compound is Cl, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

12. A ２ However, CH ２ A compound according to any one of claims 9 to 11, or S, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

13. - R ９ However, H or -C(O)NR ｘ R ｙ And R ｘ and R ｙ Each of them independently, H or C １～６ It is alkyl, - R １１ However, H or -O(C) １～３ Alkyl) or R ９ and R １１ However, R ９ and R １１ Together with the carbon atom to which it is bonded, it forms a ring that may be substituted. The compound according to claim 9, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

14. 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4-(7-hydroxy-2,3-dihydrobenzofuran-6-yl)phenyl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(2'-hydroxy-4',6'-dimethyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(3'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-fluoro-2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 3-(6-chloro-5-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)butanoic acid; 3-(6-chloro-5-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid; 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; and A compound according to claim 1, selected from the group consisting of 6-((4'-(3-(2-carboxyethyl)-6-chloro-1H-indazole-5-yl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

15. The compound according to claim 1, which is 3-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, which is 3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, which is 4-(6-chloro-5-(2'-hydroxy-3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)butanoic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, which is 3-(6-chloro-5-(2'-hydroxy-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound is 6-((3-(6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-yl)propanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer thereof, and a pharmaceutically acceptable additive.

21. A method for treating a condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the condition is an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

22. The method according to claim 21, wherein 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. The method according to claim 21, wherein the functional gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, functional diarrhea, celiac disease, and functional constipation.

24. The method according to claim 21, wherein the administration is by oral ingestion.

25. The method according to claim 21, wherein the therapeutically effective dose is approximately 1 mg to approximately 2500 mg.

26. Use of a compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for treating an inflammatory condition, an autoimmune condition, or a functional gastrointestinal disorder.

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