Thyroid hormone analogue prodrugs, methods of making and using same - Patent Application 20070122997

Abstract

The present invention relates to a thyroid hormone receptor β subtype agonist derivative, a method for producing the same, and uses thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of Chinese Patent Application No. 202310113004.X filed on February 7, 2023, Chinese Patent Application No. 202310267006.4 filed on March 15, 2023, Chinese Patent Application No. 202310571548.0 filed on May 18, 2023, Chinese Patent Application No. 202310733484.X filed on June 20, 2023, and U.S. Patent Application No. 63 / 4 filed on March 1, 2023. No. 87,794, filed March 27, 2023, U.S. Patent Application No. 63 / 492,398, filed May 30, 2023, U.S. Patent Application No. 63 / 504,832, filed May 30, 2023, U.S. Patent Application No. 63 / 510,810, filed June 28, 2023, and U.S. Patent Application No. 63 / 514,925, filed July 21, 2023, all of which are incorporated by reference herein in their entireties.

[0002] The present invention relates generally to prodrugs of thyroid hormone analogs, methods for their preparation, and uses thereof. [Background technology]

[0003] Thyroid hormones are crucial for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological Review, Vol. 81(3):1097-1126 (2001)). Circulating thyroid hormone concentrations are tightly regulated by feedback mechanisms in the hypothalamus-pituitary-thyroid (HPT) axis. Thyroid dysfunction, leading to hypothyroidism or hyperthyroidism, clearly demonstrates the profound effects of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior. Thyroid hormone receptors are derived from two distinct genes, α and β. These distinct gene products generate multiple forms of each receptor through differential RNA processing. The major thyroid receptor isoforms are α1, α2, β1, and β2. α1, β1, and β2 thyroid hormone receptors bind to thyroid hormones. Thyroid hormone receptor subtypes have been shown to differ in their contribution to specific biological responses. Recent studies suggest that TRβ1 plays an important role in regulating TRH (thyrotropin-releasing hormone) and the action of thyroid hormones in the liver. TRβ2 plays an important role in regulating TSH (thyroid-stimulating hormone). TRβ1 plays an important role in regulating heart rate. Summary of the Invention [Means for solving the problem]

[0004] One aspect of the present application relates to compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof. JPEG2026506777000002.jpg3555, wherein G is selected from the group consisting of -O-, and -C(X9X8)-; T is -(CR d ) m - and -O-(CR d ) m - selected from the group consisting of m is an integer from 0 to 3; X is selected from the group consisting of: JPEG2026506777000003.jpg3928 and JPEG2026506777000004.jpg3939R a and R b are each independently selected from the group consisting of CH3, CD3, Cl, Br, I, and CF3; R c is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 Alkyl, optionally substituted -C-C 12 Alkenyl, optionally substituted -C-C 12 Alkynyl, optionally substituted -C 0-6 Alkylaryl, optionally substituted -C 0-6 Alkylcycloalkyl, optionally substituted -C 0-6 Alkylheterocycloalkyl, and optionally substituted -C 3-8 cycloalkyl; R c is optionally substituted with 1 to 10 halogens, H or D; R d are each independently hydrogen, halogen, and C 1-6 is selected from the group consisting of alkyl, R1 and R2 are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl, or R1 and R2, when combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Haloalkyl, C6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, and R3 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, -CONR7R 10 , -CONR6R7, -CH2OCOR6, -CH2OCONHR6, and JPEG2026506777000005.jpg2526, R6 is independently C 1-30 Alkyl, C 1-30 Alkenyl, and C 1-30 Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, and C 1-30 Each alkynyl is independently selected from halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is independently selected from halo and C 1-3 optionally substituted with one or more substituents selected from the group consisting of alkyl; R7 is H, -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Alkenyl, -C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 alkynyl, wherein -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Each alkenyl is —C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 Alkynyl is halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; or R6 and R7, taken together with the atoms to which they are attached, form a 5- to 10-membered heterocyclyl, the 5- to 10-membered heterocyclyl being selected from halo, NH2, NO2, OH, CN, -C1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R8 and R9 are H, OH, and C, respectively. 1-6 Alkyl, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from the group consisting of OH, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; or R8 and R9, taken together with the atoms to which they are attached, form a 3-10 membered heterocycle, which is optionally substituted with 1-4 R6, each R6 independently being H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, or alkoxy; R 10 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) nAryl, and -(CH2) n Each heteroaryl may be selected from halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; X8 and X9 are independently H, D or halo; n=0, 1, 2 or 3; The above 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each independently being N, O or S; The compound of formula I is not isopropyl(((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate.

[0005] Another aspect of the present application also relates to a pharmaceutical composition comprising a compound of formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a hydrate thereof or a solvate thereof.

[0006] Another aspect of the present application relates to a method for treating or preventing obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), fatty liver, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present application. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the mean plasma concentration-time profiles of the compounds of the present application.

[0008] [Figure 2] FIG. 2 shows the mean plasma concentration-time profiles of the compounds of the present application.

[0009] [Figure 3] FIG. 3 shows the mean plasma concentration-time profile of Compound 31 after subcutaneous injection.

[0010] [Figure 4] FIG. 4 shows the mean plasma concentration-time profile of Compound 32 after subcutaneous injection.

[0011] [Figure 5] FIG. 5 shows the mean plasma concentration-time profile of Compound 34 after subcutaneous injection.

[0012] [Figure 6] FIG. 6 shows the mean plasma concentration-time profile of Compound 36 after subcutaneous injection.

[0013] [Figure 7] FIG. 7 shows the plasma concentration-time profile of Compound 54 after subcutaneous injection.

[0014] [Figure 8] FIG. 8 shows the plasma concentration-time profile of Compound 52 after subcutaneous injection.

[0015] [Figure 9] FIG. 9 shows the plasma concentration-time profile of compound 53 after subcutaneous injection.

[0016] [Figure 10] FIG. 10 shows the plasma concentration-time profiles of compounds 29 and 30 after subcutaneous injection.

[0017] [Figure 11] FIG. 11 shows the plasma concentration-time profile of Compound 52 after subcutaneous injection. DETAILED DESCRIPTION OF THE INVENTION

[0018] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the beginning or end of a chemical group is for convenience to indicate the point of attachment to the parent group, and a chemical group can be written with or without one or more dashes without losing its ordinary meaning. "C u-v " or "C u -C v " indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0019] "Alkyl" refers to a monovalent or divalent straight- or branched-chain saturated hydrocarbon group. For example, an alkyl group can be any group containing 1 to 10 carbon atoms (i.e., C 1-10 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3). , 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2C and octyl (-(CH)CH), and the like. Alkyl groups may be substituted or unsubstituted.

[0020] "Alkenyl" refers to a monovalent or divalent straight- or branched-chain hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH), allyl (-CHCH=CH), and -CH-CH=CH-CH. Alkenyl groups can be unsubstituted or substituted.

[0021] "Alkynyl" refers to a monovalent or divalent straight- or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkynyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CHC≡CH), and -CH-C≡C-CH. Alkynyl groups can be unsubstituted or substituted.

[0022] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. For example, C 1-4 Alkoxy refers to an —O-alkyl group having 1 to 4 carbon atoms. The alkoxy group may be unsubstituted or substituted.

[0023] "Halogen" or "halo" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0024] "Haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced with a halogen, which may be the same or different, making the alkyl divalent. The alkyl group and halogen can be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms in the alkyl portion, e.g., C 1-4Haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

[0025] As used herein, the term "aryl" refers to a monovalent or divalent all-carbon aromatic ring or a fused all-carbon ring system that is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl groups. Aryl also includes fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) having approximately 9 to 20 carbon atoms, where multiple rings are aromatic. The rings in a fused ring system can be connected to each other via fused bonds, if permitted by valence requirements. Furthermore, when a specific range of atoms of an aryl ring (e.g., a 6- to 10-membered aryl ring) is referred to, it is understood that the atom range refers to the range of all ring atoms of the aryl. For example, a 6-membered aryl group includes a phenyl group, and a 10-membered aryl group includes a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. The aryl group can be unsubstituted or substituted.

[0026] "5-10-membered heteroaryl" or "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. "5-10-membered heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which are further described below. Thus, "5-10-membered heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, so long as the ring is aromatic. Exemplary 5-10-membered heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "5-10-membered heteroaryl" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which the 5-10-membered heteroaryl group defined above is fused with one or more rings selected from 5-10-membered heteroaryls (e.g., forming a 1,8-naphthyridinyl group) and aryls (e.g., forming a benzimidazolyl or indazolyl group) to form a multiple condensed ring system. Thus, a 5-10-membered heteroaryl (single aromatic ring or multiple condensed ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the 5-10-membered heteroaryl ring. For example, tetrazolyl has one carbon atom and four nitrogen heteroatoms in the ring. The rings of a multiple condensed ring system can be connected to each other via fused bonds, as long as valence requirements permit. It is understood that the individual rings of a multiple condensed ring system can be connected to each other in any order. It is understood that the point of attachment of a 5-10 membered heteroaryl or a 5-10 membered heteroaryl multiple condensed ring system can be any suitable atom of the 5-10 membered heteroaryl or a 5-10 membered heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Also, when referring to a particular atom range of member numbers (e.g., a 5-10 membered heteroaryl), it is understood that the atom range is for all ring atoms of the 5-10 membered heteroaryl and includes carbon atoms and heteroatoms.It should also be understood that rings in multiple condensed ring systems can include aryl rings fused to saturated or partially unsaturated heterocycles (e.g., 3-, 4-, 5-, 6-, or 7-membered rings). These heterocycles have about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. For example, heteroaryls having 5 to 10 ring members include thiazolyl, and heteroaryls having 5 to 10 ring members include quinolinyl. Exemplary 5- to 10-membered heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The 5- to 10-membered heteroaryl group may be unsubstituted or substituted.

[0027] "Cycloalkyl" refers to a monovalent or divalent monocyclic all-carbocyclic ring or multiple fused all-carbocyclic ring system, each ring being a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple fused ring systems (e.g., ring systems containing two rings) having about 7 to 12 carbon atoms. The rings of multiple fused ring systems can be joined together through fused, spiro, or bridged bonds, if valence requirements permit. Examples of multi-ring cycloalkyl groups include octahydropentalene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0028] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system having at least one heteroatom within the ring (i.e., at least one annular (i.e., cyclic) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 annular carbon atoms and about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The rings of fused ring (e.g., bicyclic heterocyclyl) systems can be connected to each other via fused, spiro, and bridged bonds, as valence requirements permit. Heterocyclic compounds include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-6-yl, and 1-azaspiro[3.3]heptan-6-yl. Examples include heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, etc. The heterocyclic group may be unsubstituted or substituted.

[0029] As used herein, "substituted" refers to one or more hydrogen atoms of a group being independently replaced with one or more substituents (eg, 1, 2, 3, or more) as indicated.

[0030] "Compounds of the present application" include compounds disclosed herein, for example, compounds of the present application include compounds of Formula I, including compounds of the Examples. In some embodiments, "compounds of the present application" include compounds of Formula I.

[0031] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0032] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound sufficient to affect treatment of a disease when administered to a subject for the treatment of that disease. The effective amount will vary depending on the compound, the disease, its severity, and the age, weight, etc., of the subject being treated. An effective amount can include a variety of amounts. As understood in the art, an effective amount can be one or more doses. That is, a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents; a single dose of an agent can be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result is likely or actually occurs. The appropriate dosage of a compound administered in combination can be reduced, if necessary, due to the combined effects (e.g., additive or synergistic) of the compounds.

[0033] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed a certain time (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the body of a subject.

[0034] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0035] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0036] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or in appropriate cases as free bases.Pharmaceutically acceptable salts are non-toxic salts of the free base form of compounds that have the desired pharmacological activity of the free base.These salts can be derived from inorganic or organic acids or bases.For example, compounds that contain basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexaphosphate ... Syn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmacologically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams and Wilkins, Philadelphia, PA, 2006).

[0037] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include those obtained by rinsing with a suitable base, such as an alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, N(C1-C4 alkyl)4 +Also included are salts derived from, for example, base addition salts such as sodium and potassium salts.

[0038] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof. In these compounds, 1 to n hydrogen atoms bonded to carbon atoms are replaced by deuterium atoms ( 2 H or D), where n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds (also called "deuterium substitutes" or "deuterated compounds") may have increased resistance to metabolism and thus may be useful for extending the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0039] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n atoms can be independently replaced by 1 to n corresponding isotopes. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as -, ... 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F,36 Cl, 123 I, and 125 I can be mentioned. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples below, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0040] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, tautomers, diastereomers, and other stereoisomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids, as well as deuterated analogs thereof. The chemical formulas shown in this application are intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. When compounds are represented in chiral form, it is understood that embodiments include, but are not limited to, specific diastereomers or enantiomerically enriched forms. When chirality is not specified, it is understood that embodiments relate to either specific diastereomers or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0041] As used herein, "stereoisomers" refer to compounds that are composed of identical atoms joined by identical bonds but have different, incompatible three-dimensional structures. This application encompasses various stereoisomers and mixtures thereof, and also includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0042] As used herein, the term "tautomer" refers to the migration of a proton from one atom in a molecule to another atom in the same molecule. In some embodiments, the present application includes tautomers of the compounds.

[0043] As used herein, the term "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0044] As used herein, "hydrate" refers to a compound of the present disclosure chemically bound to one or more water molecules.

[0045] "Prevention" or "preventing" refers to any treatment that inhibits the development of clinical symptoms of a disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or with a family history of the disease or condition.

[0046] As used herein, the term "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug by some chemical or enzymatic pathway. In some embodiments, a prodrug is a biologically inactive derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug by some chemical or enzymatic pathway.

[0047] As used herein, "treatment" or "treating" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this application, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the severity and / or preventing worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition); b) delaying or preventing the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., regression of clinical symptoms, improvement of disease symptoms, delay in disease progression, improved quality of life, and / or prolonged survival. As used herein, an "at-risk individual" refers to an individual who is at risk of developing the condition being treated. An "at-risk" individual may have a detectable disease or condition and may or may not exhibit detectable disease prior to treatment with the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals who have one or more of these risk factors have a higher probability of developing the disease or condition than individuals who do not have these risk factors.

[0048] II. Compounds and Compositions One aspect of the present application relates to compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof. JPEG2026506777000006.jpg3555, wherein G is selected from the group consisting of -O-, and -C(X9X8)-; T is -(CR d ) m - and -O-(CR d ) m - selected from the group consisting of m is an integer from 0 to 3; X is selected from the group consisting of: JPEG2026506777000007.jpg3928 and JPEG2026506777000008.jpg3939R a and R b are each independently selected from the group consisting of CH3, CD3, Cl, Br, I, and CF3; R c is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 Alkyl, optionally substituted -C-C 12 Alkenyl, optionally substituted -C-C 12 Alkynyl, optionally substituted -C 0-6 Alkylaryl, optionally substituted -C 0-6 Alkylcycloalkyl, optionally substituted -C 0-6 Alkylheterocycloalkyl, and optionally substituted -C 3-8 cycloalkyl; R c is optionally substituted with 1 to 10 halogens, H or D; R d are each independently hydrogen, halogen, and C 1-6 is selected from the group consisting of alkyl, R1 and R2 are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl, or R1 and R2, when combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C1-30 Haloalkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, and R3 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, -CONR7R 10 , -CONR6R7, -CH2OCOR6, -CH2OCONHR6, and JPEG2026506777000009.jpg2526, R6 is independently C 1-30 Alkyl, C 1-30 Alkenyl, and C 1-30 Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, and C 1-30 Each alkynyl is independently selected from halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is independently selected from halo and C 1-3optionally substituted with one or more substituents selected from the group consisting of alkyl; R7 is H, -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Alkenyl, -C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 alkynyl, wherein -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Each alkenyl is —C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 Alkynyl is halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; or R6 and R7, taken together with the atoms to which they are attached, form a 5- to 10-membered heterocyclyl, the 5- to 10-membered heterocyclyl being selected from halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R8 and R9 are H, OH, and C, respectively. 1-6 Alkyl, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from the group consisting of OH, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; or R8 and R9, taken together with the atoms to which they are attached, form a 3-10 membered heterocycle, which is optionally substituted with 1-4 R6, each R6 independently being H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, or alkoxy; R 10 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n Each heteroaryl may be selected from halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; X8 and X9 are independently H, D or halo; n=0, 1, 2 or 3; The above 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each independently being N, O or S; The compound of formula I is not isopropyl(((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate.

[0049] In some embodiments, G is -O-; T is -O-(CR d ) m - and; m is an integer from 0 to 3; X is JPEG2026506777000010.jpg3825; R c is hydrogen, halogen, -CF3, -OCF3, cyano, and optionally substituted -C1-C 12 selected from the group consisting of alkyl; R d are hydrogen, halogen, and C 1-6 alkyl.

[0050] In some embodiments, Rd is hydrogen.

[0051] In some embodiments, m is 1.

[0052] In some embodiments, Formula I is Formula II. JPEG2026506777000011.jpg5475Here, R5 is -COR6, -COOR6, CONR7R 10 , -CH2OCOR6, CH2OC(O)OR7, and JPEG2026506777000012.jpg2526, R6 is independently C 13-30 Alkyl, C 13-30 Alkenyl, and C 13-30 Alkynyl, C 13-30 Alkyl, C 13-30 Alkenyl, and C 13-30 Each alkynyl is selected from halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R7 is H, -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Alkenyl, -C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30Alkenyl, and -C(O)NRcC 2-30 alkynyl, wherein -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Each alkenyl is —C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 Alkynyl is halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R8 and R9 are H, OH, and C, respectively. 1-6 Alkyl, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -SSC(O)OC 2-30 Alkyl, -C 3-10 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from the group consisting of OH, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; or R8 and R9, taken together with the atoms to which they are attached, form a 3-10 membered heterocycle, which is optionally substituted with 1-4 R6, each R6 independently being H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, or alkoxy; R 10 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n Each heteroaryl may be selected from halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; n=0, 1, 2 or 3; The above 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each of which is independently N, O or S.

[0053] In some embodiments, R5 is -COR6, -COOR6, CONR7R 10 , -CH2OCOR6, and JPEG2026506777000013.jpg2526.

[0054] In some embodiments, each R6 is independently C 13-30 Alkyl and C 13-30 It is alkenyl.

[0055] In some embodiments, the compound of the present application is selected from the group consisting of: JPEG2026506777000014.jpg176150 JPEG2026506777000015.jpg226150

[0056] In some embodiments, Formula I is Formula III. JPEG2026506777000016.jpg4183where, R a and R b are each independently selected from the group consisting of CH3, CD3, Cl, Br, I, and CF3; Each Rc is hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C-C 12 Alkenyl, optionally substituted -C-C 12 Alkynyl, optionally substituted -C 0-6 Alkylaryl, optionally substituted -C 0-6 Alkylcycloalkyl, optionally substituted -C 0-6 Alkylheterocycloalkyl, optionally substituted -C 3-8 cycloalkyl; R c is optionally substituted with 1-10 halogens, H or D; X8, X9, Z1 and Z2 are each independently H, D or halo; Z3 is independently O or -CH2-; R1 and R2 are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl, or R1 and R2, when combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Haloalkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, and R3 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl is halo, NH2, NO2, OH, CN, OC1-6 Alkyl, C 6-10 or R6 and R7 are optionally substituted with one or more substituents each independently selected from the group consisting of aryl, and heteroaryl, or R6 and R7 are joined to the atoms to which they are attached to form a 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl is selected from halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0057] In some embodiments, Z is O.

[0058] In some embodiments, each of Z 1 and Z 2 is H.

[0059] In some embodiments, R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R4 is halo, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 Optionally substituted with alkyl.

[0060] In some embodiments, R3 is C 1-30 Alkyl, and C 5-10 cycloalkyl.

[0061] In some embodiments, R c is -C1-C6 alkyl, -C 0-6 Alkyl-aryl, -C 0-6 Alkyl-cycloalkyl, -C 0-6 Alkyl-heterocycloalkyl, and -C 3-8 cycloalkyl, wherein R c is optionally substituted with halo.

[0062] In some embodiments, Formula I is Formula IV. JPEG2026506777000017.jpg4792 where R1 and R2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl C 6-10 Aryl, and C 1-6 alkylheteroaryl, or R1 and R2, combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Haloalkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, where R3 is halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein R4 is halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; X1, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently H, D or halo; Z1 and Z2 are each independently H, D, or halo; R a and R b are each independently selected from the group consisting of CH3, CD3, Cl, Br, I, or CF3; R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl is halo, NH2, NO2, OH, CN, OC 1-6 Alkyl, C 6-10 or R6 and R7 are optionally substituted with one or more substituents each independently selected from the group consisting of aryl, and heteroaryl, or R6 and R7 are joined to the atoms to which they are attached to form a 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl is selected from halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0063] In some embodiments, each of Z 1 and Z 2 is H.

[0064] In some embodiments, R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 Optionally substituted with alkyl.

[0065] In some embodiments, R3 is C 1-30 Alkyl, and C 5-10cycloalkyl.

[0066] In some embodiments, Formula I is Formula V. JPEG2026506777000018.jpg4185 where R1 and R2 are independently H, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl; R3 is H, C 1-30 Alkyl, and C 5-10 cycloalkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 Optionally substituted with alkyl.

[0067] In some embodiments, R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 Optionally substituted with alkyl.

[0068] In some embodiments, as used herein, R3 is C 1-30 Alkyl, and C 5-10 cycloalkyl.

[0069] In some embodiments, Formula I is Formula VI. JPEG2026506777000019.jpg5398 where R1 and R2 are H, C 1-6Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl; each of the alkyl, aryl, and heteroaryl is independently selected from the group consisting of halogen, C 1-6 Alkyl, and C 1-6 optionally substituted with haloalkyl; R3 is H, C 1-30 Alkyl, and C 5-10 cycloalkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5-10 membered heteroaryl; R4 is selected from the group consisting of halo, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with alkyl; p is an integer from 0 to 3.

[0070] In some embodiments, R3 is C 1-6 Alkyl, or C 5-10 It is cycloalkyl.

[0071] In some embodiments, R3 is C 7-30 Alkyl, or C 5-10 It is cycloalkyl.

[0072] In some embodiments, R4 is C 6-10 aryl, C 6-10 Aryl is halogen, C 1-6 Optionally substituted with alkyl.

[0073] In some embodiments, the compound of the present application is selected from the group consisting of: JPEG2026506777000020.jpg157150 JPEG2026506777000021.jpg191150 JPEG2026506777000022.jpg219150 JPEG2026506777000023.jpg219150 In some embodiments, the compound of Formula I has the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, and deuterium-substituted versions thereof: JPEG2026506777000024.jpg5382Here, R5 is -C(O)R6, -C(O)OR6, CONR7R 10 , C.R. 12 R 13 OC(O)R7, CR 12 R 13 OC(O)OR7, and JPEG2026506777000025.jpg2526, R6 is C 13-30 Alkyl, C 13-30 Alkenyl, and C 13-30 Alkynyl, C 13-30 Alkyl, C 13-30 Alkenyl, and C 13-30 Each alkynyl is selected from halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R7 is H, -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Alkenyl, -C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 alkynyl, wherein -C 1-30 Alkyl, -C 2-30 Alkenyl, -C 2-30 Alkynyl, -C(O)C 1-30 Alkyl, -C(O)C 2-30 Each alkenyl is —C(O)C 2-30 Alkynyl, -C(O)OC 1-30 Alkyl, -C(O)OC 2-30 Alkenyl, -C(O)OC 2-30 Alkynyl, -C(O)NRcC 1-30 Alkyl, -C(O)NRcC 2-30 Alkenyl, and -C(O)NRcC 2-30 Alkynyl is halo, -OC 1-30 Alkyl, -SC 1-30 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1-30 Alkyl, -SC 1-30 Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C 1-3 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R 10 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl, and -(CH2) n heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Cycloalkyl, -(CH2)n Aryl, and -(CH2) n Each heteroaryl may be selected from halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; R 12 and R 13 are H, deuterium, and C, respectively. 1-6 Alkyl, halo, and C 1-6 haloalkyl; 1-6 Alkyl, halo, and C 1-6 Each haloalkyl is halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; R8 and R9 are H, OH, and C, respectively. 1-6 Alkyl, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -SSC(O)OC 2-30 Alkyl, -C 3-10 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from the group consisting of OH, halo, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; or R8 and R9, taken together with the atoms to which they are attached, form a 3-10 membered heterocycle, which is optionally substituted with 1-4 R6, each R6 independently being H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, or alkoxy; n=0, 1, 2 or 3; The above 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each of which is independently N, O or S. In some embodiments, the compound of Formula I has the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, and deuterium-substituted versions thereof: JPEG2026506777000026.jpg3287 where R1 and R2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl, and C 1-6 alkyl-heteroaryl, or R1 and R2, when combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Haloalkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, and R3 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl; R4 is selected from the group consisting of halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl is halo, NH2, NO2, OH, CN, OC 1-6 Alkyl, C 6-10 or R6 and R7 are optionally substituted with one or more substituents each independently selected from the group consisting of aryl, and heteroaryl, or R6 and R7 are joined to the atoms to which they are attached to form a 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl is selected from halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl. In some embodiments, the compound of Formula I has the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, and deuterium-substituted versions thereof: JPEG2026506777000027.jpg3993 where R1 and R2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, heteroaryl, C1-6 Alkyl C 6-10 Aryl, and C 1-6 alkylheteroaryl, or R1 and R2, combined with the atoms to which they are attached, are selected from the group consisting of C 3-10 forming a cycloalkyl or heterocyclyl, R3 is H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Haloalkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-8 alkyl, where R3 is halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R4 is C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein R4 is halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R5 is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; X1, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently H, D or F; Z1 and Z2 are each independently H or D; R a and R b are each independently selected from the group consisting of CH3, CD3, Cl, Br, I, or CF3; R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30Alkynyl, C 1-30 Alkyl, C 1-30 Alkenyl, or C 1-30 Alkynyl is halo, NH2, NO2, OH, CN, OC 1-6 Alkyl, C 6-10 or R6 and R7 are optionally substituted with one or more substituents each independently selected from the group consisting of aryl, and heteroaryl, or R6 and R7 are joined to the atoms to which they are attached to form a 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl is selected from halo, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Haloalkyl, and OC 1-6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0074] Another aspect of the present application relates to a pharmaceutical composition comprising (1) a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a hydrate or solvate thereof, and (2) a pharmaceutically acceptable carrier.

[0075] III. Treatment method Another aspect of the present application relates to a method for preventing, treating, or ameliorating symptoms of a disease or condition in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present application. Examples of the disease or condition include, but are not limited to, obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), fatty liver, arteriosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer. The present application also relates to a compound of formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a hydrate or a solvate thereof in the manufacture of a medicament for the treatment and / or prevention of obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), fatty liver, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer. [Example]

[0076] synthesis The compounds of the present disclosure can be prepared by the methods disclosed herein and their routine modifications apparent from the disclosure of the present specification, as well as by methods well known in the art.In addition to the teachings of the present specification, conventional well-known synthetic methods can also be used.The synthesis of a typical compound of formula I, or its pharmaceutically acceptable salt, for example, a compound having one or more structures represented by formula I, or other formulas or compounds disclosed herein can be carried out as described in the following examples.

[0077] General Synthesis Exemplary embodiments of the compounds of the present application can be synthesized using the general reaction schemes and / or examples set forth below. As is apparent from the description herein, the general schemes can be modified to yield different corresponding products by substituting starting materials with other materials of similar structure. The synthetic description below provides numerous examples of how starting materials can be varied to produce the corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds of the present invention. The identity of each substituent is revealed by inspection of the structure of the compound to be synthesized. The identity of the final product, as judged by the examples herein, generally reveals the identity of the necessary starting materials through a simple inspection process. Group labels (e.g., R1, R2) used in the reaction schemes herein are for illustrative purposes only and, unless otherwise specified, do not necessarily correspond in name or function to labels used elsewhere to describe compounds of Formula I or aspects or fragments thereof.

[0078] Synthesis reaction parameters The compounds of the present disclosure can be prepared from readily available starting materials, for example, using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, although such conditions can be determined by one skilled in the art by routine optimization procedures.

[0079] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, T.W. Greene and G.M.Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein, describe numerous protecting groups.

[0080] Furthermore, the compounds of the present application may contain one or more chiral centers. Thus, if desired, these compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or as mixtures containing stereoisomers. Unless otherwise specified, all stereoisomers (and mixtures containing them) are within the scope of the present disclosure. Pure stereoisomers (or mixtures containing them) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0081] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Other compounds can be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser, "Reagents for Organic Synthesis," Vols. 1-15 (John Wiley and Sons, 1991), Rodd, "Chemistry of Carbon Compounds," Vols. 1-5 and Supplemental (Elsevier Science Publishers, 1989), "Organic Reactions," Vols. 1-40 (John Wiley and Sons, 1991), March, "Advanced Organic Chemistry" (John Wiley and Sons, 5th ed., 2001), and Larock, "Comprehensive Organic Transformations" (VCH Publishers Inc., 1989).

[0082] The terms "solvent," "inert organic solvent," or "inert solvent" refer to a solvent that is inert under the reaction conditions described therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of the present application are inert organic solvents, and the reactions are conducted under an inert gas, preferably nitrogen.

[0083] The term "appropriate amount" means adding a quantity sufficient to achieve a stated function, for example, a quantity sufficient to bring a solution to the desired volume (ie, 100%). The compounds described herein can be synthesized according to the general schemes shown below. In the schemes below, it should be understood that each compound shown therein may have protecting groups at any step, as necessary. Standard protecting groups are within the understanding of those skilled in the art.

[0084] Production Example 1: Production of Compound 1 4-(4-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenylpentadecanoate (Compound 1) JPEG2026506777000028.jpg6671 JPEG2026506777000029.jpg107150

[0085] (1) Synthesis of intermediate 1-3: To a solution of 1-1 (1 g, 3.18 mmol) in THF (10 ml) was added NaH (153 mg, 3.816 mmol) at 0 °C and stirred for 0.5 h, followed by the addition of a solution of 1-2 (1.60 g, 3.816 mmol) in THF (10 ml). The mixture was stirred at room temperature for 2 h. The reaction was quenched with HO and extracted with EA. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 1-3 (1.0 g, 56% yield).

[0086] (2) Synthesis of intermediate 1-4: To a solution of 1-3 (1 g, 1.78 mmol) in MeOH (10 ml), 1N NaOH (5 ml) was added and stirred at room temperature (RT) for 16 hours. The reaction mixture was extracted with EA. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 1-4 (0.56 g, 65% yield).

[0087] (3) Synthesis of intermediate 1-6: A solution of 1-4 (0.56 g, 1.15 mmol), (COCl) (0.439 g, 3.46 mmol), and DMF (catalyst) in DCM (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, followed by the addition of DCM (10 mL), TEA (0.929 g, 9.2 mmol), DAMP (14 mg, 0.115 mmol), and 1-5 (0.384 g, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with HO, and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 1-6 (0.35 g, 50% yield).

[0088] (4) Synthesis of intermediate 1-7: A solution of 1-6 (0.35 g, 0.58 mmol) and TsOH (0.3 g, 1.74 mmol) in methanol (5 mL) was stirred at 50 °C for 4 h. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 1-7 (0.21 g, 65% yield).

[0089] (5) Synthesis of Compound 1: The reaction mixture of 1-7 (0.21 g, 0.38 mmol), TEA (77 mg, 0.76 mmol), DAMP (5 mg, 0.038 mmol), and 1-8 (0.114 g, 0.418 mmol) was dissolved in DCM (5 ml) and stirred at room temperature for 2 h. The reaction was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give compound 1 (150 mg, 50% yield).

[0090] Preparation Example 2: Synthesis of Compound 6 4-(4-(((benzyloxy)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl docosanoate (Compound 6) JPEG2026506777000030.jpg5177 JPEG2026506777000031.jpg104150

[0091] (1) Synthesis of intermediate 6-3: To a solution of 1-1 (1 g, 3.18 mmol) in THF (10 ml) was added NaH (153 mg, 3.816 mmol) at 0°C. After stirring for 0.5 h, a solution of 6-2 (1.7 g, 3.816 mmol, see Example 4) in THF (10 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO and extracted with EA. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 6-3 (1.2 g, 64% yield).

[0092] (2) Synthesis of intermediate 6-4: To a solution of 6-3 (1.2 g, 2.03 mmol) in MeOH (10 ml), 1N NaOH (5 ml) was added and stirred at room temperature for 16 hours. The reaction mixture was extracted with EA. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 6-4 (0.50 g, 49% yield).

[0093] (3) Synthesis of intermediate 6-6: A solution of 6-4 (0.50 g, 1.0 mmol), (COCl) (0.254 g, 2 mmol), and DMF (catalyst) in DCM (10 mL) was stirred at room temperature for 1 h. After concentrating the reaction mixture in vacuo, DCM (10 mL), TEA (0.929 g, 9.2 mmol), DAMP (14 mg, 0.115 mmol), and 1-5 (0.384 g, 2.3 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 6-6 (0.27 g, 44% yield).

[0094] (4) Synthesis of intermediate 6-7: A solution of 6-6 (0.27 g, 0.44 mmol) and TsOH (0.151 g, 0.88 mmol) in MeOH (5 mL) was stirred at 50 °C for 4 h. The reaction was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 6-7 (0.15 g, 60% yield).

[0095] (5) Synthesis of Compound 6: A solution of 6-7 (0.15 g, 0.26 mmol), TEA (55 mg, 0.53 mmol), DAMP (5 mg, 0.028 mmol), and 6-8 (0.112 g, 0.418 mmol) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give compound 6 (100 mg, 43% yield).

[0096] Preparation Example 3: Synthesis of Compound 13 Octadecyl(((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (Compound 13) JPEG2026506777000032.jpg5471 JPEG2026506777000033.jpg85150

[0097] (1) Synthesis of intermediate 13-6: A solution of 1-4 (0.50 g, 1.0 mmol), (COCl) (0.254 g, 2 mmol), and DMF (catalyst) in DCM (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and DCM (10 mL), TEA (0.929 g, 9.2 mmol), DAMP (14 mg, 0.115 mmol), and 13-5 (0.756 g, 2.0 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give intermediate 13-6 (0.30 g, 37% yield).

[0098] (3) Synthesis of compound 13: A solution of 13-6 (0.30 g, 0.37 mmol) and TsOH (0.128 g, 0.75 mmol) in MeOH (5 mL) was stirred at 50 °C for 4 h. The reaction was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica gel to give compound 13 (0.17 g, 60% yield).

[0099] Production Example 4: Synthesis of Intermediate 1-2 (Diphenoxyphosphoryl)methyl 4-methylbenzenesulfonate (Intermediate 1-2) JPEG2026506777000034.jpg32150

[0100] (1) Synthesis of intermediate 1-2-B: A solution of 1-2-A (1 g, 3.1 mmol) and TMSBr (3.3 g, 21.7 mmol) in DCM (10 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. MTBE and 2-3N NaOH were added, followed by extraction with MTBE. The pH of the aqueous phase was adjusted to 1-2 with 3N HCl. After extraction with EA, the organic phase was concentrated in vacuo to give intermediate 1-2-B (0.6 g, 72% yield).

[0101] (2) Synthesis of intermediate 1-2: A solution of intermediate 1-2-B (0.6 g, 2.25 mmol), (COCl) (0.856 g, 6.75 mmol), and DMF (catalyst) in DCM (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Next, DCM (10 mL), TEA (1.36 g, 13.5 mmol), DAMP (27 mg, 0.225 mmol), and phenol (0.528 g, 5.625 mmol) were added to the reaction mixture and stirred at room temperature for 2 h. The reaction was quenched with HO and extracted with DCM. The organic phase was concentrated in vacuo and purified on silica to give intermediate 1-2 (0.36 g, 38% yield).

[0102] Preparation Example 5: Amino acid ester (Int A) JPEG2026506777000035.jpg27150

[0103] Pentan-3-ol (28 g, 318 mmol) was added to a solution of Int A-1 (60 g, 317 mmol), imidazole (21 g, 323 mmol), HATU (180 g, 473 mmol), and TEA (64 g, 633 mmol) in DMF / DCM (500 ml / 500 ml) and stirred overnight at room temperature. The reaction was concentrated in vacuo to remove DCM. The residue was added to water and stirred for 1 hour. The mixture was filtered to obtain a solid. The solid was dried to give Int A-2 (80.0 g, 97.3% yield).

[0104] Int A-2 (50 g, 193 mmol) was dissolved in a 4 M HCl solution in dioxane (500 ml) at 0-5°C and stirred for 1 hour. The reaction mixture was concentrated in vacuo to give a solid. The resulting solid was added to DCM (500 ml) and saturated sodium carbonate solution (500 ml) and stirred for 15 minutes. The organic layer was separated and concentrated in vacuo to give Int A (27.0 g, 87.9% yield).

[0105] Preparation Example 6: (4-Hydroxy-2,6-dimethylphenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanone (Int B) JPEG2026506777000036.jpg30150

[0106] A solution of compound 1-1 (1.0 g, 3.18 mmol), Pd / C (0.05 g, 30 wt%), and HO (0.2 ml) in DMA (2 ml) was stirred under a nitrogen atmosphere at 130-135 °C for 48 hours. After cooling, the mixture was filtered to obtain the filtrate. The filtrate was added to ethyl acetate (15 ml), washed with saturated brine, concentrated in vacuo, and purified with silica gel to obtain Int B (0.35 g, 33.5% yield).

[0107] Preparation Example 7: 4-((3-isopropyl-4-(methoxymethoxy)phenyl)methyl-d2)-3,5-dimethylphenol (Int C) JPEG2026506777000037.jpg30150

[0108] LiAlD (25.6 mg, 0.6 mmol) was added to a solution of compound B (0.1 g, 0.3 mmol) in THF (1 mL) at 0°C and stirred for 1 hour. The mixture was quenched with saturated NH Cl solution, and then EtOAc (20 mL) was added. The organic phase was separated, washed with water and saturated brine, dried over MgSO, and then concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give compound C (56 mg, yield 58.1%).

[0109] Preparation Example 8: 4-(difluoro(3-isopropyl-4-(methoxymethoxy)phenyl)methyl)-3,5-dimethylphenol (Int D) JPEG2026506777000038.jpg31150

[0110] Int B (0.1 g, 0.3 mmol) was dissolved in 1,2-dichloroethane (1 mL), BAST (0.2 g, 0.9 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL). The organic phase was then separated, washed with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give Int D (66 mg, 61.9% yield).

[0111] Preparation Example 9: 4-(4-(methoxymethoxy)-3-(propan-2-yl-1,1,1,3,3,3-d6)benzyl)-3,5-dimethylphenol (Int E) JPEG2026506777000039.jpg59150

[0112] To a solution of Int E-1 (5.0 g, 16.7 mmol) in THF (50 ml) was added iPrMgCl (1 M in THF, 50 ml) dropwise at -20 °C and stirred for 2 hours. Acetone-D6 (0.5 ml) was added dropwise to the solution, and the mixture was stirred for 2 hours, then allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl solution (30 ml), and EtOAc (50 ml) was added to the reaction mixture. The organic phase was then separated, washed with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give Int E-2 (3.2 g, 80.1% yield).

[0113] To a solution of Int E-2 (3.0 g, 12.6 mmol) and TFA (0.1 mL) in DCE (30 mL) was added EtSiH (2.94 g, 25.3 mmol) and stirred for 4 hours. Water (30 mL) was added to the reaction mixture. The organic phase was then separated, washed with water and saturated brine, dried over MgSO, and concentrated in vacuo to give Int E-3 (2.6 g, 92.9% yield).

[0114] To a solution of Int E-3 (2.6 g, 11.7 mmol) in THF (30 mL) was added tBuOK (1.98 g, 17.6 mmol) at 0 °C and stirred for 1 hour. Then, MOMBr (1.62 g, 12.9 mmol) was added and stirred for 2 hours. The mixture was quenched with saturated NH4Cl solution (30 mL), and EtOAc (50 mL) was added to the mixture. The organic phase was then separated, washed with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give Int E-4 (1.9 g, 60.9% yield).

[0115] To a solution of Int E-4 (1.9 g, 7.16 mmol) in THF (20 mL), n-BuLi (4.3 mL, 2.5 M in hexane) was added at -78 °C and stirred for 30 minutes. Next, 2,6-dimethyl-4-((triisopropylsilyl)oxy)benzaldehyde (2.31 g, 7.52 mmol) was added dropwise and stirred at -78 °C for 1 hour. The mixture was quenched with saturated NH4Cl solution (20 mL), and EtOAc (40 mL) was added to the mixture. The organic phase was then separated, washed with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give Int E-5 (2.43 g, 68.8% yield).

[0116] To a solution of Int E-5 (2.43 g, 4.93 mmol) in EtOAc (20 ml), a solution of TBAF (5 ml, 1 M in EA) was added and stirred for 30 minutes. Water (20 ml) was added and stirred for 15 minutes. The organic phase was then separated, washed with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from n-heptane to give Int E-6 (1.32 g, 79.6% yield).

[0117] To a solution of Int E-6 (1.32 g, 3.92 mmol) and TFA (2 drops) in DCM (15 mL) was added Pd / C (0.1 g, 30 wt%). The solution was stirred at room temperature under a H atmosphere for 4 hours. After filtration, the solution was concentrated in vacuo to give Int E (1.15 g, 91.5% yield).

[0118] Preparation 10: Phenyl hydrogen ((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonate (Int F) JPEG2026506777000040.jpg74150

[0119] Potassium carbonate (3.30 g, 23.85 mmol) was added to a solution of 4-[(4-(methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5-dimethylphenol (5 g, 15.90 mmol) and diethyl [(4-methylbenzenesulfonyl)oxy]methanephosphonate (5.12 g, 15.9 mmol) in acetonitrile (30 mL), and the mixture was stirred at 80-85 °C for 4 hours. After cooling, water and ethyl acetate were added to the mixture. The organic layer was separated and concentrated under reduced pressure to give diethyl [(4-[(4-(methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl]phosphonate (7.2 g, 97.47% yield) as an oil.

[0120] TMSBr (3.30 g, 21.6 mmol) was added dropwise to a solution of diethyl [(4-[(4-(methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl]phosphonate (5 g, 10.76 mmol) in dichloromethane (25 ml), and the mixture was stirred at 10-15°C for 4 hours. Water was added dropwise to the mixture. The organic layer was separated and concentrated under reduced pressure to give compound A (3.6 g, 92% yield).

[0121] A solution of compound A (55 g, 151 mmol) and phenol (28.4 g, 302 mmol) in DMF (1 L) was added with pyridine (200 mL), DCC (92 g, 451 mmol), and DMAP (18 g, 147 mmol) and stirred at 80–85 °C overnight. After cooling, ethyl acetate was added to the mixture and the pH was adjusted to 3.0 with 1N HCl solution. The organic layer was separated, washed with water, dried (NaSO), and evaporated to dryness to obtain the crude product. The crude product was then purified by silica gel chromatography (eluting with PE:EtOAc = 10:1) to obtain Int F (26 g, 39% yield) as a white solid. Preparation Example 11 Pentan-3-yl((R)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (29) and pentan-3-yl((S)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (30) JPEG2026506777000041.jpg104150

[0122] Oxalyl chloride (8.6 g, 67.7 mmol) was added dropwise to a solution of Int F (10 g, 22.7 mmol) and DMF (166 mg, 2.27 mmol) in DCM (100 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give an oil. This oil was dissolved in DCM (100 mL), and pentan-3-yl L-alaninate (18.05 g, 113.5 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gel chromatography eluting with PE:EtOAc (10:1) to give compound 25 (yield 3.0 g). Compound 25 was purified on a chiral column (Welch XT C18 150 mm × 21.2 mm, 5 μm) to give compound 28 (yield 1.5 g) and compound 29 (yield 1.2 g). Preparation Example 12 Pentan-3-yl(((4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (52) To a solution of 1-(benzyloxy)-2-bromobenzene (21 g, 79.81 mmol) in THF (SO, 100 mL) was added butyllithium (5.62 g, 87.79 mmol) dropwise under a nitrogen atmosphere at −70°C. The resulting mixture was stirred at −70°C for 0.5 h under a nitrogen atmosphere. 4-Fluorobenzaldehyde (R1, 9.91 g, 79.81 mmol, 100% purity) was added dropwise to the above mixture at −70°C over 15 min. The resulting mixture was stirred at 0°C for an additional 1 h. The reaction was quenched by the addition of water (50 mL) at 25°C. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. A solution of (2-(benzyloxy)phenyl)(4-fluorophenyl)methanol (27 g, 87.56 mmol), hydrogen chloride (0.32 g, 8.76 mmol), and Pd / C (4.92 g, 35.02 mmol) in methanol (60 mL) was stirred under an H atmosphere at 25 °C for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was neutralized to pH 7-8 with NaHCO (aq). The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. To a solution of 2-[(4-fluorophenyl)methyl]phenol (15 g, 74.18 mmol) in DCM (50 mL) was added tetrabutylammonium tribromide (37.56 g, 77.89 mmol) in small portions at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water (50 mL) at 25 °C. The resulting mixture was extracted with EA (2 × 100 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:10) to give 4-bromo-2-[(4-fluorophenyl)methyl]phenol (12 g, 57.55% yield) as a yellow oil. To a stirred solution of 4-bromo-2-[(4-fluorophenyl)methyl]phenol (12 g, 42.69 mmol) in THF (50 mL) was added sodium hydride (2.22 g, 55.50 mmol, 60% purity) in small portions at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 h. To the above mixture was added chloro(methoxy)methane (4.12 g, 51.23 mmol) dropwise over 15 min at 0 °C. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction was quenched by the addition of water (30 mL) at 25 °C. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography eluting with [EA:PE (1:10)] to give 4-bromo-2-[(4-fluorophenyl)methyl]-1-(methoxymethoxy)benzene (10 g, yield 72.04%) as a yellow oil. To a stirred solution of 4-bromo-2-[(4-fluorophenyl)methyl]-1-(methoxymethoxy)benzene (15 g, 46.13 mmol) in THF (50 mL) was added dropwise butyllithium (3.10 g, 48.44 mmol) under a nitrogen atmosphere at −70°C. The resulting mixture was stirred at −70°C for 0.5 h under a nitrogen atmosphere. To the above mixture, 2,6-dimethyl-4-[(tris(propan-2-yl)silyl)oxy]benzaldehyde (14.14 g, 46.13 mmol) was added dropwise over 15 min at −70°C. The resulting mixture was stirred at 0°C for an additional 1 h. The reaction was quenched by the addition of water (30 mL) at 25°C. The resulting mixture was extracted with EA (2 × 50 mL). The combined organic layer was washed with saturated brine (20 mL × 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (0-1:10) to give (2,6-dimethyl-4-[(tris(propan-2-yl)silyl)oxy]phenyl)(3-[(4-fluorophenyl)methyl]-4-(methoxymethoxy)phenyl)methanol (10 g, 39.22% yield) as a yellow oil. To a stirred solution of 4-[(3-[(4-fluorophenyl)methyl]-4-(methoxymethoxy)phenyl)(hydroxy)methyl]-3,5-dimethylphenol (3.5 g, 9.20 mmol) and Pd / C (0.26 g, 1.84 mmol) in methanol (40 mL) was added hydrogen chloride (0.050 g, 1.38 mmol) dropwise at 25 °C. The resulting mixture was stirred under an H atmosphere at 25 °C for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was basified to pH 7-8 with NaHCO (aq). The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). After filtration, the filtrate was concentrated under reduced pressure. As a result, 4-[(3-[(4-fluorophenyl)methyl]-4-(methoxymethoxy)phenyl)methyl]-3,5-dimethylphenol (2 g, yield 54.84%) was obtained as a yellow oil. To a solution of (2,6-dimethyl-4-[(tris(propan-2-yl)silyl)oxy]phenyl)(3-[(4-fluorophenyl)methyl]-4-(methoxymethoxy)phenyl)methanol (10 g, 18.09 mmol) in THF (50 mL) was added tetrabutylammonium fluoride (4.73 g, 18.09 mmol) dropwise at 0° C. The resulting mixture was stirred at 25° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (100 mL). The organic layer was washed with water (2 × 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with heptane (20 mL). The precipitated solid was collected by filtration and washed with heptane (3 × 5 mL). This resulted in the production of 4-[(3-[(4-fluorophenyl)methyl]-4-(methoxymethoxy)phenyl)(hydroxy)methyl]-3,5-dimethylphenol (5.5 g, 76.69% yield) as a yellow solid. The following synthesis methods can be followed in Preparations 10 and 11 to give Compound 52. Preparation Example 13 Pentan-3-yl((4-(3-(sec-butyl)-4-hydroxybenzyl)-3,5-dimethylphenethyl)(phenoxy)phosphoryl)-L-alaninate (53) To a solution of 4-bromo-2-(butan-2-yl)-1-(methoxymethoxy)benzene (6.11 g, 22.37 mmol) in THF (40 mL) was added butyllithium (1.58 g, 24.61 mmol) dropwise at -70 °C, and the reaction mixture was stirred for 1 h. Next, a solution of 4-bromo-2,6-dimethylbenzaldehyde (4.77 g, 22.37 mmol) in THF (20 mL) was added to the above solution at -70 °C under a nitrogen atmosphere. The reaction mixture was stirred at -70 °C for 0.5 h. After warming to room temperature, NH4Cl solution was added and stirred for 30 min. The mixture was extracted with ethyl acetate. The reaction mixture was concentrated and purified by silica gel chromatography eluting with PE:EtOAc = 20:1 to give compound 53-2 (5.23 g, yield: 57.4%). A solution of 53-2 (3.78 g, 9.28 mmol), diethyl ethenylphosphonate (1.68 g, 10.21 mmol), palladium(II) acetate (0.21 g, 0.93 mmol), potassium carbonate (1.54 g, 11.14 mmol), and tri(m-tolyl)phosphine (0.28 g, 0.93 mmol) in DMF (20 mL) was degassed and heated at 110 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and HO was added to the above solution. The mixture was extracted with EA (100 mL × 3). The combined organic phase was washed with brine, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 5:1 to 1:2) to give the pure product 53-3 (2.78 g, 61.1% yield) as a yellow oil. 53-3 (40 mg, 0.082 mmol), Pd / C (0.00087 g, 0.0082 mmol), and trifluoroacetic acid (0.00047 g, 0.0041 mmol) were dissolved in dichloromethane (2 mL). The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by TLC (PE:EA = 1:1) to give the pure product 53-4 (21 mg, 54.04% yield) as a white oil. The following synthesis can be carried out according to Preparation 10 and Example 11 to give Compound 53.

[0123] The following compounds (Table 1) were prepared according to the procedures described herein, using appropriate starting materials and appropriate protecting group chemistry where necessary: 1 Characterized by HNMR as follows: [Table 1] JPEG2026506777000044.jpg192150 JPEG2026506777000045.jpg205150 JPEG2026506777000046.jpg225150 JPEG2026506777000047.jpg210150 JPEG2026506777000048.jpg201150 JPEG2026506777000049.jpg195150 JPEG2026506777000050.jpg203150 JPEG2026506777000051.jpg202150 JPEG2026506777000052.jpg219150 JPEG2026506777000053.jpg222150 JPEG2026506777000054.jpg225150 JPEG2026506777000055.jpg177150 JPEG2026506777000056.jpg214150 JPEG2026506777000057.jpg52150 Example 14. Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxide-1,3,2-dioxaphosphinan-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl stearate (Compound 54) To a solution of compound A (4.25 g, 8.25 mmol) in dichloromethane (50 ml), stearoyl chloride (5.0 g, 16.5 mmol), triethylamine (1.67 g, 16.5 mmol), and DMAP (2 mg) were added at 0 °C and stirred at room temperature overnight. Water (50 ml) was added to the mixture, and the organic layer was extracted. The resulting organic layer was concentrated in vacuo, and the resulting solid was purified by flash column chromatography (DCM / MeOH 10:1) to give compound 54 (4.6 g, 71.3% yield). Example 15 Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxide-1,3,2-dioxaphosphinan-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl docosyl carbonate (Compound 57) JPEG2026506777000059.jpg5588 n-Docosanol (1.90 g, 5.83 mmol), EtN (3.5 g, 35 mmol), and DMAP (2 mg) were added to dichloromethane (50 ml) at 0 °C and stirred for 1 hour. Next, a solution of compound A (2.0 g, 3.88 mmol, 10 ml) was added to the mixture and stirred at 0 °C for 2 hours. Water (50 ml) was added to the mixture, and the organic layer was extracted. The resulting organic layer was concentrated in vacuo, and the resulting oil was purified by flash column chromatography (DCM / MeOH 10:1) to give compound 57 (1.2 g, 35.6% yield). Example 16 Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxide-1,3,2-dioxaphosphinan-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl L-alaninate (Compound 65) JPEG2026506777000061.jpg93150 Compound A (2.5 g, 4.85 mmol), HATU (2.21 g, 5.82 mmol), and EtN (0.74 g, 7.28 mmol) were added to dichloromethane (25 ml) at room temperature and stirred for 3 hours. Water (50 ml) was added to the mixture, and the organic layer was extracted. The resulting organic layer was concentrated in vacuo, and the resulting oil was added to dichloromethane (25 ml). Next, trifluoroacetic acid (6 ml) was added, and the mixture was stirred for 2 hours, after which a white solid precipitated. After filtration, compound 65 (2.6 g, 91.4% yield) was obtained. Example 17 Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxide-1,3,2-dioxaphosphinan-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl 2-(((decyloxy)carbonyl)disulfanyl)acetate (Compound 70) Compound A (5.14 g, 10 mmol), dithiodiglycolic acid (3.64 g, 20 mmol), HATU (3.8 g, 10 mmol), and EtN (2.02 g, 20 mmol) were added to dichloromethane (50 ml) at room temperature and stirred for 3 hours. Water (50 ml) was added to the mixture, and the organic layer was extracted. The resulting organic layer was concentrated in vacuo, and the resulting oil was purified by flash column chromatography (DCM / MeOH 8:1) to give compound 70-1 (2.3 g, 33.9% yield). Compound 70-1 (2.0 g, 2.95 mmol), HATU (1.23 g, 3.25 mmol), and EtN (0.60 g, 5.9 mmol) were added to dichloromethane (20 ml) at room temperature and stirred for 3 hours. Water (30 ml) was added to the mixture, and the organic layer was extracted. The resulting organic layer was concentrated in vacuo, and the resulting oil was purified by flash column chromatography (DCM / MeOH 15:1) to give compound 70 (1.5 g, 63.3% yield). The following compounds (Table 2) were prepared according to the procedures described herein, using appropriate starting materials and appropriate protecting group chemistry where necessary: 1 It was characterized by HNMR as follows: [Table 2] JPEG2026506777000063.jpg231150 JPEG2026506777000064.jpg221150 JPEG2026506777000065.jpg221150 JPEG2026506777000066.jpg189150

[0124] Pharmacokinetic studies

[0125] 1. Absorption and pharmacokinetics in rats

[0126] The compounds of formula I are prodrugs of Protide, which is metabolized to the active moiety Compound A or an analogue. JPEG2026506777000067.jpg3564

[0127] a. Individual plasma concentrations of Compound A (14 mg / kg equivalent of the active moiety) following a single subcutaneous administration of Compounds 1, 10, 13, 14, 16, 22, 23, 24, 25, 26, 28, 29, 30, 38, 39, 40, and 50 in SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figures 1 and 2. b. In vivo, compound 31 is metabolized to compound C, compound 32 is metabolized to compound D, compound 34 is metabolized to compound E, and compound 36 is metabolized to compound F. JPEG2026506777000068.jpg87120Individual plasma concentrations of Compound C (14 mg / kg, equivalent to Compound C) after a single subcutaneous administration of Compound 31 (equivalent to Compound C) to SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 3. Individual plasma concentrations of Compound D (14 mg / kg, equivalent to Compound D) following a single subcutaneous dose of Compound 32 (equivalent to Compound D) in SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 4. Individual plasma concentrations of Compound E (14 mg / kg, equivalent to Compound E) following a single subcutaneous dose of Compound 34 (equivalent to Compound E) in SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 5. Individual plasma concentrations of Compound F following a single subcutaneous dose of Compound 36 (equivalent to 14 mg / kg of Compound F) in SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 6. c. The compound of Formula II is a prodrug and is metabolized in vivo to Compound A. Therefore, individual plasma concentrations of Compound A were monitored after a single subcutaneous dose of Compound 54 (20 mg / kg) in rats, and mean pharmacokinetic parameters were calculated. The results are shown in Figure 7. d. In vivo, compound 52 is metabolized to compound G, and compound 53 is metabolized to compound H. JPEG2026506777000069.jpg37150The individual plasma concentrations of compound G after a single subcutaneous administration of compound 52 (equivalent to 14 mg / kg of compound G) to SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 8. Individual plasma concentrations of Compound H following a single subcutaneous dose of Compound 53 (equivalent to Compound H at 14 mg / kg) in SD rats were used to calculate the mean pharmacokinetic parameters summarized in Figure 9. 2. Absorption and pharmacokinetics in male cynomolgus monkeys a. Plasma concentrations of Compound A following a single subcutaneous administration of Compounds 29 and 30 to male cynomolgus monkeys were used to calculate the mean pharmacokinetic parameters shown in Figure 10. Dosage information: Formulation concentration: 10 mg / kg; Formulation concentration: 20 mg / ml. b. Plasma concentrations of Compound G following a single subcutaneous dose of Compound 52 to male cynomolgus monkeys were used to calculate the mean pharmacokinetic parameters shown in Figure 11. Dosage information: Formulation concentration: 10 mg / kg; Formulation concentration: 20 mg / ml. 3. Distribution and Pharmacokinetics in Rats After a single subcutaneous administration of Compound A, the distribution in plasma and liver was summarized as follows: [Table 3] JPEG2026506777000070.jpg31150

Claims

1. Compounds of Formula I, their stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof. Here, G is —O— and —C(X ９ X ８ )- is selected from the group consisting of T is -(CR ｄ ) ｍ -, and -O-(CR ｄ ) ｍ - selected from the group consisting of m is an integer from 0 to 3; X is selected from the group consisting of: and R ａ and R ｂ are respectively CH ３ , CDs ３ , Cl, Br, I and CF ３ are independently selected from the group consisting of R ｃ represents hydrogen, halogen, -CF ３ , -OCF ３ , cyano, optionally substituted —C １ -C １２ Alkyl, optionally substituted -C ２ -C １２ Alkenyl, optionally substituted -C ２ -C １２ Alkynyl, optionally substituted -C ０－６ alkylaryl, optionally substituted -C ０－６ alkylcycloalkyl, optionally substituted -C ０－６ alkylheterocycloalkyl, and optionally substituted —C ３－８ cycloalkyl; R ｃ is optionally substituted with 1 to 10 halogen, H or D; R ｄ are each independently hydrogen, halogen, and C １－６ is selected from the group consisting of alkyl, R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl-C ６－１０ Aryl, and C １－６ alkyl-heteroaryl or R １ and R ２ are bonded to the atom to which they are attached and C ３－１０ forming a cycloalkyl or heterocyclyl, R ３ is H, C １－３０ Alkyl, C ５－１０ Cycloalkyl, C １－３０ Haloalkyl, C ６－１０ Aryl, and C ６－１０ Aryl-C １－８ alkyl; R ３ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ５ is H, -COR ６ , -COOR ６ , C.H. ２ OC(O)OR ７ , -CONHR ６ , -CONR ７ R １０ , -CONR ６ R ７ , -CH ２ OCOR ６ , -CH ２ OCONHR ６ , and is selected from the group consisting of R ６ are each independently C １－３０ Alkyl, C １－３０ alkenyl, and C １－３０ alkynyl, C １－３０ Alkyl, C １－３０ alkenyl, and C １－３０ Each alkynyl is independently halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is independently selected from halo and C １－３ optionally substituted with one or more substituents selected from the group consisting of alkyl; R ７ is H, -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Alkenyl, —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ alkynyl, wherein -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Each alkenyl is —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ Alkynyl is halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C １－３ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; Or, R ６ and R ７ are joined to the atom to which they are attached to form a 5- to 10-membered heterocyclyl, which is substituted with halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ８ and R ９ are H, OH, and C, respectively. １－６ Alkyl, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C １－６ Alkyl, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from OH, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; Or, R ８ and R ９ are joined to the atoms to which they are attached to form a 3- to 10-membered heterocyclic ring, which is formed by 1-4 R ６ and each R ６ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, or alkoxy; R １０ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ Each heteroaryl is selected from halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; X ８ and X ９ are independently H, D or halo; n=0, 1, 2 or 3; The 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O, or S; The 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each independently being N, O, or S; The compound of formula I is not isopropyl(((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate.

2. In the formula I, G is —O—; T is -O-(CR ｄ ) ｍ - and m is an integer from 0 to 3; X is and R ｃ represents hydrogen, halogen, -CF ３ , -OCF ３ , cyano, and optionally substituted —C １ -C １２ is selected from the group consisting of alkyl, R ｄ are each independently hydrogen, halogen, and C １－６ 10. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof.

3. In the formula I, R ｄ 3. The compound of claim 1 or 2, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof, wherein each of is hydrogen.

4. A compound according to any one of claims 1 to 3, wherein in formula I, m is 1, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof.

5. The compound of claim 1, wherein said Formula I is Formula II, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof. Here, R ５ is -COR ６ , -COOR ６ , C.O.R. ７ R １０ , -CH ２ OCOR ６ , C.H. ２ OC(O)OR ７ , and is selected from the group consisting of R ６ are each independently C １３－３０ Alkyl, C １３－３０ alkenyl, and C １３－３０ alkynyl, C １３－３０ Alkyl, C １３－３０ alkenyl, and C １３－３０ Each alkynyl is selected from halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is selected from halo and C １－３ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ７ is H, -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Alkenyl, —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ alkynyl, wherein -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Each alkenyl is —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ Alkynyl is halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C １－３ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ８ and R ９ are H, OH, and C, respectively. １－６ Alkyl, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C １－６ Alkyl, —O—C １－３ Alkyl, —S—C １－３ Alkyl, —S—S—C(O)OC ２－３０ Alkyl, -C ３－１０ Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from OH, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; Or, R ８ and R ９ are joined to the atoms to which they are attached to form a 3- to 10-membered heterocyclic ring, which is formed by 1-4 R ６ and each R ６ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, or alkoxy; R １０ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ Each heteroaryl is selected from halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; n=0, 1, 2 or 3; The 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O, or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each independently being N, O or S.

6. In the formula II, R ５ is -COR ６ , -COOR ６ , C.O.R. ７ R １０ , -CH ２ OCOR ６ , and 6. The compound of claim 5, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, selected from the group consisting of:

7. In the formula II, R ６ Each of these is independently C １３－３０ Alkyl and C １３－３０ The compound according to claim 5 or 6, which is alkenyl, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof.

8. The compound is selected from the group consisting of a compound according to any one of claims 1 to 7, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound thereof, an isomer thereof, a prodrug thereof, and a metabolite thereof.

9. The compound of claim 1, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof, wherein Formula I is Formula III: Here, R ａ and R ｂ are each independently CH ３ , CDs ３ , Cl, Br, I and CF ３ is selected from the group consisting of Rc is hydrogen, halogen, or —CF ３ , -OCF ３ , cyano, optionally substituted —C １ -C １２ Alkyl, optionally substituted -C ２ -C １２ Alkenyl, optionally substituted -C ２ -C １２ Alkynyl, optionally substituted -C ０－６ alkylaryl, optionally substituted -C ０－６ alkylcycloalkyl, optionally substituted -C ０－６ alkylheterocycloalkyl, optionally substituted —C ３－８ cycloalkyl; R ｃ is optionally substituted with 1-10 halogen, H or D; X ８ , X ９ , Z １ and Z ２ are each independently H, D, or halo; Z ３ are independently O, —CH ２ - and R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl-C ６－１０ Aryl, and C １－６ alkyl-heteroaryl or R １ and R ２ are bonded to the atom to which they are attached and C ３－１０ forming a cycloalkyl or heterocyclyl, R ３ is H, C １－３０ Alkyl, C ５－１０ Cycloalkyl, C １－３０ Haloalkyl, C ６－１０ Aryl, and C ６－１０ Aryl-C １－８ alkyl; R ３ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ５ is H, -COR ６ , -CONHR ６ , -COOR ６ , -CONR ６ R ７ , -CH ２ OCOR ６ , and -CH ２ OCONHR ６ is selected from the group consisting of R ６ and R ７ are each independently １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ alkynyl, C １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ Alkynyl is halo, NH ２ , NO ２ , OH, CN, OC １－６ Alkyl, C ６－１０ aryl, and heteroaryl, or R ６ and R ７ are joined to the atom to which they are attached to form a 5- to 10-membered heterocyclyl, which is substituted with halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

10. 10. The compound of claim 9, wherein Z is O in Formula III, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof.

11. In the formula III, Z １ and Z ２ is H, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof.

12. In the formula III, R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein R ４ is halo, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ 12. A compound according to any one of claims 9 to 11, optionally substituted with alkyl, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted derivatives thereof, isomers thereof, prodrugs thereof, and metabolites thereof.

13. In the formula III, R ３ is C １－３０ Alkyl, and C ５－１０ 12. The compound of any one of claims 9 to 11, selected from the group consisting of cycloalkyl, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted derivatives thereof, isomers thereof, prodrugs thereof, and metabolites thereof.

14. In the formula III, R ｃ is -C １ -C ６ Alkyl, -C ０－６ Alkyl-aryl, -C ０－６ Alkyl-cycloalkyl, -C ０－６ alkyl-heterocycloalkyl, and —C ３－８ cycloalkyl, wherein R ｃ is optionally substituted with halo, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterium-substituted product thereof, an isomer thereof, a prodrug thereof, and a metabolite thereof according to any one of claims 9 to 13.

15. The compound of claim 1, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof, wherein Formula I is Formula IV: Here, R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl C ６－１０ Aryl, and C １－６ alkylheteroaryl, or R １ and R ２ are bonded to the atoms to which they are attached and C ３－１０ forming a cycloalkyl or heterocyclyl, R ３ is H, C １－３０ Alkyl, C ５－１０ Cycloalkyl, C １－３０ Haloalkyl, C ６－１０ Aryl, and C ６－１０ Aryl-C １－８ alkyl, where R ３ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein R ４ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ５ is H, -COR ６ , -CONHR ６ , -COOR ６ , -CONR ６ R ７ , -CH ２ OCOR ６ , and -CH ２ OCONHR ６ is selected from the group consisting of X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ and X ９ are each independently H, D, or halo; Z １ and Z ２ are each independently H, D, or halo; R ａ and R ｂ are each independently CH ３ , CDs ３ , Cl, Br, I or CF ３ is selected from the group consisting of R ６ and R ７ are each independently １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ alkynyl, C １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ Alkynyl is halo, NH ２ , NO ２ , OH, CN, OC １－６ Alkyl, C ６－１０ aryl, and heteroaryl, or R ６ and R ７ are joined to the atom to which they are attached to form a 5- to 10-membered heterocyclyl, which is substituted with halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

16. In the formula IV, Z １ and Z ２ is H, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof.

17. In the formula IV, R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ is halo, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ 17. The compound of claim 15 or 16, optionally substituted with alkyl, its stereoisomers, its pharmaceutically acceptable salts, its deuterium-substituted derivatives, its isomers, its prodrugs, and metabolites thereof.

18. In the formula IV, R ３ is C １－３０ Alkyl, and C ５－１０ 18. The compound of any one of claims 15 to 17, wherein the compound is selected from the group consisting of cycloalkyl, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted derivatives thereof, isomers thereof, prodrugs thereof, and metabolites thereof.

19. The compound of claim 1, wherein Formula I is Formula V, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof. Here, R １ and R ２ are each independently H, C １－６ Alkyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl-C ６－１０ Aryl, and C １－６ alkyl-heteroaryl; R ３ is H, C １－３０ Alkyl, and C ５－１０ cycloalkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ is halo, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ Optionally substituted with alkyl.

20. In the formula V, R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ is halo, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ 20. The compound of claim 19, optionally substituted with alkyl, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted versions thereof, isomers thereof, prodrugs thereof, and metabolites thereof.

21. In the formula V, R ３ is C １－３０ Alkyl, and C ５－１０ 21. The compound of claim 19 or 20, wherein the compound is selected from the group consisting of cycloalkyl, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof.

22. The compound of claim 1, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted derivatives, isomers, prodrugs, and metabolites thereof, wherein Formula I is Formula VI: Here, R １ and R ２ is H, C １－６ Alkyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl-C ６－１０ Aryl, and C １－６ alkyl-heteroaryl; each of the alkyl, aryl, and heteroaryl is independently selected from the group consisting of halogen, C １－６ Alkyl, and C １－６ optionally substituted with haloalkyl; R ３ is H, C １－３０ Alkyl, and C ５－１０ cycloalkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5-10 membered heteroaryl; R ４ is halo, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with alkyl; p is an integer from 0 to 3;

23. In the formula VI, R ３ is C １－６ Alkyl, or C ５－１０ 23. The compound of claim 22, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof, which is cycloalkyl.

24. In the formula VI, R ３ is C ７－３０ Alkyl, or C ５－１０ 23. The compound of claim 22, its stereoisomers, pharmaceutically acceptable salts, deuterium-substituted forms, isomers, prodrugs, and metabolites thereof, which is cycloalkyl.

25. In the formula VI, R ４ is C ６－１０ aryl, C ６－１０ Aryl is halogen, C １－６ 25. The compound of claim 23 or 24, optionally substituted with alkyl, its stereoisomers, its pharmaceutically acceptable salts, its deuterium-substituted derivatives, its isomers, its prodrugs, and metabolites thereof.

26. The compound is selected from the group consisting of a compound of any one of claims 9 to 25, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterium-substituted product thereof, an isomer thereof, a prodrug thereof, and a metabolite thereof.

27. A compound represented by the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted compounds thereof, isomers thereof, prodrugs thereof, and metabolites thereof: Here, R ５ is -C(O)R ６ , -C(O)OR ６ , C.O.R. ７ R １０ , C.R. １２ R １３ O.C.(O.)R. ７ , C.R. １２ R １３ OC(O)OR ７ , and is selected from the group consisting of R ６ is C １３－３０ Alkyl, C １３－３０ alkenyl, and C １３－３０ alkynyl, C １３－３０ Alkyl, C １３－３０ alkenyl, and C １３－３０ Each alkynyl is selected from halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is selected from halo and C １－３ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ７ is H, -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Alkenyl, —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ alkynyl, wherein -C １－３０ Alkyl, -C ２－３０ Alkenyl, -C ２－３０ Alkynyl, —C(O)C １－３０ Alkyl, —C(O)C ２－３０ Each alkenyl is —C(O)C ２－３０ Alkynyl, —C(O)OC １－３０ Alkyl, —C(O)OC ２－３０ Alkenyl, —C(O)OC ２－３０ Alkynyl, —C(O)NRcC １－３０ Alkyl, —C(O)NRcC ２－３０ Alkenyl, and —C(O)NRcC ２－３０ Alkynyl is halo, —O—C １－３０ Alkyl, —S—C １－３０ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl; １－３０ Alkyl, —S—C １－３０ Each of alkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from halo and C １－３ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R １０ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ heteroaryl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｎ C ３－１０ Cycloalkyl, -(CH ２ ) ｎ Aryl, and -(CH ２ ) ｎ Each heteroaryl is selected from halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; R １２ and R １３ are H, deuterium, and C, respectively. １－６ Alkyl, halo, and C １－６ haloalkyl; １－６ Alkyl, halo, and C １－６ Each haloalkyl is halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; R ８ and R ９ are H, OH, and C, respectively. １－６ Alkyl, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C １－６ Alkyl, —O—C １－３ Alkyl, —S—C １－３ Alkyl, —S—S—C(O)OC ２－３０ Alkyl, -C ３－１０ Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from OH, halo, —O—C １－３ Alkyl, —S—C １－３ Alkyl, -C ３－１０ optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; Or, R ８ and R ９ are joined to the atoms to which they are attached to form a 3- to 10-membered heterocyclic ring, which is formed by 1-4 R ６ and each R ６ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, or alkoxy; n=0, 1, 2 or 3; The 5- to 10-membered heteroaryls each have 1 to 4 heteroatoms, each independently being N, O, or S; The above 3- to 10-membered heterocyclyls each have 1 to 4 heteroatoms, each independently being N, O or S.

28. A compound represented by the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted compounds thereof, isomers thereof, prodrugs thereof, and metabolites thereof: Here, R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl-C ６－１０ Aryl, and C １－６ alkyl-heteroaryl or R １ and R ２ are bonded to the atom to which they are attached and C ３－１０ forming a cycloalkyl or heterocyclyl, R ３ is H, C １－３０ Alkyl, C ５－１０ Cycloalkyl, C １－３０ Haloalkyl, C ６－１０ Aryl, and C ６－１０ Aryl-C １－８ alkyl; R ３ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ４ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ５ is H, -COR ６ , -CONHR ６ , -COOR ６ , -CONR ６ R ７ , -CH ２ OCOR ６ , and -CH ２ OCONHR ６ is selected from the group consisting of R ６ and R ７ are each independently １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ alkynyl, C １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ Alkynyl is halo, NH ２ , NO ２ , OH, CN, OC １－６ Alkyl, C ６－１０ aryl, and heteroaryl, or R ６ and R ７ are joined to the atom to which they are attached to form a 5- to 10-membered heterocyclyl, which is substituted with halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

29. A compound represented by the following formula, its stereoisomers, pharmaceutically acceptable salts thereof, deuterium-substituted compounds thereof, isomers thereof, prodrugs thereof, and metabolites thereof: Here, R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ６－１０ Aryl, heteroaryl, C １－６ Alkyl C ６－１０ Aryl, and C １－６ alkylheteroaryl, or R １ and R ２ are bonded to the atoms to which they are attached and C ３－１０ forming a cycloalkyl or heterocyclyl, R ３ is H, C １－３０ Alkyl, C ５－１０ Cycloalkyl, C １－３０ Haloalkyl, C ６－１０ Aryl, and C ６－１０ Aryl-C １－８ alkyl, where R ３ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ４ is C ６－１０ Aryl, C １－６ Alkyl-C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein R ４ Ha, Halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R ５ is H, -COR ６ , -CONHR ６ , -COOR ６ , -CONR ６ R ７ , -CH ２ OCOR ６ , and -CH ２ OCONHR ６ is selected from the group consisting of X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ and X ９ are each independently H, D, or F; Z １ and Z ２ are each independently H or D; R ａ and R ｂ are each independently CH ３ , CDs ３ , Cl, Br, I or CF ３ is selected from the group consisting of R ６ and R ７ are each independently １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ alkynyl, C １－３０ Alkyl, C １－３０ alkenyl, or C １－３０ Alkynyl is halo, NH ２ , NO ２ , OH, CN, OC １－６ Alkyl, C ６－１０ aryl, and heteroaryl, or R ６ and R ７ are joined to the atom to which they are attached to form a 5- to 10-membered heterocyclyl, which is substituted with halo, NH ２ , NO ２ , OH, CN, -C １－６ Alkyl, C １－６ Haloalkyl, and O—C １－６ and optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

30. A compound according to any one of claims 1 to 29, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound thereof, an isomer thereof, a prodrug thereof, or a metabolite thereof; A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

31. A method for treating or preventing obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), fatty liver, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer in a subject, comprising administering to the subject an effective amount of a compound described in any one of claims 1 to 29, a pharmaceutically acceptable salt thereof, a deuterium-substituted form thereof, an isomer thereof, a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition described in claim 30.

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