Prodrugs of thyroid hormone analogs, methods of making and methods of use thereof

Abstract

The invention discloses thyroid hormone receptor beta subtype agonist derivatives, and a preparation method and application thereof.

Description

[0001] REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of all of the following: Chinese Patent Application No. 202310113004.X, filed February 7, 2023; Chinese Patent Application No. 202310267006.4, filed March 15, 2023; Chinese Patent Application No. 202310571548.0, filed May 18, 2023; Chinese Patent Application No. 202310733484.X, filed June 20, 2023; U.S. Application No. 63 / 487,794, filed March 1, 2023; U.S. Application No. 63 / 492,398, filed March 27, 2023; U.S. Application No. 63 / 504,832, filed May 30, 2030; U.S. Application No. 63 / 510,810, filed June 28, 2023; and U.S. Application No. 63 / 514,925, filed July 21, 2023, the entire contents of which are incorporated herein by reference.

[0003] TECHNICAL FIELD

[0004] The present invention relates generally to prodrugs of thyroid hormone analogs and methods of making and using the same.

[0005] BACKGROUND

[0006] Thyroid hormones are essential for normal growth and development as well as for maintaining metabolic homeostasis (Paul M. Yen Physiological Review, Vol. 81(3): pp 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus / pituitary / thyroid (HPT) axis. Thyroid dysfunction, which results in hypothyroidism or hyperthyroidism, clearly demonstrates that thyroid hormones have profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior. Thyroid hormone receptors arise from two separate genes, alpha and beta. These different gene products produce multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms are alpha 1, alpha 2, beta 1, and beta 2. Thyroid hormone receptors alpha 1, beta 1, and beta 2 bind thyroid hormone. It has been shown that thyroid hormone receptor subtypes can differ in their contribution to specific biological responses. Recent studies suggest that TR beta 1 plays an important role in modulating TRH (thyrotropin releasing hormone) and modulating thyroid hormone action in the liver. TR beta 2 plays an important role in the modulation of TSH (thyrotropin). TR beta 1 plays an important role in modulating heart rate.

[0007] SUMMARY

[0008] One aspect of the present application relates to compounds of Formula I:

[0009]

[0010] stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof,

[0011] wherein:

[0012] G is selected from -0- and -C(X9X8)-;

[0013] T is selected from -(CR d ) m - and -0-(CR d ) m -;

[0014] m is an integer from 0-3;

[0015] X is selected from:

[0016]

[0017] R a and R b are each independently selected from CH3, CD3, Cl, Br, I, and CF3;

[0018] wherein R c is selected from hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl, and optionally substituted -C 3-8 cycloalkyl;

[0019] wherein R c is optionally substituted with 1 to 10 halogen, H, or D;

[0020] R d are each independently selected from hydrogen, halogen, and C 1-6 alkyl;

[0021] wherein R1and R2are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl and C 1-6 alkyl-heteroaryl, or R1and R2, together with the atoms to which they are attached, form a C 3-10 cycloalkyl or heterocyclyl;

[0022] wherein R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0023] wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0024] wherein R5is selected from H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, -CONR7R 10 , -CONR6R7, -CH2OCOR6, -CH2OCONHR6and

[0025] wherein each R6is independently C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl, wherein C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from halo, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, and C1-30alkyl; 1-3 alkyl;

[0026] wherein R7is selected from the group consisting of 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 2-30 alkynyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C1-30alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, and C1-30alkyl; 1-3 alkyl;

[0027] or R6and R7, together with the atom to which they are attached, combine to form a 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;

[0028] wherein R8and R9are each independently selected from H, OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein C 1-6 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from OH, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0029] or wherein R8and R9, together with the atom to which they are attached, combine to form a 3-10 membered heterocyclyl, which is optionally substituted with 1-4 R6, wherein each R6is independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl, or alkoxy;

[0030] wherein R 10 is selected from 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, wherein 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, wherein C 1-3 alkyl, -S-C1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0031] wherein X8and X9are independently H, D, or halogen;

[0032] wherein n = 0, 1, 2, or 3;

[0033] wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms, and each is independently N, O, or S; and

[0034] wherein each of the above 3-10 membered heterocyclyl groups has 1 to 4 heteroatoms, and each is independently N, O, or S,

[0035] with the proviso that the compound of Formula I is not (((4-(4-hydroxy-3- isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine isopropyl ester.

[0036] 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 form thereof, a hydrate thereof, or a solvate thereof.

[0037] Another aspect of the present application relates to a method of treating or preventing obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer in an individual. The method comprises administering to the individual an effective amount of a compound or a pharmaceutical composition of the present application.

[0038] BRIEF DESCRIPTION OF DRAWINGS

[0039] FIG. 1 Average plasma concentration-time curves of the compounds of the present application are shown;

[0040] FIG. 2 Average plasma concentration-time curves of the compounds of the present application are shown;

[0041] FIG. 3 Average plasma concentration-time curves of Compound 31 after subcutaneous injection are shown;

[0042] FIG. 4 Average plasma concentration-time curves of Compound 32 after subcutaneous injection are shown;

[0043] FIG. 5 Average plasma concentration-time curves of Compound 34 after subcutaneous injection are shown;

[0044] FIG. 6Mean plasma concentration-time curves for compound 36 following subcutaneous injection are shown;

[0045] FIG. 7 Plasma concentration-time curves for compound 54 following subcutaneous injection are shown;

[0046] FIG. 8 Plasma concentration-time curves for compound 52 following subcutaneous injection are shown.

[0047] FIG. 9 Plasma concentration-time curves for compound 53 following subcutaneous injection are shown.

[0048] FIG. 10 Plasma concentration-time curves for compounds 29 and 30 following subcutaneous injection are shown; and

[0049] FIG. 11 Plasma concentration-time curves for compound 52 following subcutaneous injection are shown.

[0050] DETAILED DESCRIPTION I. DEFINITIONS

[0051] 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 of a chemical group denotes the point of attachment of the group to the parent moiety; chemical groups can be described with or without one or more dashes without loss of their ordinary meaning. Prefixes such as “C u-v ” or “C u -C v ” indicate that the following group has u to v carbon atoms, where u and v are integers. For example, “C 1-6 alkyl” or “C1-C6alkyl” indicates that the alkyl group has 1 to 6 carbon atoms.

[0052] “Alkyl” is a monovalent or divalent straight-chain or branched-chain saturated hydrocarbon radical. For example, alkyl can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 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, but are not limited to, 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), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 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 (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3). An alkyl group can be unsubstituted or substituted.

[0053] An "alkenyl" is a monovalent or divalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl). Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. An alkenyl group can be unsubstituted or substituted. 2-8 An "alkenyl" is a monovalent or divalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-6 An "alkenyl" is a monovalent or divalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-4 An "alkenyl" is a monovalent or divalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C

[0054] "Alkynyl" is a monovalent or divalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl) or 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 Alkynyl). Examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl can be unsubstituted or substituted.

[0055] "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined above. For example, C 1-4 Alkoxy refers to an -O-alkyl group having 1 to 4 carbon atoms. Alkoxy groups can be unsubstituted or substituted.

[0056] "Halogen" or "halo" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0057] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halogen, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen group may be any of those described above. In some embodiments, haloalkyl defines the number of carbon atoms in the alkyl moiety, for example, C1-4 haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups may be unsubstituted or substituted.

[0058] As used herein, "aryl" refers to a monovalent or divalent single all-carbon aromatic ring or a multi-condensed all-carbon ring system, wherein the ring is aromatic. For example, in some embodiments, the 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. Aryl also includes a polycondensed ring system (for example, a ring system comprising 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein multiple rings are aromatic. When valence requirements permit, the rings of the polycondensed ring system can be connected to each other by fused bonds. It should also be understood that when referring to a metaaryl within a certain atomic range (for example, a 6-10 metaaryl), the atomic range is for the total ring atoms of the aryl group. For example, a 6-membered aryl includes phenyl, and a 10-membered aryl includes naphthyl. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, etc. Aryl can be unsubstituted or substituted.

[0059] "5-10 membered heteroaryl" or "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from 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 from about 1-6 carbon atoms and from about 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms can also exist in oxidized forms, provided the ring is aromatic. Exemplary 5-10 membered heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "5-10 membered heteroaryl" also includes multiple fused ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a 5-10 membered heteroaryl as defined above is fused to one or more rings selected from 5-10 membered heteroaryl (to form, e.g., 1,8-naphthyridinyl) and aryl (to form, e.g., benzimidazolyl or indazolyl) to form the multiple fused ring system. Thus, a 5-10 membered heteroaryl (single aromatic ring or multiple fused ring system) can have from about 1-20 carbon atoms and from about 1-6 heteroatoms within the 5-10 membered heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. When valence requirements permit, the rings of the multiple fused ring system can be connected to one another through a fused bond. It will be appreciated that the individual rings of the multiple fused ring system can be connected in any order relative to one another. It will be appreciated that the point of attachment of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple fused ring system can be at any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It will also be appreciated that when referring to a member of a certain range of atoms (e.g., 5-10 membered heteroaryl), the range of atoms is to the total ring atoms of the 5-10 membered heteroaryl and includes both carbon atoms and heteroatoms. It will also be appreciated that the rings of the multiple fused ring system can include an aryl ring fused to a heterocyclic ring having saturated or partially unsaturated bonds (e.g., 3, 4, 5, 6, or 7 membered ring) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-10 membered heteroaryl includes thiazolyl, 5-10 membered heteroaryl includes quinolinyl. Exemplary 5-10 membered heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridyl, quinazolin-4(3H)-one, triazolyl, and tetrazolyl. The 5-10 membered heteroaryl can be unsubstituted or substituted.

[0060] "Cycloalkyl" is a monovalent or divalent single fully carbon ring or multiple fused fully carbon ring system, where in each case the ring is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, cycloalkyl 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 comprising 2 rings) having about 7 to 12 carbon atoms. When valence requirements permit, the rings of the multiple fused ring system can be connected to one another by fusion, spiro, or bridged bonds. Exemplary polycyclic cycloalkyl groups include octahydrocyclopenta-cyclopenta-diene, bicyclo[2.2.1]heptane, bicyclo[2.2.1]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0061] "Heterocyclyl" or "heterocycle" or "heterocycloalkyl" as used herein means a single saturated or partially unsaturated non-aromatic ring or non-aromatic multiple ring system having at least one heteroatom (i.e., at least one cyclic (i.e., ring) heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, for example 3 to 12 ring atoms, for example 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 a single saturated or partially unsaturated ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. When valence requirements permit, the rings of the multiple fused ring (e.g., bicyclic heterocyclyl) system can be connected to one another by fusion, spiro, and bridged bonds. Heterocycles include, but are not limited to, azetidine, propyline, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydro-pyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-6-yl, 2-thia-6-azaspiro[3.3]hept-1-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like. Heterocyclyl groups can be unsubstituted or substituted.

[0062] As used herein, "substituted" means that one or more hydrogen atoms of a group are independently replaced with one or more substituents (e.g., 1, 2, 3, or 4 or more) as indicated.

[0063] "Compounds of the application" include the compounds disclosed herein, for example, the compounds of the application include compounds of Formula I, including the compounds of the Examples. In certain embodiments, "compounds of the application" include compounds of Formula I.

[0064] "Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluting, preservative, dye / colorant, flavor-enhancing, surfactant, wetting, dispersing, suspending, stabilizing, isotonic, solvent, or emulsor that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0065] As used herein, "therapeutically effective amount" or "effective amount" means an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to an individual for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease and its severity and the age, body weight, etc., of the individual to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses can be needed to achieve the desired therapeutic endpoint. An effective amount can be considered to have been administered in an individual dose when, in the case of one or more therapeutic agents, the dose produces the desired or beneficial results, either alone or in combination with one or more other agents. Any suitable dose of any co-administered compound can optionally be reduced due to the combined action (e.g., additive or synergistic action) of the compounds.

[0066] "Co-administration" as used herein means administration of a unit dose of a compound disclosed herein prior to or following administration of a unit dose of one or more additional therapeutic agents, e.g., within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in certain embodiments, a unit dose of a compound of the present application is administered first, followed within seconds or minutes by administration of 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 administration of a unit dose of a compound of the present application. In certain embodiments, a unit dose of a compound of the present application is administered first, followed within hours (e.g., 1-12 hours) by administration of 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 within hours (e.g., 1-12 hours) by administration of a unit dose of a compound of the present application. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to concurrent 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 the individual.

[0067] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0068] Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions that are suitable for veterinary or human pharmaceutical use.

[0069] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base forms of the compounds which possess the desired pharmacological activity of the free bases. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, phenylsulfonate, xylene sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott Wiliams and Wilkins, Philadelphia, Pa, 2006.

[0070] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from the appropriate bases, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and N(C1-C4 alkyl)4 + Alkali addition salts, such as sodium or potassium salts, are also included.

[0071] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced with deuterium atoms (also known as2H or D), wherein n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds (also known as "deuterated" or "deuterium- substituted compounds") can increase metabolic resistance, and thus can be useful for increasing the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, when administered to a mammal. See, e.g., Foster, "Deuterium isotope effects in studies of drug metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized by methods well known in the art, e.g., by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0072] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n atoms can be independently replaced with 1 to n corresponding isotopes. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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. Substitution with positron emitting isotopes (e.g. 11 C, 18 F, 15 O, and 13 N) are useful for positron emission tomography (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 processes analogous to those described below, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used.

[0073] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers and thus can exist in enantiomeric, rotomeric, diastereomeric, and other stereoisomeric forms. The absolute stereochemistry is not necessarily specified unless otherwise indicated. It is intended that the embodiments disclosed herein include both the (+) and (-) enantiomeric, (R)- and (S)-rotomeric, as well as the (D)- and (L)- diastereomeric forms of the compounds. The chemical formulas presented herein are intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical 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 the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor (e.g., an alcohol) or resolvation of a racemic form (or salt or derivative of the racemic form) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds, other geometric isomers are intended unless otherwise specified. Likewise, when the compounds described herein contain other geometrically isomeric centers, such as the aspartyl moiety, all geometric isomeric forms are also intended. When the compounds are represented by structural formulas, unless otherwise specified, the structures include both the E and Z geometric isomers. Likewise, all tautomeric forms of the compounds are also intended to be included.

[0074] As used herein, “stereoisomers” refer to compounds which are not interchangeable with one another by simple physical processes such as conformational epitomization, and which are mirror images of one another. The present application contemplates various stereoisomers and mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers of a compound whose molecules are non-superimposable mirror images of one another.

[0075] As used herein, “tautomers” refer to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, the present application includes tautomers of the compounds described.

[0076] As used herein, “solvate” refers to a compound of the present disclosure in interaction with one or more solvent molecules. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0077] As used herein, “hydrate” refers to a compound of the present disclosure in chemical association with one or more water molecules.

[0078] “Prevention” or “preventing” refers to any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, a compound can be administered to an individual (including a human) at risk or having a family history of the disease or condition.

[0079] “Prodrug” as used herein refers to a derivative of a drug that is converted into the parent drug, following administration to a human, by some chemical or enzymatic process. In some embodiments, a prodrug is a biologically inactive derivative of a drug that is converted into the biologically active parent drug, following administration to a human, by some chemical or enzymatic process.

[0080] “Treatment” or “treat” or “treatment” as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the application, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or diminishment of extent of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing extent of the disease or condition); b) slowing or arresting progression of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing regression of clinical symptoms, improving disease state, delaying progression of the disease, improving quality of life, and / or prolonging survival. “Individual at risk” as used herein refers to an individual who is at risk of developing the disorder being treated. An individual “at risk” can or can not have detectable disease or disorder and can or can not have shown detectable disease prior to treatment of the methods described herein. “At risk” indicates that the individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition, and are known in the art. An individual having one or more of these risk factors has a higher likelihood of developing the disease or condition than an individual without these risk factors.

[0081] II. COMPOUNDS AND COMPOSITIONS

[0082] One aspect of the present application relates to a compound of Formula I:

[0083]

[0084] stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof,

[0085] wherein:

[0086] G is selected from -0- and -C(X9X8)-;

[0087] T is selected from -(CR d ) m - and -0-(CR d ) m -;

[0088] m is an integer from 0 to 3;

[0089] X is selected from:

[0090]

[0091] R a and R b are each independently selected from CH3, CD3, Cl, Br, I and CF3;

[0092] wherein R c is selected from hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl and optionally substituted -C 3-8 cycloalkyl;

[0093] wherein R c is optionally substituted with 1 to 10 halogen, H or D;

[0094] R d are each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0095] wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atoms to which they are attached, form C 3-10 cycloalkyl or heterocyclyl;

[0096] wherein R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0097] wherein R4is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0098] wherein R5is selected from the group consisting of H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, -CONR7R 10 , -CONR6R7, -CH2OCOR6, -CH2OCONHR6and

[0099] wherein each R6is independently C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl, wherein C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl;

[0100] wherein R7is selected from the group consisting of 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)OC1-30 alkyl, -C(O)OC 2-30 alkenyl, -C(O)OC 2-30 alkynyl, -C(O)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl and -C(O)NR c C 2-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C1-30alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl;

[0101] or R6and R7, together with the atoms to which they are attached, form a 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0102] wherein R8and R9are each independently selected from the group consisting of H, OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, -O-C1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, can be optionally substituted with one or more substituents each independently selected from OH, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0103] or wherein R8and R9, together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclyl, optionally substituted with 1-4 R6, wherein each R6is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or alkoxy;

[0104] wherein R 10 is selected from 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, wherein each of 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, can be optionally substituted with one or more substituents each independently selected from halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0105] wherein X8and X9are independently H, D, or halogen;

[0106] wherein n = 0, 1, 2, or 3;

[0107] wherein each of the above 5-10 membered heteroaryl has 1-4 heteroatoms, and each is independently N, O, or S; and

[0108] wherein each of the above 3-10 membered heterocyclyl has 1 to 4 heteroatoms, and each is independently N, O, or S,

[0109] with the proviso that the compound of formula I is not (( (4- (4-hydroxy-3-isopropylbenzyl) -3, 5-dimethylphenoxy) methyl) (phenoxy) phosphoryl) -L-alanine isopropyl ester.

[0110] In certain embodiments,

[0111] G is -O-;

[0112] T is -O- (CR d ) m -;

[0113] m is an integer from 0 to 3;

[0114] X is

[0115] R c is selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, and optionally substituted -C1-C 12 alkyl; and

[0116] R d each is independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl.

[0117] In certain embodiments, R d is hydrogen.

[0118] In certain embodiments, m is 1.

[0119] In certain embodiments, formula I is formula II,

[0120]

[0121] wherein R5is selected from the group consisting of -COR6, -COOR6, CONR7R 10 , -CH2OCOR6, CH2OC(O)OR7, and

[0122] wherein each R6is independently C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl, wherein each C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30alkyl, -S-Ci-30alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl;

[0123] wherein R7is selected from the group consisting of 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 2-30 alkynyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl;

[0124] wherein R8and R9are each independently selected from the group consisting of H, OH, C 1-6 alkyl, halogen, -O-C 1-3alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein 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 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from OH, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0125] or wherein R8and R9, together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclyl optionally substituted with 1-4 R6, wherein each R6is independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl or alkoxy;

[0126] wherein R 10 is selected from 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, wherein 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 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0127] wherein n = 0, 1, 2, or 3;

[0128] wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms each independently N, O, or S; and

[0129] wherein each of the above 3-10 membered heterocyclyl groups has 1-4 heteroatoms, each independently N, O, or S.

[0130] In certain embodiments, R5is selected from -COR6, -COOR6, CONR7R 10 , -CH2OCOR6, and

[0131] In certain embodiments, wherein each R6is independently C 13-30 alkyl and C 13-30 alkenyl.

[0132] In certain embodiments, the compounds of the present application are selected from:

[0133]

[0134]

[0135] and

[0136]

[0137] In certain embodiments, Formula I is Formula III,

[0138]

[0139] wherein R a and R b are each independently selected from CH3, CD3, Cl, Br, I, and CF3;

[0140] each R c is selected from hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl, optionally substituted -C 3-8 cycloalkyl;

[0141] wherein R c is optionally substituted with 1 to 10 halogen, H, or D;

[0142] wherein X8, X9, Z1, and Z2 are each independently H, D, or halogen;

[0143] Z3is independently O, -CH2-;

[0144] Wherein R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, together with the atoms to which they are attached, form a C 3-10 a cycloalkyl group or a heterocyclic group;

[0145] Wherein R3 is selected from H, C 1-30 Alkyl, C 5-10 Cycloalkyl, C 1-30 Halogenated alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-8 Alkyl, wherein R3 is optionally substituted by one or more substituents, each of which is independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl;

[0146] wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted with one or more substituents, each of which is independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl;

[0147] wherein R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6 and -CH2OCONHR6;

[0148] Wherein R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl or C 1-30 Alkynyl, wherein the C 1-30 Alkyl, C 1-30 Alkenyl or C 1-30 Alkynyl is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, OC 1-6 Alkyl, C 6-10Aryl and heteroaryl; or R6 and R7 are combined with the atoms to which they are attached to form a 5-10 membered heterocyclic group, and wherein the 5-10 membered heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl.

[0149] In certain embodiments, Z is O.

[0150] In certain embodiments, Z1 and Z2 are each H.

[0151] In certain embodiments, R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted by halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 Alkyl substitution.

[0152] In certain embodiments, R3 is selected from C 1-30 Alkyl and C 5-10 Cycloalkyl.

[0153] In certain embodiments, R c Independently selected from -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 Optionally substituted with halogen.

[0154] In certain embodiments, Formula I is Formula IV,

[0155]

[0156] Wherein R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, together with the atoms to which they are attached, form a C 3-10 a cycloalkyl group or a heterocyclic group;

[0157] R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0158] wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0159] wherein R5is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6and -CH2OCONHR6;

[0160] wherein X1, X2, X3, X4, X5, X6, X7, X8and X9are each independently H, D or halogen,

[0161] wherein Z1and Z2are each independently H, D or halogen;

[0162] wherein R a and R b are each independently selected from CH3, CD3, Cl, Br, I or CF3;

[0163] wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, O-C 1-6 alkyl, C 6-10Aryl and heteroaryl; or R6 and R7 are combined with the atoms to which they are attached to form a 5-10 membered heterocyclic group, and wherein the 5-10 membered heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl.

[0164] In certain embodiments, Z1 and Z2 are each H.

[0165] In certain embodiments, R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted by halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 Alkyl substitution.

[0166] In certain embodiments, R3 is selected from C 1-30 Alkyl and C 5-10 Cycloalkyl.

[0167] In certain embodiments, Formula I is Formula V,

[0168]

[0169] Wherein R1 and R2 are independently selected from H, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl and C 1-6 alkyl-heteroaryl;

[0170] Wherein R3 is selected from H, C 1-30 Alkyl, and C 5-10 Cycloalkyl;

[0171] wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted by halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 Alkyl substitution.

[0172] In certain embodiments, R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted by halogen, -C 1-6alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl-substituted.

[0173] In certain embodiments, R3is selected from C 1-30 alkyl and C 5-10 cycloalkyl.

[0174] In certain embodiments, Formula I is Formula VI,

[0175]

[0176] wherein R1and R2are independently selected from H, C 1-6 alkyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl and C 1-6 alkyl-heteroaryl; wherein the alkyl, aryl and heteroaryl are optionally substituted with halo, C 1-6 alkyl and C 1-6 haloalkyl and O-C 1-6 alkyl-substituted.

[0177] wherein R3is selected from H, C 1-30 alkyl, and C 5-10 cycloalkyl.

[0178] wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl-substituted.

[0179] p is an integer from 0-3.

[0180] In certain embodiments, R3is C 1-6 alkyl or C 5-10 cycloalkyl.

[0181] In certain embodiments, R3is C 7-30 alkyl or C 5-10 cycloalkyl.

[0182] In certain embodiments, R4is C 6-10 aryl; and C 6-10 aryl is optionally substituted with halo, C 1-6 alkyl.

[0183] In certain embodiments, the compounds of the present application are selected from:

[0184]

[0185]

[0186]

[0187]

[0188] and

[0189] In certain embodiments, the compound of Formula I has the following formula

[0190]

[0191] stereoisomers thereof, pharmaceutically acceptable salts thereof, and deuterated isomers thereof,

[0192] wherein R5is selected from the group consisting of -C(O)R6, -C(O)OR6, -C(O)NR7R 10 , CR 12 R 13 OC(O)R7, CR 12 R 13 OC(O)OR7;

[0193] wherein R6is selected from the group consisting of C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl, wherein each of C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl;

[0194] wherein R7is selected from the group consisting of 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)NR c C 1-30 Alkyl, -C(O)NR c C 2-30 Alkenyl and -C(O)NR c C 2-30 Alkynyl, where -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)NR c C 1-30 Alkyl, -C(O)NR c C 2-30 Alkenyl and -C(O)NR c C 2-30 Alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from halogen and C 1-3 alkyl;

[0195] where R 10 Selected from 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, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Each of the cycloalkyl groups, -(CH2) n Aryl and -(CH2) n Heteroaryl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, -OC 1-3 Alkyl, -SC1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0196] wherein R 12 and R 13 each is independently selected from H, deuterium, C 1-6 alkyl, halogen, and C 1-6 haloalkyl, wherein C 1-6 alkyl, halogen, and C 1-6 haloalkyl are each optionally substituted with one or more substituents each independently selected from halogen, -O-C 1- 3alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0197] wherein R8and R9are each independently selected from H, OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein C 1-6 alkyl, -O-C 1-3 alkyl, S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl optionally substituted with one or more substituents each independently selected from OH, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;

[0198] or wherein R8and R9, in combination with the atoms to which they are attached, form a 3-10 membered heterocyclyl optionally substituted with 1-4 R6, wherein each R6is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or alkoxy;

[0199] wherein n = 0, 1, 2, or 3;

[0200] wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms each independently N, O, or S; and

[0201] wherein each of the above 3-10 membered heterocyclyl groups has 1-4 heteroatoms each independently N, O, or S.

[0202] In certain embodiments, the compound of Formula I has the following formula

[0203]

[0204] stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein

[0205] R1and R2are each independently selected from 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 R1and R2, together with the atoms to which they are attached, combine to form a C 3-10 cycloalkyl or heterocyclyl;

[0206] R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0207] R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0208] R5is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6and -CH2OCONHR6;

[0209] wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl or C1-30 alkyl, C 1-6 alkyl, C 6-10 aryl and heteroaryl; or R6and R7, together with the atoms to which they are attached, combine to form a 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

[0210] In certain embodiments, the compound of Formula I has the following formula

[0211]

[0212] stereoisomers, pharmaceutically acceptable salts, deuterated forms, isomers, prodrugs, and metabolites thereof,

[0213] wherein R1and R2are each independently selected from the group consisting of 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 R1and R2, together with the atoms to which they are attached, combine to form a C 3-10 cycloalkyl or heterocyclyl;

[0214] wherein R3is selected from the group consisting of 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, wherein R3is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl;

[0215] wherein R4is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10Aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted with one or more substituents, each of which is independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl;

[0216] wherein R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6 and -CH2OCONHR6;

[0217] wherein X1, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently H, D or F;

[0218] wherein Z1 and Z2 are each independently H or D;

[0219] where R a and R b Each independently selected from CH3, CD3, Cl, Br, I or CF3;

[0220] Wherein R6 and R7 are each independently C 1-30 Alkyl, C 1-30 Alkenyl or C 1-30 Alkynyl, wherein the C 1-30 Alkyl, C 1-30 Alkenyl or C 1-30 Alkynyl is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, OC 1-6 Alkyl, C 6-10 Aryl and heteroaryl; or R6 and R7 are combined with the atoms to which they are attached to form a 5-10 membered heterocyclic group, and wherein the 5-10 membered heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl.

[0221] 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 form thereof, or a hydrate or solvate thereof, and (2) a pharmaceutically acceptable carrier.

[0222] III. METHODS OF TREATMENT

[0223] Another aspect of the present application relates to a method for preventing, treating or ameliorating a disease or condition in an individual. The method includes administering to the individual an effective amount of a pharmaceutical composition of the present application. Examples of the disease or condition include, but are not limited to, obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0224] The present application also relates to the use of a compound of Formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated form thereof, a hydrate thereof, or a solvate thereof, in the manufacture of a medicament for the treatment and / or prevention of obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer. Examples

[0225] Synthesis

[0226] The compounds of the present disclosure can be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic procedures can be used. Synthesis of a typical compound of Formula I, or a pharmaceutically acceptable salt thereof (e.g., a compound having a structure described by one or more of Formula I or other formulae disclosed herein, or a compound disclosed herein) can be accomplished as described in the following examples.

[0227] General Synthesis

[0228] Typical embodiments of compounds according to the present application can be synthesized using the general reaction schemes and / or examples described below. It will be apparent to one of ordinary skill in the art, in light of the description herein, that the general schemes can be altered by substituting starting materials of similar structure to produce correspondingly different products. The description of the synthesis that follows provides many examples of how the starting materials can be varied to provide corresponding products. The starting materials are generally obtained from commercial sources or synthesized using methods that have been published for the synthesis of compounds that are embodiments of the present application, an inspection of the structure of the compound to be synthesized will provide the identity of each substituent. The identity of the necessary starting materials will generally become apparent by simple inspection methods (given in the examples herein). The group designations used in the reaction schemes herein (e.g., R1, R2) are for illustrative purposes only and, unless otherwise specified, do not have to match designations used elsewhere herein to describe compounds of Formula I or aspects or fragments thereof by name or function.

[0229] Synthetic Reaction Parameters

[0230] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary depending on the particular reactants or solvent used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0231] Additionally, as will be apparent to those skilled in the art, conventional protecting groups can 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 particular functional groups, are well known in the art. For example, many protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0232] Furthermore, the compounds of the present application can contain one or more chiral centers. Thus, if desired, pure stereoisomers can be prepared or isolated, i.e., as individual enantiomers, or as enriched mixtures of stereoisomers. All such stereoisomers (and enriched mixtures thereof) are included within the scope of the present disclosure unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0233] The starting materials used in the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures or obvious modifications thereof described in standard reference texts, such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0234] The term “solvent”, “inert organic solvent”, or “inert solvent” means a solvent that is inert under the conditions of the reaction in which it is employed (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), N,N-dimethylformamide (“DMF”), chloroform, dichloromethane (or methylene chloride), diethyl ether, methanol, pyridine, and the like). Unless otherwise stated, the solvents used in the reactions of the application are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0235] The term “q.s.” means the addition of an amount sufficient to achieve the stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0236] The compounds provided herein can be synthesized according to the general schemes provided below. In the schemes below, it will be understood that each compound shown therein can have protecting groups required in any step. Standard protecting groups are well within the scope of one skilled in the art.

[0237] Preparation of Example 1: Preparation of 14-(4-((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl pentadecanoate (Compound 1)

[0238]

[0239]

[0240] (1) Synthesis of intermediate 1-3:

[0241] NaH (153 mg, 3.816 mmol) was added to a solution of 1-1 (1 g, 3.18 mmol) in THF (10 ml) at 0 °C and stirred for 0.5 h, then a solution of 1-2 (1.60 g, 3.816 mmol) in THF (10 ml) was added to the above reaction. The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O and extracted with EA. The organic phase was concentrated in vacuo and purified by silica to give intermediate 1-3 (1.0 g, yield 56%).

[0242] (2) Synthesis of intermediate 1-4:

[0243] 1 N NaOH (5 ml) was added to a solution of 1-3 (1 g, 1.78 mmol) in MeOH (10 ml) and stirred at room temperature (RT) for 16 h. The reaction was extracted with EA. The organic phase was concentrated in vacuo and purified by silica to give intermediate 1-4 (0.56 g, yield 65%).

[0244] (3) Synthesis of intermediate 1-6:

[0245] A reaction mixture of 1-4 (0.56 g, 1.15 mmol), (COCl)2(0.439 g, 3.46 mmol) and DMF (cat) in DCM (10 ml) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, then 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. The reaction was stirred at room temperature for 2 h, quenched by H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate 1-6. (0.35 g, yield 50%).

[0246] (4) Synthesis of intermediate 1-7:

[0247] A reaction mixture of 1-6 (0.35 g, 0.58 mmol) and TsOH (0.3 g, 1.74 mmol) in MeOH (5 ml) was stirred at 50 °C for 4 h. The reaction was quenched by H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate 1-7 (0.21 g, yield 65%).

[0248] (5) Synthesis of compound 1:

[0249] The reaction mixture of a solution of I-7 (0.21 g, 0.38 mmol), TEA (77 mg, 0.76 mmol), DMAP (5 mg, 0.038 mmol) and I-8 (0.114 g, 0.418 mmol) in DCM (5 ml) was stirred at room temperature for 2 h, then quenched with H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give compound 1 (150 mg, yield 50%).

[0250] Preparation Example 2: Synthesis of compound 64-(4-(((benzyloxy)(((S)-1- isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methoxy)-2,6-dimethylbenzyl)-2- isopropylphenyl docosanoate (compound 6)

[0251]

[0252]

[0253] (1) Synthesis of intermediate 6-3:

[0254] NaH (153 mg, 3.816 mmol) was added to a solution of I-1 (1 g, 3.18 mmol) in THF (10 ml) at 0 °C and stirred for 0.5 h, then a solution of 6-2 (1.7 g, 3.816 mmol, refer to example 4) in THF (10 ml) was added to the above reaction. The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O and extracted with EA. The organic phase was concentrated in vacuo and purified by silica to give intermediate 6-3 (1.2 g, yield 64%).

[0255] (2) Synthesis of intermediate 6-4:

[0256] 1 N NaOH (5 ml) was added to a solution of 6-3 (1.2 g, 2.03 mmol) in MeOH (10 ml) and stirred at room temperature for 16 h. The reaction was extracted with EA. The organic phase was concentrated in vacuo and purified by silica to give intermediate 6-4 (0.50 g, yield 49%).

[0257] (3) Synthesis of intermediate 6-6:

[0258] A reaction mixture of 6-4 (0.50 g, 1.0 mmol), (COCl)2(0.254 g, 2 mmol) and DMF (cat) in DCM (10 ml) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, then DCM (10 ml), TEA (0.929 g, 9.2 mmol), DAMP (14 mg, 0.115 mmol) and I-5 (0.384 g, 2.3 mmol) were added and stirred at room temperature for 2 h. The reaction was quenched with H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate 6-6 (0.27 g, yield 44%).

[0259] (4) Synthesis of intermediate 6-7:

[0260] A solution of 6-6 (0.27 g, 0.44 mmol), TsOH (0.151 g, 0.88 mmol) in MeOH (5 ml) was stirred at 50 °C for 4 h. The reaction was quenched by H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate 6-7 (0.15 g, yield 60%).

[0261] (5) Synthesis of compound 6:

[0262] 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 then quenched by H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give compound 6 (100 mg, yield 43%).

[0263] Preparation Example 3: Synthesis of compound 13 (((4-(4-hydroxy-3- isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine octadecyl ester (compound 13)

[0264]

[0265] (1) Synthesis of intermediate 13-6:

[0266] A solution of I-4 (0.50 g, 1.0 mmol), (COCl)2(0.254 g, 2 mmol) and DMF (cat) in DCM (10 ml) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, then DCM (10 ml), TEA (0.929 g, 9.2 mmol), DMAP (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 was quenched with H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate 13-6 (0.30 g, yield 37%).

[0267] (3) Synthesis of compound 13:

[0268] 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 by H2O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give compound 13 (0.17 g, yield 60%).

[0269] Preparation Example 4: Synthesis of intermediate I-24-methylbenzenesulfonic acid (diphenoxyphosphoryl) methyl ester (intermediate I-2)

[0270]

[0271] (1) Synthesis of intermediate 1-2-B:

[0272] 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 h. The reaction was concentrated in vacuo, MTBE and 2-3 N NaOH were added and extracted with MTBE. The pH of the aqueous phase was adjusted to pH = 1-2 with 3 N HC1. After extraction with EA, the organic phase was concentrated in vacuo to give intermediate 1-2-B (0.6 g, yield 72%).

[0273] (2) Synthesis of intermediate I-2:

[0274] A solution of intermediate 1-2-B (0.6 g, 2.25 mmol), (COCl) 2 (0.856 g, 6.75 mmol) and DMF (cat) in DCM (10 ml) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. 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 then added to the reaction mixture and stirred at room temperature for 2 h. The reaction was quenched with H 2 O and extracted with DCM. The organic phase was concentrated in vacuo and purified by silica to give intermediate I-2 (0.36 g, 38% yield).

[0275] Preparation Example 5: Amino Acid Ester (Intermediate A)

[0276]

[0277] 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 at room temperature overnight. The reaction was concentrated in vacuo to remove the DCM. The residue was added to water and stirred for 1 h. The mixture was filtered to obtain a solid. The solid was dried to afford Intermediate A-2 (80.0 g, 97.3% yield).

[0278] Int A-2 (50 g, 193 mmol) was dissolved in a solution of HCl in dioxane (4 M, 500 ml) at 0-5°C and stirred for 1 hour. The reaction was concentrated in vacuo to obtain a solid. The 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 Intermediate A (27.0 g, 87.9% yield).

[0279] Preparation Example 6: (4-Hydroxy-2,6-dimethylphenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanone (Intermediate B)

[0280]

[0281] A solution of compound 1-1 (1.0 g, 3.18 mmol), Pd / C (0.05 g, 30 wt%), H2O (0.2 ml) in DMA (2 ml) was stirred at 130-135 °C under N2for 48 h. After cooling, the mixture solution was filtered to get the filtrate. The filtrate was added to ethyl acetate (15 ml) and washed with brine, then concentrated in vacuum and purified by silica to get intermediate B (0.35 g, yield 33.5%).

[0282] Preparation Example 7: 4-((3-isopropyl-4-(methoxymethoxy)phenyl)methyl-d2)-3,5- dimethylphenol (Intermediate C)

[0283]

[0284] LiAlD4(25.6 mg, 0.6 mmol) was added to a solution of Int B (0.1 g, 0.3 mmol) in THF (1 ml) at 0 °C and stirred for 1 h. The mixture was quenched with saturated NH4Cl solution, then EtOAc (20 ml) was added to the mixture. The organic phase was separated, washed with water and brine, dried over MgSO4, concentrated in vacuum. The concentrated product was purified by silica gel column chromatography to get intermediate C (56 mg, yield 58.1%).

[0285] Preparation Example 8: 4-(difluoro(3-isopropyl-4-(methoxymethoxy)phenyl)methyl)-3,5- dimethylphenol (Intermediate D)

[0286]

[0287] A mixture of Int B (0.1 g, 0.3 mmol) in 1,2-dichloroethane (1 ml) was stirred at room temperature under N2for 72 h. The reaction was quenched with saturated aqueous NaHCO3solution (1 ml). Then the organic phase was separated, washed with water and brine, dried over MgSO4, concentrated in vacuum. The concentrated product was purified by silica gel column chromatography to get intermediate D (66 mg, yield 61.9%).

[0288] Preparation Example 9: 4-(4-(methoxymethoxy)-3(prop-2-yl-1,1,1,3,3,3-d6)benzyl)-3,5- dimethylphenol (Intermediate E)

[0289]

[0290] iPrMgCl (1 M in THF, 50 ml) was added dropwise to a solution of Int E-1 (5.0 g, 16.7 mmol) in THF (50 ml) at -20 °C and stirred for 2 h. Acetone-D6 (0.5 ml) was added dropwise to the solution and stirred for 2 h, then naturally warmed to room temperature. The mixture reaction was quenched with saturated NH4Cl solution (30 ml), and EtOAc (50 ml) was added to the mixture reaction. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The concentrated product was purified by silica gel column chromatography to give intermediate E-2 (3.2 g, yield 80.1%).

[0291] Et3SiH (2.94 g, 25.3 mmol) was added to a solution of Int E-2 (3.0 g, 12.6 mmol) and TFA (0.1 ml) in DCE (30 ml) and stirred for 4 h. Water (30 ml) was added to the mixture reaction. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give intermediate E-3 (2.6 g, yield 92.9%).

[0292] tBuOK (1.98 g, 17.6 mmol) was added to a solution of Int E-3 (2.6 g, 11.7 mmol) in THF (30 ml) at 0 °C and stirred for 1 h. MOMBr (1.62 g, 12.9 mmol) was then added and stirred for 2 h. The mixture reaction was quenched with saturated NH4Cl solution (30 ml), and EtOAc (50 ml) was added to the mixture reaction. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The concentrated product was purified by silica gel column chromatography to give intermediate E-4 (1.9 g, yield 60.9%).

[0293] n-BuLi (4.3 ml, 2.5 M in hexane) was added to a solution of Int E-4 (1.9 g, 7.16 mmol) in THF (20 ml) at -78 °C and stirred for 30 min. 2,6-Dimethyl-4-((triisopropylsilyl)oxy)benzaldehyde (2.31 g, 7.52 mmol) was then added dropwise and stirred at -78 °C for 1 h. The mixture reaction was quenched with saturated NH4Cl solution (20 ml), and EtOAc (40 ml) was added to the mixture reaction. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The concentrated product was purified by silica gel column chromatography to give intermediate E-5 (2.43 g, yield 68.8%).

[0294] TBAF solution (5 ml, 1 M in EA) was added to a solution of Int E-5 (2.43 g, 4.93 mmol) in EtOAc (20 ml) and stirred for 30 min. Water (20 ml) was added and stirred for 15 min. The organic phase was then separated, washed with water and brine, dried over MgS04and concentrated in vacuo. The residue was crystallized by n-heptane to obtain Int E-6 (1.32 g, yield 79.6%).

[0295] Pd / C (0.1 g, 30 wt%) was added to a solution of Int E-6 (1.32 g, 3.92 mmol) and TFA (2 drops) in DCM (15 ml). The solution was stirred under H2at room temperature for 4 h. After filtration, the solution was concentrated in vacuo to obtain Int E (1.15 g, yield 91.5%).

[0296] Preparation Example 10: Phenyl hydrogen ((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)phosphonate (Int F)

[0297]

[0298] 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 stirred at 80-85 °C for 4 h. Water and ethyl acetate were added to the mixture, the organic layer was separated and concentrated under reduced pressure to obtain diethyl [(4-[(4- (methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl] phosphonate as an oil (7.2 g, yield 97.47%).

[0299] 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 stirred at 10-15 °C for 4 h. Water was added dropwise to the mixture. The organic layer was separated and concentrated under reduced pressure to obtain Compound A (3.6 g, yield 92%).

[0300] Pyridine (200 ml), DCC (92 g, 451 mmol) and DMAP (18 g, 147 mmol) were added to a solution of Compound A (55 g, 151 mmol) and phenol (28.4 g, 302 mmol) in DMF (1 L) and stirred at 80-85 °C overnight. After cooling, ethyl acetate was added to the mixture and the pH was adjusted to 3.0 by 1 N HCI solution. The organic layer was separated, washed with water, dried (Na2S04) and evaporated to dryness to give the crude product. The crude product was then purified by silica gel chromatography eluting with PE:EtOAc = 10:1 to give Int F (26 g, yield: 39%) as a white solid.

[0301] Preparation Example 11 ((R)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine pent-3-yl ester (29) and ((S)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine pent-3-yl ester (30)

[0302]

[0303] 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 h. The reaction mixture was concentrated to dryness to give an oil. The oil was dissolved in DCM (100 ml), then pent-3-yl L-alanine (18.05 g, 113.5 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by silica gel chromatography eluting with PE:EtOAc = 10:1 to give compound 25 (3.0 g, yield). Compound 25 was purified by a chiral column (WelchXT C18 150 mm*21.2 mm, 5 pm) to give compound 28 (1.5 g, yield) and compound 29 (1.2 g, yield).

[0304] Preparation Example 12 ((4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)-3,5- dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine pent-3-yl ester (52)

[0305]

[0306] To a stirred solution of 1-(benzyloxy)-2-bromobenzene (21 g, 79.81 mmol) in THF (So, 100 mL) was added dropwise butyllithium (5.62 g, 87.79 mmol) at -70 °C under nitrogen atmosphere. The resulting mixture was stirred at -70 °C under nitrogen atmosphere for 0.5 h. To the above mixture was added dropwise 4-fluorobenzaldehyde (R1, 9.91 g, 79.81 mmol, purity 100%) at -70 °C over a period of 15 min. The resulting mixture was stirred for another 1 h at 0 °C. The reaction was quenched by adding [water] (50 mL) at 25 °C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with [brine] (2 x 50 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure.

[0307] 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 at 25 °C under H2atmosphere for 16 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was neutralized with NaHC03(aq.) to pH 7-8. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used as such for the next step without further purification.

[0308] To a stirred solution of 2-[(4-fluorophenyl)methyl]phenol (15 g, 74.18 mmol) in DCM (50 mL) was added portion wise tetrabutylammonium tribromide (37.56 g, 77.89 mmol) 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 x 100 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2S04. 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 afford 4-bromo-2-[(4-fluorophenyl)methyl]phenol (12 g, yield 57.55%) as yellow oil.

[0309] 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% pure) portion wise 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) drop wise at 0 °C over a period of 15 min. The resulting mixture was stirred at 25 °C for another 1 h. The reaction was quenched by the addition of water (30 mL) at 25 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2S04. 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 afford 4-bromo-2-[(4-fluorophenyl)methyl]-1- (methoxymethoxy)benzene (10 g, yield 72.04%) as yellow oil.

[0310] 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 butyllithium (3.10 g, 48.44 mmol) drop wise at -70 °C under nitrogen atmosphere. The resulting mixture was stirred at -70 °C under nitrogen atmosphere for 0.5 h. To the above mixture was added 2,6-dimethyl-4-[(tri(prop-2-yl)silyl)oxy]benzaldehyde (14.14 g, 46.13 mmol) drop wise at -70 °C over a period of 15 min. The resulting mixture was stirred at 0 °C for another 1 h. The reaction was quenched by the addition of water (30 mL) at 25 °C. The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2S04. 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 afford (2,6-dimethyl-4-[(tri(prop-2-yl)silyl)oxy]phenyl)(3-[(4-fluorophenyl)methyl]-4- (methoxymethoxy)phenyl)methanol (10 g, yield 39.22%) as yellow oil.

[0311] 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) drop wise at 25 °C. The resulting mixture was stirred at 25 °C under H2atmosphere for 16 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was basified with aqueous NaHC03solution to pH 7-8). The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. 4-[(3-[(4-Fluorophenyl)methyl]-4- (methoxymethoxy)phenyl)methyl]-3,5-dimethylphenol was obtained as yellow oil (2 g, yield 54.84 %).

[0312] To a stirred 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) drop wise 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 x 30 mL) and dried over anhydrous Na2S04. 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 x 5 mL). 4-[(3-[(4-Fluorophenyl)methyl]-4- (methoxymethoxy)phenyl)(hydroxy)methyl]-3,5-dimethylphenol was obtained as yellow solid (5.5 g, yield 76.69 %).

[0313] The following synthesis can follow the preparation of Example 10 and Example 11 to obtain compound 52.

[0314] Preparation Example 13 ((4-(3-(sec-butyl)-4-hydroxybenzyl)-3,5-dimethylphenethyl)(phenoxy) phosphoryl)-L-alaninyl pentan-3-yl ester (53)

[0315]

[0316] To a solution of 4-bromo-2-(butan-2-yl)-1-(methoxymethoxy)benzene (6.11 g, 22.37 mmol) in THF (40 mL) at -70°C was added butyl lithium (1.58 g, 24.61 mmol), and the reaction mixture was stirred for 1 hour. A solution of 4-bromo-2,6-dimethylbenzaldehyde (4.77 g, 22.37 mmol) in THF (20 mL) was then added to the above solution at -70°C under N2. The reaction mixture was stirred at -70°C for 0.5 hours. After warming to room temperature, aqueous NH4Cl solution was added and stirred for 30 minutes. Extraction was performed with ethyl acetate. The reaction mixture was concentrated and purified by silica gel chromatography using PE:EtOAc = 20:1 as the eluent to obtain compound 53-2, 5.23 g, yield: 57.4%.

[0317] A DMF (20 mL) solution of 53-2 (3.78 g, 9.28 mmol), diethyl vinylphosphonate (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) was degassed and then heated to 110 ° C for 16 hours under N2. The reaction was cooled to room temperature and H2O was added to the above solution. The mixture was extracted with EA (100 mL * 3), the combined organic phases were washed with brine, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 5: 1-1: 2) to obtain the pure product, 53-3, 2.78 g, yield: 61.1% as a yellow oil.

[0318] A solution of 53-3 (40 mg, 0.082 mmol), Pd / C (0.00087 g, 0.0082 mmol), and trifluoroacetic acid (0.00047 g, 0.0041 mmol) in dichloromethane (2 mL) was added. The reaction was filtered and concentrated in vacuo. The residue was purified by TLC (PE:EA=1:1) to give the pure product, 53-4, 21 mg, in a 54.04% yield as a white oil.

[0319] The following synthetic method can be followed by preparing Example 10 and Example 11 to obtain Compound 53.

[0320] The following compounds (Table 1) were prepared according to the procedures described herein using appropriate starting materials and appropriate protecting group chemistry as needed, and 1 HNMR characterization is as follows:

[0321] Table 1. Compound list

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] Example 14

[0349] Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinane-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl stearate (Compound 54)

[0350]

[0351] At 0 ° C, stearoyl chloride (5.0 g, 16.5 mmol), triethylamine (1.67 g, 16.5 mmol) and DMAP (2 mg) were added to a solution of compound A (4.25 g, 8.25 mmol) in dichloromethane (50 ml) and stirred at room temperature overnight. Water (50 ml) was added to the mixture, and the organic layer was extracted. The organic layer was concentrated in vacuo to obtain a solid, which was purified by flash column chromatography (DCM / MeOH 10: 1) to produce compound 54, 4.6 g, yield: 71.3%.

[0352] Example 15

[0353] Preparation of 4-(4-(((2R,4S)-4(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinane-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl behenyl carbonate (Compound 57)

[0354]

[0355]

[0356] n-Docosanol (1.90 g, 5.83 mmol), Et3N (3.5 g, 35 mmol) and DMAP (2 mg) were added to dichloromethane (50 ml) at 0°C and stirred for 1 hour. A solution of compound A (2.0 g, 3.88 mmol, 10 ml) was then added to the mixture solution and stirred at 0°C for 2 hours. Water (50 ml) was added to the mixture, and the organic layer was extracted. The organic layer was concentrated in vacuo to obtain an oil, which was purified by flash column chromatography (DCM / MeOH 10:1) to produce compound 57, 1.2 g, yield: 35.6%.

[0357] Example 16

[0358] Preparation of L-alanine 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinane-2-yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl ester (Compound 65)

[0359]

[0360] Compound A (2.5 g, 4.85 mmol), HATU (2.21 g, 5.82 mmol) and Et3N (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 organic layer was concentrated in vacuum to obtain an oil which was added to dichloromethane (25 ml). Then trifluoroacetic acid (6 ml) was added to the solution and stirred for 2 hours after which a white solid was precipitated. After filtration, compound 65 was obtained, 2.6 g, yield: 91.4%.

[0361] Example 17

[0362] Preparation of 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2- yl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl 2-(((decaoxy)carbonyl)disulfanyl)acetate (Compound 70)

[0363]

[0364] Compound A (5.14 g, 10 mmol), dithiodiglycolic acid (3.64 g, 20 mmol), HATU (3.8 g, 10 mmol) and Et3N (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 organic layer was concentrated in vacuum to obtain an oil which was purified by flash column chromatography (DCM / MeOH 8:1) to yield compound 70-1, 2.3 g, yield: 33.9%.

[0365] Compound 70-1 (2.0 g, 2.95 mmol), HATU (1.23 g, 3.25 mmol) and Et3N (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 organic layer was concentrated in vacuum to obtain an oil which was purified by flash column chromatography (DCM / MeOH 15:1) to yield compound 70, 1.5 g, yield: 63.3%.

[0366] The following compounds (Table 2) were prepared according to the procedures described herein using appropriate starting materials and appropriate protecting group chemistry as required, and characterized by 1 HNMR was characterized as follows:

[0367] Table 2. List of compounds

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] Pharmacokinetic studies

[0379] 1. Absorption pharmacokinetics in rats

[0380] The compound of Formula I is a prodrug of a protide which will metabolize to the active moiety Compound A or analogs.

[0381]

[0382] a. Individual plasma concentrations of Compound A were used to calculate the mean pharmacokinetic parameters summarized in Table 1 following a single subcutaneous administration of Compound 1, 10, 13, 14, 16, 22, 23, 24, 25, 26, 28, 29, 30, 38, 39, 40 and 50 to SD rats (14 mg / kg equivalent to active moiety). FIG. 1 and FIG. 2 Table 1. Mean pharmacokinetic parameters following a single subcutaneous administration of Compound 1, 10, 13, 14, 16, 22, 23, 24, 25, 26, 28, 29, 30, 38, 39, 40 and 50 to SD rats (14 mg / kg equivalent to active moiety).

[0383] b. In vivo, Compound 31 will metabolize to Compound C; Compound 32 will metabolize to Compound D; Compound 34 will metabolize to Compound E; Compound 36 will metabolize to Compound F;

[0384]

[0385] Individual plasma concentrations of Compound C were used to calculate the mean pharmacokinetic parameters summarized in Table 2 following a single subcutaneous administration of Compound 31 to SD rats (14 mg / kg equivalent to Compound C). FIG. 3 Table 2. Mean pharmacokinetic parameters following a single subcutaneous administration of Compound 31 to SD rats (14 mg / kg equivalent to Compound C).

[0386] Following a single subcutaneous administration of compound 32 (14 mg / kg equivalent to Compound D) to SD rats, the individual plasma concentrations of Compound D were used to calculate FIG. 4 The mean pharmacokinetic parameters summarized in Table 6.

[0387] Following a single subcutaneous administration of compound 34 (14 mg / kg equivalent to Compound E) to SD rats, the individual plasma concentrations of Compound E were used to calculate FIG. 5 The mean pharmacokinetic parameters summarized in Table 7.

[0388] Following a single subcutaneous administration of compound 36 (14 mg / kg equivalent to Compound F) to SD rats, the individual plasma concentrations of Compound F were used to calculate FIG. 6 The mean pharmacokinetic parameters summarized in Table 8.

[0389] c. Compound of Formula II is a prodrug that will be metabolized in vivo to Compound A. Therefore, following a single subcutaneous administration of compound 54 to rats (20 mg / kg), the individual plasma concentrations of Compound A were monitored and used to calculate the mean pharmacokinetic parameters. The results are shown in Table 9. FIG. 7

[0390] d. In vivo, compound 52 will be metabolized to Compound G; compound 53 will be metabolized to Compound H;

[0391]

[0392] Following a single subcutaneous administration of compound 52 (14 mg / kg equivalent to Compound G) to SD rats, the individual plasma concentrations of Compound G were used to calculate FIG. 8 The mean pharmacokinetic parameters summarized in Table 10.

[0393] Following a single subcutaneous administration of compound 53 (14 mg / kg equivalent to Compound H) to SD rats, the individual plasma concentrations of Compound H were used to calculate FIG. 9 The mean pharmacokinetic parameters summarized in Table 11.

[0394] 2. Absorption pharmacokinetics in male cynomolgus monkeys

[0395] a. Following a single subcutaneous administration of compounds 29 and 30 to male cynomolgus monkeys, the individual plasma concentrations of Compound A were used to calculate FIG. 10 The mean pharmacokinetic parameters summarized in Table 12.

[0396] Dosing information: Formulation concentration: 10 mg / kg; Formulation concentration: 20 mg / ml.

[0397] b. Following a single subcutaneous administration of compound 52 to male cynomolgus monkeys, the individual plasma concentrations of Compound G were used to calculate FIG. 11 The mean pharmacokinetic parameters summarized in Table 13. ​

[0398] Dosing information: Formulation concentration: 10 mg / kg; Formulation concentration: 20 mg / ml.

[0399] 3. Rat in vivo distribution pharmacokinetics

[0400] Distribution of Compound A in plasma and liver was examined following a single subcutaneous administration of the compound and is summarized below:

[0401]

Claims

1. A compound of Formula I: Formula I stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein: G is selected from -0- and -C(X9X8)-; m is an integer from 0-3; T is selected from -(CR d ) m - and -O-(CR d ) m -; X is selected from: wherein X8and X9are independently H, D, or halogen; R a and R b are each independently selected from CH3, CD3, Cl, Br, I and CF3; wherein R c selected from hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl and optionally substituted -C 3-8 cycloalkyl; wherein R c optionally substituted with 1 to 10 halogen, H or D; R d each independently is selected from hydrogen, halogen and C 1-6 alkyl; wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atom to which they are attached, form C 3-10 cycloalkyl or heterocyclyl; R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R5is selected from H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, -CONR7R 10 , -CONR6R7, -CH2OCOR6, -CH2OCONHR6and wherein each R6is independently C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl, wherein C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl; wherein R7is selected from 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 2-30 alkynyl is optionally substituted with one or more substituents each independently selected from halo, -O-C1-30alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from halo and C 1-3 alkyl; Or R6 and R7 are combined with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl and OC 1-6 alkyl; wherein R8and R9are each independently selected from H, OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein C 1-6 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from OH, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; or wherein R8and R9, together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclyl, which is optionally substituted with 1-4 R6, wherein each R6is independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl or alkoxy; wherein R 10 is selected from 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, wherein each of 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 is optionally substituted with one or more substituents each independently selected from halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl and 5-10 membered heteroaryl; wherein n = 0, 1, 2, or 3; wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms, and each is independently N, O, or S; and wherein each of the above 3-10 membered heterocyclyl groups has 1-4 heteroatoms, and each is independently N, O, or S, with the proviso that the compound of Formula I is not (( (4-(4-hydroxy-3- isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine isopropyl ester.

2. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein G is -0-; m is an integer from 0-3; T is -O-(CR d ) m -; 4. The compound of any one of claims 1-3, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein m is 1. X is R c selected from hydrogen, halogen, -CF3, -OCF3, cyano, and optionally substituted -C1-C 12 alkyl; and R d each independently is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl.

3. The compound of claim 1 or 2, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R d each is hydrogen.

5. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Formula I is Formula II, wherein n = 0, 1, 2, or 3; wherein R5is selected from -COR6, -COOR6, CONR7R 10 , -CH2OCOR6, CH2OC(O)OR7and wherein each R6is independently C 13-30 alkyl, C 13-30 alkenyl and C 13-30 alkynyl, wherein C 13-30 alkyl, C 13-30 alkenyl and C 13-30 alkynyl are each optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C1-30alkyl, cycloalkyl, heterocyclyl, aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from the group consisting of halogen and C 1-3 alkyl; R7is selected from 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 2-30 alkynyl is optionally substituted with one or more substituents each independently selected from halo, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from halo and C 1-3 alkyl; wherein R8and R9are each independently selected from H, OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein 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 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from OH, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; or wherein R8and R9, together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclyl, which is optionally substituted with 1-4 R6, wherein each R6is independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl or alkoxy; wherein R 10 is selected from 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, wherein each of 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 is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms, and each is independently N, O, or S; and wherein each of the above 3-10 membered heterocyclyl groups has 1-4 heteroatoms, and each is independently N, O, or S.

6. The compound of claim 5, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein 8. The compound of any one of claims 1-7, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein the compound is selected from: wherein R5is selected from -COR6, -COOR6, CONR7R 10 , -CH2OCOR6and 7. The compound of claim 5 or 6, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein each R6is independently C 13-30 alkyl and C 13-30 alkenyl.

9. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Formula I is Formula III, wherein X8, X9, Z1, and Z2are each independently H, D, or halogen; wherein R a and R b are each independently selected from CH3, CD3, Cl, Br, I, and CF3; Each R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C2-C 12 Alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted-C 0-6 Alkyl-cycloalkyl, optionally substituted-C 0-6 Alkyl-heterocycloalkyl, optionally substituted-C 3-8 Cycloalkyl; wherein R c optionally substituted with 1 to 10 halogen, H or D; Z3is independently O, -CH2-; wherein R5is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atom to which they are attached, form C 3-10 cycloalkyl or heterocyclyl; R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; 10. The compound of claim 9, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Z is O. wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, O- 1-6 alkyl, C 6-10 aryl and heteroaryl; or R6and R7, in combination with the atom to which they are attached, form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

11. The compound of claim 9 or 10, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Z1and Z2are each H.

15. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Formula I is Formula IV, 12. The compound as claimed in any one of claims 9 to 11, stereoisomers, pharmaceutically acceptable salts, deuterides, isomers, prodrugs, and metabolites thereof, wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

13. The compound as claimed in any one of claims 9 to 11, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R3is selected from C 1-30 alkyl and C 5-10 cycloalkyl.

14. The compound as claimed in any one of claims 9 to 13, stereoisomers, pharmaceutically acceptable salts, deuterated forms, isomers, prodrugs, and metabolites thereof, wherein R c is independently selected from -Ci-C6alkyl, -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 halogen. ​ wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atom to which they are attached, form C 3-10 cycloalkyl or heterocyclyl; R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R5is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; wherein X1, X2, X3, X4, X5, X6, X7, X8, and X9are each independently H, D, or halogen, wherein Z1and Z2are each independently H, D, or halogen; wherein R a and R b are each independently selected from CH3, CD3, Cl, Br, I, or CF3; wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl, or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl, or C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 6-10 aryl and heteroaryl; or R6and R7, together with the atoms to which they are attached, combine to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

16. The compound of claim 15, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Z1and Z2are each H.

17. The compound of claim 15 or 16, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R4 is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4 is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

18. The compound as claimed in any one of claims 15 to 17, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R3is selected from C 1-30 alkyl and C 5-10 cycloalkyl.

19. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Formula I is Formula V, wherein R1and R2are independently selected from H, C 1-6 alkyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl and C 1-6 alkyl-heteroaryl; wherein R3is selected from H, C 1-30 alkyl, and C 5-10 cycloalkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

20. The compound as claimed in claim 19, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

21. The compound of claim 19 or 20, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R3is selected from C 1-30 alkyl and C 5-10 cycloalkyl.

22. The compound of claim 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein Formula I is Formula VI, wherein R1and R2are independently selected from H, C 1-6 alkyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl and C 1-6 alkyl-heteroaryl; wherein the alkyl, aryl and heteroaryl groups are optionally substituted with halogen, C 1-6 alkyl and C 1-6 haloalkyl; wherein R3is selected from H, C 1-30 alkyl, and C 5-10 cycloalkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with halo, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; p is an integer from 0 to 3.

23. The compound of claim 22, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R3is C 1-6 alkyl or C 5-10 cycloalkyl.

24. The compound of claim 22, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R3is C 7-30 alkyl or C 5-10 cycloalkyl.

25. The compound of claim 23 or 24, stereoisomers thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R4is C 6-10 aryl; and C 6-10 aryl is optionally substituted with halo, C 1-6 alkyl.

26. The compound of any one of claims 9 to 25, stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein the compound is selected from the group consisting of:

27. A compound having the following formula: stereoisomers thereof, pharmaceutically acceptable salts thereof, and deuterated forms thereof, wherein R5is selected from -C(O)R6, -C(O)OR6, -C(O)NR7R 10 , CR 12 R 13 OC(O)R7, CR 12 R 13 OC(O)OR7; R6is selected from C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl, wherein C 13-30 alkyl, C 13-30 alkenyl, and C 13-30 alkynyl are each optionally substituted with one or more substituents each independently selected from halo, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from halo and C 1-3 alkyl; R7is selected from 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 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 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)NR c C 1-30 alkyl, -C(O)NR c C 2-30 alkenyl, and -C(O)NR c C 2-30 alkynyl is optionally substituted with one or more substituents each independently selected from halo, -O- 1-30 alkyl, -S- 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein -O- 1-30 alkyl, -S- 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents each independently selected from halo and C 1-3 alkyl; where R 10 Selected from 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, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) n C 3-10 Each of the cycloalkyl groups, -(CH2) n Aryl and -(CH2) n Heteroaryl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, aryl and 5-10 membered heteroaryl; wherein R 12 and R 13 each independently is selected from H, deuterium, C 1-6 alkyl, halogen, and C 1-6 haloalkyl, wherein C 1-6 alkyl, halogen, and C 1-6 haloalkyl are each optionally substituted with one or more substituents each independently selected from halogen, -O-C 1- 3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; wherein R8and R9are each independently selected from H, OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein C 1-6 alkyl, -O-C 1-3 alkyl, S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from OH, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; or wherein R8and R9, together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclyl, which is optionally substituted with 1-4 R6, wherein each R6is independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl or alkoxy; wherein n = 0, 1, 2, or 3; wherein each of the above 5-10 membered heteroaryl groups has 1-4 heteroatoms, each independently N, O, or S; and wherein each of the above 3-10 membered heterocyclyl groups has 1-4 heteroatoms, each independently N, O, or S.

28. A compound having the following formula: stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atom to which they are attached, form C 3-10 cycloalkyl or heterocyclyl; R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R5is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, O- 1-6 alkyl, C 6-10 aryl and heteroaryl; or R6and R7, in combination with the atom to which they are attached, form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

29. A compound having the following formula stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, and metabolites thereof, wherein R1and R2are each independently selected from 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 R1and R2, in combination with the atom to which they are attached, form C 3-10 cycloalkyl or heterocyclyl; R3is selected from 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, wherein R3is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R4is selected from C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl and 5-10 membered heteroaryl, wherein R4is optionally substituted with one or more substituents each independently selected from halo, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl; wherein R5is selected from the group consisting of H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, and -CH2OCONHR6; wherein X1, X2, X3, X4, X5, X6, X7, X8, and X9are each independently H, D, or F; wherein Z1and Z2are each independently H or D; wherein R a and R b are each independently selected from CH3, CD3, Cl, Br, I, or CF3; wherein R6and R7are each independently C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl, wherein the C 1-30 alkyl, C 1-30 alkenyl or C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, O- 1-6 alkyl, C 6-10 aryl and heteroaryl; or R6and R7, together with the atoms to which they are attached, combine to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NH2, NO2, OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl and O-C 1-6 alkyl.

30. A pharmaceutical composition comprising: a compound of any one of claims 1 to 29, pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, prodrugs thereof, or metabolites thereof; and a pharmaceutically acceptable excipient.

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

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