Thyroid hormone analog prodrug and use thereof

Abstract

Disclosed are a compound of formula I and a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof, wherein each substituent is as defined in the present disclosure.

Description

Thyroid hormone analog prodrugs and uses thereof

[0001] Reference to Related Applications

[0002] This disclosure claims the entire benefit of Chinese Patent Application No. 202411008314.6, filed on July 25, 2024, entitled “Thyroid hormone analog prodrugs and uses thereof,” which is incorporated by reference in its entirety.

[0003] TECHNICAL FIELD

[0004] The present disclosure relates to thyroid hormone derivative prodrugs, methods of making, and uses thereof.

[0005] BACKGROUND

[0006] Thyroid hormones are essential for normal growth and development and for maintaining metabolic balance (Paul M. Yen Physiological Review, Vol. 81(3): pp. 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms of the hypothalamus / pituitary / thyroid (HPT) axis. Thyroid dysfunction leading to 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. The major thyroid receptor isoforms are α1, α2, β1, and β2. Thyroid hormone receptors α1, β1, and β2 bind thyroid hormone. The thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses. Recent studies have shown that TRβ1 plays an important role in the liver in mediating the effects of TRH (thyrotropin releasing hormone) and mediating thyroid hormone. TRβ2 plays a major role in mediating TSH (thyroid stimulating hormone) (Abel et al., J. Clin. Invest., Vol. 104: pp. 291-300 (1999)). TRβ1 plays an important role in mediating heart rate (B. Gloss et al., Endocrinology, Vol. 142: pp. 544-550 (2001); C. Johansson et al., Am. J. Physiol., Vol. 275: pp. R640-R646 (1998)).

[0007] SUMMARY

[0008] In one aspect, the present disclosure relates to a compound of Formula I:

[0009] wherein,

[0010] ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0011] ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0012] R a selected from 1 to 4 hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, aryl, -C 1-6 alkyl-aryl, heteroaryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-C 3-8 cycloalkyl, -SO2-R1, -COR1, -COOR1, -CONR2R3, -NHCOR1, -NHS(O)2R1, -O-CH2-COR4, -OCOR4 or -O-CO-NR2R3;

[0013] or, optionally, any two R a may combine with the atom to which they are attached to form a 5-10 membered heterocyclyl or C 3-8 cycloalkyl, the 5-10 membered heterocyclyl or C 3-8 cycloalkyl is optionally substituted with 1 to 4 C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or halogen; or the any 2 C 1-6 alkyl, cycloalkyl and haloalkyl may combine with the atom to which they are attached to form a 5-10 membered heterocyclyl or 3-8 membered cycloalkyl;

[0014] R b selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogen or C 1-6 haloalkyl;

[0015] G is selected from O or -CH2-;

[0016] T is selected from -(CR d ) m - or -O-(CR d ) m -;

[0017] each R d is independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or, optionally, any two Rd may combine with the atom to which they are attached to form a C 3-8 cycloalkyl group, said C 3-8 cycloalkyl group is optionally substituted with C 1-6 alkyl or haloalkyl; 1-6 haloalkyl;

[0018] X is selected from -P(O)(OH)2, -COOH, -P(O)(OR X3 )(OR X4 ) or -COOR x3 ;

[0019] m is 0, 1, 2, 3 or 4;

[0020] n is 0, 1, 2, 3 or 4;

[0021] R1, R2, R3and R4are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl or C 1-30 alkyl-heteroaryl, or R2and R3may optionally combine with the atom to which they are attached to form a 5-10 membered heterocyclyl or C 3-8 cycloalkyl group, wherein said 5-10 membered heterocyclyl or C 3-8 cycloalkyl group is optionally substituted with 1 to 4 C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or halo;

[0022] R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or R x1 and R X2 may optionally combine with the atom to which they are attached to form a C 3-8 cycloalkyl group, said C 3-8 cycloalkyl group is optionally substituted with C 1-6 alkyl or haloalkyl;

[0023] R X3 and R X4 are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl, C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl or CH2-O-C 2-30 alkynyl, or, R X3 and R X4 optionally combine with the atoms to which they are attached to form a 3-8 membered heterocycloalkyl group, which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0024] Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0025] wherein R a , R b , R1, R2, R3, R x1 , R X2 , R X3 and R X4 are independently optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl, C 1-30 haloalkyl, aryl, heteroaryl, heterocycloalkyl or C 3-8 cycloalkyl, wherein said aryl and heteroaryl are optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl or C 1-30 haloalkyl;

[0026] Ar is optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-6 alkyl, C 1-30 haloalkyl or C 3-8 cycloalkyl.

[0027] On the other hand, this disclosure relates to pharmaceutical compositions comprising: any one of the compounds provided in this disclosure and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds; and pharmaceutically acceptable carriers and excipients.

[0028] On the other hand, this disclosure relates to methods for treating and / or preventing thyroid hormone-related diseases, comprising administering to an individual requiring the method a therapeutic and / or preventative effective amount of any of the compounds provided in this disclosure, their stereoisomers, their pharmaceutically acceptable salts or their deuterated compounds, or a pharmaceutical composition comprising a compound of formula I, its stereoisomers, its pharmaceutically acceptable salts or their deuterated compounds.

[0029] In some implementation schemes, thyroid hormone-related diseases are selected from obesity, hair loss, overweight, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), hepatic steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

[0030] On the other hand, this disclosure relates to weight management and methods for long-term weight management, which include administering to an individual requiring the method a therapeutic and / or preventative effective amount of any of the compounds provided in this disclosure, their stereoisomers, their pharmaceutically acceptable salts or their deuterated compounds, or pharmaceutical compositions comprising a compound of formula I, its stereoisomers, its pharmaceutically acceptable salts or their deuterated compounds.

[0031] Detailed Explanation

[0032] 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. Dashes at the beginning or end of chemical groups are for convenience in indicating the connection point with the parent molecule; chemical groups may or may not be described with one or more dashes without losing their ordinary meaning. Prefixes such as "C" u-v "or"C u -C v "This indicates that the following groups have u to v carbon atoms, where u and v are integers. For example, "C 1-6 "alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0033] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon group. For example, alkyl groups can have 1 to 30 carbon atoms (i.e., C64-C ... 1-30 Alkyl groups or 1 to 10 carbon atoms (i.e., C14) 1-10 Alkyl groups or 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups or 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Examples of alkyl groups include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH3), 2-methyl-1 -propyl (i-Bu, 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, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH3), 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 (-CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH3), 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). Alkyl groups can be unsubstituted or substituted.

[0034] "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 30 carbon atoms (i.e., C2-30alkenyl), or 2 to 10 carbon atoms (i.e., C2-10alkenyl), or 2 to 8 carbon atoms (i.e., C2-8alkenyl), or 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, ethylenyl (i.e., -CH=CH2), propylenyl (i.e., -CH=CHCH3), butylenyl (i.e., -CH=CHCH2CH3), and the like. 2-30 Alkenyl groups can be unsubstituted or substituted. 2-10 Alkenyl groups can be unsubstituted or substituted. 2-8 Alkenyl groups can be unsubstituted or substituted. 2-6 Alkenyl groups can be unsubstituted or substituted. 2-4"Alkenyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 30 carbon atoms (i.e., C

[0035] "Alkynyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 30 carbon atoms (i.e., C 2-30 or 2 to 10 carbon atoms (i.e., C 2-10 or 2 to 8 carbon atoms (i.e., C 2-8 or 2 to 6 carbon atoms (i.e., C 2-6 or 2 to 4 carbon atoms (i.e., C 2-4 Alkynyl groups include, but are not limited to, ethynyl (-CºCH), propynyl (-CH2CºCH), and -CH2-CºC-CH3. Alkynyl groups can be unsubstituted or substituted.

[0036] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups can be unsubstituted or substituted.

[0037] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0038] "Haloalkyl" is an alkyl group as defined herein, wherein one or more of the hydrogen atoms of the alkyl group are independently replaced with a halogen, which can be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen can be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms of the alkyl portion, e.g., C 1-4 Haloalkyl groups include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

[0039] "Aryl" means a monovalent or divalent mono- or polycyclic all-carbon aromatic ring system, wherein the ring is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl group. Aryl also includes polycyclic ring systems having about 9 to 20 carbon atoms (e.g., ring systems composed of 2, 3, or 4 rings), wherein the rings are aromatic. Where valence permits, the rings of the polycyclic ring system can be connected to each other through a fused bond. It is also understood that when referring to an aryl group as a member of an atomic range (e.g., aryl groups of 6-10 members), the atomic range refers to the total ring atoms of the aryl group. For example, a 6-membered aryl group includes a phenyl group, and a 10-membered aryl group includes a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and the like. An aryl group can be unsubstituted or substituted.

[0040] "5-10 membered heteroaryl" refers to a single aromatic ring having at least one atom in the ring that is not carbon, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "5-10 membered heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "5-10 membered heteroaryl" includes a single aromatic ring of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The sulfur and nitrogen atoms can also exist in oxidized forms, so long as 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 condensed ring systems (e.g., ring systems composed of 2, 3, or 4 rings) in which a 5-10 membered heteroaryl as defined above is condensed with one or more rings selected from 5-10 membered heteroaryl (forming, for example, 1,8-naphthyridinyl) and aryl (forming, for example, benzimidazolyl or indazolyl), forming a multiple condensed ring system. Thus, a 5-10 membered heteroaryl (either a single aromatic ring or a multiple condensed ring system) can have about 1-20 carbon atoms, with about 1-6 heteroatoms in the 5-10 membered heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms in the ring. Where valence permits, the rings of a multiple condensed ring system can be connected to one another through a fused bond. It will be appreciated that the individual rings of a multiple condensed ring system can be connected to one another in any order. It will be appreciated that the point of attachment of a 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system can be any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It will also be appreciated that when referring to a membered heteroaryl of a certain range of atoms (e.g., 5 to 10 membered heteroaryl), the range of atoms is with respect to the total ring atoms of the heteroaryl, including both carbon atoms and heteroatoms. It will also be appreciated that the rings of a multiple condensed ring system can include an aryl ring fused to a heterocyclic ring (e.g., 3, 4, 5, 6, or 7 membered ring) having saturated or partially unsaturated bonds, the ring having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. 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, quinoxazolyl, quinazolinyl, benzofuranyl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridyl, quinazolin-4(3H)-one, triazolyl, and tetrazolyl. A 5-10 membered heteroaryl can be unsubstituted or substituted.

[0041] "Cycloalkyl" is a monovalent or divalent single fully carbon ring or multiple condensed fully carbon ring system in which the ring in each instance 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, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems (e.g., ring systems including 2 rings) having about 7 to 12 carbon atoms. Where valence permits, the rings of a multiple condensed ring system can be connected to one another by a fused bond, a spiro bond, or a bridged bond. Exemplary polycyclic cycloalkyl groups include octahydro-pentene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0042] "Heterocycle" or "heterocyclyl" as used herein means a single saturated or partially unsaturated non-aromatic ring or non-aromatic multiple ring system in which at least one of the ring atoms is a heteroatom (i.e., at least one ring-forming atom is selected from the group consisting of oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 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 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes single saturated or partially unsaturated rings having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms, the ring heteroatoms being selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence permits, the rings of a multiple condensed ring (e.g., bicyclic heterocycle) system can be connected to one another by a fused bond, a spiro bond, and a bridged bond. Heterocycles include, but are not limited to, azepine, aziridine, imidazolidine, morpholine, oxirane, oxepine, thiepine, piperazine, piperidine, pyrazolidine, pyrrolidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydro-pyridine, tetrahydropyridine, quinuclidine, 2-oxo-6-azaspiro[3.3]heptane-6-yl, 6-oxa-l-azaspiro[3.3]heptane-l-yl, 2-thia-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hexane-2-yl, 3-azabicyclo[3.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptane-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like. Heterocyclyl groups can be unsubstituted or substituted.

[0043] 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) with the proviso that the substituents are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy, aryloxy, thiohydroxy, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl as defined in this disclosure), or protected amino.

[0044] "Optionally" or "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and encompasses the two instances in which the event or circumstance occurs and in which it does not.

[0045] "Optionally substituted" means that the group can or can not be substituted and, unless otherwise specified, the types and number of substituents are any that are chemically possible. For example, "optionally (option) substituted alkyl substituted with halo or cyano" includes instances in which the alkyl is substituted with halo or cyano and instances in which the alkyl is not substituted with halo or cyano.

[0046] It is understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position independent of any other substituents; and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.

[0047] "Compounds of the disclosure" include the compounds disclosed herein, e.g., the compounds of the disclosure include the compounds of Formula I, including the compounds of the Examples. In some embodiments, "compounds of the disclosure" include the compounds of Formula I.

[0048] "Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, lubricant, sweetening, diluent, preservative, dye / colorant, flavor-enhancing, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that has been approved by the U.S. Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0049] As used herein, "therapeutic effective amount" or "effective amount" means an amount that effectively elicits the desired biological or medical response, including, when administered to a subject treating a disease, an amount sufficient to affect the treatment of that disease. Effective amounts will vary depending on the compound, the disease and its severity, and factors such as the age and weight of the subject being treated. Effective amounts can include a range of amounts. As understood in the art, an effective amount can be one or more doses, meaning that one or more doses may be required to achieve the desired therapeutic endpoint. An effective amount can be considered when administering one or more therapeutic agents, and if, when used with one or more other agents, a desired or beneficial result may have been achieved, the single agent may be considered to have been administered at an effective amount. Due to the combined effects of compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compound may be selectively reduced.

[0050] As used herein, "co-administration" means administering a unit dose of the disclosed compound before or after administration of a unit dose of one or more additional therapeutic agents, for example, administering the disclosed compound within seconds, minutes, or hours after administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the disclosed compound within seconds or minutes. In some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the disclosed compound several hours later (e.g., 1-12 hours). Co-administration of the disclosed compound with one or more additional therapeutic agents generally means administering the disclosed compound and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject.

[0051] Pharmaceutically acceptable salts, hydrates, solutions, isomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0052] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human use.

[0053] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base forms of the compounds which are

[0054] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from the appropriate base, such as an alkali metal (for example, sodium and potassium), an alkaline earth (for example, magnesium), ammonium and N(Ci-C4alkyl)4ammonium. 4+ Base addition salts, such as sodium or potassium salts, are also included.

[0055] Also provided are compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein, wherein from 1 to n hydrogen atoms attached to a carbon atom can be replaced with deuterium atoms 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 can increase resistance to metabolism, and thus can be useful to increase the half-life of a compound or pharmaceutically acceptable salt, isomer, or mixture thereof described herein when administered to a mammal. See "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, for example, using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0056] Examples of isotopes of atoms which can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 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, such as 11 C, 18 F, 15 O and 13 N are useful in Positron Emission Topography (PET) studies for examining occupancy of substrate receptors. Isotopically-labeled compounds of Formula (I-A-1) 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.

[0057] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or, as (D)- or (L)- for amino acids, and are encompassed within the scope of the embodiments. The present statement is intended to include all such possible isomers, as well as, their racemic and optically pure forms. Optical isomers (+) and (-), (R) and (S), or (D) and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating single enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or salt or derivative of the racemate) using, for example, chiral high pressure liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds, unless otherwise specified, these compounds are intended to include E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0058] As used herein, "stereoisomers" refers to compounds which are not superimposable mirror images of one another. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0059] As used herein, "tautomer" refers to a proton shift from one molecule of an atom to another molecule of the same atom. In some embodiments, the present disclosure includes tautomers of the compounds described.

[0060] As used herein, "solvate" refers to an interaction between a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0061] As used herein, "hydrate" refers to a compound of the present disclosure in chemical combination with one or more water molecules.

[0062] "Prevention" refers to any treatment that results in the non-development of clinical symptoms of a disease or condition. In some embodiments, the compounds can be administered to a subject (including a human) at risk or family history of the disease or condition.

[0063] As used herein, "prodrug" means a derivative of a drug that is converted into the parent drug following administration to the human body by some chemical or enzymatic process. In some embodiments, a prodrug is a biologically active derivative of a drug that is converted into the biologically active parent drug following administration to the human body by some chemical or enzymatic process.

[0064] As used herein, "treatment" means an approach for obtaining beneficial or desired results. For the purposes of this disclosure, 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" or "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 the extent of the disease or condition); b) slowing or arresting the development 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 the disease state, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, "at risk individual" means an individual who is at risk of developing a disease for which treatment is desired. An "at risk" individual can or can not have a detectable disease or condition, and can or can not have exhibited detectable disease prior to the treatment methods described herein. "At risk" indicates that the individual has one or more so-called risk factors, which are measurable parameters associated 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 probability of developing the disease or condition than an individual who does not have these risk factors.

[0065] Compound

[0066] In one aspect, the present disclosure provides a compound of Formula I:

[0067] wherein,

[0068] Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0069] Ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0070] R a is selected from 1 to 4 hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, aryl, -C 1-6 alkyl-aryl, heteroaryl, -C1-6 alkyl-heteroaryl, -C 1-6 alkyl-C 3-8 cycloalkyl, -SO2-R1, -COR1, -COOR1, -CONR2R3, -NHCOR1, -NHS(O)2R1, -O-CH2-COR4, -OCOR4or -O-CO-NR2R3;

[0071] or, any two R a optionally combined with the atom to which they are attached to form a 5-10 membered heterocyclyl or C 3-8 cycloalkyl, said 5-10 membered heterocyclyl or C 3-8 cycloalkyl is optionally substituted with 1 to 4 C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or halogen; or said any two C 1-6 alkylcycloalkyl and haloalkyl can be combined with the atom to which they are attached to form a 5-10 membered heterocyclyl or 3-8 membered cycloalkyl;

[0072] R b is selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogen or C 1-6 haloalkyl;

[0073] G is selected from O or -CH2-;

[0074] T is selected from -(CR d ) m - or -O-(CR d ) m -;

[0075] each R d is independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or, any two R d may be combined with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl;

[0076] X is selected from -P(O)(OH)2, -COOH, -P(O)(OR X3 )(OR X4 ) or -COOR x3 ;

[0077] m is 0, 1, 2, 3 or 4;

[0078] n is 0, 1, 2, 3 or 4;

[0079] R1, R2, R3, and R4 are independently selected from hydrogen, C 1-30 Alkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, C 1-30 Alkoxy, C 1-30 Haloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-30 alkyl-aryl or C 1-30 Alkyl-heteroaryl groups, or alternatively, R2 and R3, can be bonded to the atoms they are attached to, forming 5-10 membered heterocyclic groups or C groups. 3-8 cycloalkyl, wherein the 5-10 membered heterocyclic group or C 3-8 The cycloalkyl group is optionally surrounded by 1 to 4 carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or halogen substitution;

[0080] R x1 and R X2 Independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 Optionally, they combine with the atoms they are attached to to form C 3-8 cycloalkyl, the C 3-8 cycloalkyl groups are optionally C 1-6 Alkyl or haloalkyl substitution;

[0081] R X3 and R X4 Independently selected from hydrogen, C 1-30 Alkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkyl-OH, 3-8 membered heterocyclic alkyl, alkoxy, C 1-30 Haloalkyl, C 6-10 Aryl, heteroaryl compounds of 5-10 yuan, C 1-30 Alkyl-aryl, C 1-30alkyl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl or CH2-O-C 2-30 alkynyl, or, R X3 and R X4 optionally combined with the atom to which they are attached to form a 3-8 membered heterocycloalkyl group, which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0082] Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0083] wherein R a , R b , R1, R2, R3, R x1 , R X2 , R X3 and R X4 are independently optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl, C 1-30 haloalkyl, aryl, heteroaryl, heterocycloalkyl or C 3-8 cycloalkyl, wherein said aryl and heteroaryl are optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl or C 1-30 haloalkyl;

[0084] Ar is optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-6 alkyl, C 1-30 haloalkyl or C 3-8 cycloalkyl.

[0085] In some embodiments, ring A is selected from phenyl, pyridyl or indolyl.

[0086] In some embodiments, ring B is selected from phenyl or pyridyl.

[0087] In some embodiments, is selected from:

[0088] wherein R5and R6are independently selected from C 1-6 alkyl or C 3-8 cycloalkyl; or, R5and R6optionally combine with the atom to which they are attached to form a C 3-8 cycloalkyl;

[0089] wherein Ra1 selected from hydrogen, -COR1, -COOR1, -CONR2R3, -CH2-COR4or 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 or C(O)NR c C 2-30 alkynyl, wherein R7is optionally substituted with one or more halogen, -O-C 1-30 alkyl, -S-C 1-30 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl or 5-10 membered heteroaryl, wherein the -O-C 1-30 alkyl, -S-C 1-30 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more halogen and C 1-3 alkyl;

[0090] R8and R9are independently selected from H, OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 5-10 membered heterocycloalkyl, aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 5-10 membered heterocycloalkyl, aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more selected from OH, C 1-6 alkyl, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl or 5-10 membered heterocycloalkyl;

[0091] or, R8and R9are optionally combined with the atoms to which they are attached to form a 3-8 membered heterocycloalkyl, wherein the 3-8 membered heterocycloalkyl is optionally substituted with hydroxyl, halogen, C 1-6 alkyl or C3-6 cycloalkyl substituted;

[0092] R c is selected from H, C 1-6 alkyl, -C 3-8 cycloalkyl, or C 1-6 haloalkyl.

[0093] In some embodiments, G is selected from O.

[0094] In some embodiments, G is selected from CH2.

[0095] In some embodiments, T is selected from -O-(CH2) m -.

[0096] In some embodiments, T is selected from -(CH2) m -.

[0097] In some embodiments, R X3 is

[0098] In some embodiments, X is selected from wherein R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl, or C 1-6 alkyl-heteroaryl, or R x1

[0099] and R X2 combine with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or haloalkyl;

[0100] R X3 is selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl, or C 1-30alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl, -CH2-O-C 2-30 alkynyl, or, R X3 and R X4 together with the atom to which they are attached form a 3-8 membered heterocycloalkyl group, which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0101] Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl.

[0102] In some embodiments, R x3 is selected from H, C 1-30 alkyl, C 3-8 cycloalkyl, C 1-30 haloalkyl,

[0103] C 6-10 aryl, C 1-30 alkyl-aryl or -C 1-30 alkyl-heteroaryl.

[0104] In some embodiments, the compound of formula I has the structure of formula II:

[0105] wherein R a1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 halogen, hydroxyl, amino, cyano, aryl, C 1-6 alkyl-aryl, heteroaryl, C 1-6 alkyl-heteroaryl,

[0106] C 1-6 alkyl-C 3-8 cycloalkyl, -SO2-R1, -COR1, -COOR1, -CONR2R3, -NHCOR1, -NHS(O)2R1, -O-CH2-COR4, -OCOR4 or -O-CO-NR2R3;

[0107] R a2 and R a3 are independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 haloalkyl, or, R a2 and R a3each independently taken together with the atom to which they are attached to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally substituted with hydroxy, halo, C 1-6 alkyl or C 3-6 haloalkyl;

[0108] R b1 and R b2 are independently selected from H or C 1-6 alkyl;

[0109] G is selected from O or CH2;

[0110] T is selected from -(CR d ) m - or -O-(CR d ) m -;

[0111] R d is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or, any two R d taken together with the atom to which they are attached to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally substituted with C 1-6 alkyl or haloalkyl;

[0112] X is selected from -P(O)(OH)2, -COOH, -P(O)(OR X3 )(OR X4 ) or -COOR x3 ;

[0113] R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 taken together with the atom to which they are attached to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally substituted with C 1-6 alkyl or haloalkyl;

[0114] RX3 and R X4 is independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl, C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl or -CH2-O-C 2-30 alkynyl, or, R X3 and R X4 combine with the atom to which they are attached to form a 3-8 membered heterocycloalkyl group, which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0115] Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl;

[0116] m is 0, 1, 2, 3 or 4;

[0117] p is selected from 0, 1 or 2.

[0118] In some embodiments, R b1 and R b2 are independently selected from chloro, bromo or methyl.

[0119] In some embodiments, wherein R a1 is selected from hydrogen.

[0120] In some embodiments, G is selected from CH2.

[0121] In some embodiments, T is selected from -CH2CH2- or -O-CH2-.

[0122] In some embodiments, wherein X is selected from -P(O)(OH)2, or -P(O)(OR X3 )(OR X4 ); wherein R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C1-6 Haloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 They combine with the atoms they are connected to to form C 3-8 cycloalkyl, the C 3-8 cycloalkyl groups are optionally C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0123] R X3 and R X4 Independently selected from hydrogen, C 1-30 Alkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkyl-OH, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-30 alkyl-aryl or C 1-30 Alkyl-heteroaryl, -CH2-OC 1-30 Alkyl, -CH2-OC 2-30 alkenyl-,-CH2-OC 2-30 alkynyl group, or R X3 and R X4 They combine with the atoms to form 3-8 membered heterocyclic alkyl groups, which are optionally C-shaped. 1-6 Alkyl, C 1-6 Halogenated alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0124] In some embodiments, the compound of formula I is selected from:

[0125] Pharmaceutical Composition

[0126] On the other hand, this disclosure relates to pharmaceutical compositions comprising: any one of the compounds provided in this disclosure and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds; and pharmaceutically acceptable carriers and excipients.

[0127] In certain embodiments, a pharmaceutical composition comprising a compound of the disclosure, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, can be prepared with one or more pharmaceutically acceptable excipients, the selection of which can be made according to conventional practices. Tablets can contain excipients including flow-aids, fillers, binders, and the like. Aqueous compositions can be prepared in sterile form, and are generally isotonic when administered to humans.

[0128] In some embodiments, the composition can include excipients, such as those set forth in Rowe et al. Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as ethylenediaminetetraacetic acid, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. In some embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.

[0129] The compositions include those suitable for various routes of administration, including oral administration. The compositions can be in unit dosage form and can be prepared by any methods known to the pharmaceutical art. These methods include the step of bringing into association the active ingredient (e.g., a compound of the disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or fine solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0130] Compositions described herein suitable for oral administration can be presented in discrete units (unit dosage form), including but not limited to capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition of the disclosure is a tablet.

[0131] Pharmaceutical compositions disclosed herein include one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient can be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preservative agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient are also acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, and humectants, such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or they can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0132] The amount of active ingredient that can be combined with the non-active ingredients to produce a dosage form can vary depending on the intended subject of treatment and the method of administration. For example, in some embodiments, a dosage form for oral administration to a human can contain from about 1 to 1000 mg of active substance, formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises from about 5% to about 95% (weight: weight) of the total composition.

[0133] In some embodiments, in one variation, a composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, does not comprise an agent that affects the rate of metabolism of the active ingredient. Thus, it should be understood that, in one aspect, a composition comprising a compound of the present disclosure does not comprise an agent that would affect (e.g., slow, hinder, or delay) the metabolism of a compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with a compound of the present disclosure. It should also be understood that, in one aspect, any method, kit, article of manufacture, etc. detailed herein does not comprise an agent that would affect (e.g., slow, hinder, or delay) the metabolism of a compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with a compound of the present disclosure.

[0134] In some embodiments, the above pharmaceutical compositions are for use in humans or animals.

[0135] The present disclosure also includes the compounds of the present disclosure administered as the sole active ingredient in a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example, by incorporating the active ingredient into a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing with the same.

[0136] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient which has a synergistic effect with other active ingredients in known drugs, or the use of a compound of the present disclosure together with such drugs.

[0137] The compounds of the present disclosure can also be used in the form of prodrugs or other suitable modified forms which release the active ingredient in vivo.

[0138] Therapeutic methods

[0139] In another aspect, the present disclosure relates to a method of treating and / or preventing a thyroid hormone related disease, comprising administering to an individual in need of the method a therapeutically and / or prophylactically effective amount of any one of the compounds provided by the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0140] In certain embodiments, the thyroid hormone related disease is selected from obesity, hair loss, overweight, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

[0141] In another aspect, the present disclosure relates to a method of weight management, long-term weight management, comprising administering to an individual in need of the method a therapeutically and / or prophylactically effective amount of any one of the compounds provided by the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0142] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated, according to the dosage and regimen. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal and epidural). It will be appreciated that the preferred route can vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0143] The compounds of the present disclosure can be administered to an individual for a desired period of time or duration of time, e.g., at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, in an effective dosing regimen. In one embodiment, the compound is administered daily or intermittently over the duration of the individual's life.

[0144] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted based on the judgment of the administering physician over the course of the treatment.

[0145] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0146] The compound can be administered by any useful route and means, e.g., by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0147] The compounds of the disclosure can be combined with one or more additional therapeutic agents in any dosage amount of the compounds of the disclosure (e.g., from 1 mg to 1000 mg of the compound). A therapeutically effective amount can include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. Single doses can be administered every hour, every day, or every week. For example, single doses can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16, or 24 hours. Single doses can also be administered once every 1 day, 2, 3, 4, 5, 6, or 7 days. Single doses can also be administered once every 1 week, 2, 3, or 4 weeks. In some embodiments, single doses can be administered once per week. Single doses can also be administered once per month.

[0148] Kits comprising a compound of the disclosure, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, are also included in the disclosure.

[0149] In one embodiment, a kit further comprises instructions for use. In one aspect, a kit comprises a compound of the disclosure, or a pharmaceutically acceptable salt, mixture of isomers, stereoisomer, prodrug, or deuterated analog thereof, and a label and / or instructions for using the compound in treating an indication, such as a disease or disorder described herein. In one embodiment, a kit comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents is provided. Specific Embodiments

[0150] The compounds of the disclosure can be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the methods disclosed 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 one or more of the structures described in Formula I, or other formulas or compounds disclosed herein, can be accomplished as described in the following examples.

[0151] Synthetic Methods

[0152] Typical embodiments of compounds according to the disclosure 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 with other materials of similar structure to generate a corresponding different product. The later synthetic descriptions provide many examples of how the starting materials can be varied to provide the corresponding product. The starting materials are generally obtained from commercial sources or synthesized using published methods of synthesizing compounds, which are embodiments of the disclosure, an inspection of the structure of the compound to be synthesized will provide the identity of each substituent, and given the examples herein, the identity of the necessary starting materials will generally become apparent through a simple inspection process. The labels used in the reaction schemes herein (e.g., R1, R2) are for illustrative purposes only and do not necessarily correspond to the labels or functionalities used elsewhere to describe the compounds of Formula I or aspects or fragments thereof, unless otherwise noted.

[0153] Synthetic Reaction Parameters

[0154] The compounds of the 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.

[0155] In addition, for those skilled in the art, conventional protecting groups can be necessary to prevent certain functional groups from undergoing undesired reactions. Protecting groups suitable 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) Protective Groups in Organic Synthesis 3rd Edition, Wiley, New York, and references cited therein.

[0156] In addition, the compounds of the disclosure can contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as stereoisomeric mixtures enriched in the desired stereoisomer. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of the present statement. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. In addition, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0157] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures described in standard reference texts or obvious modifications thereof, such as 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 Volumes (Elsevier Science Publishers, 1989); Organic Reactions: Volumes 1-40 (John Wiley, and Sons, 1991); March's Advanced Organic Chemistry 5th Ed. (John Wiley, and Sons, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers, 1989).

[0158] The term "solvent", "inert organic solvent", or "inert solvent" denotes a solvent that is inert under the conditions of the reaction in which it is employed (e.g. 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 present disclosure are inert organic solvents and the reactions are carried out under an inert atmosphere, most preferably nitrogen.

[0159] The term "q.s." means the addition of a quantity sufficient to achieve the stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0160] The compounds provided herein can be synthesized according to the general schemes provided below. In the schemes below, it should be understood that each compound shown therein can have protecting groups present as required at any step. Standard protecting groups are within the purview of one skilled in the art.

[0161] General Synthetic Method One:

[0162] wherein: Rais a common hydroxyl protecting agent such as CH3OCH2-, arylalkyl, silane, and the like;

[0163] R a2 and R a3 are independently selected from H, C 1-6 alkyl, -C 3-8 cycloalkyl, C 1-6 haloalkyl, wherein R a2 and Ra3 may be combined with the atom to which they are attached to form a 3-8 membered cycloalkyl group, wherein said cycloalkyl group can be substituted with hydroxy, halo, C 1-6 alkyl, C 3-6 cycloalkyl;

[0164] p is selected from 0, 1 or 2.

[0165] Synthetic process description: In this synthetic route, take Ra1 is CH3OCH2- as an example. Intermediate A reacts with aldehyde compound B under the action of butyl lithium to generate C; C is reduced (such as silicon hydrogen, palladium carbon hydrogen) under the catalysis of acid to generate D, and then deprotected by TABF to generate E; intermediate E reacts with p-toluenesulfonic acid phosphate under alkaline conditions (such as sodium hydroxide, potassium carbonate, cesium carbonate, triethylamine and common organic or inorganic bases) to generate F; F generates intermediate G under the action of TMSBr; G is condensed with phenol to generate H; H is chlorinated by reacting with a chlorinating agent (such as thionyl chloride, oxalyl chloride or triphosgene) to generate I, and I reacts with an amino acid ester to generate the target compound.

[0166] Example 1: Preparation of 4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)methoxy)-2,6-dimethylbenzyl-2-isopropyl stearate (compound 1)

[0167] 1) Synthesis of intermediate 1-3:

[0168] To the solution of 1-1 (1 g, 3.18 mmol) in THF (10 mL) was added NaH (153 mg, 3.816 mmol) slowly at 0 °C, and the reaction was kept for 0.5 h, and then the solution of 1-2 (1.60 g, 3.816 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EA. The organic phase was concentrated and purified by silica gel column to give intermediate 1-3 (1.0 g, 56%).

[0169] 2) Synthesis of intermediate 1-4:

[0170] To the solution of 1-3 (1 g, 1.78 mmol) in methanol (10 mL) was added 1 N NaOH (5 mL), and the reaction was stirred at room temperature for 16 h. The reaction was extracted with EA, and the organic phase was concentrated and purified by silica gel column to give intermediate 1-4 (0.56 g, 65%).

[0171] Synthesis of intermediate 1-6:

[0172] To a solution of 1-4 (0.56 g, 1.15 mmol) in DCM (10 ml), DMF (catalytic amount), oxalyl chloride (0.439 g, 3.46 mmol) was added. Stirring at room temperature for 1 h, concentration, 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 mixture was stirred at room temperature for 2 h, quenched with water, extracted with DCM. The organic phase was concentrated, purified by silica gel column to give intermediate 1-6 (0.35 g, 50%).

[0173] 4) Synthesis of intermediate 1-7:

[0174] To a solution of 1-6 (0.35 g, 0.58 mmol) in methanol (5 mL), TsOH (0.3 g, 1.74 mmol) was added, stirring at 50 °C for 4 h. Quenched with water, extracted with DCM. The organic phase was concentrated, purified by silica gel column to give intermediate 1-7 (0.21 g, 65%).

[0175] 5) Synthesis of compound 1:

[0176] A solution of 1-7 (0.21 g, 0.38 mmol), TEA (77 mg, 0.76 mmol), DAMP (5 mg, 0.038 mmol) and 1-8 (0.114 g, 0.418 mmol) in DCM (5 mL) was stirred at room temperature for 2 h, quenched with water, extracted with DCM. The organic phase was concentrated, purified by silica gel column to give compound 1 (150 mg, 50%).

[0177] Example 2: Preparation of 4-(4-(((benzyloxy)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methoxy)-2,6-dimethylbenzyl)-2-isopropylphenyl docosanoate (compound 6)

[0178] 1) Synthesis of intermediate 6-3:

[0179] To a solution of 1-1 (1 g, 3.18 mmol) in THF (10 mL), NaH (153 mg, 3.816 mmol) was added slowly at 0 °C, and the reaction was kept for 0.5 h, then a solution of 6-2 (1.7 g, 3.816 mmol, Reference Example 4) in THF (10 mL) was added. The mixture was stirred at room temperature for 2 h, quenched with water, extracted with EA. The organic phase was concentrated, purified by silica gel column to give intermediate 6-3 (1.2 g, 64%).

[0180] Synthesis of intermediate 6-4:

[0181] To a solution of 6-3 (1.2 g, 2.03 mmol) in MeOH (10 mL), 1 N NaOH (5 ml) was added and stirred at room temperature for 16 h. EA extraction. The organic phase was concentrated and purified by silica gel column to give the intermediate 6-4 (0.50 g, 49%).

[0182] 3) Synthesis of intermediate 6-6:

[0183] To a solution of 6-4 (0.50 g, 1.0 mmol), oxalyl chloride (0.254 g, 2 mmol), DMF (catalytic amount) in DCM (10 mL), stirred at room temperature for 1 h. Concentrated, then added DCM (10 ml), TEA (0.929 g, 9.2 mmol), DMAP (14 mg, 0.115 mmol) and 1-5 (0.384 g, 2.3 mmol). The mixture was stirred at room temperature for 2 h, quenched with water and extracted with DCM. The organic phase was concentrated and purified by silica gel column to give the intermediate 6-6 (0.27 g, 44%).

[0184] 4) Synthesis of intermediate 6-7:

[0185] To a solution of 6-6 (0.27 g, 0.44 mmol) in MeOH (5 ml), TsOH (0.151 g, 0.88 mmol) was added and stirred at 50 °C for 4 h. Quenched with water and extracted with DCM. The organic phase was concentrated and purified by silica gel column to give the intermediate 6-7 (0.15 g, 60%).

[0186] 5) Synthesis of compound 6:

[0187] To a solution of 6-7 (0.15 g, 0.26 mmol), TEA (55 mg, 0.53 mmol), DMAP (5 mg, 0.028 mmol) and 6-8 (0.112 g, 0.418 mmol) in DCM (5 ml), stirred at room temperature for 2 h, quenched with water and extracted with DCM. The organic phase was concentrated and purified by silica gel column to give compound 6 (100 mg, 43%).

[0188] Example 3: Preparation of octadecyl(((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninamide (compound 13)

[0189] 1) Synthesis of intermediate 1-4, reference example 1:

[0190] 2) Synthesis of intermediate 13-6:

[0191] 6-4 (0.50 g, 1.0 mmol), oxalyl chloride (0.254 g, 2 mmol), DMF (catalytic amount) in DCM (10 mL), stirred at room temperature for 1 h. Concentrated, then added 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). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with DCM. The organic phase was concentrated and purified on silica gel column to give intermediate 13-6 (0.30 g, 37%).

[0192] 4) Synthesis of intermediate 13:

[0193] To a solution of 13-6 (0.30 g, 0.37 mmol) in MeOH (5 ml), TsOH (0.128 g, 0.75 mmol) was added and stirred at 50 °C for 4 h. Quenched with water, extracted with DCM. The organic phase was concentrated and purified on silica gel column to give compound 13 (0.17 g, 60%).

[0194] The synthesis of other similar compounds can refer to Example 1, only replace the corresponding raw materials.

[0195] Example 4 Preparation of (Phenoxyphosphoryl)methyl 4-methylenebenzenesulfonate (intermediate 1-2)

[0196] 1) Synthesis of intermediate 1-2-B:

[0197] To a solution of 1-2-A (1 g, 3.1 mmol) in DCM (5 ml), TMSBr (3.3 g, 21.7 mmol) was added and stirred at room temperature for 16 h. Concentrated, added MTBE and 2-3 N NaOH aq.. The aqueous phase was retained, and the pH of the aqueous phase was adjusted to 1-2 with 3 N HCl. Extracted with EA, and the organic phase was concentrated to give intermediate 1-2-B (0.6 g, 72%).

[0198] 2) Synthesis of intermediate 1-2:

[0199] To a solution of intermediate 1-2-B (0.6 g, 2.25 mmol) in DCM (10 ml), oxalyl chloride (0.856 g, 6.75 mmol), DMF (catalytic amount) was added and stirred at room temperature for 1 h. Concentrated, then added DCM (10 ml), TEA (1.36 g, 13.5 mmol), DMAP (27 mg, 0.225 mmol) and phenol (0.528 g, 5.625 mmol). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with DCM. The organic phase was concentrated and purified on silica gel column to give intermediate 1-2 (0.36 g, 38%).

[0200] Example 5: Synthesis of amino acid ester (Int A)

[0201] Int A-1 (60 g, 317 mmol), imidazole (21 g, 323 mmol), HATU (180 g, 473 mmol) and TEA (64 g, 633 mmol) were dissolved in DMF / DCM (500 ml / 500 ml), 3-pentanol (28 g, 318 mmol) was added and stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove dichloromethane and then added to water and stirred for 1 hour. The mixture was filtered to obtain a solid which was dried to obtain Int A-2, 80.0 g, yield: 97.3%.

[0202] Int A-2 (50 g, 193 mmol) was dissolved in a solution of diethyl acid dichloride in HCl (4 M, 500 ml) and stirred at 0-5 °C for 1 hour. The reaction was concentrated under reduced pressure, DCM (500 ml) and saturated sodium carbonate solution (500 ml) were added and stirred for 15 minutes. The organic layer was separated and concentrated to obtain Int A, 27.0 g, yield: 87.9%.

[0203] Example 6: (4-Hydroxy-2,6-dimethylphenyl)(3-isopropyl-4- (methoxymethoxy)phenyl)methanone (Int B)

[0204] Compound 1-1 (1.0 g, 3.18 mmol), Pd / C (0.05 g, 30% wt) and H2O (0.2 ml) were added to DMA (2 ml) under nitrogen protection and stirred at 130-135 °C for 48 hours. After cooling, it was filtered, the filtrate was taken, ethyl acetate (15 ml) and water (15 ml) were added. After extraction, washing, concentration and drying under reduced pressure, Int B, 0.35 g, yield: 33.5% was obtained.

[0205] Example 7: 4-((3-Isopropyl-4-(methoxymethoxy)phenyl)methyl-d2)-3,5- dimethylphenol (Int C)

[0206] Int B (0.1 g, 0.3 mmol) was dissolved in THF (1 ml), LiAlD4 (25.6 mg, 0.6 mmol) was added at 0 °C and stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl solution and then ethyl acetate (20 ml) was added. After extraction, separation of the organic phase, concentration and purification on a silica gel column, Int C, 56 mg, yield: 58.1% was obtained.

[0207] Example 8: 4-(Difluoro(3-isopropyl-4-(methoxymethoxy)phenyl)methyl)-3,5- dimethylphenol (Int D)

[0208] To a solution of Int B (0.1 g, 0.3 mmol) in 1,2-dichloroethane (1 ml) was added BAST (0.2 g, 0.9 mmol) and stirred at room temperature for 72 hours under N2. Quenched with saturated aqueous NaHC03solution (1 ml). The organic phase was then separated, washed with water and brine, dried over MgS04, and concentrated in vacuo. Purification by silica gel column chromatography gave Int D, 66 mg, yield: 61.9%.

[0209] Example 9: 4-(4-(Methoxymethoxy)-3-(propan-2-yl-1,1,1,3,3-d6)benzyl)-3,5- dimethylphenol (Int E)

[0210] To a solution of Int E-1 (5.0 g, 16.7 mmol) in THF (50 ml) was added iPrMgCl (1 M in THF, 50 ml) dropwise at -20 °C and stirred for 2 hours. Deuterated acetone-D6 (0.5 ml) was added dropwise to the solution and stirred for 2 hours, then allowed to warm to room temperature naturally. The reaction was quenched by adding saturated NH4CI solution (30 ml) and then EtOAc (50 ml) was added. The organic phase was separated by extraction, washed with water and brine, dried over MgS04, concentrated under reduced pressure and then purified by silica gel column chromatography to give Int E-2, 3.2 g, yield: 80.1%.

[0211] To a solution of Int E-2 (3.0 g, 12.6 mmol) and TFA (0.1 ml) in 1,2-dichloroethane (30 ml) was added Et3SiH (2.94 g, 25.3 mmol) and stirred for 4 hours. Water (30 ml) was added, then the organic phase was separated, washed with water and brine, dried over MgS04, and concentrated under reduced pressure to give Int E-3, 2.6 g, yield: 92.9%.

[0212] To a solution of Int E-3 (2.6 g, 11.7 mmol) in THF (30 ml) was added t-BuOK (1.98 g, 17.6 mmol) at 0 °C and stirred for 1 h. Then MOMBr (1.62 g, 12.9 mmol) was added and stirred for 2 h. The reaction was quenched by adding saturated NH4Cl solution (30 ml) and then ethyl acetate (50 ml) was added. The organic phase was separated and washed with water and brine, dried over MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography to give Int E-4, 1.9 g, yield: 60.9%.

[0213] To a solution of Int E-4 (1.9 g, 7.16 mmol) in THF (20 ml) was added n-BuLi (4.3 ml, 2.5 M in hexane) at -78 °C and stirred for 30 min. Then 2,6-dimethyl-4-((triisopropylsily)oxy)benzaldehyde (2.31 g, 7.52 mmol) was added dropwise and stirred for 1 h. The reaction was quenched by adding saturated NH4Cl solution (20 ml) and then ethyl acetate (40 ml) was added. The organic phase was separated and washed with water and brine, dried over MgSO4, concentrated and purified by silica gel column chromatography to give Int E-5, 2.43 g, yield: 68.8%.

[0214] To a solution of Int E-5 (2.43 g, 4.93 mmol) in EtOAc (20 ml) was added TBAF (5 ml, 1 M in EA) and stirred for 30 min. Water (20 ml) was added and stirred for 15 min. The organic phase was separated and washed with water and brine, dried over MgSO4, concentrated under reduced pressure and crystallized from n-heptane to give Int E-6, 1.32 g, yield: 79.6%.

[0215] To a solution of Int E-6 (1.32 g, 3.92 mmol) and TFA (2 drops) in DCM (15 ml) was added Pd / C (0.1 g, 30% wt). The solution was stirred under hydrogen atmosphere at room temperature for 4 h. After filtration, the filtrate was concentrated under reduced pressure to give Int E, 1.15 g, yield: 91.5%.

[0216] Example 10 Preparation of phenyl hydrogen ((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)phosphonate (Int F)

[0217] 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]methyl phosphonate (5.12 g, 15.9 mmol) in acetonitrile (30 ml), potassium carbonate (3.30 g, 23.85 mmol) was added and stirred at 80-85 °C for 4 h. After cooling, water and ethyl acetate were added to the mixture and the organic layer was separated. The organic layer was concentrated under reduced pressure to get [(4-[(4-(methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl] diethyl phosphonate (7.2 g, yield 97.47%) as an oil.

[0218] To a solution of [(4-[(4-(methoxymethoxy)-3-(propan-2-yl)phenyl)methyl]-3,5- dimethylphenoxy)methyl] diethyl phosphonate (5 g, 10.76 mmol) in dichloromethane (25 ml), TMSBr (3.30 g, 21.6 mmol) was added dropwise at 10-15 °C and stirred for 4 h. To the mixture, water was added dropwise and the organic layer was separated. The organic layer was concentrated under reduced pressure to get Compound A, 3.6 g, yield: 92%.

[0219] To a solution of Compound A (55 g, 151 mmol) and phenol (28.4 g, 302 mmol) in DMF (1 L), pyridine (200 ml), DCC (92 g, 451 mmol), DMAP (18 g, 147 mmol) were added and stirred at 80-85 °C overnight. After cooling, ethyl acetate was added to the mixture and the pH was adjusted to 3.0 with 1 N hydrochloric acid solution. The separated organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to get the crude product. The crude product was then purified by silica gel chromatography (PE: EtOAc = 10: 1 eluent) to get Int F, 26 g, yield: 39%.

[0220] Example 11: 4'-Bromo-7'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-l,l'- indene] (Int G)

[0221] To a solution of 4-bromo-7-hydroxy-2,3-dihydro-lH-inden-l-one (15 g, 66.06 mmol) in tetrahydrofuran (200 mL) was added sodium hydride (5.28 g, 132.12 mmol) slowly at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. Chloro(methoxy)methane was added at 0 °C and stirred at 0 °C for 1 h. The reaction mixture was concentrated to dryness and extracted with ethyl acetate (200 mL) and water (50 mL x 3). The separated organic layer was washed with water, dried over Na2S04and concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with PE:EtOAc (0% to 60%) to afford Int G-l, 26 g.

[0222] To a solution of methyltriphenylphosphonium bromide (35.66 g, 99.81 mmol) in tetrahydrofuran (250 mL) was added potassium tert-butoxide in tetrahydrofuran (12.22 g, 108.89 mmol, 1 M) slowly at -15 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. 4-bromo-7-(methoxymethoxy)-2,3-dihydro-lH-inden-l-one (dissolved in tetrahydrofuran) was added at 0 °C and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated and extracted with ethyl acetate (200 mL) and water (100 mL). The separated organic layer was washed with water, dried over Na2S04and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE:EtOAc (0% to 10%) to afford Int G-2, 11 g.

[0223] To a solution of diethylzinc (15.15 g, 122.61 mmol) in toluene (110 mL) was added chloroiodomethane (43.25 g, 245.22 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 45 min and then a solution of Int G-2 in toluene (11 g, 40.87 mmol, 110 mL) was added at 0 °C. The mixture was stirred at 0 °C for 16 h under nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (300 mL) and aqueous ammonium chloride solution (100 mL). The separated organic layer was washed with water, dried over Na2S04and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE:EtOAc (0% to 10%) to afford Int G, 11 g.

[0224] Example 12: 4'-Bromo-7'-(methoxymethoxy)-2',3'-dihydrospiro[cyclobutane-l,l'- indan] (Int H) and 4'-Bromo-7'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopentane-l,l'- indan] (Int I)

[0225] Dissolve compound Int H-1 (1 eq) in methanol (12.5 V), slowly add sodium borohydride (0.6 eq), and react for 1 hour. Add water to the reaction mixture to quench the reaction, and then concentrate under reduced pressure to obtain an oil. Dissolve the oil in ethyl acetate (20 V), wash with brine (10 V), and separate the organic phase. Dry the organic phase over anhydrous sodium sulfate, and then concentrate under reduced pressure to dryness to obtain Int H-2, with a yield of 87%.

[0226] Dissolve Int H-2 (1 eq) in tetrahydrofuran (10 V), and add p-toluenesulfonic acid (0.5 eq) under ice bath, and react for 3 hours. Concentrate the reaction mixture to dryness, dissolve in ethyl acetate (50 V), wash with brine, and concentrate the obtained organic phase to dryness under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (mobile phase: n-hexane) to obtain Int H-3, with a yield of 69%.

[0227] Dissolve Int H-3 (1 eq), dibromide (1.05 eq), and benzyltriethylammonium chloride (0.2 eq) in DMSO (5 V) and stir to dissolve. At 0°C, dropwise add sodium hydroxide solution (50%, 2 eq) to the reaction mixture. After dropping, warm to 50°C and react for 2 hours. Cool to room temperature, add n-hexane to the reaction mixture, extract the organic phase, and concentrate the obtained organic phase to dryness under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (mobile phase: n-hexane) to obtain Int H-4.

[0228] Dissolve Int H-4 (1 eq) in isopropanol (7.5 V), and add 10% wet palladium on carbon (10% w / w). React for 3 hours under a hydrogen balloon. Filter the reaction mixture, and take the filtrate. Concentrate the filtrate to dryness, and purify the obtained crude product by silica gel column chromatography (mobile phase: n-hexane) to obtain Int H-5.

[0229] Dissolve Int H-5 (1 eq) in acetonitrile (10 V), and add NBS (1.01 eq). React for 2 hours at 0°C under nitrogen protection. Pour the reaction mixture into water, extract the organic phase with ethyl acetate. Dry the obtained organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Int H-6.

[0230] Dissolve Int H-6 (1 eq) in dichloromethane (20 V). Dropwise add boron tribromide (5 eq) under ice bath, and react for 2 hours. Quench the reaction by dropwise adding water to the reaction mixture, and then concentrate under reduced pressure to obtain an oil. Add dichloromethane and water to the oil, extract and wash, and then concentrate the obtained organic phase under reduced pressure. Purify the obtained organic phase by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) to obtain Int H-7.

[0231] Int H-7 (1 eq) was dissolved in THF (10 V). NaH (1.5 eq) was added slowly under ice bath, and stirred for 15 min. To the reaction, MOMCI (1.2 eq) was added dropwise, and the reaction was allowed to proceed for 3 h. To the reaction, saturated NaHC03 solution and ethyl acetate were added, and the organic phase was extracted. The obtained organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: n-hexane) to give the target compound.

[0232] Example 13: Preparation of pentan-3-yl ((R)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (29) and pentan-3-yl ((S)- ((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)- L-alaninate (30)

[0233] To a solution of Int F (10 g, 22.7 mmol) and DMF (166 mg, 2.27 mmol) in DCM (100 ml), oxalyl chloride (8.6 g, 67.7 mmol) was added dropwise 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 pentan-3-yl L-alaninate (18.05 g, 113.5 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel chromatography eluted with PE:EtOAc = 10:1 to give compound 25, 3.0 g. Compound 25 was purified by chiral column (Welch XT CI 150 mm*21.2 mm, 5 um) to give compound 28, 1.5 g and compound 29, 1.2 g.

[0234] The following compounds (in Table 1) were prepared according to the procedures described herein (general synthetic methods and corresponding example descriptions) using appropriate starting materials and appropriate protecting group chemistry, and characterized by 1 HNMR characterization is as follows:

[0235] Example 2 in vitro biological activity evaluation

[0236] 1. Evaluation of the agonistic activity of the compounds on TRa and TRP receptors

[0237] A. Compound configuration

[0238] a) Preparation of test compound stock solution: Compound was dissolved in DMSO and prepared as 5 mM stock solution.

[0239] b) Preparation of positive compound (T3) stock solution: T3 was dissolved in DMSO and prepared as 0.25 mM stock solution.

[0240] B. Test method:

[0241] a) All cells were cultured according to the ATCC recommended method. HEK293T (pBIND-TRalpha Vector or pBIND-TRbeta Vector) cells were used in exponential growth phase for testing.

[0242] b) The culture medium was removed from the flask.

[0243] c) The cells were rinsed with PBS.

[0244] d) TrypLE solution was added to the flask to detach the cells. The cells were washed once with complete growth medium.

[0245] e) The cells were trituated and rinsed twice with PBS to remove the phenol red, then resuspended in culture medium to the appropriate concentration.

[0246] f) Only cells with a viability greater than 90% could be used for testing.

[0247] g) 6.0*106HEK293T cells were cultured in a 100 mm dish.

[0248] h) The cells were incubated at 37°C in a 5% CO2 environment for 16 hours.

[0249] i) The plasmid was transfected into the cells, which were incubated at 37°C in a 5% CO2 environment

[0250] j) 50 nl of compound dilution was transferred to a 384-well test plate using an Echo 550;

[0251] k) 17,000 cells / well of HEK293T were cultured in a 384-well test plate

[0252] l) The cells were incubated at 37°C in a 5% CO2 environment for 18-20 hours

[0253] m) 25 μl of britelite plus Luciferase reagent was added to each well of the 384-well plate.

[0254] C. Reading data

[0255] Light emission values dd were recorded on Envision plate reader. Add 25 μΐ of Britelite plus luciferase detection reagent to each well of the 384-well assay plate.

[0256] a) Calculate RLU signal for each well

[0257] b) % Activity is calculated as follows: %Activity = (Signal cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC ) x 100.

[0258] Signalave_pc: Average signal of positive controls across the plate.

[0259] Signalave_vc: Average signal of negative controls across the plate.

[0260] c) Calculate EC 50 and plot the dose response curve for the test compound

[0261] Activity (%) and compound concentration log were fitted with non-linear regression (dose response - variable slope) using Graphpad 8.0 to calculate EC 50 . Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC50 - X) * HillSlope))

[0262] X: Compound log concentration; Y: % Activity.

[0263] D. The results of the experiment are as follows:

Claims

1. A compound of Formula I: ###0001### Formula I and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof. wherein, Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl; Ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl; R a selected from 1 to 4 hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, hydroxy, amino, cyano, aryl, -C 1-6 alkyl-aryl, heteroaryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-C 3-8 cycloalkyl, -SO2-R1, -COR1, -COOR1, -CONR2R3, -NHCOR1, -NHS(O)2R1, -O-CH2-COR4, -OCOR4or -O-CO-NR2R3; or, any two R a optionally taken together with the atom to which they are attached to form a 5-10 membered heterocyclyl or C 3-8 cycloalkyl, said 5-10 membered heterocyclyl or C 3-8 cycloalkyl is optionally substituted with 1 to 4 C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or halogen; or said any two C 1-6 alkyl, cycloalkyl and haloalkyl can be taken together with the atom to which they are attached to form a 5-10 membered heterocyclyl or 3-8 membered cycloalkyl; R b selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogen or C 1-6 haloalkyl; G is selected from O or -CH2-; T is selected from -(CR d ) m - or -O-(CR d ) m -; each R d is independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or, any two R d may combine with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl; X is selected from -P(O)(OH)2, -COOH, -P(O)(OR X3 )(OR X4 ) or -COOR x3 ; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; R1, R2, R3and R4are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl or C 1-30 alkyl-heteroaryl, or, R2and R3optionally combine with the atoms to which they are attached to form a 5-10 membered heterocyclyl or C 3-8 cycloalkyl, wherein the 5-10 membered heterocyclyl or C 3-8 cycloalkyl is optionally substituted with 1 to 4 C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or halogen; R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 optionally combine with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or haloalkyl; R X3 and R X4 are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl, C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl or CH2-O-C 2-30 alkynyl, or, R X3 and R X4 optionally combine with the atoms to which they are attached to form a 3-8 membered heterocycloalkyl group, said 3-8 membered heterocycloalkyl group being optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl; Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl; wherein R a , R b , R1, R2, R x1 , R X2 , R X3 and R X4 are independently optionally substituted with hydroxy, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl, C 1-30 haloalkyl, aryl, heteroaryl, heterocycloalkyl or C 3-8 cycloalkyl, wherein said aryl and heteroaryl are optionally substituted with hydroxy, cyano, halogen, C 1-6 alkoxy, C 1-30 alkyl or C 1-30 haloalkyl; Ar is optionally substituted with hydroxyl, cyano, halogen, C 1-6 alkoxy, C 1-6 alkyl, C 1-30 haloalkyl or C 3-8 cycloalkyl.

2. The compound of Formula I according to claim 1, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein ring A is selected from phenyl, pyridyl, or indolyl.

3. The compound of Formula I according to claim 1 or 2, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein ring B is selected from phenyl or pyridyl.

4. The compound of claim 1 of formula I and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein selected from: wherein R5and R6are independently selected from C 1-6 alkyl or C 3-8 cycloalkyl; or, R5and R6optionally combine with the atoms to which they are attached to form a C 3-8 cycloalkyl; wherein R a1 is selected from hydrogen, -COR1, -COOR1, -CONR2R3, -CH2-COR4or R7 is selected from H and C. 1-30 Alkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C(O)C 1-30 Alkyl, C(O)C 2-30 alkenyl, C(O)C 2-30 alkynyl group, C(O)OC 1-30 Alkyl, C(O)OC 2-30 alkenyl, C(O)OC 2-30 alkynyl group, C(O)NR c C 1-30 Alkyl, C(O)NR c C 2-30 alkenyl or C(O)NR c C 2-30 Alkyne group, wherein R7 is optionally substituted by one or more of the following groups: halogen, -OC 1-30 Alkyl, -SC 1-30 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the -OC 1-30 Alkyl, -SC 1-30 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, and 5-10 membered heteroaryl groups are each independently and optionally bound by one or more halogens and C. 1-3 Alkyl substitution; R8and R9are independently selected from H, OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 5-10 membered heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 5-10 membered heterocycloalkyl, aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, or 5-10 membered heterocycloalkyl; or, R8and R9are optionally combined with the atoms to which they are attached to form a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group is optionally substituted with hydroxyl, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; R c selected from H, C 1-6 alkyl, -C 3-8 cycloalkyl or C 1-6 haloalkyl.

5. The compound of Formula I according to any one of claims 1 to 4, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein G is selected from O.

6. The compound of Formula I according to any one of claims 1 to 4, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein G is selected from CH2.

7. The compound of Formula I according to any one of claims 1 to 6, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein T is selected from -0-(CH2) m - 8. The compound of Formula I according to any one of claims 1 to 6, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein T is selected from -(CH2) m - 9. The compound of claim 1 of Formula I and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein is R X3 is 10. The compound of Formula I according to any one of claims 1 to 8, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein X is selected from wherein R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl, or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 combine with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or haloalkyl; R X3 selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl or C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl, -CH2-O-C 2-30 alkynyl, or, R X3 and R X4 combine with the atom to which they are attached to form a 3-8 membered heterocycloalkyl, said 3-8 membered heterocycloalkyl being optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl; Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl.

11. The compound of claim 10 of formula I and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein R x3 is selected from H, C 1-30 alkyl, C 3-8 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, C 1-30 alkyl-aryl or -C 1-30 alkyl-heteroaryl.

12. The compound of claim 1 having the structure of formula II: ###0002### II and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof. ​ Where R a1 Selected from hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogen, hydroxyl, amino, cyano, aryl, C 1-6 Alkyl-aryl, heteroaryl, C 1-6 Alkyl-heteroaryl, C 1-6 Alkyl-C 3-8 Cycloalkyl, -SO2-R1, -COR1, -COOR1, -CONR2R3, -NHCOR1, -NHS(O)2R1, -O-CH2-COR4, -OCOR4 or -O-CO-NR2R3; R a2 and R a3 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 haloalkyl, or R a2 and R a3 each independently, together with the atom to which they are attached, form a C 3-8 cycloalkyl group, wherein said C 3-8 cycloalkyl group is optionally substituted with hydroxy, halo, C 1-6 alkyl or C 3-6 cycloalkyl; R b1 and R b2 are independently selected from H or C 1-6 alkyl; G is selected from O or CH2; T is selected from -(CR d ) m - or -O-(CR d ) m -; R d selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or, any two R d form, together with the atom to which they are attached, a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or haloalkyl; X is selected from -P(O)(OH)2, -COOH, -P(O)(OR X3 )(OR X4 ) or -COOR x3 ; R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 combine with the atom to which they are attached to form a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 alkyl or haloalkyl; R X3 and R X4 are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, C 1-30 alkoxy, C 1-30 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl, C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl or -CH2-O-C 2-30 alkynyl, or, R X3 and R X4 form, together with the atom to which they are attached, a 3-8 membered heterocycloalkyl group, said 3-8 membered heterocycloalkyl group being optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl; Ar is selected from C 6-10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.

13. The compound of claim 12 of formula I and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein R b1 and R b2 are independently selected from chloro, bromo, or methyl.

14. The compound of formula I according to claim 12 or 13, and the stereoisomers, the pharmaceutically acceptable salts, or the deuterated compounds thereof, wherein R a1 is selected from hydrogen.

15. The compound of Formula I according to any one of claims 12 to 14, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein G is selected from CH2.

16. The compound of Formula I according to any one of claims 12 to 15, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein T is selected from -CH2CH2- or -O-CH2-.

17. The compound of Formula I according to any one of claims 12 to 16, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein X is selected from -P(O)(OH)2, -P(O)(OH)(OR , -P(O)(OR X3 )(OR X4 ); wherein R x1 and R X2 are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkyl-aryl, or C 1-6 alkyl-heteroaryl, or, R x1 and R X2 combine with the atom to which they are attached to form C 3-8 cycloalkyl, said C 3-8 cycloalkyl optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl; R X3 and R X4 are independently selected from hydrogen, C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-8 cycloalkyl, C 1-6 alkyl-OH, 3-8 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-30 alkyl-aryl or C 1-30 alkyl-heteroaryl, -CH2-O-C 1-30 alkyl, -CH2-O-C 2-30 alkenyl, -CH2-O-C 2-30 alkynyl, or, R X3 and R X4 form, together with the atom to which they are attached, a 3-8 membered heterocycloalkyl group, said 3-8 membered heterocycloalkyl group being optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

18. The compound of Formula I according to any one of claims 1 to 17, and stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, wherein the compound is selected from:

19. A pharmaceutical composition comprising: a compound of any one of claims 1 to 18, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof; and a pharmaceutically acceptable carrier or excipient.

20. A method of treating and / or preventing a thyroid hormone related disease, comprising administering to an individual in need of said method a therapeutically and / or prophylactically effective amount of a compound of any one of claims 1 to 18, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, or a pharmaceutical composition of claim 19.

21. The method of claim 20, wherein the thyroid hormone related disease is selected from obesity, hair loss, overweight, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

22. A method of weight management, long-term weight management, comprising administering to an individual in need of said method a therapeutically and / or prophylactically effective amount of a compound of any one of claims 1 to 18, a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, or a pharmaceutical composition of claim 19.

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