Thyroxine hormone formulation and preparation method therefor

Abstract

The present disclosure provides a formulation and a preparation method therefor. The formulation comprises a compound represented by formula (I) and at least one pharmaceutically acceptable carrier.

Description

Preparations of thyroxine hormones and their preparation methods

[0001] Citation of relevant applications

[0002] This disclosure claims all the rights of Chinese invention patent application No. 202411178390.1, filed with the State Intellectual Property Office of the People's Republic of China on August 26, 2024, entitled "Preparations of Thyroxine Hormones and Methods for their Preparation Thereof", the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This disclosure relates to the pharmaceutical field, and more specifically, to formulations of thyroid hormone drugs and methods for their preparation.

[0005] background

[0006] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH), which is secreted by the pituitary gland in response to various stimulants, such as thyrotropin-releasing hormone (TRH) from the hypothalamus. Thyroid hormones are iodinated oxy-aryl tyrosine analogs, primarily excreted into circulation as 3,3',5,5'-tetraiodothyronine (T4). T4 is rapidly deiodinated in local tissues by thyroxine 5'-deiodinase to 3,3',5'-triiodothyronine (T3), the most potent thyroid hormone. T3 is metabolized into inactive metabolites via multiple pathways, including those involving deiodination, glucuronidation, sulfation, deamination, and decarboxylation. Most circulating T4 and T3 are excreted via the liver, which has profound physiological effects in both animals and humans.

[0007] Hyperthyroidism is associated with elevated body temperature, generalized stress, weight loss despite increased appetite, muscle weakness and fatigue syndrome, increased bone resorption and calcification, and various cardiovascular changes, including increased heart rate, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure. Hypothyroidism is usually associated with the opposite effects.

[0008] The biological activity of THs is primarily mediated through thyroid hormone receptors (TRs). TRs belong to the nuclear receptor superfamily and, together with their common chaperone retinoid X receptor, form heterodimers, acting as ligand-induced transcription factors. Like other nuclear receptors, TRs possess ligand-binding and DNA-binding domains and regulate gene expression through ligand-dependent interactions with DNA response elements (thyroid response elements, TREs). Currently, the literature shows that TRs are encoded by two distinct genes (TRa and TRβ), which generate several subtypes through alternative splicing (Williams, MoI. Cell Biol. 20(22):S329-42(2000); Nagaya et al, Biochem. Biophys. Res. Commun. 226(2):426-30(1996)). The major subtypes identified to date are Trα-1, Trα-2, Trβ-1, and Trβ-2. Trα-1 is universally expressed in rats, with the highest expression in skeletal muscle and brown adipose tissue. Trβ-1 is also universally expressed, with the highest expression in the liver, brain, and kidneys. TRβ-2 is expressed in specific regions of the anterior pituitary and hypothalamus, as well as in the developing brain and inner ear. In the livers of rats and mice, TRβ-1 is the predominant isotype (80%). The TR isotypes found in humans and rats are highly homologous in terms of amino acid sequence, suggesting that each isotype has a specific function.

[0009] WO2024167961A2 discloses a class of prodrugs of effective thyroid hormone receptor β subtype (TRβ) agonists, but no prior art has been disclosed for drug formulations targeting this class of compounds. Therefore, developing formulations of these compounds is of great significance in ensuring patient accessibility.

[0010] Overview

[0011] This application relates to formulations of prodrugs of TRβ agonists, which have high bioavailability, release stability and long release period.

[0012] On the one hand, this disclosure provides a formulation comprising a compound of formula I or a stereoisomer thereof, pharmaceutically acceptable.

[0013] An acceptable salt or deuterated compound and at least one pharmaceutically acceptable carrier:

[0014] in:

[0015] G is selected from -O- or -C(X9X8)-;

[0016] T is selected from: -(C(R) d )2) m -or-O-(C(R) d )2)m -;

[0017] m is an integer between 0 and 3;

[0018] X is selected from:

[0019] Each R a and R b It is independently selected from CH3, CD3, Cl, Br, I or CF3;

[0020] Where R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted -C 0-6 Alkyl-cycloalkyl, optionally substituted -C 0-6 Alkyl-heterocyclic alkyl, or optionally substituted -C 3-8 cycloalkyl;

[0021] Where R c It can be substituted by 1-10 halogens, H or D;

[0022] Each R d Independently selected from hydrogen, halogen, or C 1-6 alkyl;

[0023] Each of R1 and R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups;

[0024] R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0025] R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0026] R5 is selected from H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, and -CONR7R. 10 -CONR6R7, -CH2OCOR6, -CH2OCONHR6 or

[0027] R6 is independently selected from C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, wherein the C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups, wherein the -OC group is... 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0028] 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)OC2-30 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 alkynyl group; wherein -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0029] Alternatively, R6 and R7 may combine with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally composed of one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C. 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0030] Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-3 Alkyl, -SC1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0031] Alternatively, when n is 1, R8 and R9 combine with the atoms they are attached to to form 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally bonded by 1-4 R atoms. 11 Substituents of R, wherein R 11 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or alkoxy;

[0032] Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl and -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0033] The X8 or X9 is selected from H, D or halogen;

[0034] Where n is 0, 1, 2 or 3;

[0035] The 5-10 membered heteroaryl group has 1-4 heteroatoms, each independently selected from N, O, or S; and

[0036] The 3-10 membered heterocyclic group has 1-4 heteroatoms, and each is independently N, O or S.

[0037] On the other hand, this application relates to a method for treating and / or preventing thyroid hormone disorders, comprising administering to a subject requiring the method a therapeutic and / or preventative amount of the formulation provided in this disclosure.

[0038] In some embodiments, the diseases include obesity, weight management, long-term weight management, overweight, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), hepatic steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

[0039] Brief description of the attached figures

[0040] Figure 1: In vivo blood drug concentration curves of oil solutions of prescriptions 1 to 5 after administration to SD rats via SC.

[0041] Figure 2: In vivo blood drug concentration curves of oil solutions of prescriptions 6-9 after administration to SD rats via SC.

[0042] Figure 3: In vivo blood drug concentration curves of hydrophilic solutions of prescriptions 11 and 12 after administration to SC rats.

[0043] Figure 4: In vivo blood drug concentration curves of hydrophilic solutions of prescriptions 13-15 after administration to cynomolgus monkeys (SC).

[0044] Figure 5: In vivo blood drug concentration curves of the polymeric gel formulations 18-19 after administration to cynomolgus monkeys (SC).

[0045] Detailed Explanation

[0046] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that the embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0047] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0048] When used in this disclosure and the appended claims, a singular designation without a quantity indication includes a plural designation unless the context clearly specifies otherwise.

[0049] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0050] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated in the text. Thus, for example, a sustained-release tablet containing “pharmaceutically acceptable excipients” includes one, two, or more pharmaceutically acceptable excipients.

[0051] definition

[0052] 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.

[0053] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon group. For example, alkyl groups can have 1 to 10 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 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) 1-4Alkyl groups. Examples 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)CH2CH2C H3), 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). The alkyl group can be unsubstituted or substituted.

[0054] "Alkenyl" is 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 8 carbon atoms (i.e., C2C ... 2-8 alkenyl) or 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0055] "Alynyl" is 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 8 carbon atoms (i.e., C64-C ... 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyne group. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkyne groups can be unsubstituted or substituted.

[0056] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, thus making the alkyl group 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 may be unsubstituted or substituted.

[0057] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0058] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a halogen, which may 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 group determines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). The alkyl halogens can be unsubstituted or substituted.

[0059] "Aryl" refers to a monovalent or divalent mono- or divalent all-carbon aromatic ring or a multi-condensed all-carbon 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. An aryl group includes a phenyl group. An aryl group also includes multiple condensed ring systems having about 9 to 20 carbon atoms (e.g., ring systems consisting of 2, 3, or 4 rings), wherein the rings are aromatic. Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds. It is also understood that when referring to a member aryl group within a certain atomic range (e.g., a 6-10 member aryl group), the atomic range refers to the total number of ring atoms in the aryl group. For example, a 6-member aryl group includes a phenyl group, and a 10-member aryl group includes a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. An aryl group can be unsubstituted or substituted.

[0060] "5-10 membered aromatic heterocycle" or "heteroaromatic ring" refers to a single aromatic ring having at least one atom other than a carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple condensation ring systems having at least one such aromatic ring, which will be further described below. Thus, "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. Sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple condensation ring systems (e.g., ring systems consisting of 2, 3, or 4 rings), wherein the heteroaryl as defined above is condensed with one or more rings selected from heteroaryl (forming, for example, 1,8-naphthidyl) and aryl (forming, for example, benzimidazolyl or indazolyl) to form multiple condensation ring systems. Therefore, a heteroaryl group (a single aromatic ring or multiple condensed ring system) can have approximately 1-20 carbon atoms and approximately 1-6 heteroatoms within the heteroaryl ring. For example, a tetrazolium group has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds. It should be understood that the individual rings of multiple condensed ring systems can be interconnected in any order. It should be understood that the connection points of a heteroaryl group or a heteroaryl multiple condensed ring system can be any suitable atom of the heteroaryl group or a heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a member heteroaryl group of a certain atomic range (e.g., a heteroaryl group with 5 to 10 members), that atomic range refers to the total ring atoms of the heteroaryl group, including carbon atoms and heteroatoms. It should also be understood that the rings in a multi-condensation ring system may include an aryl ring fused to a heterocycle (e.g., a 3, 4, 5, 6, or 7-membered ring) having saturated or partially unsaturated bonds, the ring having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. For example, 5-membered heteroaryl groups include thiazolyl groups, and 10-membered heteroaryl groups include quinolinyl groups. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazole, quinoxazolyl, quinazolyl, benzofuranyl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group may be unsubstituted or substituted.

[0061] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a system of multiple condensed all-carbon rings, wherein the ring in each instance is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the 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 includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems having about 7 to 12 carbon atoms (e.g., ring systems comprising 2 rings). Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds, solenoids, or bridging bonds. Exemplary polycyclic cycloalkyl groups include octahydropentene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2ene, and spiro[2.5]octane. The cycloalkyl groups may be unsubstituted or substituted.

[0062] As used herein, "heterocycle" or "heterocyclic group" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system containing at least one heteroatom (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to approximately 20 cyclic atoms, for example, 3 to 12 cyclic atoms, 4 to 12 cyclic atoms, 4 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Therefore, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence requirements permit, the rings of a system of multiple condensed rings (such as bicyclic heterocycles) can be interconnected by fusion bonds, solenoids, and bridging bonds. Heterocycles include, but are not limited to, nitrogen heterocycles, aziridines, imidazolides, morpholine, ethylene oxide, oxygen heterocycles, thioheterocycles, piperazines, and piperidines. Pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxo-6-azaspiro[3.3]heptane-6-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2-thia-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hex-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. The heterocyclic group may be unsubstituted or substituted.

[0063] As used herein, "substituted" means that one or more hydrogen atoms of a group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more). This refers to hydrogen atoms being replaced by one or more (e.g., 1, 2, 3, or 4 or more) groups independently selected from the following substituents: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, Thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure) or protected amino.

[0064] "Optional" or "optional" means that the event or circumstances described below may but not necessarily occur, including both the occurrence of the event or circumstances and the non-occurrence of the event or circumstances.

[0065] "Optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary as long as it is chemically feasible. For example, "alkyl group optionally substituted with a halogen or cyano group" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0066] It should be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”. Unless otherwise stated, an optionally substituted group may have a substituent at each substituted position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituent may be the same or different at each position.

[0067] "Compounds of this disclosure" includes compounds disclosed herein, such as compounds of general formula of this disclosure and specific compounds or others, such as compounds of formula (I) and compounds of the examples. In some embodiments, "compounds of this disclosure" includes compounds 24, 25, 26, 28, 29, 30, 29-1, 30-1.

[0068] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0069] 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.

[0070] 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.

[0071] Pharmaceutically acceptable salts, hydrates, solutions, isomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0072] "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.

[0073] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of compounds in their free base form, possessing the pharmacological activity required for a free base. These salts can be extracted from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, disulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propoxides, oxalates, malonates, ferrousates, sebates, and fumarates. Maleate, butyn-1,4-diacidate, hexyn-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propanesulfonate. Benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in *Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006*.

[0074] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N (C1-C4 alkyl). 4+ It also includes base addition salts, such as sodium or potassium salts.

[0075] Also provided are compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein, wherein one to n hydrogen atoms attached to a carbon atom may be substituted with a deuterium atom or D, where 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 are therefore used to increase the half-life of the compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein when administered to mammals. 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 substituted with deuterium.

[0076] Examples of isotopes that can be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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. Using positron emission of isotopes, such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compound of formula (IA-1) can generally be prepared using conventional techniques known to those skilled in the art, or by a process similar to that described in the examples below, replacing the previously used unlabeled reagent with a suitable isotopically labeled reagent.

[0077] The compounds of embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus potentially yielding enantiomers, diastereomers, and other stereoisomers that are (R)- or (S)- in absolute stereochemistry, or, for amino acids, (D)- or (L)-. This statement is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)- isomers can be prepared using chiral synthesis or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these compounds are intended to include E and Z geometric isomers unless otherwise specified. Similarly, all isomer forms are included. When a compound is represented in its chiral form, it should be understood that the embodiment includes, but is not limited to, a specific diastereomer or enantiomer-enriched form. If chirality is not specified but present, it can be understood that the embodiment is for a specific diastereomer or enantiomer-enriched form; or a racemic or scalar mixture of such a compound. As used herein, a "scalar mixture" means a mixture of stereoisomers in a non-1:1 ratio.

[0078] As used herein, "stereoisomers" refers to compounds composed of identical atoms but with different three-dimensional structures, and they are not interchangeable. This disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0079] As used herein, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, this disclosure includes tautomers of the compounds.

[0080] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0081] As used herein, “hydrate” refers to the compound of this invention that is chemically bonded to one or more water molecules.

[0082] "Prevention" or "protection" means any treatment that results in the non-development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition.

[0083] As used in this article, "prodrug" refers to a derivative of a drug that, after being administered to the human body, is converted into the parent drug via a chemical or enzymatic pathway. In some implementations, the prodrug is a bioactive derivative of the drug that, after being administered to the human body, is converted into the bioactive parent drug via a chemical or enzymatic pathway.

[0084] As used herein, “treatment” refers to a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” or “curative therapy” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, for example, resulting in the resolution of clinical symptoms, improvement of disease status, 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 requiring treatment. An individual “at risk” may or may not have a detectable disease or condition and may or may not have a detectable disease prior to the treatments described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters related to the development of a disease or condition and are known in the art to have a higher probability of developing the disease or condition than an individual without such risk factors.

[0085] preparation

[0086] On the one hand, this disclosure provides a formulation comprising a compound of formula I or a stereoisomer thereof, pharmaceutically acceptable.

[0087] An acceptable salt or deuterated compound and at least one pharmaceutically acceptable carrier:

[0088] in:

[0089] G is selected from -O- or -C(X9X8)-;

[0090] T is selected from: -(C(R) d )2) m -or-O-(C(R) d )2) m -;

[0091] m is an integer between 0 and 3;

[0092] X is selected from:

[0093] Each R a and R b It is independently selected from CH3, CD3, Cl, Br, I or CF3;

[0094] Where R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted -C 0-6 Alkyl-cycloalkyl, optionally substituted -C 0-6 Alkyl-heterocyclic alkyl, or optionally substituted -C 3-8 cycloalkyl;

[0095] Where R c It can be substituted by 1-10 halogens, H or D;

[0096] Each R d Independently selected from hydrogen, halogen, or C 1-6 alkyl;

[0097] Each of R1 and R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups;

[0098] R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0099] R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0100] R5 is selected from H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, and -CONR7R. 10 -CONR6R7, -CH2OCOR6, -CH2OCONHR6 or

[0101] R6 is independently selected from C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, wherein the C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups, wherein the -OC group is... 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0102] 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 2-30alkenyl or -C(O)NR c C 2-30 alkynyl group; wherein -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0103] Alternatively, R6 and R7 may combine with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally composed of one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C. 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0104] Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0105] Alternatively, when n is 1, R8 and R9 combine with the atoms they are attached to to form 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally bonded by 1-4 R atoms. 11 Substituents of R, wherein R 11 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or alkoxy;

[0106] Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl and -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0107] The X8 or X9 is selected from H, D or halogen;

[0108] Where n is 0, 1, 2 or 3;

[0109] The 5-10 membered heteroaryl group has 1-4 heteroatoms, each independently selected from N, O, or S; and

[0110] The 3-10 membered heterocyclic group has 1-4 heteroatoms, and each is independently N, O or S.

[0111] In some embodiments, according to the compound of formula (I), G is -O-;

[0112] T is -O-(C(R) d )2) m -;

[0113] m is an integer between 0 and 3;

[0114] X is

[0115] R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl groups; and

[0116] Each R d Independently selected from hydrogen, halogen, or C 1-6 alkyl.

[0117] In some implementations, each Rd is hydrogen according to the compound of formula (I).

[0118] In some implementations, according to the compound of formula (I), m is 1.

[0119] In some embodiments, the compound of formula I has the structure of formula II.

[0120] R5 is selected from -COR6, -COOR6, and CONR7R. 10 -CH2OCOR6, CH2OC(O)OR7 or

[0121] Each R6 is independently selected from C 13-30 Alkyl, C 13-30 alkenyl or C 13-30 alkynyl group, wherein the C 13-30 Alkyl, C 13-30 alkenyl or C 13-30 The alkynyl group is selected by one or more elements, each independently chosen from halogens, -OC. 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substituents of alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups; wherein the -OC group is... 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10 membered heteroaryl groups are affected by one or more halogens or C. 1-3 Alkyl substituents;

[0122] 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)OC1-30 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 alkynyl group, wherein the -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups may be selected independently by one or more halogens or C. 1-3 Alkyl substituents;

[0123] Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0124] Alternatively, when n is 1, R8 and R9 combine with the atoms they are attached to to form 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally bonded by 1-4 R atoms. 11 Replace, where each R 11 Independently selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or alkoxy;

[0125] Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0126] Where n = 0, 1, 2 or 3;

[0127] The 5-10 membered heteroaryl group has 1-4 heteroatoms, each heteroatom being independently N, O, or S; and

[0128] The 3-10 membered heterocyclic group has 1-4 heteroatoms, each heteroatom being independently N, O, or S. In some embodiments, according to the compound of formula (II), R5 is selected from -COR6, -COOR6, CONR7R. 10 -CH2OCOR6 or

[0129] In some embodiments, according to the compound of formula (II), R6 is selected from C 13-30 Alkyl or C 13-30 Alkenyl group.

[0130] In some embodiments, the compound of formula I is selected from:

[0131] In some embodiments, the compound of formula I has the structure of formula III:

[0132] Each R a Or R b It is independently selected from CH3, CD3, Cl, Br, I or CF3;

[0133] Each R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, and optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted -C 0-6 Alkyl-cycloalkyl, optionally substituted -C 0-6 Alkyl-heterocyclic alkyl or optionally substituted -C 3-8 cycloalkyl;

[0134] Where R c It can be substituted by 1-10 halogens, H or D;

[0135] Each of X8, X9, Z1 or Z2 is independently selected from H, D or halogen;

[0136] Z3 is independently O or -CH2-;

[0137] Each R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups;

[0138] R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0139] R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0140] R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6;

[0141] Each R6 or R7 is independently selected from C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, where C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be selected independently by one or more halogens, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0142] In some embodiments, the compound is according to formula (III), where Z is O.

[0143] In some embodiments, according to the compound of formula (III), Z1 and Z2 are H.

[0144] In some embodiments, according to the compounds of formula (I), formula (II) and formula (III), R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0145] In some embodiments, the compound is according to formula (III), wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl.

[0146] In some embodiments, according to the compound of formula (III), wherein R c Independently selected from -C1-C6 alkyl, -C 0-6 Alkyl-aryl, -C 0-6 Alkyl-cycloalkyl, -C 0-6 alkyl-heterocyclic alkyl or -C 3-8 cycloalkyl; wherein R c It can be arbitrarily replaced by halogens.

[0147] In some embodiments, the compound of formula I has the structure of formula IV.

[0148] R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups;

[0149] R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally separated from one or more halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0150] R4 is selected from C. 6-10 Aryl, C 1-6Alkyl-C 6-10 Aryl or 5-10 heteroaryl groups, wherein R4 is optionally surrounded by one or more elements independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents

[0151] R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6;

[0152] X1, X2, X3, X4, X5, X6, X7, X8 or X9 are each independently H, D or halogen;

[0153] Z1 or Z2 is independently H, D or halogen;

[0154] Ra or Rb are each independently selected from CH3, CD3, Cl, Br, I or CF3;

[0155] R6 or R7 are each independently C 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, wherein the C 1-30 Alkyl, C 2-30 alkenyl or C 2-30 The alkynyl group is optionally selected by one or more elements, each independently chosen from halogen, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0156] In some embodiments, the compound is according to formula (IV), wherein Z1 and Z2 are H.

[0157] In some embodiments, the compound is according to formula (IV), wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0158] In some embodiments, the compound according to formula (IV) is wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl.

[0159] In some embodiments, the compound of formula I has the structure of formula V:

[0160] R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 alkyl-heteroaryl;

[0161] R3 is selected from H and C. 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 cycloalkyl;

[0162] R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0163] In some embodiments, according to the compound of formula (V), R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl or 5-10 heteroaryl, wherein R4 is optionally selected from halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0164] In some embodiments, the compound according to formula (V) is wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl.

[0165] In some embodiments, the compound of formula I has the structure of formula VI:

[0166] R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl; wherein the alkyl, aryl, or heteroaryl group is optionally coated with a halogen, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups;

[0167] R3 is selected from H and C. 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 cycloalkyl;

[0168] R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl or 5-10 heteroaryl, wherein R4 is optionally selected from halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0169] p is an integer between 0 and 3.

[0170] In some embodiments, according to the compound of formula (VI), R3 is selected from C 1-6 Alkyl or C 5-10 Cycloalkyl.

[0171] In some embodiments, according to the compound of formula (VI), R3 is selected from C 7-30 Alkyl or C 5-10 Cycloalkyl.

[0172] In some embodiments, according to the compound of formula (VI), R4 is C 6-10 Aryl; and the C 6-10 The aryl group is optionally selected from halogens or C 1-6 Alkyl substituents.

[0173] In some embodiments, the compound of formula (I) is selected from:

[0174] In some embodiments, the compound of formula I has the structure of formula VII.

[0175] Its stereoisomers, its pharmaceutically acceptable salts, or its deuterium substitutes,

[0176] R5 is selected from -C(O)R6, -C(O)OR6, -C(O)NR7R 10 CR 12 R 13 OC(O)R7, CR 12 R 13 OC(O)OR7 or

[0177] R6 is selected from C. 13-30 Alkyl, C 13-30 alkenyl or C 13-30 alkynyl group, where C 13-30 Alkyl, C 13-30 alkenyl and C 13-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0178] 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 alkynyl group, where -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)OC1-30 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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents;

[0179] Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl and -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0180] Each R 12 Or R 13 Independently selected from H, deuterium, and C 1-6 Alkyl, halogen or C 1-6 Haloalkyl, wherein C 1-6 Alkyl, halogen or C 1-6 The haloalkyl group may optionally be replaced by one or more elements, each independently selected from halogens, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0181] Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups;

[0182] Or, when n is 1, R8 and R9 combine with the atoms they are attached to to form arbitrarily 1-4 R... 11 Substituents of 3-10 membered heterocyclic groups, wherein each R 11 Independently selected from H, halogens, C 1-6 Alkyl C 1-6 Halogenated alkyl or alkoxy;

[0183] Where n = 0, 1, 2 or 3;

[0184] Each of the above-mentioned 5-10 membered heteroaryl groups has 1-4 heteroatoms, each heteroatom being independently N, O, or S; and

[0185] Each of the above 3-10 membered heterocyclic groups has 1-4 heteroatoms, each heteroatom being independently N, O, or S.

[0186] In some embodiments, the compound of formula I has the structure of formula VIII.

[0187] in

[0188] Each R1 or R2 is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6Alkyl-heteroaryl groups, or R1 and R2 combined with the atoms to which they are attached, form C 3-10 cycloalkyl or heterocyclic groups;

[0189] R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0190] R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents;

[0191] R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6;

[0192] Each R6 or R7 is an independent C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, where C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be selected independently by one or more halogens, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents.

[0193] In some embodiments, the formulation is an oil solution, which further comprises a lipophilic solvent;

[0194] The compound of formula I or its stereoisomers, pharmaceutically acceptable salts or deuterated compounds are dissolved in the lipophilic solvent to form an oil solution;

[0195] The lipophilic solvent is selected from one or a mixture of two or more of castor oil, rapeseed oil, sesame oil, fractionated coconut oil, or fatty acid glycerides;

[0196] More preferably, the lipophilic solvent comprises medium-chain fatty acid glycerides.

[0197] In some embodiments, the formulation comprises, or consists of, a lipophilic solvent and a compound selected from, a group consisting of, a lipophilic solvent and a group consisting of, a group consisting of, castor oil or medium-chain triglycerides or mixtures thereof.

[0198] In some embodiments, the formulation may optionally contain an organic solvent; the organic solvent is selected from one or a mixture of two or more of benzyl alcohol, ethanol, and benzyl benzoate.

[0199] In some embodiments, the formulation comprises, by weight percentage of the lipophilic solvent and the organic solvent, 70% to 100% of the lipophilic solvent and 0% to 30% of the organic solvent.

[0200] In some embodiments, the formulation is a hydrophilic solution and further comprises a hydrophilic solvent;

[0201] The compound of formula I or its stereoisomers, pharmaceutically acceptable salts or deuterated compounds are dissolved in the hydrophilic solvent to form a hydrophilic solution;

[0202] The hydrophilic solvent is selected from one or a mixture of two or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, water, or glycerin;

[0203] More preferably, the hydrophilic solvent comprises polyethylene glycol 300.

[0204] In some embodiments, the formulation is a hydrophilic solution comprising, or consisting of, a hydrophilic solvent and a compound selected from, a group consisting of, or a group consisting of, a hydrophilic solvent selected from, polyethylene glycol 300, or a mixture of polyethylene glycol 300 and water.

[0205] In some embodiments, the hydrophilic solvent is a mixture of polyethylene glycol 300 and water, wherein the weight ratio of polyethylene glycol 300 to water is from 99.9:0.1 to 70:30, preferably from 99.9:0.1 to 87:13.

[0206] In some embodiments, the formulation is a hydrophilic solution and optionally contains an organic solvent and / or a release inhibitor; preferably, the organic solvent is selected from one or a mixture of two or more of benzyl alcohol, ethanol, and N-methylpyrrolidone.

[0207] Preferably, the release inhibitor is selected from polylactic acid-glycolic acid copolymer or polylactic acid.

[0208] In some embodiments, the formulation is a hydrophilic solution comprising, by weight percentage of the hydrophilic solvent, organic solvent, and release inhibitor, wherein the hydrophilic solvent comprises 50% to 100% by weight; the organic solvent comprises 0% to 30% by weight; and the release inhibitor preferably comprises 0% to 20% by weight.

[0209] In some embodiments, the formulation is a hydrophilic solution comprising, by weight percentage of the hydrophilic solvent, organic solvent and release inhibitor, wherein the hydrophilic solvent comprises 70% to 100% by weight; the organic solvent comprises 0% to 15% by weight; and the release inhibitor preferably comprises 0% to 15% by weight.

[0210] In some embodiments, the formulation is a polymeric gelling agent, which further comprises a polymeric gelling material and an organic solvent;

[0211] The compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, and the polymeric gel material are dissolved in the organic solvent to form a polymeric gel agent;

[0212] Preferably, the polymeric gel material is selected from polylactic acid-glycolic acid copolymer or polylactic acid or a mixture thereof;

[0213] Preferably, the organic solvent is selected from one or a mixture of two or more of N-methylpyrrolidone, dimethyl sulfoxide, benzyl alcohol, and benzyl benzoate.

[0214] In some embodiments, the polymeric gel material is a polylactic acid-glycolic acid copolymer, preferably with an intrinsic viscosity range of 0.1 to 0.3 dL / g; preferably, the ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer molecule is 75:25 or 50:50.

[0215] In some embodiments, the polymeric gelling agent, as a percentage of the total weight of the polymeric gelling material and the organic solvent,

[0216] The weight ratio of the polymeric gel material is 10% to 60%;

[0217] The organic solvent accounts for 40% to 90% by weight.

[0218] In some embodiments, the formulation is a suspension of micron or nanoparticles, which also contains a stabilizer and water;

[0219] The active ingredients are dispersed in the aqueous solution of the stabilizer and then prepared into a micron or nanoparticle suspension by media grinding or high-pressure homogenization process.

[0220] The active ingredient is selected from compounds of formula I and their stereoisomers, pharmaceutically acceptable salts, or deuterated compounds;

[0221] Preferably, the stabilizer is selected from one or a mixture of two or more of mannitol, polyethylene glycol 3350, poloxamer, Tween, vitamin E polyethylene glycol succinate, and polyoxyethylene 35 castor oil.

[0222] Preferably, the stabilizer accounts for 1% to 10% by weight in the suspension;

[0223] Preferably, the active ingredient in the micron or nanoparticle suspension exists in the form of particles with a median particle size of about 0.1 to 10 μm;

[0224] Preferably, the median particle size of the active ingredient in the micron suspension ranges from 1 to 10 μm;

[0225] Preferably, the median particle size range of the active ingredients in the nanosuspension is 100–1000 nm.

[0226] In some embodiments, the formulation is a self-microemulsion solution, which further comprises a lipophilic solvent, a surfactant, and an organic solvent.

[0227] Preferably, the compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds are dissolved in the mixture of the lipophilic solvent, the surfactant and the organic solvent to form a self-microemulsion solution;

[0228] Preferably, the lipophilic solvent is selected from one or a mixture of two or more of the following: castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glycerides, benzyl benzoate, etc.

[0229] Preferably, the surfactant is selected from one or a mixture of two or more of the following: polyoxyethylene 35 castor oil, polyethylene glycol 15 hydroxystearate, vitamin E polyethylene glycol succinate, polyoxyethylene hydrogenated castor oil, poloxamer, or Tween 80.

[0230] Preferably, the organic solvent is selected from one or a mixture of two or more of ethanol, benzyl alcohol, and NMP.

[0231] In some embodiments, the self-microemulsion solution contains, by weight percentage of the lipophilic solvent, surfactant, and organic solvent, 30% to 95% of the lipophilic solvent, 5% to 50% of the surfactant, and 0% to 40% of the organic solvent.

[0232] In some embodiments, the self-microemulsion solution contains, by weight percentage of the oleophilic solvent (60%–90%), the surfactant (5%–20%), and the organic solvent (0%–30%).

[0233] In some embodiments, the concentration of the Formula I compound and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds in the formulation is from 0.1 to 400 mg / mL, preferably from 1 to 300 mg / mL, more preferably from 50 to 300 mg / mL, even more preferably from 50 mg / mL, 200 mg / mL or 300 mg / mL.

[0234] In some embodiments, the formulation is administered via intramuscular or subcutaneous administration.

[0235] On the other hand, this application relates to a method for treating and / or preventing thyroid hormone disorders, comprising administering to a subject requiring the method a therapeutic and / or preventative amount of the formulation provided in this disclosure.

[0236] In some embodiments, the diseases include obesity, long-term weight management, overweight, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), hepatic steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

[0237] Treatment

[0238] This application relates to a method for treating and / or preventing thyroid hormone disorders, comprising administering to an individual in need of the method a therapeutic and / or preventative amount of the formulation described in this disclosure. Example

[0239] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0240] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0241] The features mentioned above in this disclosure, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0242] Synthesis of active compounds:

[0243] Preparation of 29-1 and 30-1

[0244] Phenylhydro-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonate (intermediate F)

[0245] Potassium carbonate (3.30 g, 23.85 mmol) was added to a solution of 4-[(4-(methoxymethoxy)-3-(propane-2-yl)phenyl)methyl]-3,5-dimethylphenol (5 g, 15.90 mmol) and diethyl[(4-methylbenzenesulfonyl)oxy]methylphosphonate (5.12 g, 15.9 mmol) in acetonitrile (30 ml), and the mixture was stirred at 80-85 °C for 4 hours. After cooling, water and ethyl acetate were added to the mixture. The organic layer was separated and concentrated under reduced pressure to give diethyl[(4-[(4-(methoxymethoxy)-3-(propane-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl]phosphonate (7.2 g, 97.47% yield) as an oil. Trimethylbromosilane (TMSBr) (3.30 g, 21.6 mmol) was added dropwise to a solution of diethyl[(4-[(4-(methoxymethoxy)-3-(propane-2-yl)phenyl)methyl]-3,5-dimethylphenoxy)methyl]phosphonate (5 g, 10.76 mmol) in dichloromethane (25 mL), and stirred at 10–15 °C for 4 hours. Water was added dropwise to the mixture. The organic layer was separated and concentrated under reduced pressure to give compound A (3.6 g, 92% yield). Pyridine (200 mL), dicyclohexylcarbodiimide (DCC) (92 g, 451 mmol) and DMAP (18 g, 147 mmol) were added to a solution of compound A (55 g, 151 mmol) and phenol (28.4 g, 302 mmol) in DMF (1 L), and stirred overnight at 80–85 °C. After cooling, ethyl acetate was added to the mixture, and the pH was adjusted to 3.0 with 1N HCl solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate (Na₂SO₄), and evaporated to dryness to obtain the crude product. The crude product was then purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 10:1 to give intermediate F (26 g, yield: 39%) as a white solid.

[0246] 3-Pentyl((R)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine ester (29-1) and 3-Pentyl((S)-((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alanine ester (30-1)

[0247] Oxaloyl chloride (8.6 g, 67.7 mmol) was added dropwise to a solution of intermediate F (10 g, 22.7 mmol) and DMF (166 mg, 2.27 mmol) in 100 mL of dichloromethane (DCM), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give an oil. This oil was dissolved in 100 mL of dichloromethane, followed by the addition of 3-pentyl L-alanine ester (18.05 g, 113.5 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 10:1, to give compound 25-1 (3.0 g, yield not specified). Compound 25-1 was purified by a chiral column (Welch XT C18 150 mm*21.2 mm, 5 μm) to give compound 29-1 (1.6 g, yield: 12.3%) and compound 30-1 (1.5 g, yield: 12%).

[0248] The synthesis of other active compounds (i.e., APIs) in the pharmaceutical compositions disclosed herein is carried out in accordance with the method described in WO2024167961A, the entire contents of which are incorporated herein by reference.

[0249] All other auxiliary materials were obtained through market procurement.

[0250] Formulation Examples

[0251] abbreviation:

[0252] MCT: Medium-chain triglycerides;

[0253] PLGA: Poly(lactic-co-glycolic acid) copolymer;

[0254] PLA: Polylactic acid;

[0255] NMP: N-methylpyrrolidone;

[0256] DMSO: Dimethyl sulfoxide;

[0257] TPGS: Alcohol Succinate;

[0258] Cremophor ELP: Polyoxyethylene 35 castor oil;

[0259] Solutol HS15: Polyethylene glycol 15% hydroxystearate;

[0260] TPGS: Vitamin E polyethylene glycol succinate;

[0261] PEG: Polyethylene glycol;

[0262] KolliphorELP: Polyoxyethylene 35 castor oil;

[0263] Example 1: Preparation of oil solution

[0264] The compounds disclosed herein (active drug, i.e., API) are prepared into an oil solution injection. The types and amounts of each component in the formulation are shown in Table 1. In the examples, the compounds disclosed herein refer to the specific compounds provided in this disclosure (including but not limited to compounds 24, 25, 26, 28, 29, 30, 25-1, 29-1, and 30-1). The amounts of the compounds disclosed herein in the table are expressed in terms of concentration, which is the ratio of the weight (mg) of the active drug to the total volume (mL) of the formulation (W / V). The amounts of various excipients are expressed as a percentage of the total weight of the excipients (W / W).

[0265] Preparation method: Add the excipients to the mixing container and stir until they are evenly mixed. Then add the active pharmaceutical ingredient to the mixing container and prepare a clear oil solution by ultrasound and stirring.

[0266] Table 1: Oil Solution Formula

[0267] Example 2: Subcutaneous PK test of oil solution in SD rats

[0268] Drugs: Samples of formulations 1 to 5 in Example 1.

[0269] Animals: Male SD rats were randomly divided into 5 groups of 3 rats each.

[0270] Dosage information is shown in Table 2:

[0271] Table 2: Information on oil solution administration

[0272] Blood collection time points: 0h, 1h, 3h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 216h, 312h, 480h, and 696h. Approximately 0.2mL of blood was collected from the jugular sinus at each time point. 0.2mL of the collected whole blood was placed in an anticoagulant tube containing EDTA-K2 pre-added with 4µL of dichlorvos (DDV) aqueous solution (10mg / mL). The mixture was vortexed until homogeneous, stored on wet ice, and centrifuged (1500-1600g) for 10 minutes at 4°C within 30 minutes to separate the plasma. A liquid chromatography-mass spectrometry (LC / MS / MS) system was used to determine the concentration of compound A in the plasma of SD rats (the individual plasma concentration of compound A was used to calculate the average pharmacokinetic parameters summarized in Figures 1 and 2. In vivo, compounds 25 and 29 are both metabolized to compound A; therefore, the individual plasma concentration of compound A was used to calculate the pharmacokinetic parameters). Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software.

[0273] The AUC of the oil solutions of prescriptions 1-9 after administration to the SC in SD rats is shown in Table 3 below, and the corresponding PK curves are shown in Figures 1 and 2.

[0274] Table 3: AUC of lipophilic solution after administration to SC in SD rats

[0275] The PK curves show that all formulations of the oil solution maintained a long-acting release for at least one month after SC administration, thus sustaining their pharmacological effects. Furthermore, based on the AUC results of formulations 1–9, the formulations containing MCT in the oil solvent exhibited higher bioavailability; the bioavailability of the oil solution was further significantly improved upon the addition of organic solvents such as benzyl benzoate and / or benzyl alcohol.

[0276] Example 3: Preparation of hydrophilic solution

[0277] The compounds disclosed herein (active drug, i.e., API) are prepared into hydrophilic solution injections. The types and amounts of each component in the formulation are shown in Table 4. In the examples, the compounds disclosed herein refer to the specific compounds provided in this disclosure (including but not limited to compounds 24, 25, 26, 28, 29, 30, 25-1, 29-1, and 30-1). The amounts of the compounds disclosed herein in the table are expressed in terms of concentration, which is the ratio of the weight (mg) of the active drug to the total volume (mL) of the excipients (W / V). The amounts of each excipient are expressed as a percentage of the total weight of the excipients (W / W).

[0278] Preparation method: Add the excipients to the mixing container, stir and mix evenly, then add the active pharmaceutical ingredient to the mixing container, and prepare a clear hydrophilic solution by ultrasound and stirring.

[0279] Table 4: Hydrophilic Solution Formulations

[0280] Comparative Examples: Solubility of the Compounds of this Disclosure in Different Hydrophilic Solvents

[0281] Table 5: Solubility of the compounds disclosed herein in different hydrophilic solvents

[0282] As shown in Table 5, the compounds disclosed herein, such as compound 25, have poor solubility in other hydrophilic solvents such as glycerol, water, and propylene glycol. When the material is fed at a low concentration (50 mg / mL), compound 25 cannot be dissolved.

[0283] Example 4: Subcutaneous PK test of hydrophilic solution in SD rats

[0284] Drug: Formulation samples of prescriptions 11 and 12 in Example 3 (where prescriptions 11-1, 11-2, 11-3, and 11-4 are hydrophilic solutions prepared by adding compounds 25, 28, 24, and 26 to the excipients according to the excipient amounts and compound concentrations of prescription 11 in Example 3).

[0285] Animals: Male SD rats were randomly divided into 5 groups of 3 rats each.

[0286] Dosage information is shown in Table 6:

[0287] Table 6: Dosing information of hydrophilic solutions in SD rats

[0288] Blood collection time points: 0h, 1h, 3h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 216h, 312h, 480h, and 696h. Approximately 0.2mL of blood was collected from the jugular sinus at each time point. 0.2mL of the collected whole blood was placed in an anticoagulant tube containing EDTA-K2 pre-added with 4µL of dichlorvos (DDV) aqueous solution (10mg / mL). The mixture was vortexed until homogeneous, stored on wet ice, and centrifuged (1500-1600g) for 10 minutes at 4°C within 30 minutes to separate the plasma. A liquid chromatography-mass spectrometry (LC / MS / MS) system was used to determine the concentration of compound A in the plasma of SD rats (the individual plasma concentration of compound A was used to calculate the average pharmacokinetic parameters summarized in Figure 3. In vivo, compounds 24, 25, 26, and 28 are all metabolized to compound A; therefore, the individual plasma concentration of compound A was used to calculate the pharmacokinetic parameters). Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software.

[0289] The AUC of the hydrophilic solution after administration to the SC in SD rats is shown in Table 7 below, and the corresponding PK curve is shown in Figure 3.

[0290] Table 7: AUC of hydrophilic solution after administration to SC rats

[0291] The PK curves show that all formulations of the hydrophilic solution (SC) maintained a long-acting release for at least one month after administration, thus sustaining their pharmacological effects. The formulation with an appropriate amount of water showed reduced viscosity, which is beneficial for improving drug compliance.

[0292] Example 5: Subcutaneous PK test of hydrophilic solution in cynomolgus monkeys

[0293] Drugs: Formulation samples of prescriptions 13, 14 and 15 in Example 3.

[0294] Animals: Crab-eating macaques, male, randomly divided into 3 groups of 3 each.

[0295] Dosage information is shown in Table 8:

[0296] Table 8: Administration information of hydrophilic solutions in cynomolgus monkeys

[0297] Blood collection time points: 0h, 1h, 3h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 216h, 312h, 480h, 672h. At each collection time point, approximately 0.5mL of blood was collected from a peripheral vein. The collected whole blood was placed in an EDTA-K2 anticoagulant tube, inverted several times to mix thoroughly, and stored on moist ice. Immediately, 0.2mL of whole blood was accurately pipetted into a centrifuge tube pre-filled with 4μL of dichlorvos (DDVP) aqueous solution (10mg / mL), vortexed to mix thoroughly, stored on moist ice, and centrifuged at 4℃ (1500-1600g) for 10 minutes within 30 minutes to separate the plasma. A system for determining compound A in monkey plasma was established using liquid chromatography-mass spectrometry (LC / MS / MS). Individual plasma concentrations of compound A were used to calculate the average pharmacokinetic parameters summarized in Figure 4. In vivo, compound 29 is metabolized to compound A; therefore, individual plasma concentrations of compound A were used to calculate the pharmacokinetic parameters. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software.

[0298] The AUC of the hydrophilic solution after administration to SC in cynomolgus monkeys is shown in Table 9 below, and the corresponding PK curve is shown in Figure 4.

[0299] Table 9: AUC of hydrophilic solution after administration to cynomolgus monkey SC

[0300] As shown by the PK curves, all formulations of the hydrophilic solution maintained a long-acting release for at least one month after administration, thus sustaining their pharmacological effects. Adding appropriate amounts of organic solvents and release inhibitors can significantly improve the bioavailability of the drug.

[0301] Example 6: Preparation of Polymer Gel

[0302] The compounds disclosed herein (active drug, i.e., API) are prepared into a polymeric gel. The types and amounts of each component in the formulation are shown in Table 10. In the examples, the compounds disclosed herein refer to the specific compounds provided in this disclosure (including but not limited to compounds 24, 25, 26, 28, 29, 30, 25-1, 29-1, and 30-1). The amounts of the compounds disclosed herein in the table are expressed in terms of concentration, which is the ratio of the weight (mg) of the active drug to the total volume (mL) of the excipients (W / V). The amounts of each excipient are expressed as a percentage of the total weight of the excipients (W / W).

[0303] Preparation method: Add the excipients to the mixing container and stir until homogeneous. Then add the active pharmaceutical ingredient to the mixing container and prepare a clear polymeric gel by ultrasound and stirring.

[0304] Table 10: Polymer Gel Formulation

[0305] Example 7: Subcutaneous PK test of polymeric gel in cynomolgus monkeys

[0306] Drugs: Formulation samples of prescriptions 18 and 19 in Example 6.

[0307] Animals: Crab-eating macaques were randomly divided into 2 groups of 3 each.

[0308] Dosage information is shown in Table 11:

[0309] Table 11: Administration information of polymeric gel in cynomolgus monkeys

[0310] Blood collection time points: 0h, 1h, 3h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 216h, 312h, 480h, and 672h. Approximately 0.2mL of blood was collected from the jugular sinus at each time point. 0.2mL of the collected whole blood was placed in an anticoagulant tube containing EDTA-K2 pre-added with 4µL of dichlorvos (DDV) aqueous solution (10mg / mL). The mixture was vortexed until homogeneous, stored on wet ice, and centrifuged at 4°C (1500-1600g) for 10 minutes within 30 minutes to separate the plasma. A liquid chromatography-mass spectrometry (LC / MS / MS) system was used to determine the concentration of compound A in the plasma of SD rats (the individual plasma concentration of compound A was used to calculate the average pharmacokinetic parameters summarized in Figure 5. In vivo, compound 29 is metabolized to compound A; therefore, the individual plasma concentration of compound A was used to calculate the pharmacokinetic parameters). Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software.

[0311] The AUC of the polymeric gel after administration to cynomolgus monkey SC is shown in Table 12 below, and the corresponding drug-time curve is shown in Figure 5 (the compound detected is the active metabolite GLC02-306).

[0312] Table 12: AUC of polymeric gel after administration to cynomolgus monkey SC

[0313] As shown by the PK curves, all formulations of the polymer gel can maintain a long-term release for at least one month after administration, thus continuously exerting their pharmacological effects.

[0314] Example 8: Preparation of micron or nanoparticle suspensions

[0315] The compounds disclosed herein (active drug, i.e., API) are prepared into micron or nanoparticle suspension injections. The types and amounts of each component in the formulation are shown in Table 13. In the examples, the compounds disclosed herein refer to the specific compounds provided in this disclosure (including but not limited to compounds 24, 25, 26, 28, 29, 30, 25-1, 29-1, and 30-1). The amounts of the compounds disclosed herein in the table are expressed in terms of concentration, which is the ratio of the weight (mg) of the active drug to the total volume (mL) of the formulation (W / V). The amounts of various excipients are expressed as a percentage of the total weight of the excipients (W / W).

[0316] Preparation method: Take the prescribed amount of stabilizer, place it in a container, add water for injection and stir or sonicate to dissolve it, then add the active pharmaceutical ingredient and make up the volume with water for injection to form a preliminary suspension. The above preliminary suspension is broken up by wet ball milling or high pressure homogenization to form a micron or nano suspension.

[0317] Table 13: Formulations for Micron or Nanoparticle Suspensions

[0318] Example 8: Preparation of self-microemulsion solution

[0319] The compounds disclosed herein are selected to prepare a self-microemulsion solution, the excipients of which include polycast castor oil, MCT, polyoxyethylene 35 castor oil (Kolliphor ELP), and benzyl benzoate, and the self-microemulsion solution is prepared by ultrasonic dissolution.

[0320] The compounds disclosed herein (active drug, i.e., API) are prepared into an oil solution injection. The types and amounts of each component in the formulation are shown in Table 14. In the examples, the compounds disclosed herein refer to the specific compounds provided in this disclosure (including but not limited to compounds 24, 25, 26, 28, 29, 30, 25-1, 29-1, and 30-1). The amounts of the compounds disclosed herein in the table are expressed in terms of concentration, which is the ratio of the weight (mg) of the active drug to the total volume (mL) of the formulation (W / V). The amounts of various excipients are expressed as a percentage of the total weight of the excipients (W / W).

[0321] Preparation method: Add the excipients to the mixing container and stir until homogeneous. Then add the active pharmaceutical ingredient to the mixing container and prepare a clear self-microemulsion solution by ultrasound and stirring.

[0322] Table 14: Self-microemulsion solution formulations

[0323] As will be understood from the foregoing, although specific embodiments of this disclosure have been described for illustrative purposes, various modifications or alterations can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or alterations should fall within the scope of the appended claims.

Claims

Formulations comprising a compound of formula I or a stereoisomer thereof, a pharmaceutically acceptable salt or deuterated compound, and at least one pharmaceutically acceptable carrier: in: G is selected from -O- or -C(X9X8)-; T is selected from: -(C(R) d )2) m -or-O-(C(R) d )2) m -; m is an integer between 0 and 3; X is selected from: Each R a and R b It is independently selected from CH3, CD3, Cl, Br, I or CF3; Where R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted -C 0-6 Alkyl-cycloalkyl, optionally substituted -C 0-6 Alkyl-heterocyclic alkyl, or optionally substituted -C 3-8 cycloalkyl; Where R c It can be substituted by 1-10 halogens, H or D; Each R d Independently selected from hydrogen, halogen, or C 1-6 alkyl; Each of R1 and R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups; R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R5 is selected from H, -COR6, -COOR6, CH2OC(O)OR7, -CONHR6, and -CONR7R. 10 -CONR6R7, -CH2OCOR6, -CH2OCONHR6 or R6 is independently selected from C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, wherein the C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups, wherein the -OC group is... 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents; 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 alkynyl group; wherein -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents; Alternatively, R6 and R7 may combine with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally composed of one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C. 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Alternatively, when n is 1, R8 and R9 combine with the atoms they are attached to to form 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally bonded by 1-4 R atoms. 11 Substituents of R, wherein R 11 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or alkoxy; Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl and -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; The X8 or X9 is selected from H, D or halogen; Where n is 0, 1, 2 or 3; The 5-10 membered heteroaryl group has 1-4 heteroatoms, each independently selected from N, O, or S; and The 3-10 membered heterocyclic group has 1-4 heteroatoms, and each is independently N, O or S. The formulation of claim 1, wherein G is -O-; T is -O-(C(R) d )2) m -; m is an integer between 0 and 3; X is R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl; and Each R d Independently selected from hydrogen, halogen, or C 1-6 alkyl. The formulation as described in claim 1 or 2, wherein Each Rd is hydrogen. The formulation according to any one of claims 1-3, wherein m is 1. The formulation of claim 1, wherein the compound of formula I has the structure of formula II, R5 is selected from -COR6, -COOR6, and CONR7R. 10 -CH2OCOR6, CH2OC(O)OR7 or Each R6 is independently selected from C 13-30 Alkyl, C 13-30 alkenyl or C 13-30 alkynyl group, wherein the C 13-30 Alkyl, C 13-30 alkenyl or C 13-30 The alkynyl group is selected by one or more independently from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substituents of alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups; wherein the -OC group is... 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10 membered heteroaryl groups are affected by one or more halogens or C. 1-3 Alkyl substituents; 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 alkynyl group, wherein the -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, or 5-10-membered heteroaryl groups may be selected independently by one or more halogens or C. 1-3 Alkyl substituents; Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Alternatively, when n is 1, R8 and R9 combine with the atoms they are attached to to form 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally bonded by 1-4 R atoms. 11 Replace, where each R 11 Independently selected from H, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl or alkoxy; Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Where n = 0, 1, 2 or 3; The 5-10 membered heteroaryl group has 1-4 heteroatoms, each heteroatom being independently N, O, or S; and The 3-10 membered heterocyclic group has 1-4 heteroatoms, each heteroatom being independently N, O or S. The formulation of claim 5, wherein R5 is selected from -COR6, -COOR6, and CONR7R. 10 -CH2OCOR6 or The formulation of claim 5 or 6, wherein R6 is selected from C 13-30 Alkyl or C 13-30 Alkenyl group. The formulation according to any one of claims 1 to 7, wherein the compound of formula I is selected from: The formulation of claim 1, wherein the compound of formula I has the structure of formula III: Each R a Or R b It is independently selected from CH3, CD3, Cl, Br, I or CF3; Each R c Selected from hydrogen, halogen, -CF3, -OCF3, cyano, and optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -C 0-6 Alkyl-aryl, optionally substituted -C 0-6 Alkyl-cycloalkyl, optionally substituted -C 0-6 Alkyl-heterocyclic alkyl or optionally substituted -C 3-8 cycloalkyl; Where R c It can be substituted by 1-10 halogens, H or D; Each of X8, X9, Z1 or Z2 is independently selected from H, D or halogen; Z3 is independently O or -CH2-; Each R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups; R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6; Each R6 or R7 is independently selected from C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, where C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be selected independently by one or more halogens, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation of claim 9, wherein Z is O. The formulation of claim 9 or 10, wherein Z1 and Z2 are H. The formulation according to any one of claims 9 to 11, wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation according to any one of claims 9 to 12, wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl. The formulation according to any one of claims 9 to 13, wherein R c Independently selected from -C1-C6 alkyl, -C 0-6 Alkyl-aryl, -C 0-6 Alkyl-cycloalkyl, -C 0-6 alkyl-heterocyclic alkyl or -C 3-8 cycloalkyl; wherein R c It can be arbitrarily replaced by halogens. The formulation of claim 1, wherein the compound of formula I has the structure of formula IV, R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl, or R1 and R2 combined with the atoms they are attached to form C 3-10 cycloalkyl or heterocyclic groups; R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally separated from one or more halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl groups, wherein R4 is optionally surrounded by one or more elements independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6; X1, X2, X3, X4, X5, X6, X7, X8 or X9 are each independently H, D or halogen; Z1 or Z2 is independently H, D or halogen; Ra or Rb are each independently selected from CH3, CD3, Cl, Br, I or CF3; R6 or R7 are each independently C 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, wherein the C 1-30 Alkyl, C 2-30 alkenyl or C 2-30 The alkynyl group is optionally selected by one or more elements, each independently chosen from halogen, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation of claim 15, wherein Z1 and Z2 are H. The formulation of claim 15 or 16, wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation according to any one of claims 15 to 17, wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl. The formulation of claim 1, wherein the compound of formula I has the structure of formula V: R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 alkyl-heteroaryl; R3 is selected from H and C. 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 cycloalkyl; R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally halogenated or -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation of claim 19, wherein R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl or 5-10 heteroaryl, wherein R4 is optionally selected from halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation of claim 19 or 20, wherein R3 is selected from C 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 Cycloalkyl. The formulation of claim 1, wherein the compound of formula I has the structure of formula VI: R1 or R2 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl; wherein the alkyl, aryl, or heteroaryl group is optionally coated with a halogen, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups; R3 is selected from H and C. 1-30 Alkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl or C 5-10 cycloalkyl; R4 is selected from C. 6-10 Aryl, C 1-6 Alkyl-C 6-10 aryl or 5-10 heteroaryl, wherein R4 is optionally selected from halogen, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; p is an integer between 0 and 3. The formulation of claim 22, wherein R3 is selected from C 1-6 Alkyl or C 5-10 Cycloalkyl. The formulation of claim 22, wherein R3 is selected from C 7-30 Alkyl or C 5-10 Cycloalkyl. The formulation as described in claim 23 or 24, wherein R4 is C 6-10 Aryl; and the C 6-10 The aryl group is optionally selected from halogens or C 1-6 Alkyl substituents. The formulation according to any one of claims 9-25, wherein the compound of formula (I) is selected from: The formulation of claim 1, wherein the compound of formula I has the structure of formula VII, Its stereoisomers, its pharmaceutically acceptable salts, or its deuterium substitutes, R5 is selected from -C(O)R6, -C(O)OR6, -C(O)NR7R 10 CR 12 R 13 OC(O)R7, CR 12 R 13 OC(O)OR7 or R6 is selected from C. 13-30 Alkyl, C 13-30 alkenyl or C 13-30 alkynyl group, where C 13-30 Alkyl, C 13-30 alkenyl and C 13-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, -SSC(O)OC 2-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents; 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 alkynyl group, where -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 and -C(O)NR c C 2-30 The alkynyl group may be optionally selected by one or more independently chosen from halogens, -OC 1-30 Alkyl, -SC 1-30 Substitution with alkyl, cycloalkyl, heterocyclic, aryl, or 5-10 membered heteroaryl groups, wherein each -OC 1-30 Alkyl, -SC 1-30 Alkyl, cycloalkyl, heterocyclic, aryl, and 5-10-membered heteroaryl groups may be optionally selected by one or more independently chosen from halogens or C. 1-3 Alkyl substituents; Where R 10 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl or -(CH2) n heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n C 3-10 Cycloalkyl, -(CH2) n Aryl and -(CH2) n The heteroaryl group is optionally selected by one or more independently chosen from halogens, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Each R 12 Or R 13 Independently selected from H, deuterium, and C 1-6 Alkyl, halogen or C 1-6 Haloalkyl, wherein C 1-6 Alkyl, halogen or C 1-6 The haloalkyl group may optionally be replaced by one or more elements, each independently selected from halogens, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Each R8 or R9 is independently selected from H, OH, C. 1-6 Alkyl, halogen, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Cycloalkyl, 3-10-membered heterocyclic, aryl, and 5-10-membered heteroaryl groups may optionally be replaced by one or more groups, each independently selected from OH, halogen, -OC. 1-3 Alkyl, -SC 1-3 Alkyl, -C 3-10 Substitution with cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-10 membered heteroaryl groups; Or, when n is 1, R8 and R9 combine with the atoms they are attached to to form arbitrarily 1-4 R... 11 Substituents of 3-10 membered heterocyclic groups, wherein each R 11 Independently selected from H, halogens, C 1-6 Alkyl C 1-6 Halogenated alkyl or alkoxy; Where n = 0, 1, 2 or 3; Each of the above-mentioned 5-10 membered heteroaryl groups has 1-4 heteroatoms, each heteroatom being independently N, O, or S; and Each of the above 3-10 membered heterocyclic groups has 1-4 heteroatoms, each heteroatom being independently N, O, or S. The formulation of claim 1, wherein the compound of formula I has the structure of formula VIII, in Each R1 or R2 is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 6-10 Aryl or C 1-6 Alkyl-heteroaryl groups, or R1 and R2 combined with the atoms to which they are attached, form C 3-10 cycloalkyl or heterocyclic groups; R3 is selected from H and C. 1-30 Alkyl, C 5-10 cycloalkyl, C 5-10 Heterocyclic group, C 5-10 heteroaryl, C 1-30 Haloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Alkyl group, wherein R3 is optionally selected by one or more elements, each independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R4 is selected from C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl or 5-10 heteroaryl, wherein R4 is optionally selected by one or more independently selected from halogen, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents; R5 is selected from H, -COR6, -CONHR6, -COOR6, -CONR6R7, -CH2OCOR6, or -CH2OCONHR6; Each R6 or R7 is an independent C. 1-30 Alkyl, C 2-30 alkenyl or C 2-30 alkynyl group, where C 1-30 Alkyl, C 2-30 alkenyl and C 2-30 The alkynyl group may be selected independently by one or more halogens, NH2, NO2, OH, CN, OC. 1-6 Alkyl, C 6-10 Substitution with aryl or heteroaryl substituents; or combination of R6 and R7 with the atoms to which they are attached to form a 5-10 membered heterocyclic group, wherein said 5-10 membered heterocyclic group is optionally substituted by one or more elements, each independently selected from halogens, NH2, NO2, OH, CN, -C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl substituents. The formulation according to any one of claims 1-28 further comprises a lipophilic solvent; The compound of formula I or its stereoisomers, pharmaceutically acceptable salts or deuterated compounds are dissolved in the lipophilic solvent to form an oil solution; The lipophilic solvent is selected from one or more of castor oil, rapeseed oil, sesame oil, fractionated coconut oil, or fatty acid glycerides; more preferably, the lipophilic solvent comprises medium-chain fatty acid glycerides. The formulation of claim 29 comprises, or is composed of, a lipophilic solvent and a compound selected from, a group consisting of, or a group consisting of, a lipophilic solvent selected from, castor oil or medium-chain fatty acid glycerides or mixtures thereof. The formulation according to any one of claims 29-30 may optionally further comprise an organic solvent; said organic solvent is selected from one or a mixture of two or more of benzyl alcohol, ethanol, and benzyl benzoate. The formulation of claim 31, wherein the weight percentage of the lipophilic solvent is 70% to 100% and the weight percentage of the organic solvent is 0% to 30%. The formulation according to any one of claims 1-28 further comprises a hydrophilic solvent; The compound of formula I or its stereoisomers, pharmaceutically acceptable salts or deuterated compounds are dissolved in the hydrophilic solvent to form a hydrophilic solution; The hydrophilic solvent is selected from one or a mixture of two or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, water, or glycerin; More preferably, the hydrophilic solvent comprises polyethylene glycol 300. The formulation of claim 33 comprises, or is composed of, a hydrophilic solvent and a compound selected from, a group consisting of a hydrophilic solvent and a compound selected from, wherein the hydrophilic solvent is selected from polyethylene glycol 300, or a mixture of polyethylene glycol 300 and water. The formulation of claim 34, wherein the hydrophilic solvent is a mixture of polyethylene glycol 300 and water, wherein the weight ratio of polyethylene glycol 300 to water is 99.9:0.1 to 70:30, preferably 99.9:0.1 to 87:

13. The formulation according to any one of claims 33-35 may optionally further comprise an organic solvent and / or a release inhibitor; preferably, the organic solvent is selected from one or a mixture of two or more of benzyl alcohol, ethanol, and N-methylpyrrolidone; Preferably, the release inhibitor is selected from polylactic acid-glycolic acid copolymer or polylactic acid. The formulation of claim 36, wherein the hydrophilic solvent comprises 50% to 100% by weight of the total weight of the hydrophilic solvent, organic solvent, and release inhibitor; the organic solvent comprises 0% to 30% by weight; and the release inhibitor preferably comprises 0% to 20% by weight. The formulation of claim 37, wherein the hydrophilic solvent comprises 70% to 100% by weight of the total weight of the hydrophilic solvent, organic solvent, and release inhibitor; the organic solvent comprises 0% to 15% by weight; and the release inhibitor preferably comprises 0% to 15% by weight. The formulation according to any one of claims 1-28 further comprises a polymeric gel material and an organic solvent; The compound of formula I or its stereoisomer, a pharmaceutically acceptable salt or deuterated compound, and the polymeric gel material are dissolved in the organic solvent to form a polymeric gel agent; Preferably, the polymeric gel material is selected from polylactic acid-glycolic acid copolymer or one or a mixture of polylactic acid; Preferably, the organic solvent is selected from one or a mixture of two or more of N-methylpyrrolidone, dimethyl sulfoxide, benzyl alcohol, and benzyl benzoate. The formulation of claim 39, wherein, The polymeric gel material is a polylactic acid-glycolic acid copolymer, preferably with an intrinsic viscosity range of 0.1 to 0.3 dL / g; preferably, the ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer molecule is 75:25 or 50:

50. The formulation according to any one of claims 39-40, wherein, As a percentage of the total weight of the polymer gel material and organic solvent, The weight ratio of the polymeric gel material is 10% to 60%; The organic solvent accounts for 40% to 90% by weight. The formulation according to any one of claims 1-28 further comprises a stabilizer and water; The active ingredients are dispersed in the aqueous solution of the stabilizer and then prepared into a micron or nanoparticle suspension by media grinding or high-pressure homogenization process. The active ingredient is selected from compounds of formula I or their stereoisomers, pharmaceutically acceptable salts, or deuterated compounds; Preferably, the stabilizer is selected from one or a mixture of two or more of mannitol, polyethylene glycol 3350, poloxamer, Tween, vitamin E polyethylene glycol succinate, and polyoxyethylene 35 castor oil. Preferably, the stabilizer accounts for 1% to 10% by weight in the suspension; Preferably, the active ingredient in the micron or nanoparticle suspension exists in the form of particles with a median particle size of about 0.1 to 10 μm; Preferably, the median particle size of the active ingredient in the micron suspension ranges from 1 to 10 μm; Preferably, the median particle size range of the active ingredients in the nanosuspension is 100–1000 nm. The formulation according to any one of claims 1-28 further comprises a lipophilic solvent, a surfactant, and an organic solvent. Preferably, the compound of formula I or its stereoisomer, pharmaceutically acceptable salt or deuterated compound is dissolved in the mixture of the lipophilic solvent, the surfactant and the organic solvent to form a self-microemulsion solution; Preferably, the lipophilic solvent is selected from one or a mixture of two or more of the following: castor oil, rapeseed oil, sesame oil, fractionated coconut oil, fatty acid glycerides, benzyl benzoate, etc. Preferably, the surfactant is selected from one or a mixture of two or more of the following: polyoxyethylene 35 castor oil, polyethylene glycol 15 hydroxystearate, vitamin E polyethylene glycol succinate, polyoxyethylene hydrogenated castor oil, poloxamer, or Tween 80. Preferably, the organic solvent is selected from one or a mixture of two or more of ethanol, benzyl alcohol, and NMP. The formulation of claim 43, wherein the oily solvent comprises 30% to 95% by weight, the surfactant comprises 5% to 50% by weight, and the organic solvent comprises 0% to 40% by weight, based on the total weight percentage of the lipophilic solvent, the surfactant, and the organic solvent. The formulation of claim 44, wherein the oily solvent comprises 60% to 90% by weight, the surfactant comprises 5% to 20% by weight, and the organic solvent comprises 0% to 30% by weight, based on the total weight percentage of the lipophilic solvent, the surfactant, and the organic solvent. The formulation according to any one of claims 1-45, wherein the concentration of the compound of formula I or its stereoisomer, pharmaceutically acceptable salt or deuterated compound in the formulation is from 0.1 to 400 mg / mL, preferably from 1 to 300 mg / mL, more preferably from 50 to 300 mg / mL, even more preferably from 50 mg / mL, 200 mg / mL or 300 mg / mL. The formulation of claim 46, wherein the formulation is administered via intramuscular or subcutaneous administration. A method for treating and / or preventing thyroid hormone disorders, comprising administering to an individual in need of the method a therapeutic and / or preventative amount of the preparation of any one of claims 1-47. The method of claim 48, wherein the disease is selected from obesity, weight management, long-term weight management, overweight, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), hepatic steatosis, arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

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