Novel compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a novel compound as well as a pharmaceutical composition and application thereof, the novel compound is represented by formula I or pharmaceutically acceptable salt, tautomer, isotope substitute or solvate, the definition of substituent groups is detailed in the specification, and the novel compound can prevent and / or treat thyroid hormone receptor related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, but is not limited thereto, and in particular to a novel compound and a pharmaceutical composition and use thereof. Background Art

[0002] Thyroid hormone (TH) is a thyroid stimulating hormone secreted in response to the pituitary gland. Thyroid hormone plays a key role in growth, development, metabolism and homeostasis. There are two main types of thyroid hormones, 3,5,3`-triiodo-L-thyroxine (T3) and thyroxine (T4). (T3, triiodothyronine) is an important component of thyroid hormone. The human body mainly secretes T4. In peripheral organs, T4 is converted into more active T3 by deiodinase. 20% of T3 is produced by the thyroid gland itself, and the other 80% is converted from serum total thyroxine in peripheral tissues.

[0003] Studies have shown that the effects of thyroid hormone T3 on the heart, especially on heart rate, are mediated by THRɑ. The effects of thyroid hormone T3 on the liver, muscles and other tissues are mainly mediated by THRβ. Therefore, selective THRβ agonists should be able to treat obesity, hyperlipidemia, thyroid disease, and non-alcoholic fatty liver disease without affecting heart rate and rhythm. Therefore, finding an efficient selective THRβ agonist drug has important social significance and economic value. Summary of the invention

[0004] The present invention provides a novel compound and a pharmaceutical composition thereof, which have a longer half-life in the body, a higher maximum blood drug concentration and a higher plasma exposure, and can be used to prevent or treat thyroid hormone receptor-related diseases, including obesity, diabetes, hypothyroidism, thyroid cancer, thrombosis, hyperlipidemia, cardiac hypertrophy, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia, fatty liver lesions, liver fibrosis, moderate to severe liver scarring, cirrhosis, hepatocellular adenoma and hepatocellular carcinoma, etc.

[0005] On the one hand, the present invention provides

[0006] 9.1. A compound of formula I, its tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof:

[0007]

[0008] In formula I, M is selected from alkylene, O, S and NH; wherein the alkylene is optionally substituted by one or more hydrogen, deuterium, halogen, C1-C8 alkyl;

[0009] R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl substituted or unsubstituted by a substituent A, or C3-C6 cycloalkyl substituted or unsubstituted by a substituent A, wherein the substituent A is selected from hydrogen, deuterium, halogen, hydroxyl and C1-C8 alkoxy;

[0010] R3 and R4 are each independently selected from hydrogen, halogen, amino, and cyano;

[0011] R5 is selected from

[0012] in,

[0013] L is selected from alkylene, O, S and NH; wherein the alkylene is optionally substituted with one or more hydrogen, deuterium, halogen, C1-C8 alkyl;

[0014] R a Selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl, deuterated C3-C6 cycloalkyl;

[0015] R b Selected from hydrogen;

[0016] R c , R d Each is independently selected from hydrogen, halogen, amino, cyano;

[0017] R e Selected from -OH, -SH, -SO2H, -SO2NH2, -NH2, carboxyl, halogen, cyano, trifluoromethyl;

[0018] X and Y are each independently selected from -O-, -S- and -NH-;

[0019] When R a When selected from deuterated C1-C8 alkyl or deuterated C3-C6 cycloalkyl, R6 and R7 are each independently selected from hydrogen, metal ion, C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl, -(CH2) m OR8, or R6, R7 and the phosphate group form a cyclic group The C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl may be optionally substituted with one or more hydrogen, deuterium, halogen, methyl, amino, carboxyl, -O(CO)R9, -(CO)OR 10 、-O(CO)OR 11 、-(CO)NH(CHR x )(CO)NH(CHR y )COOR z replace;

[0020] m is an integer selected from 1 to 5;

[0021] R8 is selected from C1-C18 alkyl, C6-C12 aryl and C3-C10 heteroaryl;

[0022] R9, R 10 , R 11 Each is independently selected from C1-C8 alkyl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, amino, mercapto, mercaptomethyl, mercaptoethyl, C6-C12 aryl, C3-C10 heteroaryl, and deuterated C6-C12 aryl;

[0023] R x , R y , R z Each is independently selected from hydrogen, C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl;

[0024] R f , R g , R h , R i , R j , R k Each is independently hydrogen, deuterium, C1-C8 alkyl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxy, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl, C6-C12 aryl, or C3-C10 heteroaryl;

[0025] When R a When selected from hydrogen, C1-C8 alkyl, or C3-C6 cycloalkyl, R6 and R7 are each independently selected from hydrogen, C6-C12 aryl, deuterated C6-C12 aryl, -R 12 , -CR n R p (CO)NHR 13 , or R6, R7 and the phosphate group form a cyclic group R6 and R7 are not hydrogen or C6-C12 aryl groups at the same time;

[0026] R n , R p Each is independently selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy;

[0027] R 12 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR 14 replace;

[0028] R 13 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR15 replace;

[0029] R 14 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 16 replace;

[0030] R 15 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 17 replace;

[0031] R 16 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl;

[0032] R 17 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl.

[0033] 10. In some embodiments, the present invention provides a compound as shown in Formula I, its tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof, whose structure is as shown in Formula II:

[0034]

[0035] The substituents in formula II are as defined in formula I.

[0036] In some embodiments, the present invention provides a compound as shown in Formula I, tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof, whose structure is as shown in Formula III:

[0037]

[0038]

[0039] The substituents in formula III are as defined in formula I.

[0040] In some embodiments, the present invention provides a compound as shown in Formula I, tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof, whose structure is as shown in Formula IV:

[0041]

[0042] The substituents in formula IV are as defined in formula I.

[0043] In some embodiments, in the above formula I-IV, M is selected from alkylene, O, S, or NH; wherein the alkylene is optionally substituted by one or more hydrogen, deuterium, halogen, C1-C8 alkyl; preferably, M is O.

[0044] In some embodiments, in the above formulas I-IV, R1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from hydrogen, deuterium, halogen, hydroxyl, or C1-C8 alkoxy; preferably, R1 is selected from halogen, cyano, or C1-C8 alkyl; more preferably, R1 is selected from Cl, Br, I, or -CH3.

[0045] In some embodiments, in the above formulas I-IV, R2 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from hydrogen, deuterium, halogen, hydroxyl, or C1-C8 alkoxy; preferably, R2 is selected from hydrogen, halogen, cyano, or C1-C8 alkyl; more preferably, R2 is selected from Cl, Br, I, or -CH3.

[0046] In some embodiments, in the above formula I-IV, R3 is selected from hydrogen, halogen, amino, cyano; preferably, R3 is selected from hydrogen.

[0047] In some embodiments, in the above formula I-IV, R4 is selected from hydrogen, halogen, amino, cyano; preferably, R4 is selected from hydrogen.

[0048] In some embodiments, in the above formula I-IV, R5 is selected from

[0049] In some embodiments, in the above formula I-IV, L is selected from alkylene, O, S, or NH; wherein the alkylene is optionally substituted with one or more hydrogen, deuterium, halogen, C1-C8 alkyl; preferably, L is selected from alkylene, wherein the alkylene is optionally substituted with one or more hydrogen, deuterium, halogen, C1-C8 alkyl; more preferably, L is selected from -CH2-.

[0050] In some embodiments, in the above formula I-IV, R a is selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl, or deuterated C3-C6 cycloalkyl; preferably, R a Selected from C1-C8 alkyl, or deuterated C1-C8 alkyl.

[0051] In some embodiments, in the above formula I-IV, Rb Selected from hydrogen;

[0052] In some embodiments, in the above formula I-IV, R c is selected from hydrogen, halogen, amino, cyano; preferably, R c Selected from hydrogen.

[0053] In some embodiments, in the above formula I-IV, R d is selected from hydrogen, halogen, amino, cyano; preferably, R d Selected from hydrogen.

[0054] In some embodiments, in the above formula I-IV, R e is selected from -OH, -SH, -SO2H, -SO2NH2, -NH2, carboxyl, halogen, cyano, trifluoromethyl; preferably, R e is selected from -OH, -SH, -SO2H, -SO2NH2, -NH2; more preferably, R e Selected from -OH.

[0055] In some embodiments, in the above formula I-IV, when R a When selected from deuterated C1-C8 alkyl or deuterated C3-C6 cycloalkyl, R6 is selected from hydrogen, metal ion, C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl, -(CH2) m OR8, or R6, R7 and the phosphate group form a cyclic group The C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl may be optionally substituted with one or more hydrogen, deuterium, halogen, methyl, amino, carboxyl, -O(CO)R9, -(CO)OR 10 、-O(CO)OR 11 、-(CO)NH(CHR x )(CO)NH(CHR y )COOR z replace.

[0056] In some embodiments, in the above formula I-IV, when R a When R is selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, R6 is selected from hydrogen, C6-C12 aryl, deuterated C6-C12 aryl, -R 12 , -CR n R p (CO)NHR 13 , or R6, R7 and the phosphate group form a cyclic group Furthermore, R6 and R7 are not hydrogen or C6-C12 aryl groups at the same time.

[0057] In some embodiments, in the above formula I-IV, when R a When selected from C1-C8 alkyl substituted with one or more deuteriums, R7 is selected from hydrogen, metal ions, C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl, -(CH2) m OR8, or R6, R7 and the phosphate group form a cyclic group The C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl may be optionally substituted with one or more hydrogen, deuterium, halogen, methyl, amino, carboxyl, -O(CO)R9, -(CO)OR 10 、-O(CO)OR 11 、-(CO)NH(CHR x )(CO)NH(CHR y )COOR z replace.

[0058] In some embodiments, in the above formula I-IV, when R a When R7 is selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, R7 is selected from hydrogen, C6-C12 aryl, deuterated C6-C12 aryl, -R 12 , -CR n R p (CO)NHR 13 , or R6, R7 and the phosphate group form a cyclic group Furthermore, R6 and R7 are not hydrogen or C6-C12 aryl groups at the same time.

[0059] In some embodiments, in the above formulas I-IV, m is selected from an integer of 1 to 5; preferably, m is selected from 2, 3, or 5.

[0060] In some embodiments, in the above formula I-IV, R8 is selected from C1-C18 alkyl, C6-C12 aryl, or C3-C10 heteroaryl; preferably, R8 is selected from C1-C18 alkyl.

[0061] In some embodiments, in the above formula I-IV, R9 is selected from C1-C8 alkyl substituted with one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, amino, thiol, mercaptomethyl, mercaptoethyl, C6-C12 aryl, C3-C10 heteroaryl, or deuterated C1-C8 alkyl, deuterated C6-C12 aryl; preferably, R9 is selected from C1-C8 alkyl substituted with one or more hydrogen, deuterium; more preferably, R9 is selected from methyl, deuterated methyl, isopropyl, deuterated isopropyl, tert-butyl, or deuterated tert-butyl.

[0062] In some embodiments, in the above formula I-IV, R 10is selected from C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl, or deuterated C1-C8 alkyl, deuterated C6-C12 aryl substituted with one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, amino, mercapto, mercaptomethyl, mercaptoethyl; preferably, R 10 is selected from C1-C8 alkyl substituted by one or more hydrogen or deuterium; more preferably, R 10 is selected from methyl, deuterated methyl, isopropyl, deuterated isopropyl, tert-butyl, or deuterated tert-butyl.

[0063] In some embodiments, in the above formula I-IV, R 11 is selected from C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl, or deuterated C1-C8 alkyl, deuterated C6-C12 aryl substituted with one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, amino, mercapto, mercaptomethyl, mercaptoethyl; preferably, R 11 is selected from C1-C8 alkyl substituted by one or more hydrogen or deuterium; more preferably, R 11 is selected from methyl, deuterated methyl, isopropyl, deuterated isopropyl, tert-butyl, or deuterated tert-butyl.

[0064] In some embodiments, in the above formula I-IV, R f is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R f is selected from C6-C1 aryl substituted by one or more halogens; more preferably, R f Selected from deuterium, or 2-chlorophenyl.

[0065] In some embodiments, in the above formula I-IV, R g is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R g Selected from hydrogen, or deuterium.

[0066] In some embodiments, in the above formula I-IV, R h is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R h Selected from hydrogen, or deuterium.

[0067] In some embodiments, in the above formula I-IV, Ri is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R i Selected from hydrogen, or deuterium.

[0068] In some embodiments, in the above formula I-IV, R j is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R j Selected from hydrogen, or deuterium.

[0069] In some embodiments, in the above formula I-IV, R k is selected from hydrogen, deuterium, or C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl; preferably, R k Selected from hydrogen, or deuterium.

[0070] In some embodiments, in the above formula I-IV, Rn is selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy; preferably, R n Selected from hydrogen.

[0071] In some embodiments, in the above formula I-IV, R p is selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy; preferably, R p Selected from hydrogen.

[0072] In some embodiments, in the above formula I-IV, R x is selected from hydrogen, C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl; preferably, R x Selected from hydrogen.

[0073] In some embodiments, in the above formula I-IV, R y is selected from hydrogen, C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl; preferably, R y Selected from C1-C8 alkyl.

[0074] In some embodiments, in the above formula I-IV, R z is selected from hydrogen, C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl; preferably, R z Selected from hydrogen.

[0075] In some embodiments, in the above formula I-IV, R 12 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR 14 replace.

[0076] In some embodiments, in the above formula I-IV, R 13 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR 15 replace.

[0077] In some embodiments, in the above formula I-IV, R 14 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 16 replace.

[0078] In some embodiments, in the above formula I-IV, R 15 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 17 replace.

[0079] In some embodiments, in the above formula I-IV, R 16 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl.

[0080] In some embodiments, in the above formula I-IV, R 17 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl.

[0081] In some embodiments, in the above formula I-III, X is selected from -O-, -S-, or -NH-; preferably, X is selected from -O-.

[0082] In some embodiments, in the above formula I and / or IV, X is selected from -O-, -S-, or -NH-; preferably, X is selected from -NH-.

[0083] In some embodiments, in the above formula I-II, Y is selected from -O-, -S-, or -NH-; preferably, Y is selected from -O-.

[0084] In some embodiments, in the above formula I, III and / or IV, Y is selected from -O-, -S-, or -NH-; preferably, Y is selected from -NH-.

[0085] In some embodiments, in the above formula I, X is selected from -O-, -S-, or -NH-; preferably, X is selected from -O-.

[0086] In some embodiments, in the above formula I, Y is selected from -O-, -S-, or -NH-; preferably, Y is selected from -S-.

[0087] In some embodiments, the compounds, tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof provided by the present invention include but are not limited to the following compounds:

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound, tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compounds of the present invention can be formulated into pharmaceutical compositions and administered to patients according to a variety of suitable administration routes, including systemic administration such as oral or parenteral, intravenous, intramuscular, transdermal or subcutaneous.

[0096] In another aspect, the present invention provides use of the above-mentioned compounds, tautomers, stereoisomers, isotope derivatives, solvates, and pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions for preparing drugs for preventing or treating thyroid hormone receptor-related diseases.

[0097] The present invention provides the above-mentioned pharmaceutical composition which can be used to prepare a method for preventing or treating thyroid hormone receptor-related diseases such as obesity, diabetes, hypothyroidism, thyroid cancer, thrombosis, hyperlipidemia, cardiac hypertrophy, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia, fatty liver lesions, liver fibrosis, moderate to severe liver scarring, cirrhosis, hepatocellular adenoma and hepatocellular carcinoma.

[0098] The compounds disclosed in the present invention have highly selective THRβ agonistic effect.

[0099] The compounds disclosed in the present invention have better metabolic properties, longer half-life, higher maximum blood drug concentration and plasma exposure.

[0100] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0101] Certain compounds of the present invention may exist in unsolvated or solvated forms, such as hydrates and ethanolates. Generally speaking, the solvated forms are equivalent to the unsolvated forms and are all included in the scope of the present invention.

[0102] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0104] The term "alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched groups. Alkyl groups may be substituted or unsubstituted. When substituted alkyl groups, the substituents are preferably one or more, more preferably 1 to 3, and most preferably 1 or 2 substituents.

[0105] The term "alkylene" refers to -CH2-.

[0106] The term "cycloalkyl" refers to a monocyclic or fused ring ("fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with other rings in the system) group that is all carbon, wherein one or more rings do not have a completely connected π electron system, examples of cycloalkyl (not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted.

[0107] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two.

[0108] The term "heteroaryl" refers to a monocyclic or fused ring group of multiple atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and having a completely conjugated π electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole.

[0109] The term "alkoxy" refers to a group in which an alkyl group is linked to an oxygen group, where the alkyl group may be a straight chain, branched chain or cyclic alkyl group.

[0110] The term "hydrogen" refers to -H.

[0111] The term "deuterium" means -D.

[0112] The term "methyl" refers to a -CH3 group.

[0113] The term "hydroxy" refers to an -OH group.

[0114] The term "amino" refers to a -NH2 group.

[0115] The term "cyano" refers to a -CN group.

[0116] The term "mercapto" refers to a -SH group.

[0117] The term "mercaptomethyl" refers to a -SCH3 group.

[0118] The term "mercaptoethyl" refers to a -SC2H5 group.

[0119] The term "methoxy" refers to the -OCH3 group.

[0120] The term "carboxy" refers to a -COOH group.

[0121] The term "halogen" denotes fluorine, chlorine, bromine or iodine.

[0122] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc.

[0123] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0124] The numerical ranges mentioned in this application, such as "C1-C18", mean that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 18 carbon atoms. DETAILED DESCRIPTION

[0125] Many exemplary preparation methods of the compounds of the present invention are provided in the following examples. The present invention is described in detail below by specific examples, but it is not intended to limit the present invention in any adverse way. The present invention has been described in detail herein, and its specific embodiments are also disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Certain compounds of the present invention can be used as intermediates for preparing other compounds of the present invention, and the structures of all compounds are determined by liquid chromatography.

[0126] Unless otherwise specified, the materials in the examples of this application were purchased through commercial channels.

[0127] Example 1: Synthesis of Compound V-01

[0128] Reaction:

[0129]

[0130] Preparation method:

[0131] Step 1: Preparation of compound IM01:

[0132] Under nitrogen protection, 4-bromo-2-iodophenol (10.0 g, 33.46 mmol) was dissolved in THF (100 mL) dried by 4A molecular formula, cooled to 0°C, and isopropylmagnesium chloride (2.0 M, 41.8 mL, 83.64 mmol) was added dropwise. After the addition was completed, the system naturally warmed to room temperature and stirred for 3 hours. The system temperature was then lowered to -78°C, and deuterated acetone (10.73 g, 167.3 mmol) was slowly added dropwise to the system. After the addition was completed, the system naturally warmed to room temperature and reacted for 8 hours. The reaction system was poured into 1M hydrochloric acid (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). After the organic phase was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue.

[0133] The concentrated residue was dissolved in dichloromethane (100 mL), triethylsilane (19.45 g, 167.3 mmol) was added, and then trifluoroacetic acid (25 mL) was slowly added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 24 hours, and the system was directly concentrated. The residue was subjected to column chromatography to obtain IM01: 6.14 g, with a yield of 83%.

[0134] ESI-MS (-): m / z = 220.37,

[0135] 1 HNMR (400MHz) δ: 7.32 (s, 1H), 7.16 (d, J = 6.8HZ, 1H), 6.78 (d, J = 6.8Hz, 1H), 2.56 (s, 1H).

[0136] Step 2: Preparation of compound IM02:

[0137] IM01 (6.0 g, 27.1 mmol) was dissolved in dichloromethane (60 mL), and imidazole (5.54 g, 81.4 mmol) was added. The mixture was cooled to 5 °C and MOMOCl (4.37 g, 54.27 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was maintained and stirred for 2 hours, and then the temperature was naturally raised to room temperature for reaction for 16 hours. The system was poured into 1N hydrochloric acid (100 mL), extracted with dichloromethane, and the organic phases were combined after separation. After washing with saturated brine, the mixture was dried, the system was filtered, and the filtrate was concentrated. IM02 was obtained by column chromatography: 5.11 g, yield: 71%.

[0138] Step 3: Preparation of compound IM03:

[0139] 2,6-Dimethyl-4-hydroxybenzaldehyde (10.0 g, 66.59 mmol) was dissolved in dichloromethane (100 mL), and imidazole (13.60 g, 199.76 mmol) was added. The mixture was cooled to 5 °C and TIPSCl (19.26 g, 99.88 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was maintained and stirred for 2 hours, and then the temperature was naturally raised to room temperature for reaction for 16 hours. The system was poured into 1N hydrochloric acid (100 mL), extracted with dichloromethane, and the organic phases were combined after separation. After washing with saturated brine, the mixture was dried, the system was filtered, and the filtrate was concentrated. IM03 was obtained by column chromatography: 16.94 g, yield: 83%.

[0140] Step 4: Preparation of compound IM04:

[0141] IM02 (5.0 g, 18.86 mmol) was dissolved in anhydrous THF (50 mL), cooled to -78 ° C, and n-BuLi (2.5 M, 7.5 mL, 18.86 mmol) was slowly added dropwise under stirring. After the addition was completed, the reaction temperature was maintained and stirred for 1 hour. Subsequently, IM03 (5.20 g, 16.97 mmol) was dissolved in anhydrous THF (50 mL) and slowly added dropwise to the reaction system. After the addition was completed, the reaction temperature was maintained and stirred for 1 hour. Then, the reaction system was poured into an ice-cold saturated aqueous ammonium chloride solution (200 mL), and the aqueous phase was extracted with ethyl acetate. After separation, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography to obtain IM04: 6.94 g, yield: 83%.

[0142] ESI-MS (-): m / z = 491.43,

[0143] 1 HNMR(400MHz)δ:7.47(s,1H),7.26(d,J=6.8Hz,1H),6.82(d,J=6.8Hz,1H),6.35(s,2H),6.16(s ,1H),5.98(s,2H),3.30(s,3H),2.75(s,1H),2.30(s,6H),1.39(m,3H),0.95(d,J=1.8Hz,18H).

[0144] Step 5: Preparation of compound IM05:

[0145] IM04 (6.0 g, 12.18 mmol) was dissolved in acetic acid:ethyl acetate (1:9) (60 mL), Pd / C (5%, 1.2 g) was added, H2 was introduced, and the reaction was carried out at room temperature for 18 hours. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain IM05 crude product: 5.6 g, which was directly used in the next step without purification;

[0146] Step 6: Preparation of compound IM06:

[0147] IM05 (5.6 g, 11.74 mmol) was dissolved in THF (60 mL), TBAF (4.92 g, 17.62 mmol) was added at room temperature, stirred for 1 hour, and then the system was poured into water (150 mL), separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the residue was subjected to column chromatography to obtain IM06: 3.46 g, yield: 92%,

[0148] ESI-MS (+): m / z = 319.78,

[0149] 1 HNMR(400MHz)δ:7.30(s,1H),7.01(d,J=6.8Hz,1H),6.59(d,J=6.8Hz,1H),6 .28(s,2H),5.89(s,2H),4.00(s,2H),3.30(s,3H),2.86(s,1H),2.30(s,6H).

[0150] Step 7: Preparation of compound IM07:

[0151] IM06 (3.2 g, 10.0 mmol) was dissolved in DMF (50 mL), and NaH (60%, 0.50 g, 11.98 mmol) was added at 5°C. The mixture was stirred for 1 hour, and then TsOCH2P(O)(OEt)2 (3.22 g, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 hours. The system was then poured into ice water (250 mL), and the aqueous phase was extracted with ethyl acetate. The organic phases were combined after separation, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. IM07 was obtained by column chromatography: 2.73 g, yield: 58%.

[0152] Step 8: Preparation of compound V-01:

[0153] IM07 (2.5 g, 5.31 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 ° C, and TMSBr (12.2 g, 79.70 mmol) was slowly added dropwise. After the addition was completed, the system was warmed to room temperature and reacted for 18 hours, and then directly concentrated to remove the solvent. To the concentrated residue, acetonitrile: water (10:1, 30 mL) was added, and the solvent was concentrated again after stirring for 1 hour. Toluene (30 mL) was added to the concentrated residue. The system was ultrasonicated for half an hour to produce solids, which were filtered. The filter cake was washed with cooled n-heptane and dried to obtain V-01: 1.67 g, yield: 85%,

[0154] ESI-MS (-): m / z = 369.27,

[0155] 1 HNMR(400MHz)δ:7.03(s,1H),6.83-6.75(m,2H),6.60(s,2H),4.28(s,2H),4.00(s,2H),2.80(s,1H),2.30(s,6H).

[0156] Example 2: Synthesis of Compound V-02

[0157] Reaction:

[0158]

[0159] Referring to the operation procedure of Example 1, V-02 was prepared: 1.57 g, yield: 92%,

[0160] ESI-MS (-): m / z = 363.12

[0161] 1 HNMR(400MHz)δ:7.01(s,1H),6.92-6.65(m,2H),6.45(s,2H),4.41(s,2H),4.00(s,2H),3.07(s,1H),2.30(s,6H),1.10(d,J=1.48Hz,6H).

[0162] Example 3: Synthesis of Compound IM09

[0163] Reaction:

[0164]

[0165] Preparation method:

[0166] Step 1: Preparation of compound IM08:

[0167] V-01 (1.00 g, 2.70 mmol) was dissolved in DCM (10 mL). After cooling to 0°C, phosphorus oxychloride (0.91 g, 6.0 mmol) was slowly added dropwise to the system. After the addition was completed, the temperature was naturally raised to room temperature for 18 hours. The system was then directly concentrated to remove the solvent to obtain IM08: 1.2 g, which was used directly in the next step without purification.

[0168] Step 2: Preparation of compound IM09:

[0169] IM08 (1.2 g) was dissolved in THF (20 mL), cooled to 0°C, phenol (0.23 g, 2.60 mmol) was added to the system, and triethylamine (0.26 g, 2.60 mmol) was slowly added dropwise after the addition was completed. After the addition was completed, the temperature was naturally raised to room temperature and stirred for 4 hours. After diatomaceous earth filtration, the filtrate was directly concentrated, toluene (20 mL) was added to the concentrated residue, and solids were generated by ultrasonication for half an hour. The system was filtered, and the filter cake was washed with cooled n-heptane and dried to obtain IM09: 0.56 g, yield: 45%,

[0170] ESI-MS (-): m / z = 463.02;

[0171] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72 (m,2H),6.60(s,2H),4.30(s,2H),4.00(m,2H),2.80(s,1H),2.30(s,6H).

[0172] Example 4: Synthesis of Compound IM11

[0173]

[0174] Referring to the operating procedures of Example 3, compound IM11 was prepared: 2.17 g, yield: 37.1%;

[0175] ESI-MS (-): m / z = 467.23;

[0176] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.6 0(s,2H),4.30(s,2H),4.00(s,2H),3.00(s,1H),2.30(s,6H),1.04(d,J=7.2Hz,6H).

[0177] Example 5: Synthesis of Compound DSC188-01

[0178] Reaction:

[0179]

[0180] Preparation method:

[0181] IM11 (0.50 g, 1.09 mmol) was dissolved in DCM (10 mL), SM03 (0.28 g, 1.64 mmol) was added, the system was cooled to 0°C, DIPEA (0.28 g, 0.218 mmol) was slowly added dropwise to the system, and the reaction was carried out for 18 hours after the addition was completed. The system was poured into ice water (50 mL), extracted with DCM, separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was purified by SFC to obtain DSC188-01: 0.17 g, yield: 26.15%,

[0182] ESI-MS (-): m / z = 594.18;

[0183] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.30( s,4H),4.00(m,2H),3.58(m,1H),3.10(m,1H),2.30(s,6H),1.90(m,1H),1.20(m,13H),0.93(m,6H).

[0184] Example 6: Synthesis of Compound DSC188-02

[0185] Reaction:

[0186]

[0187] Preparation method:

[0188] IM09 (0.50 g, 1.08 mmol) was dissolved in DCM (10 mL), SM03 (0.28 g, 1.61 mmol) was added, the system was cooled to 0°C, DIPEA (0.29 g, 2.16 mmol) was slowly added dropwise to the system, and the reaction was carried out for 18 hours after the addition was completed. The system was poured into water (50 mL), extracted with DCM, and after separation, the organic phases were combined and dried over anhydrous sodium sulfate. After the system was filtered, the filtrate was concentrated, and the concentrated residue was subjected to preliminary column chromatography to obtain the racemic target product, and then purified by SFC to obtain DSC188-02: 0.12 g, yield: 18%,

[0189] ESI-MS (-): m / z = 600.23;

[0190] 1HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.30 (s,4H),4.00(m,2H),3.58(m,1H),2.80(s,1H),2.30(s,6H),1.90(m,1H),1.20(m,7H),0.93(m,6H).

[0191] Example 7: Synthesis of Compound DSC188-05

[0192]

[0193] Referring to the operation procedure of Example 5, compound DSC188-05 was prepared: 0.94 g, yield: 27.3%

[0194] ESI-MS (-): m / z = 594.13;

[0195] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.30( s,4H),4.00(s,2H),3.58(m,1H),3.05(m,1H),2.30(s,6H),1.90(m,1H),1.20(m,13H),0.93(m,6H).

[0196] Example 8: Synthesis of Compound DSC188-18

[0197] Referring to the operating procedure of Example 5, compound DSC188-18 was prepared: 0.37 g, yield: 32.7%;

[0198] ESI-MS (-): m / z = 606.11;

[0199] 1 HNMR(400MHz)δ:7.40-7.32(m,7H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H) ,5.28(s.2H),4.30(m,2H),4.00(m,2H),3.58(m,1H),2.80(s,1H),2.30(s,6H),1.23(m,3H).

[0200] Example 9: Synthesis of Compound DSC188-19

[0201] Referring to the operation procedure of Example 5, compound DSC188-19 was prepared: 0.26 g, yield: 28.7%,

[0202] ESI-MS (-): m / z = 530.27;

[0203] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H) ,4.30(m,2H),4.00(m,2H),3.66(s,3H),3.58(m,1H),2.80(s,1H),2.30(s,6H),1.29(m,3H).

[0204] Example 10: Synthesis of Compound DSC188-20

[0205] Referring to the operating procedures of Example 5, compound DSC188-20 was prepared: 0.72 g, yield: 28.8%;

[0206] ESI-MS (-): m / z = 650.23;

[0207] 1 HNMR(400MHz)δ:8.37(d,J=7.2Hz,1H),8.13(m,1H),7.80-7.62(m,3H),7.41(m,1H),7.07(s,1H),6.85-6.72(m,2H),6.60(s ,2H),6.17(m,1H),4.30(m,4H),4.00(m,2H),3.58(m,1H),2.80(s,1H),2.30(s,6H),1.90(m,1H),1.23(m,7H),0.95(m,6H).

[0208] Example 11: Synthesis of Compound DSC188-27

[0209] Reaction:

[0210]

[0211] Preparation method:

[0212] IM09 (0.50 g, 1.08 mmol) was dissolved in acetonitrile (10 mL), and SM04 (0.53 g, 2.16 mmol) was added. After cooling to 0°C, DIPEA (0.42 g, 3.24 mmol) was slowly added. After the addition was completed, the system naturally warmed to room temperature and reacted for 24 hours. After filtration through diatomaceous earth, the filtrate was concentrated and purified by SFC to obtain DSC188-27: 0.18 g, yield: 25%,

[0213] ESI-MS (-): m / z = 672.06;

[0214] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.51(m,1H),4.30(m,2 H),4.12(s,2H),4.00(m,2H),3.58(s,2H),2.80(s,1H),2.30(s,6H),1.79(m,2H),1.50(m,1H),0.90(d,J=7.6Hz,6H).

[0215] Example 12: Synthesis of Compound DSC188-31

[0216] Reaction:

[0217]

[0218] Preparation method:

[0219] V-01 (0.50 g, 1.35 mmol) and SM05 (0.76 g, 4.05 mmol) were mixed and dissolved in DMF (10 mL), and pyridine (1 mL) and DCC (0.84 g, 4.05 mmol) were added. After the addition was completed, the system was heated to 70°C for reaction for 6 hours, then cooled to room temperature, filtered with diatomaceous earth, and the filtrate was concentrated under pressure to remove the solvent. DSC188-31 was obtained by column chromatography: 0.15 g, yield: 21%,

[0220] ESI-MS (-): m / z = 519.37;

[0221] 1HNMR(400MHz)δ:7.40(s,1H),7.35(d,J=7.2Hz,2H),7.21(d,J=7.2Hz,1H),7.01(s,1H),6.85-6 .72(m,2H),6.60(s,2H),4.79(m,1H),4.30(m,2H),4.00(m,4H),2.80(s,1H),2.30-2.10(m,8H).

[0222] Example 13: Synthesis of Compound DSC188-36

[0223] Reaction:

[0224]

[0225] Preparation method:

[0226] V-01 (0.50 g, 1.35 mmol) was dissolved in acetonitrile (10 mL), and 1-bromohexadecane (0.82 g, 2.70 mmol) and DIPEA (0.53 g, 4.05 mmol) were added. After the addition was completed, the mixture was stirred at room temperature for 18 hours. After diatomaceous earth filtration, the filtrate was concentrated, and the concentrated residue was prepared by preparative liquid phase to obtain DSC188-36: 0.18 g, yield: 23%,

[0227] ESI-MS (-): m / z = 591.07;

[0228] 1 HNMR(400MHz)δ:7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.30(d,2H),4.07(m,2H),4.00 (s,2H),2.80(s,1H),2.30(s,6H),1.76(m,2H),1.34(m,2H),1.30-1.25(m,22H),0.79(m,3H).

[0229] Example 14: Synthesis of Compound DSC188-37

[0230] Reaction:

[0231]

[0232] Preparation method:

[0233] V-01 (0.50 g, 1.35 mmol) was dissolved in DMF (10 mL), pyridine (1 mL) and DCC (0.84 g, 4.05 mmol) were added, and then SM07 (0.33 g, 2.03 mmol) was added. After the addition was completed, the temperature was raised to 70°C for reaction for 18 hours, and then the temperature was lowered. The system was poured into a saturated sodium carbonate aqueous solution, extracted with EA, and the pH of the aqueous phase was adjusted to 3-4 with 2N hydrochloric acid after separation. After concentration to remove water, the liquid phase was prepared to obtain DSC188-37: 48.7 mg, yield: 7%,

[0234] ESI-MS (-): m / z = 514.24;

[0235] 1 HNMR(400MHz)δ:7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H),4.30(d,2H),4 .17(s,2H),4.00(m,2H),3.57(m,1H),2.80(s,1H),2.30(s,6H),1.46(d,3H).

[0236] Example 15: Synthesis of Compound DSC188-46

[0237] Reaction:

[0238]

[0239] Preparation method:

[0240] V-01 (0.50 g, 1.35 mmol) was dissolved in DMF (10 mL), cooled to 0°C, and NaH (60%, 0.16 g, 4.05 mmol) was added. After the addition was completed, the mixture was stirred for half an hour. Then SM08 (1.03 g, 6.75 mmol) was slowly dripped into the system. After the dripping was completed, the temperature was maintained for 2 hours. The system was then poured into a cold saturated aqueous ammonium chloride solution, extracted with DCM, and the organic phase was dried after separation. After the system was filtered, the filtrate was concentrated, and the concentrated residue was subjected to column chromatography to obtain DSC188-46: 0.30 g, yield: 37%.

[0241] ESI-MS (-): m / z = 601.11;

[0242] 1 HNMR(400MHz)δ:7.01(s,1H),6.95(s,4H),6.85-6.72(m,2H),6.60(s,2H),5. 10(m,2H),4.30(d,2H),4.00(m,2H),2.80(s,1H),2.30(s,6H),1.31(d,12H).

[0243] Example 16: Synthesis of Compound DSC188-47

[0244] Reaction:

[0245]

[0246] Preparation method:

[0247] Referring to the operation procedure of Example 5, compound DSC188-47 was prepared: 0.27 g, yield: 37.7%,

[0248] ESI-MS (-): m / z = 527.29

[0249] 1 HNMR(400MHz)δ:7.40-7.32(m,2H),7.21(m,3H),7.01(s,1H),6.85-6.72(m,2H),6.60(s,2H) ,4.30(s,2H),4.00(s,2H),3.58(m,1H),3.05(m,1H),2.30(s,6H),1.20(m,3H),0.93(m,6H).

[0250] Example 17: Synthesis of Compound DSC188-65

[0251] Reaction:

[0252]

[0253] Preparation method:

[0254] Step 1: Preparation of compound IM12: SM10 (10 g, 50.03 mmol) was dissolved in DCM (100 mL), and TEA (6.08 g, 60.04 mmol) was added under ice-water bath conditions. After the addition, a DCM solution of SM11 (12.13 g, 50.03 mmol) was slowly added dropwise to the system. After the addition, the temperature was naturally raised to room temperature and reacted for 12 hours. The system was poured into cold 1N HCl and extracted with DCM. After separation, the organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate, and concentrated to obtain an anhydrous oil IM 12: 17.68 g, which was directly used in the next step without purification;

[0255] Step 2: Take the concentrated residue IM12 (1.0 g, 2.76 mmol) from the previous step, dissolve it in DCM (10 mL), add TEA (1.11 g, 11.04 mmol) and V-02 (1.10 g, 3.03 mmol), stir at room temperature for 27 hours after the addition, and after the reaction is completed by HPLC, the system is directly concentrated, and the concentrated residue is separated by preparative liquid phase to obtain DSC188-65: 0.79 g, yield: 44.38%,

[0256] ESI-MS (-): m / z = 643.01;

[0257] 1 HNMR(400MHz)δ:7.14(s,1H),6.79(d,J=8.7Hz,2H),6.56(s,2H),4.27(s,2H),4.05(m,2H),4.0 0(s,2H),3.43(m,4H),3.05(m,1H),2.30(s,6H),1.93(m,2H),1.50-1.12(m,34H),0.78(m,3H).

[0258] Example 18: Synthesis of Compound DSC188-67

[0259] Reaction:

[0260]

[0261] Preparation method:

[0262] Referring to the operating procedures of Example 17, compound DSC188-67 was prepared: 1.02 g, yield: 56.36%;

[0263] ESI-MS (-): m / z = 649.03;

[0264] 1 HNMR(400MHz)δ:7.14(s,1H),6.79(d,J=8.7Hz,2H),6.56(s,2H),4.27(s,2H),4.05(m,2H),4.0 0(s,2H),3.43(m,4H),2.80(s,1H),2.30(s,6H),1.93(m,2H),1.50-1.12(m,28H),0.78(m,3H).

[0265] The following example compounds were synthesized by the same method as in the above examples using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] Example 19: Testing of THRα or THRβ agonist activity based on reporter gene activity detection method

[0274] Construction and preparation of pGAL4-THR-LBD plasmid and preparation of pG5-Luc and pRL-Tk plasmids:

[0275] The pGAL4-THRα-LBD and pGAL4-THRβ-LBD reporter gene detection system plasmids used were constructed according to conventional molecular cloning methods. The main steps are as follows: using PCR technology to amplify the cDNA sequences of THRα (NM-003250) and THRβ (NM-000461) corresponding to the amino acid sequences of THRα (163-407AA) and THRβ (217-461AA), respectively, extract and purify them, and insert them into the BamHI and NotI restriction sites of the pGAL4 vector to obtain plasmids pGAL4-THRα-LBD and pGAL4-THRβ-LBD; plasmids pG5-Luc (#E249A) and pRL-Tk (#E2241) were purchased from Promega; Escherichia coli DH5α competent cells were prepared by the CaCl2 method, and the above plasmids were transformed into DH5α competent cells. After further culture and amplification, the corresponding plasmid DNA was extracted and purified using a plasmid extraction kit (TIANGEN, #D107).

[0276] Plasmid co-transfection into HEK293T cells and compound treatment:

[0277] One day before plasmid transfection, HEK293T cells were cultured at 1×10 4 The cells were inoculated at a density of 100 cells / well in a 96-well plate and cultured in a 37°C, 5% CO2 incubator. When the cells entered the exponential growth phase, the transfection reagent Cell transfection was performed according to the instructions of HD (Promega, #E2311).

[0278] The main steps are as follows: taking a single culture well as an example, add 20 ng of plasmid pGAL4-THRα-LBD or pGAL4-THRβ-LBD, 50 ng of pG5-Luc, and 5 ng of pRL-TK to 10 μL of Opti-MEMTMⅠ culture medium (Gibco, #11058021), mix thoroughly, and then add DNA transfection reagent. HD (Promega, #E2311) 0.25μL, after thorough mixing, stand at room temperature for 5min to obtain a mixture; take 10μL of this mixture and add it to the cell culture well containing 100μL culture medium for cell co-transfection. 6h after cell co-transfection, add a series of concentrations of compounds to the cell culture medium for 24h treatment. The compounds are divided into 10 concentrations, with the highest final concentration of 1μM, and diluted 3 times with DMSO. There are 3 duplicate wells, triiodothyronine (T3) is used as a positive control, and a negative control well (containing cells, without drugs and plasmids) is set up.

[0279] Detection:

[0280] After the cells were treated with the compounds for 24 h, Detection was performed according to the instructions of Luciferase Assay System (Promega, #E2940).

[0281] The main steps are: aspirate 50 μL of culture medium from each culture well, discard it, and then add 50 μL Luciferase reagent, gently shake at room temperature for 10 minutes; take 80 μL of the cleavage reaction solution and add it to the white opaque optiPlate-96 well plate, and use the MD i3x multifunctional microplate reader to detect the luminescent signal value (Firefly-Luc) of firefly luciferase; then add 40 μL of the reagent was gently shaken at room temperature for 10 min; then the luminescent signal of Renilla luciferase (Renilla-Luc) was detected using an MDi3x multifunctional microplate reader.

[0282] The data is processed according to formula (1).

[0283] Formula (1): Calculation formula: F / R ratio = Firefly fluorescence signal / Renilla fluorescence signal

[0284] The agonist activity was obtained by processing according to formula (2).

[0285] Formula (2): Agonist activity (%) = (F / R test compound - F / R negative control) / (F / R positive compound - F / R negative control) × 100%

[0287] Then, Graph Pad Prism software was used to draw the curve and calculate the THRβ-EC of each test compound. 50 (nM).

[0288] The THRα-EC of the test compound was measured and calculated using the similar method of the above formula (1) and formula (2). 50 (nM).

[0289] The THRβ agonist selectivity (SI) was calculated according to formula (3).

[0290] Formula (3): THRβ agonist selectivity (SI) = THRα-EC 50 / THRβ-EC 50

[0291] The experimental results are shown in Table 1.

[0292] Table 1 Agonistic activity and agonistic selectivity of the compounds of the present invention on THR-β and THR-α

[0293]

[0294]

[0295]

[0296]

[0297] Analysis of the experimental data in the above table shows that the compound provided by the present invention exhibits THRβ agonist activity superior to that of V-01 and V-02, indicating that the compound obtained by treating the phosphate group can improve the compound's THRβ agonist activity and selectivity. The compounds provided by the present invention include DSC188-01, DSC188-02, DSC188-05, DSC188-18, DSC188-19, DSC188-20, DSC188-31, DSC188-47, DSC188-68, DSC188-69, DSC188-70, DSC188-71, DSC188-72, DSC188-73, DSC188-74, DSC188-75, DSC188-76, DSC188-77, DSC188-78, DSC188-79, DSC188-80, DSC188-81, DSC188-82, DSC188 -83, DSC188-84, DSC188-85, DSC188-86, DSC188-88, DSC188-89, DSC188-90, DSC188-91, DSC188-92, DSC188-93, DSC188-94, and DSC188-95 have selectivity for THRβ agonist activity that is 2 times or more of that exhibited by compound V-02, among which compounds DSC188-05, DSC188-20, DSC188-70, DSC188-75, DSC188-82, DSC188-88, and DSC188-91 are 2.5 times more selective than compound V-02.

[0298] Example 20: Pharmacokinetic Experiment

[0299] 72 male SD rats weighing 200±20g were selected. The rats were allowed to eat and drink freely and were adaptively raised for 3 days at room temperature of 20-26℃, humidity of 40-70%, and light illumination: dark = 12h:12h. The experimental animals began to fast at 8 pm the day before drug administration, fasted for 12-13h before drug administration, and continued to fast for 4h after drug administration, for a total of 16-17h. No water was allowed during the entire experiment.

[0300] Preparation of intragastric administration samples: Weigh appropriate amounts of the test samples, place them in reagent bottles, add appropriate amounts of mixed solution (2% Klucel LF: 0.1% Tween 80 aqueous solution / 1:1 / v:v), and prepare the administration solution. Prepare it before use.

[0301] Preparation of intravenous injection samples: Weigh appropriate amounts of test samples, place in reagent bottles, add appropriate amounts of mixed solvent (10% DMSO: 30% PEG400: 60% saline for injection / 1:1:1 / v:v:v). Prepare dosing solutions of corresponding concentrations, filter with a microporous membrane on a sterile bench before use (if there is a transfer bottle, ensure it is sterile), and prepare before use.

[0302] Experimental grouping and administration method: 72 male SD rats were randomly divided into 24 groups, 3 rats in each group, with a total of 12 test articles. Each test article was administered by oral gavage and intravenous injection, respectively, for a single dose, as shown in Table 2.

[0303] Table 2 Dosage regimen for pharmacokinetic study

[0304]

[0305]

[0306] Note: The test compound was administered in equimolar amounts to V-01 and V-02.

[0307] Blood collection after intragastric administration: About 200 μL of blood was collected from the orbital venous plexus of rats within 0.5 h before intragastric administration (0 h), and 0.5 h, 1.5 h, 3.0 h, 4.5 h, 6.0 h, 8.0 h, 10.0 h, and 24.0 h after administration. The animals were fed 4 h after administration, and water was not allowed during the whole process.

[0308] Blood collection for intravenous injection: About 200 μL of blood was collected from the orbital venous plexus of rats within 0.5 h before intravenous injection (0 h), and 0.15 h, 0.5 h, 1.0 h, 3.0 h, 5.0 h, 8.0 h, 10.0 h, and 24.0 h after administration. Animals were fed 4 h after administration, and water was not allowed during the whole process.

[0309] Plasma sample processing and testing:

[0310] Blood sample collection and processing: After each blood collection time point, immediately add blood to a sodium heparin anticoagulation centrifuge tube placed on an ice bath, then centrifuge in a centrifuge (4°C, 4000rpm, 10min) to separate plasma, take the plasma and dispense it into EP tubes with a unit volume of 50μL, and store at -80°C for later use. Determine the concentration of the target analyte in the plasma as soon as possible.

[0311] DUT information: DSC188-01, DSC188-05, DSC188-47, DSC188-65 and DSC188-67 test V-01;

[0312] DSC188-02, DSC188-18, DSC188-19, DSC188-20 and DSC188-31 test V-02.

[0313] The bioavailability (%) of oral administration was calculated according to formula (4):

[0314] Formula (4): Oral administration bioavailability (%) = (AUC inf-ig / administered dose) / (AUC inf-iv / administered dose)×100%

[0315] The pharmacokinetic parameters of injection administration are shown in Table 3, and the pharmacokinetic parameters of oral administration are shown in Table 4.

[0316] Table 3 Mean values ​​of main pharmacokinetic parameters of injection

[0317]

[0318] Table 4 Mean values ​​of main pharmacokinetic parameters after oral administration

[0319]

[0320]

[0321] The experimental compounds were compared with V-01 and V-2 in terms of exposure (AUC Inf ), peak blood concentration (C max ), half-life (T 1 / 2 ), mean residence time (MRT) and bioavailability, showing better pharmacokinetic properties. Among them, the bioavailability of DSC188-05, DSC188-18 and DSC188-20 was increased by more than 70% compared with the compound with the highest bioavailability, V-01 (29.01%), and the exposure (AUC Inf ) was more than doubled compared to the compound with the highest exposure, V-02 (15213h*ng / mL), and the peak blood concentration (C max ) increased by more than 50% compared with the compound V-02 (2177 ng / ml) with the highest peak concentration in blood, and the half-life (T 1 / 2 ) was extended by more than 23%, and the mean residence time (MRT) was extended by more than 20%, achieving unexpected results.

[0322] Example 21: Efficacy test on HFD-induced NASH model in mice

[0323] Test compounds and groups: V-01 group, V-02 group, DSC188-05 group, DSC188-18 group, and DSC188-20 group.

[0324] Preparation of test compounds: Weigh appropriate amounts of test compounds respectively, place in reagent bottles, add appropriate amount of mixed solution (2% Klucel LF: 0.1% Tween80 aqueous solution / 1:1 / v:v) to prepare dosing solution, prepare before daily administration and vortex evenly before administration.

[0325] Experimental method: 80 C57BL / 6J mice, male, SPF grade, 6 weeks old, weighing 18g-20g, were randomly divided into a normal group (n=10) and a NASH modeling group (n=70) after 7 days of adaptive feeding. The normal group was fed with a normal feed (crude protein %≥20.0% and crude fat %≥4.0% in the main nutrients), and the NASH modeling group was fed with a high-fat feed (crude fat %≥60% in the main nutrients, crude protein %≥10%, and calories (carbohydrate or sugar) %≥25%). From the end of adaptive feeding, after 40 weeks of feeding, the body weight was weighed and blood was collected to test four blood lipids and liver blood biochemistry (TC, TG, HDL, LDL, ALT, AST). Mice with obvious abnormal indicators were eliminated, and mice with uniform indicators were selected for the experiment. Eight mice were randomly selected from the normal group; 48 mice were randomly selected from the NASH model group and randomly divided into 6 groups, 8 mice in each group, namely the model group, V-01 group, V-02 group, DSC188-05 group, DSC188-18 group, and DSC188-20 group. The mice were given by gavage once a day for 6 consecutive weeks. The dosing schedule is shown in Table 5.

[0326] Table 5 Dosage regimen for efficacy test

[0327]

[0328] After the last administration, the mice were fasted but not watered for 12 h, anesthetized and killed, and the intact liver tissue was isolated.

[0329] Observation, sample processing, and testing indicators:

[0330] 1) General clinical symptom observation and body weight measurement

[0331] The general clinical symptoms of the experimental animals were observed before administration at 10 a.m. every day, and the body weight was measured once at 8 a.m. every Monday and Thursday.

[0332] Weigh the liver wet weight and calculate the liver index according to formula (5):

[0333] Formula (5): Liver index = liver weight (g) / body weight (g) × 100%.

[0334] 2) Determination of triglyceride (TG) and total cholesterol (TC) content in the liver:

[0335] TG content measurement: According to the instructions of the triglyceride detection kit (enzymatic method) (Zhejiang Dongou Diagnostic Products Co., Ltd.), the test was performed using an enzyme reader;

[0336] TC content determination: According to the instructions of the total cholesterol content detection kit (cholesterol oxidase method) (Nanjing Jiancheng Bioengineering Institute), the detection was performed using an enzyme marker.

[0337] 3) Histopathological analysis

[0338] All liver samples were dehydrated by a dehydration instrument (Leica, Germany, ASP300), then embedded by a paraffin embedding machine (Leica, Germany, EG1160), and then sliced ​​by a data scanning slicer (Leica, Germany, SCN400). Liver tissues were observed and analyzed under a microscope, and the severity of liver inflammation, necrosis, and fibrosis in each group of mice was evaluated using the NAS scoring method (see Table 6).

[0339] Table 6 NASH scoring evaluation method

[0340]

[0341] Lesion assessment criteria:

[0342] (1) Hepatocyte ballooning: Pathological changes similar to vacuoles are observed in hepatocytes. Due to vacuolar changes, the size of hepatocytes increases and the hepatocyte nuclei become centralized or deviated.

[0343] (2) Inflammatory cell infiltration: A large number of aggregated inflammatory cells, mainly neutrophils and macrophages, are found in the portal vein area, ventral venous area, or around the liver lobules.

[0344] (3) Fatty changes in hepatocytes: Regular round vacuoles were observed in hepatocytes of different sizes, with the hepatocyte nuclei located at the edges.

[0345] All picrosirius red-stained sections were scanned with a Leica Aperio AT2 Brightfield scanner, and the percentage of picrosirius red-positive staining area was calculated using the HALO AI system to assess the percentage area of ​​picrosirius red over the total scanned liver area.

[0346] Statistical analysis:

[0347] The experimental data were processed using SPSS 23.0 software, and the mean and standard deviation were calculated using The independent sample T test was used for comparison between the groups, and P < 0.05 or P < 0.01 indicated that the difference was statistically significant.

[0348] Test results:

[0349] The changes in animal body weight, liver wet weight and liver index after administration are shown in Table 7.

[0350] Table 7 Animal body weight, liver wet weight and liver index after administration

[0351]

[0352] Note: **P<0.01 compared with the normal group; #P<0.05, ##P<0.01 compared with the model group

[0353] Compared with the normal group, the body weight, wet liver weight and liver index of the model group mice increased significantly after 40 weeks of HFD diet induction. Compared with the model group, the body weight, wet liver weight and liver index of the V-01 group, V-02 group, DSC188-05 group, DSC188-18 group and DSC188-20 group decreased; compared with the V-01 group and V-02 group, the body weight, wet liver weight and liver index of the DSC188-05 group, DSC188-18 group and DSC188-20 group decreased.

[0354] The data of TG and TC content detection in the liver of animals after administration are shown in Table 8.

[0355] Table 8 TG and TC contents in animal liver after administration

[0356]

[0357]

[0358] Note: **P<0.01 compared with the normal group; #P<0.05, ##P<0.01 compared with the model group

[0359] Compared with the normal group, the triglyceride (TG) and total cholesterol (TC) contents of the model group mice increased significantly after 40 weeks of HFD diet induction. Compared with the model group, the V-01 group, V-02 group, DSC188-05 group, DSC188-18 group and DSC188-20 group decreased significantly; compared with the V-01 group and V-02 group, the TG and TC contents of the DSC188-05 group, DSC188-18 group and DSC188-20 group decreased, and the decrease was more obvious in the DSC188-18 group and DSC188-20 group.

[0360] Although the present invention has disclosed some structural examples and implementation schemes, they are not intended to limit the present invention. Any person skilled in the art may make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be based on the definition of the claims.

Claims

1. A compound as shown in formula I, its tautomers, stereoisomers, isotopic derivatives, solvates, and pharmaceutically acceptable salts thereof: In formula I, M is selected from alkylene, O, S and NH; wherein the alkylene is optionally substituted by one or more hydrogen, deuterium, halogen, C1-C8 alkyl; R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl substituted or unsubstituted by a substituent A, or C3-C6 cycloalkyl substituted or unsubstituted by a substituent A, wherein the substituent A is selected from hydrogen, deuterium, halogen, hydroxyl and C1-C8 alkoxy; R3 and R4 are each independently selected from hydrogen, halogen, amino, and cyano; R5 is selected from in, L is selected from alkylene, O, S and NH; wherein the alkylene is optionally substituted with one or more hydrogen, deuterium, halogen, C1-C8 alkyl; R a Selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl, deuterated C3-C6 cycloalkyl; R b Selected from hydrogen; R c , R d Each is independently selected from hydrogen, halogen, amino, cyano; R e Selected from -OH, -SH, -SO2H, -SO2NH2, -NH2, carboxyl, halogen, cyano, trifluoromethyl; X and Y are each independently selected from -O-, -S- and -NH-; When R a When selected from deuterated C1-C8 alkyl or deuterated C3-C6 cycloalkyl, R6 and R7 are each independently selected from hydrogen, metal ion, C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl, -(CH2) m OR8, or R6, R7 and the phosphate group form a cyclic group The C1-C18 alkyl, C6-C12 aryl, C3-C10 heteroaryl may be optionally substituted with one or more hydrogen, deuterium, halogen, methyl, amino, carboxyl, -O(CO)R9, -(CO)OR 10 、-O(CO)OR 11 、-(CO)NH(CHR x )(CO)NH(CHR y )COOR z replace; m is an integer selected from 1 to 5; R8 is selected from C1-C18 alkyl, C6-C12 aryl and C3-C10 heteroaryl; R9, R 10 , R 11 Each is independently selected from C1-C8 alkyl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxyl, methoxy, cyano, amino, mercapto, mercaptomethyl, mercaptoethyl, C6-C12 aryl, C3-C10 heteroaryl, and deuterated C6-C12 aryl; R x , R y , R z Each is independently selected from hydrogen, C1-C8 alkyl, C6-C12 aryl, C3-C10 heteroaryl; R f , R g , R h , R i , R j , R k Each is independently hydrogen, deuterium, C1-C8 alkyl substituted by one or more hydrogen, deuterium, halogen, methyl, hydroxy, methoxy, cyano, mercapto, mercaptomethyl, mercaptoethyl, C6-C12 aryl, or C3-C10 heteroaryl; When R a When selected from hydrogen, C1-C8 alkyl, or C3-C6 cycloalkyl, R6 and R7 are each independently selected from hydrogen, C6-C12 aryl, deuterated C6-C12 aryl, -R 12 , -CR n R p (CO)NHR 13 , or R6, R7 and the phosphate group form a cyclic group R6 and R7 are not hydrogen or C6-C12 aryl groups at the same time; R n , R p Each is independently selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy; R 12 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR 14 replace; R 13 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)NHR 15 replace; R 14 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 16 replace; R 15 Selected from C1-C8 alkyl; the C1-C8 alkyl is replaced by one or more -(CO)OR 17 replace; R 16 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl; R 17 Selected from hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C6-C12 aryl, deuterated C6-C12 aryl; the C1-C18 alkyl is substituted by one or more hydrogen, deuterium, halogen, mercapto, mercaptomethyl, mercaptoethyl, amino, carboxyl, hydroxyl.

2. The compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in Formula II: The substituents in formula II are as defined in formula I.

3. The compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in Formula III: The substituents in formula III are as defined in formula I.

4. The compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as follows: The substituents in formula IV are as defined in formula I.

5. The compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound includes but is not limited to the following compounds:

6. A pharmaceutical composition comprising the compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

7. Use of the compound, tautomer, stereoisomer, isotope derivative, solvate, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 6 in the preparation of a drug for preventing or treating thyroid hormone receptor-related diseases.

8. The thyroid hormone receptor-related disease as described in claim 7 is one or more of obesity, diabetes, hypothyroidism, thyroid cancer, thrombosis, hyperlipidemia, cardiac hypertrophy, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia, liver fatty lesions, liver fibrosis, moderate to severe liver scarring, cirrhosis, hepatocellular adenoma and hepatocellular carcinoma.

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