Steroid compound and application thereof

Abstract

The invention relates to a steroid compound and a composition containing the steroid compound. The compound or the composition can be used for preparing medicines for preventing, treating, treating or alleviating metabolic diseases of patients.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present invention claims priority to Chinese patent application No. 2023106722994 filed on June 7, 2023, and the entire contents of the above Chinese patent application are incorporated into this application by reference. Technical Field

[0003] The present invention relates to a steroid compound, stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and application thereof in preparing drugs for treating metabolic diseases. Background Art

[0004] With the aging of the population, more and more geriatric diseases, such as type 2 diabetes, atherosclerosis, fatty liver, hyperlipidemia and other diseases have seriously troubled the middle-aged and elderly population. It is known that the key factor in mammals regulating cholesterol and fatty acid synthesis is a type of transcription factor protein sterol response element binding protein (SREBP) (Goldstein, JL et al. (2006) Protein Sensors Formembrane Sterols. Cell 124, 35-46). The precursor of this type of protein is first synthesized on the endoplasmic reticulum (ER), and the precursor is transported to the Golgi apparatus through the SREBP cleavage activation protein (SCAP), and then cleaved by two proteases (Site-1protease (S1P) and Site-2protease (S2P)), releasing its N-terminal active domain, entering the cell nucleus to play a transcription factor role, binding to the SREBP response element (SRE) in the promoter region of the target gene, and initiating the expression of downstream genes. The shearing and maturation of SREBP protein is strictly regulated by the level of intracellular sterols (cholesterol or oxidized sterols such as 25-hydroxycholesterol). When the intracellular sterol level is too high, SCAP binds to the Insig protein on the endoplasmic reticulum to retain the SREBP precursor in the ER, reducing the expression of cellular lipid synthesis genes. On the contrary, the active form of SREBP in the nucleus increases, promoting cellular lipid synthesis. It is known that mammalian cells have three different forms of SREBP: SREBP-1a, -1c and SREBP-2 (Horton, JD et al. (2002) SREBPs: Activators Of The Complete Program Of Cholesterol And FattyAcid Synthesis In The Liver. J. Clin. Invest 109, 1125-1131), which have the same splicing and nuclear regulation characteristics, and their maturation processes are as described above. The difference between the three subtypes is that they have different target genes. SREBP-1a and -1c mainly regulate the expression of genes in the fatty acid synthesis pathway, and SREBP-2 mainly regulates the expression of genes in the cholesterol synthesis pathway and the expression of low-density lipoprotein receptor genes. In mice with liver-specific knockout of SCAP or S1P genes, the SREBP splicing and maturation process is inhibited, which results in a significant downregulation of lipid synthesis and a significant reduction in blood cholesterol and triglyceride levels. This suggests that SERBP pathway-specific inhibitors can be used as a potential lipid-lowering substance. SREBP-2, as a specific nuclear transcription factor, plays an important role in the regulation of cholesterol metabolism.When intracellular cholesterol is deficient, SREBP-2 specifically binds to cholesterol regulatory element-1 (SRE-1) on genes such as low-density lipoprotein receptor (LDLR) and hydroxymethylglutaryl coenzyme A synthase (HMG CoA synthase), and directly participates in the regulation of intracellular cholesterol metabolism to maintain cholesterol homeostasis. SREBP-2 gene polymorphism and abnormal mutation can cause changes in its function, thereby affecting the body's lipid metabolism process. Research results have shown that SREBP-2 gene polymorphism is associated with hypercholesterolemia. Summary of the invention

[0005] In a first aspect, the present invention provides a steroidal compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I):

[0006]

[0007] in:

[0008] A is -C(=O)-, -C(=S)-, -OC(=O)-, -NR 4 C(=O)-、-OP(=O)R 5 -or-NR 4 P(=O)R 5 -;

[0009] X is aminoalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl-OC(=O)-CR 6 R 7 -, alkyl-C(=O)O-CR 6 R 7 -, arylalkyl, hydroxyalkyl, mercaptoalkyl, aminoC(=O)-alkyl, arylalkyl, heteroarylalkyl or

[0010] Q is hydrogen, hydroxyl, amino, arylamino, halogen, alkyl, carboxyl, phosphate, aryl, heteroaryl, monosaccharide, polysaccharide, cycloalkyl, cycloalkylalkyl, aryl-C(=O)-, R 8 OP(=O)OR 9 -O-,

[0011] G is O or S;

[0012] n is 0, 1 or 2;

[0013] R 1 is hydrogen, deuterium, halogen, hydroxyl or alkyl;

[0014] R 2 is halogen, hydroxyl, amino, alkyl, carboxyl, phosphoric acid, sulfonic acid or alkoxy;

[0015] Or, R 1 , R 2 Together with the atoms to which it is attached, it forms a 3-7 membered ring which may or may not contain heteroatoms;

[0016] R 3 and R 3’ are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl;

[0017] R 4 and R 9 Each is independently H, alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl or alkoxyalkyl;

[0018] R 5 and R 8 Each is independently hydroxy, alkoxy, alkyl-C(=O)O-(CR 10 R 11 ) m O-, alkyl-OC(=O)-(CR 10 R 11 ) m -NR 12 - or alkyl-C(=O)S-(CR 10 R 11 ) m O-; or R 5 and R 8 Form a P-containing heterocyclic ring with P;

[0019] R 6 , R 7 , R 10 and R 11 each independently represents H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0020] R 12 is H, alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl or alkoxyalkyl;

[0021] m is 1, 2 or 3;

[0022] q is 0, 1, or 2;

[0023] The R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, X or Q group is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl or heteroaryl;

[0024] R a , R b , R c , R d , R e , R f , R g , R h each independently represents alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkylthio, halo- or hydroxy-substituted alkylthio, alkylamino, halo- or hydroxy-substituted alkylthio, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl or alkynyl;

[0025] The hydrogen atoms on ring a, ring b, ring c and ring d are unsubstituted or at least one hydrogen atom is substituted by deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halogenated or hydroxy-substituted alkoxyalkyl, alkoxy, halo-substituted or hydroxy-substituted alkoxy, alkoxyalkoxy, halo-substituted or hydroxy-substituted alkoxyalkoxy, alkylamino, halo-substituted or hydroxy-substituted alkylamino, alkylthio, halo-substituted or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy.

[0026] In some embodiments, in the general formula (I), R a , R b , R c , R d , R e , R f , R g , R h Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated or hydroxy-substituted C 1-6Alkylthio, C 1-6 Alkylamino, halogenated or hydroxy substituted C 1-6 Alkylthio, C 1-6 Alkoxy C 1-6 Alkyl, halogen or hydroxy substituted C 1-6 Alkoxy C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0027] In some embodiments, in the general formula (I), R a , R b , R c , R d , R e , R f , R g , R h Each is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl.

[0028] In some embodiments, the compound has a structure as shown in formula (II) or formula (III), or is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II) or formula (III):

[0029]

[0030] In formula (II) and formula (III), Q, X, A, R 1 , R 2 , R 3 , R 3’ , q, and n are defined as in formula (I).

[0031] In some embodiments, A is -C(=O)-.

[0032] In some embodiments, n is 0.

[0033] In some embodiments, q is 0. In some embodiments, q is 1.

[0034] In some embodiments, n is 0 and A is -C(=O)-.

[0035] In some embodiments, q is 1 and A is -C(=O)-.

[0036] In some embodiments, the R 1 is hydrogen, deuterium, halogen, hydroxyl or C 1-6 alkyl.

[0037] In some embodiments, the R1 is hydrogen, deuterium, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

[0038] In some embodiments, the R 2 For halogen, hydroxyl, amino, C 1-6 Alkyl, carboxyl, phosphate, sulfonic acid or C 1-6 Alkoxy.

[0039] In some embodiments, the R 2 It is F, Cl, Br, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, carboxyl, phosphate, sulfonate or methoxy, ethoxy or tert-butoxy.

[0040] In some embodiments, the R 1 , R 2 Together with the atoms connected to it, it forms a 3-7 membered O-containing heterocyclic ring.

[0041] In some embodiments, R 1 and R 2 is halogen or hydroxy.

[0042] In some embodiments, R 1 and R 2 It's hydroxyl.

[0043] In some embodiments, R 1 is a halogen such as bromine, R 2 It's hydroxyl.

[0044] In some embodiments, R 2 is a halogen such as bromine, R 1 It's hydroxyl.

[0045] In some embodiments, R 1 , R 2 and the atoms to which it is attached

[0046] In some embodiments, the R 3 is hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 Halogenated alkoxy C 1-6 alkyl.

[0047] In some embodiments, the R 3is hydrogen, deuterium, hydroxy, F, Cl, Br, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl.

[0048] In some embodiments, the R 3’ is hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 Halogenated alkoxy C 1-6 alkyl.

[0049] In some embodiments, the R 3’ is hydrogen, deuterium, hydroxy, F, Cl, Br, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl.

[0050] In some embodiments, the R 4 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 alkyl.

[0051] In some embodiments, the R 4 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[0052] In some embodiments, X is C 1-6 Aminoalkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 1-6 Alkyl-OC(=O)-CR 6 R 7 -、C 1-6 Alkyl-C(=O)O-CR 6 R 7 -、C 6-10 Aryl C 1-6 Alkyl, C1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, aminoC(=O)-C 1-6 Alkyl, C 2-9 Heteroaryl C 1-9 Alkyl or

[0053] In some embodiments, X is aminomethyl, aminoethyl, imidazolylmethyl, imidazolylethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thio morpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thiazolyl phenyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinoline quinolinyl, isoquinolinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, methyl-OC(=O)-CR 6 R 7 -, ethyl-OC(=O)-CR 6 R 7 -, tert-butyl-OC(=O)-CR 6 R 7 -, methyl-C(=O)O-CR 6 R 7 -, ethyl-C(=O)O-CR 6 R 7 -, tert-butyl-C(=O)O-CR 6 R 7-, phenylmethyl, phenylethyl, phenylpropyl, phenyl tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl, mercaptoethyl, mercaptopropyl, aminoC(=O)-methyl, aminoC(=O)-ethyl, aminoC(=O)-propyl, indolylmethyl, isoxazolylmethyl or

[0054] In some embodiments, Q is H, hydroxyl, amino, C 6-10 Arylamino, halogen, C 1-6 Alkyl, carboxyl, phosphate, C 6-10 Aryl, C 2-9 Heteroaryl, monosaccharide, polysaccharide, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl-C(=O)-, R 8 OP(=O)OR 5 -O-, Wherein, the G is O or S.

[0055] In some embodiments, Q is hydrogen, hydroxyl, amino, phenylamino, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carboxyl, phosphate, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, isoxazolyl, monosaccharide, polysaccharide, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylpropyl, phenyl-C(=O)-, naphthyl-C(=O)-, R 8 OP(=O)OR 9 -O-,

[0056] In some embodiments, the R 5 and R 8 Each is independently hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)O-(CR 10 R 11 ) m O-、C 1-6 Alkyl-OC(=O)-(CR 10 R 11 ) m -NR 12 - or C 1-6 Alkyl-C(=O)S-(CR 10 R 11 )m O-.

[0057] In some embodiments, the R 5 and R 8 Each is independently hydroxy, methoxy, ethoxy, tert-butoxy, methyl-C(=O)O-(CR 10 R 11 ) m O-, ethyl-C(=O)O-(CR 10 R 11 ) m O-, tert-butyl-C(=O)O-(CR 10 R 11 ) m O-, methyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, ethyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, tert-butyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, methyl-C(=O)S-(CR 10 R 11 ) m O-, ethyl-C(=O)S-(CR 10 R 11 ) m O- or tert-butyl-C(=O)S-(CR 10 R 11 ) m O-;

[0058] In some embodiments, the R 5 , R 8 It forms a P-containing heterocyclic ring with the P atom connected to it.

[0059] In some embodiments, the R 5 , R 8 It forms a six-membered P-containing heterocyclic ring with the atom P connected to it.

[0060] In some embodiments, the R 6 , R 7 , R 10 and R 11 Each is independent of H and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C2-9 Heteroaryl, C 3-8 Cycloalkyl or C 2-9 Heterocyclic group.

[0061] In some embodiments, the R 6 , R 7 , R 10 and R 11 Each is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0062] In some embodiments, the R 9 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 alkyl.

[0063] In some embodiments, the R 9 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[0064] In some embodiments, the R 12 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 alkyl.

[0065] In some embodiments, the R 12 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[0066] In some embodiments, the group R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 A, X or Q are optionally replaced by 1, 2, 3 or 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, oxo, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 2-9 The heteroaryl group is substituted with a substituent.

[0067] In some embodiments, the group R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, X or Q are optionally replaced by 1, 2, 3 or 4 selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, trifluoroethyl, difluoromethyl, deuterated methyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, trifluoromethoxymethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy yl, methoxymethoxy, ethoxymethoxy, methylamino, ethylamino, methylthio, ethylthio, chlorophenyl, phenyl, naphthyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl , diazepine, thiazepine, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl The invention may be substituted by a substituent in oxadiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazol[1,5-a]pyridinyl, pyrazol[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0068] In some embodiments, QX- is selected from the following groups:

[0069] Phenyl, selected from hydroxy, phosphoryl, C 1-6 Alkyl, halogen substituted phenyl, biphenyl, selected from hydroxy, phosphoryl, C 1-6 biphenyl substituted with an alkyl or halogen substituent,

[0070] In some embodiments, the compound has the structure shown below, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] In a second aspect, the present invention provides a composition comprising the compound described in the first aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0077] In a third aspect, the present invention provides use of the compound described in the first aspect or the composition described in the second aspect in the preparation of a medicament for preventing, treating, curing or alleviating a metabolic disease in a patient.

[0078] In some embodiments, the metabolic disease is type 2 diabetes, hyperlipidemia, fatty liver, or atherosclerosis.

[0079] The compound provided by the present invention can selectively inhibit SREBP-2, has good water solubility, is easily absorbed by the body, and has good clinical application prospects. DETAILED DESCRIPTION

[0080] Definitions and general terms

[0081] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0082] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0083] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0084] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0085] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0086] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0087] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0088] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0089] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0090] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0091] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0092] The stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0093] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0094] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0095] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0096] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0097] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0098] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0099] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0100] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0101] The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, thiocarboxylates, and the like, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarate, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0102] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

[0103] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0104] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0105] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0106] The term "protecting group" or "PG" refers to a substituent that is used to block or protect a specific functionality when reacting with another functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0107] "Pharmaceutical composition" means a mixture of one or more salts of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0108] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0109] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0110] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I), (II), (III), (IV) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparation processes of the present invention.

[0111] In addition, heavier isotopes, especially deuterium (i.e. 2The substitution of H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0112] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as specifically exemplified in the examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position. The substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O), alkyl-C (= O), alkyl-S (= O), alkyl-S (= O) 2-, hydroxy-substituted alkyl-S (= O), hydroxy-substituted alkyl-S (= O) 2, carboxyalkoxy and the like.

[0113] The term "alkyl" as used herein refers to a saturated linear or branched monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t ... -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, such examples include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0114] The term "alkoxy" used in the present invention refers to an alkyl group, as defined in the present invention, connected to the main carbon chain through an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0115] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described herein, including groups having "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0116] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0117] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocyclic rings of 7-12 atoms may be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocyclic rings of 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cyclic aliphatic groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the "cyclic aliphatic group" or "carbocycle", "carbocyclic group", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy and the like.

[0118] The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring are independently and optionally replaced by heteroatoms, the heteroatoms having the meanings as described herein, the ring may be fully saturated or contain one or more unsaturations, but are never aromatic, and have only one point of attachment to other molecules. One or more hydrogen atoms in the ring are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2).

[0119] Heterocyclic groups can be carbonyl or heteroatom groups. "Heterocyclic groups" also include groups formed by the combination of heterocyclic groups with saturated or partially unsaturated rings or heterocyclic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin 1-yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazine-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanon-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O) 2, carboxyalkoxy and the like.

[0120] The term "aryl" may be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", for example, aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like.

[0121] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein heteroatoms have the meanings as described herein, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic compound". And the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy substituted alkyl-S(=O)-, hydroxy substituted alkyl-S(=O)2-, carboxyalkoxy and the like.

[0122] In other embodiments, heteroaryl includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following di- ring, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0123] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).

[0124] The term "halogen" refers to F, Cl, Br or I.

[0125] The term "halogenated" used in the present invention means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

[0126] The term "hydroxy substituted" used in the present invention means that the group following it is substituted with a hydroxy group, and the number of the substitutions may be one or more.

[0127] When "substituted" in the present invention is used between two groups, it is preceded by a substituent, such as "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means that the alkyl group has an alkoxycarbonyl substituent.

[0128] When multiple groups of the present invention are used in combination, they are in a substitution relationship from left to right, such as "arylalkyl" means an alkyl substituted with an aryl group, and "alkoxyalkoxy" means an alkoxy substituted with an alkoxy group.

[0129] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0130] In the present invention, the substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0131] When it can be used for treatment, the therapeutically effective amount of the compound of the present invention can be given as a raw chemical drug, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" used herein refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction). When a separate active ingredient is used for separate administration, the term refers only to the ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, sequential or simultaneous administration. In terms of compatibility with other ingredients of the preparation and harmlessness to its recipient, the carrier, diluent or excipient must be acceptable. According to another aspect of the present invention, a method for preparing a pharmaceutical preparation is also provided, which includes mixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effectively used for the intended purpose.

[0132] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0133] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or alleviating the severity of one or more of the conditions mentioned herein. According to the methods of the present invention, the compounds and compositions thereof may be administered in any amount and by any route of administration to effectively treat or alleviate the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, the patient's general condition, the severity of the infection, special factors, mode of administration, and the like. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

[0134] General synthesis process

[0135] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are provided to further illustrate the present invention.

[0136] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0137] In the examples described below, all temperatures are set in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0138] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0139] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0140] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The NMR spectra were CDC13, d6-DMSO, CD3OD or d6-acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0141] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0142] Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0143] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0144] Table 1

[0145] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0146] The process conditions for HPLC preparation are:

[0147] (1) taking an appropriate amount of a mixture of diastereomers containing a compound and dissolving it in a mobile phase;

[0148] (2) Setting the flow rate of the mobile phase, detection wavelength, and column temperature;

[0149] (3) taking an appropriate amount of the sample solution in step (1) and injecting it into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and analysis of the isomers;

[0150] Chromatographic column: a normal phase chiral chromatographic column with silica gel containing polysaccharide derivatives as the stationary phase; more specifically, the chromatographic column used is Daicel AD-H (10*250nm, 5um) or Daicel AD (20*250nm, 5um).

[0151] Mobile phase: a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid; more specifically, the volume ratio of n-hexane, n-pentane, isohexane and n-heptane in the mobile phase mixture is 10-20%, the volume ratio of methanol, ethanol, isopropanol and acetonitrile is 20-95%, the volume ratio of diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid is 0-2%, and the sum of the components in the mobile phase is 100%; more specifically, the volume ratio of n-hexane in the mobile phase mixture is 15-20%, the volume ratio of isopropanol is 80-90%, the volume ratio of diethylamine and triethylamine is 0.5-1%, and the sum of the components in the mobile phase is 100%.

[0152] Detection wavelength: 250nm~320nm;

[0153] Flow rate: 0.5-10 mL / min; more specifically 2-5 mL / min;

[0154] Column temperature: 10~35℃.

[0155] The following abbreviations are used throughout this invention:

[0156] AcOH: acetic acid

[0157] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0158] Boc: tert-butyloxycarbonyl

[0159] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0160] CH3CN: Acetonitrile

[0161] CDI: N,N'-Carbonyldiimidazole

[0162] DCM: dichloromethane

[0163] DIPEA: N,N-diisopropylethylamine

[0164] EA: Ethyl acetate

[0165] HCl: Hydrogen chloride

[0166] HCl / EA: Hydrogen chloride in ethyl acetate

[0167] H2O: water

[0168] NaOH: Sodium hydroxide

[0169] NaI: Sodium iodide

[0170] K2CO3: Potassium carbonate

[0171] rt, rt: room temperature

[0172] DCC: dicyclohexylcarbodiimide

[0173] DMAP: 4-dimethylaminopyridine

[0174] Example 1: Synthesis of Compound 1

[0175]

[0176] Compound 1-1 (2 g, 3.657 mmol) (compound 1-1 was synthesized by referring to the method described in WO2018137683) was added to a 100 mL single-mouth bottle, dissolved in dichloromethane (20 mL), and stirred under an ice-water bath. Meta-chloroperbenzoic acid (0.44 g, 2.550 mmol) was added in batches, stirred under an ice bath, and then stirred at room temperature for 3.5 hours. Meta-chloroperbenzoic acid (0.44 g, 2.550 mmol) was added and stirred at room temperature for 1 hour. Filter and rinse the filter cake with dichloromethane. Wash the filtrate with 20 mL of saturated sodium bicarbonate aqueous solution and separate the liquids. The aqueous phase was extracted again with 15 mL of dichloromethane, and the combined organic phases were washed once with 30 mL of saturated brine and dried over anhydrous sodium sulfate for 2 hours. Filter and rotary evaporate the organic phase to obtain a crude product of 2.14 g of white solid. 1.3 g of white powder compound 1 was obtained after column chromatography.

[0177] 1 H NMR(500MHz,Chloroform-d)δ10.93(s,1H),7.84(dd,J=7.9,1.8Hz,1H),7.45(ddd,J=8.7,7.2, 1.8Hz,1H),6.98(dd,J=8.4,1.1Hz,1H),6.92–6.84(m,1H),4.78(dd,J=11.4,4.4Hz,1H),2.69( t,J=6.2Hz,1H),2.19–2.00(m,4H),2.00–1.89(m,1H),1.89–1.67(m,6H),1.69–1.46(m,10H),1 .46–1.34(m,3H),1.33–1.17(m,10H),1.06(d,J=4.8Hz,6H),1.02–0.84(m,9H),0.72(s,3H)ppm.

[0178] Example 2: Synthesis of Compound 2

[0179]

[0180] Compound 1 (100 mg, 0.178 mmol) was added to a 25 mL single-mouth bottle, dissolved with 2-propanol (2.5 mL) and H2O (1 mL), and then hypophosphorous acid (0.18 mL, 1.786 mmol) (50% aqueous solution) was added, and heated and stirred at 80°C for 2 hours. After TLC spot plate detection, heating was stopped, and 5 mL of purified water was added to the reaction solution to quench the reaction. A large amount of white solid precipitated, and stirred at room temperature for 1 hour. Filter, rinse the filter cake with purified water, and dry the filter cake at 50°C for 16 hours to obtain 80 mg of white solid compound 2.

[0181] 1 H NMR (500MHz, Chloroform-d) δ10.93 (s, 1H), 7.84 (dd, J=8.0, 2.0Hz, 1H), 7.45 (t, J= 7.8Hz,1H),6.98(d,J=8.4Hz,1H),6.88(t,J=7.6Hz,1H),4.78(dd,J=11.5,4.4Hz,1 H),3.39–3.24(m,1H),2.16–1.90(m,5H),1.82(dt,J=30.4,11.7Hz,4H),1.68(s,10 H),1.62–1.32(m,7H),1.31–1.11(m,10H),1.09–0.95(m,8H),0.95–0.86(m,5H)ppm.

[0182] Example 3: Synthesis of Compound 3

[0183]

[0184] Add 2g of lanosterol to a 50mL single-mouth bottle, stir with 30mL of dichloromethane at room temperature to dissolve, then add 3.4g of compound 3-1, 1.3g of DMAP, and 2.1g of DCC, and stir at room temperature for 64 hours. Filter, rinse the filter cake with dichloromethane, and spin dry the filtrate. Add 40mL of methanol and heat to reflux for 3 hours, stir at room temperature for 2 hours, filter, rinse the filter cake with methanol, and obtain 7.3g of light yellow solid filter cake, which is air-dried at 50℃ for 16 hours. Weigh 3.9g of crude product as light yellow solid, add 60mL of acetone, heat to reflux for 2 hours, then slowly cool to room temperature, stir for 2 hours, filter, rinse the filter cake with acetone, and air-dry at 50℃ for 4 hours. Weigh 2.3g of compound 3-2 as white powder, with a yield of 64%.

[0185] 1H NMR(500MHz,Chloroform-d)δ7.69–7.60(m,2H),7.51–7.43(m,2H),6.97(d,J=2.5Hz,1H),6.89(d,J=9.0Hz,1H),6.67(dd,J=9. 0,2.5Hz,1H),5.10(ddd,J=8.7,4.4,1.6Hz,1H),4.50(dd,J=11.8,4.4Hz,1H),3.83(s,3H),3.66(d,J=2.7Hz,2H),2.38(s,3H), 2.09–1.95(m,5H),1.93–1.81(m,2H),1.76–1.65(m,6H),1.64–1.58(m,4H),1.54(s,8H),1.51–1.44(m,2H),1.36–1.24(m,4H), 1.21–1.09(m,2H),1.07–1.00(m,1H),0.98(s,3H),0.91(d,J=6.3Hz,3H),0.86(s,3H),0.78(d,J=11.2Hz,6H),0.68(s,3H)ppm.

[0186] Add compound 3-2 (2g, 2.609mmol) to a 100mL single-mouth bottle, dissolve with DCM (20mL), and stir in an ice-water bath. Add 3-chloroperoxybenzoic acid (0.44g, 2.550mmol) in batches, stir and react in an ice bath, and then stir and react at room temperature for 3.5 hours. Sample TLC spot plate, the raw material has not reacted completely, add 3-chloroperoxybenzoic acid (0.44g, 2.550mmol), stir and react at room temperature for 1 hour. Filter, and rinse the filter cake with DCM. Wash the filtrate with 20mL saturated sodium bicarbonate aqueous solution and 20mL saturated sodium sulfite aqueous solution, and separate the liquids. Add 15mL DCM to the aqueous phase and extract it again, combine the organic phases, wash them once with 30mL saturated brine, and dry them over anhydrous sodium sulfate for 2 hours. Filter and concentrate the solvent under reduced pressure. The crude product is purified by column chromatography to obtain 0.33g of light yellow solid compound 3.

[0187] 1H NMR(500MHz,Chloroform-d)δ7.64(d,J=8.4Hz,2H),7.49–7.41(m,2H),6.97(d,J=2.4Hz,1H),6.88(d,J=9.2Hz,1H),6. 67(dd,J=9.2,2.4Hz,1H),4.50(dd,J=11.6,4.4Hz,1H),3.83(s,3H),3.66(d,J=2.8Hz,2H),2.68(t,J=6.4Hz,1H),2.38( s,3H),2.08–1.87(m,5H),1.78–1.66(m,3H),1.65–1.54(m,2H),1.53–1.40(m,2H),1.28(d,J=21.4Hz,7H),1.22–1.15( m,1H),1.12(d,J=12.4Hz,1H),0.98(s,3H),0.91(d,J=6.0Hz,3H),0.87(s,3H),0.78(d,J=11.2Hz,6H),0.69(s,3H)ppm.

[0188] Example 4: Synthesis of Compound 4

[0189]

[0190] Compound 3 (300 mg, 0.383 mmol) was added to a 25 mL single-mouth bottle, dissolved with 2-propanol (8 mL) and H2O (2 mL), and then hypophosphorous acid (0.29 mL, 5.751 mmol) (50% aqueous solution) was added, and heated and stirred at 80°C for 16 hours. After TLC detection, heating was stopped, and 20 mL of purified water was added to the reaction solution to quench the reaction. A large amount of white solid precipitated, and stirred at room temperature for 1 hour. Filter, rinse the filter cake with purified water, and dry the filter cake at 50°C for 2 hours. The crude product was purified by column chromatography to obtain 160 mg of light yellow solid compound 4.

[0191] 1H NMR (500MHz, DMSO-d6) δ7.65(s,4H),7.03(d,J=2.4Hz,1H),6.93(d,J=9.2Hz,1H),6.71(dd,J=9.2,2.4Hz,1H),4.37(dd,J=10.4,5.6H z,1H),4.15(dd,J=22.0,5.6Hz,1H),3.97(d,J=8.4Hz,1H),3.76(d,J=4.4Hz,5H),2.99(ddd,J=26.4,9.2,5.2Hz,1H),2.24(s,3H),2. 08–1.94(m,4H),1.95–1.83(m,1H),1.77–1.53(m,7H),1.50–1.28(m,3H),1.26–1.09(m,3H),1.06(dd,J=12.4,2.0Hz,1H),1.03(s,3H ),0.98(d,J=2.0Hz,3H),0.95(s,3H),0.87(d,J=6.8Hz,2H),0.85(d,J=3.6Hz,4H),0.74(d,J=12.0Hz,6H),0.66(d,J=2.4Hz,3H)ppm.

[0192] Example 5: Synthesis of Compound 5 and Compound 6

[0193]

[0194]

[0195] Add 0.5g lanosterol to a 25mL single-mouth bottle, stir and dissolve with 7.5mL dichloromethane at room temperature, then add 0.6g compound 5-1, 0.315g DMAP, 0.532g DCC in turn, and stir at room temperature for 64 hours. Filter, rinse the filter cake with dichloromethane, and spin dry the filtrate. Add 15mL methanol and heat to reflux for 3 hours, stir at room temperature for 16 hours, filter, rinse the filter cake with methanol, and get 1.2g white solid filter cake, which is air-dried at 40℃ for 16 hours. Weigh the crude product 0.71g white solid, add 15mL acetone and heat to reflux for 2 hours, then slowly cool to room temperature, stir for 2 hours, filter, rinse the filter cake with acetone, and air-dry at 50℃ for 4 hours. Weigh 0.55g of compound 5-2 white powder.

[0196] 1H NMR(500MHz,Chloroform-d)δ8.17(d,J=3.5Hz,1H),7.52–7.54(t,1H),7.12–7.15(d,J=16Hz,2H),7.09–7.11(d, J=8.5Hz,1H),7.03–7.04(dd,J=5Hz,1H),5.12(m,1H),4.42–4.52(dd,1H),4.09(s,2H),3.66–3.67(m,1H),2.03–2 .01(m,5H),2.01–1.99(m,2H),1.68–1.70(m,2H),1.59–1.66(m,10H),1.60(d,J=16.3Hz,6H),1.31–1.58(m,5H),1 .25–1.28(m,3H),0.97–0.98(d,J=6.5Hz,3H),0.89–0.91(m,3H),0.77–0.86(m,8H),0.67(m,2H),0.33(m,5H)ppm.

[0197] Compound 5-2 (1 g, 1.506 mmol) was added to a 100 mL single-mouth bottle, dissolved in DCM (15 mL), and stirred under an ice-water bath. 3-Chloroperoxybenzoic acid (0.61 g, 3.535 mmol) was added in batches, stirred under an ice bath, and then stirred at room temperature for 16 hours. Post-treatment purification gave compound 5 (0.25 g) as a white solid and compound 6 (0.33 g) as a white solid.

[0198] Compound 5: 1H NMR(500MHz,Chloroform-d)δ8.18(dd,J=4.8,2.0Hz,1H),7.65–7.47(m,1H),7.17(dd,J=8.4,2.0Hz,1H),7.14–7.08(m,2H),7.03( dd,J=7.4,4.8Hz,1H),4.47(dt,J=11.8,6.2Hz,1H),4.09(d,J=3.8Hz,2H),3.67(q,J=7.5Hz,1H),2.68(t,J=6.1Hz,1H),2.15–1.85 (m,5H),1.75–1.63(m,2H),1.59(td,J=13.7,13.2,7.9Hz,2H),1.50(t,J=6.9Hz,4H),1.30(s,4H),1.26(s,3H),1.21–1.13(m,1H), 1.09(d,J=12.6Hz,1H),0.98(d,J=6.1Hz,3H),0.91(d,J=6.1Hz,3H),0.88–0.82(m,5H),0.77(s,3H),0.68(s,3H),0.64(s,2H)ppm.

[0199] Compound 6: 1 H NMR(500MHz,Chloroform-d)δ8.18(dd,J=4.8,1.9Hz,1H),7.65–7.47(m,1H),7.17(dd,J=8.4,2.2Hz,1H),7.14–7.08(m,2H),7.03( dd,J=7.4,4.8Hz,1H),4.47(dt,J=11.8,6.2Hz,1H),4.09(d,J=3.8Hz,2H),3.67(q,J=7.5Hz,1H),2.68(t,J=6.1Hz,1H),2.15–1.85 (m,5H),1.75–1.63(m,2H),1.59(td,J=13.7,13.2,7.9Hz,2H),1.50(t,J=6.9Hz,4H),1.30(s,4H),1.26(s,3H),1.21–1.13(m,1H), 1.09(d,J=12.6Hz,1H),0.98(d,J=6.1Hz,3H),0.91(d,J=6.1Hz,3H),0.88–0.82(m,5H),0.77(s,3H),0.68(s,3H),0.64(s,2H)ppm.

[0200] Example 6: Synthesis of Compound 7 and Compound 8

[0201]

[0202] In a 100mL single-mouth bottle, dissolve 2g of lanosterol in 30mL of dichloromethane, stir at room temperature until dissolved, add 2.3g of compound 7-1, 1.3g of DMAP, and 2.1g of DCC, and stir at room temperature (22.4°C) for 64 hours. Filter, wash the filter cake with dichloromethane, and concentrate the filtrate to obtain a yellow oil. Add 30mL of methanol, heat and stir at 80°C for 2 hours, stir at room temperature for 3 hours, and no solid precipitates. After concentration, column chromatography purification is performed to obtain 2.7g of colorless oil compound 7-1.

[0203] 1 H NMR(500MHz,Chloroform-d)δ7.24–7.16(m,2H),7.10(dd,J=8.1,3.9Hz,2H),5.10(ddt,J=8.5,7.0,1.4Hz,1H),4.45(td,J =11.1,4.5Hz,1H),3.67(d,J=7.3Hz,1H),3.16–3.06(m,1H),2.59–2.50(m,1H),2.39–2.28(m,2H),2.14–1.80(m,10H),1.78 –1.64(m,8H),1.60(d,J=1.2Hz,3H),1.55(s,6H),1.52–1.45(m,6H),1.35–1.21(m,4H),1.19–1.12(m,1H),0.97(d,J=5.5H z,3H),0.91(d,J=6.3Hz,3H),0.86(d,J=3.1Hz,3H),0.83–0.77(m,2H),0.73(s,2H),0.68(s,3H),0.59(d,J=1.3Hz,2H)ppm.

[0204] Compound 7-1 (1 g, 1.527 mmol) was added to a 100 mL single-mouth bottle, dissolved in DCM (15 mL), and stirred under an ice-water bath. 3-Chloroperoxybenzoic acid (0.62 g, 3.593 mmol) was added in batches, stirred under an ice bath, and then stirred at room temperature for 2.5 hours. Post-treatment and purification gave compound 7 (0.4 g) as a white solid and compound 8 (0.6 g) as a white solid.

[0205] Compound 7: 1H NMR(500MHz,Chloroform-d)δ7.21(d,J=7.8Hz,2H),7.09(d,J=7.9Hz,2H),4.45(td,J=11.2,4.2Hz,1H),3.68(dq ,J=14.9,7.4Hz,1H),3.26–2.95(m,1H),2.68(t,J=6.3Hz,1H),2.55(td,J=16.2,14.0,9.3Hz,1H),2.32(q,J=8.8 Hz,2H),2.15–1.85(m,9H),1.79–1.64(m,3H),1.59(dt,J=12.6,6.7Hz,1H),1.50(dd,J=18.2,10.2Hz,5H),1.37– 1.22(m,6H),1.21–1.03(m,1H),0.97(d,J=5.8Hz,2H),0.94–0.78(m,6H),0.71(d,J=23.3Hz,4H),0.59(s,2H)ppm.

[0206] Compound 8: 1 H NMR(500MHz,Chloroform-d)δ7.20(d,J=7.7Hz,2H),7.08(d,J=7.4Hz,2H),4.42(q,J=7.7,4.7Hz,1H),3.66(dq,J=14.4,7.2Hz, 1H),3.10(td,J=10.4,9.7,4.7Hz,1H),2.67(t,J=6.2Hz,1H),2.59–2.48(m,1H),2.32(q,J=8.4Hz,2H),2.14–1.99(m,3H),1.87 (ddd,J=41.6,15.5,7.1Hz,4H),1.70(dt,J=17.5,7.6Hz,3H),1.63–1.54(m,2H),1.49(q,J=8.2,7.4Hz,4H),1.36(dd,J=18.6,7 .5Hz,1H),1.28(d,J=23.0Hz,6H),1.11(d,J=5.3Hz,3H),0.95–0.83(m,6H),0.77(d,J=8.5Hz,4H),0.69(s,2H),0.52(s,2H)ppm.

[0207] Example 7: Synthesis of Compound 9

[0208]

[0209] In a 100mL single-mouth bottle, dissolve 2g of lanosterol in 30mL of dichloromethane, stir at room temperature until dissolved, add 2.4g of compound 9-1, 1.3g of DMAP, and 2.1g of DCC, and stir at room temperature (22.4°C) for 64 hours. Filter, wash the filter cake with dichloromethane, and concentrate the filtrate to obtain a yellow oil. Add 30mL of methanol, heat and stir at 80°C for 2 hours, stir at room temperature for 3 hours, a large amount of white solid precipitates, and dilute with 10mL of methanol. Filter, wash the filter cake with methanol, and air dry at 50°C for 5 hours to obtain 2.5g of white solid crude product. Add 10mL of isopropanol and 10mL of isopropyl acetate to the crude product, stir at 50°C for 16 hours, and stir at room temperature for 3 hours. Filter, air dry the filter cake for 16 hours to obtain 1.86g of compound 9-2 as a white solid.

[0210] 1 H NMR(500MHz,Chloroform-d)δ7.82–7.73(m,3H),7.67(dq,J=7.6,1.4Hz,1H),7.62–7.53(m,2H),7.45(dt,J=22.5,7.7Hz,3H ),5.14–5.06(m,1H),4.47(dd,J=11.8,4.5Hz,1H),3.84–3.74(m,1H),2.10–1.80(m,8H),1.77–1.62(m,7H),1.63–1.52(m,11 H),1.52–1.35(m,5H),1.34–1.23(m,4H),1.16(ddd,J=12.0,9.4,2.2Hz,1H),1.12–1.07(m,1H),1.06–1.00(m,1H),0.97(d, J=2.6Hz,3H),0.91(d,J=6.3Hz,3H),0.86(d,J=3.1Hz,3H),0.81(d,J=5.8Hz,1H),0.74(s,3H),0.68(s,3H),0.64(s,2H)ppm.

[0211] Compound 9-2 (1.56 g, 2.353 mmol) was added to a 25 mL single-necked bottle, dissolved with 2-propanol (25 mL) and H2O (10 mL), and then hypophosphorous acid (2.3 mL, 22.97 mmol) (50% aqueous solution) was added, and heated and stirred at 80°C for 1 hour. After post-treatment and purification, 0.75 g of white solid compound 9 was obtained.

[0212] 1H NMR(500MHz,Chloroform-d)δ7.81–7.74(m,3H),7.71(s,2H),7.67(d,J=7.7Hz,1 H),7.59(t,J=7.5Hz,1H),7.55(d,J=7.8Hz,1H),7.48(t,J=7.6Hz,2H),7.43(t,J =7.7Hz,1H),5.48–5.41(m,1H),5.30(d,J=6.2Hz,1H),4.47(dt,J=11.0,5.4Hz,1 H),3.79(q,J=7.1Hz,1H),3.39–3.27(m,1H),2.21(d,J=17.7Hz,1H),2.12–1.93( m,5H),1.76–1.63(m,2H),1.59(t,J=10.2Hz,1H),1.54(d,J=7.3Hz,2H),1.48(dd ,J=13.4,4.1Hz,0H),1.38(ddt,J=18.0,13.9,7.2Hz,2H),1.22(s,2H),1.19–1.1 0(m,4H),0.97(s,3H),0.90(dq,J=7.3,3.2Hz,3H),0.87(s,3H),0.81(s,3H),0.7 3(s,1H),0.68(d,J=2.6Hz,1H),0.64(d,J=2.5Hz,3H),0.56(d,J=2.8Hz,3H)ppm.

[0213] Example 8: Synthesis of Compound 10 and Compound 11

[0214]

[0215] Lanosterol (0.488 g, 1.144 mmol) was added to a 50 mL single-mouth bottle, and dissolved by stirring with 10 mL of dichloromethane at room temperature, and then compound 10-1 (0.568 g, 2.325 mmol), DMAP (0.325 g, 2.66 mmol), and DCC (0.55 g, 2.66 mmol) were added, and stirred at room temperature for 70 hours. After post-treatment, silica gel column chromatography was used for purification to obtain 0.742 g of compound 10-2 as a white powder.

[0216] 1H NMR(500MHz,Chloroform-d)δ7.54(d,J=7.1Hz,2H),7.44(t,J=7.6Hz,2H),7.37(p,J=7.7Hz,2H),7.18–7.11(m,2H),5.10( t,J=7.2Hz,1H),4.51(ddd,J=11.5,9.1,4.5Hz,1H),3.86–3.63(m,1H),2.10–1.97(m,6H),1.96–1.81(m,5H),1.75–1.65(m ,7H),1.60(s,4H),1.54(q,J=5.5,5.0Hz,3H),1.48(t,J=9.2Hz,1H),1.44–1.35(m,1H),1.29(ddd,J=19.2,9.1,5.0Hz,2H) ,1.21–1.08(m,2H),0.99(d,J=4.9Hz,4H),0.91(d,J=6.3Hz,3H),0.88–0.83(m,6H),0.80(s,2H),0.68(d,J=1.9Hz,6H)ppm.

[0217] Compound 10-2 (0.4 g, 0.613 mmol) was added to a 100 mL single-mouth bottle, dissolved in DCM (10 mL), and stirred under an ice-water bath. 3-Chloroperoxybenzoic acid (0.159 g, 0.919 mmol) was added in batches, stirred under an ice bath, and then stirred at room temperature for 16 hours. Post-treatment and purification gave compound 10 (0.271 g) as a white solid and compound 11 (0.08 g) as a white solid, with a yield of 85.65%.

[0218] Compound 10: 11H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.37 (p, J = 7.8 Hz, 2H), 7.14 (dd, J = 15.2, 9.9 Hz, 2H), 4.50 (td, J = 11.6, 10.5, 4.3 Hz, 1H), 3.75 (dd, J = 10.3, 6.8 Hz, 1H), 2.68 (t, J = 6.2 Hz, 1H), 2.01 (d, J = 9.1 Hz, 5H), 1.92 (d, J = 16.1 Hz, 4H), 1.77–1.66 (m, 3H), 1.61 (d, J = 12.2 Hz, 1H), 1.57–1.51 (m, 30H), 1.28 (d, J = 21.3 Hz, 7H), 1.18 (t, J = 11.2 Hz, 1H), 1.11 (d, J = 13.2 Hz, 1H), 0.99 (d, J = 4.8 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 10.1 Hz, 5H), 0.79 (s, 2H), 0.68 (d, J = 5.6 Hz, 5H) ppm.

[0219] Compound 11: 1 1H NMR (500 MHz, Chloroform-d) δ 7.57–7.50 (m, 2H), 7.44 (dt, J = 8.8, 4.4 Hz, 2H), 7.40–7.33 (m, 2H), 7.14 (dt, J = 18.5, 9.6 Hz, 2H), 4.49 (ddt, J = 15.5, 11.4, 5.5 Hz, 1H), 3.84–3.61 (m, 1H), 2.77–2.60 (m, 1H), 2.06–1.81 (m, 2H), 1.71 (dd, J = 12.6, 5.0 Hz, 2H), 1.61 (dd, J = 15.8, 11.9 Hz, 1H), 1.53 (d, J = 6.6 Hz, 6H), 1.44–1.33 (m, 2H), 1.28 (dd, J = 22.3, 3.4 Hz, 7H), 1.12 (d, J = 5.1 Hz, 2H), 0.99 (d, J = 4.6 Hz, 1H), 0.89 (tq, J = 7.4, 3.6 Hz, 8H), 0.81 (d, J = 12.5 Hz, 1H), 0.76 (d, J = 6.6 Hz, 3H), 0.68 (d, J = 3.9 Hz, 1H), 0.62 (s, 1H), 0.57 (s, 1H) ppm.

[0220] Example 9: Synthesis of Compound 12

[0221]

[0222] Weigh the raw material (Compound 1-1) (Compound 1-1 was synthesized according to the method described in WO2018137683) (5.47 g, 10 mmol) in a reaction flask, stir and dissolve with 200 mL of tetrahydrofuran and 50 mL of water, and then cool and stir at -15 ° C. Add NBS (2.14 g, 12 mmol) in batches, and stir and react at -15 ° C for 1 hour. Sample TLC detection shows that the raw material is completely consumed. Saturated aqueous sodium sulfite solution was added at room temperature to quench the reaction, the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and brine, respectively, and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography gave 2.63 g of white solid compound 12.

[0223] 1 H NMR(500MHz,Chloroform-d)δ10.93(s,1H),7.84(dd,J=8.0,1.7Hz,1H),7.48–7.40(m,1H),6.98(d,J=8.4Hz, 1H),6.88(t,J=7.5Hz,1H),4.79(dd,J=11.4,4.4Hz,1H),3.99(ddd,J=25.3,10.4,2.8Hz,1H),2.13–1.95(m,7 H),1.88–1.67(m,6H),1.56(dddd,J=39.9,14.9,10.4,7.1Hz,3H),1.45–1.38(m,2H),1.36(d,J=11.7Hz,9H), 1.24(dt,J=11.4,4.5Hz,3H),1.06(d,J=4.9Hz,8H),0.97(s,3H),0.92–0.87(m,5H),0.72(d,J=2.6Hz,4H)ppm.

[0224] Other compounds provided by the present invention can be synthesized by replacing the corresponding raw materials according to the above-mentioned route.

[0225] Example 10: Effects of Compounds on SREBP-2 Signaling Pathway

[0226] 1. The cell line used in the experiment is human liver cancer cell HepG2 cell

[0227] 2. Test methods

[0228] 2.1. Compound preparation:

[0229] After the compound was dissolved to 100 μM in dichloromethane, an equal volume of anhydrous ethanol was added to dilute the test sample to 50 μM.

[0230] 2.2. QPCR detection of the inhibitory effect of compounds on SREBP-2 and HMGCR gene activities

[0231] Cell culture and treatment: HepG2 cells were cultured in vitro in a monolayer in DMEM high glucose supplemented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin, 37°C, 5% CO2, and a certain humidity incubator; after passage and amplification, when the cells were in the logarithmic growth phase, they were seeded in a 24-well plate at a density of 8×104 cells / well and placed at 37°C, 5% CO2 for 24 hours to allow the cells to adhere to the wall. After that, 25 μM of the compound was added to each well of the drug-treated group, and a control group (with an equal volume of solvent as the experimental group) was set up, and the pre-incubation continued for 48 hours. RNA extraction was performed after the incubation.

[0232] RNA extraction (using Vazyme's FastPure Cell / Tissue Total RNA Isolation Kit V2): Incubate the 24-well plate with the sample to be tested, discard the culture medium, add 500μL Buffer RL to each well for digestion and lysis, and repeatedly pipette 10 times to fully lyse the cells. Transfer the lysed sample to the FastPure gDNA-Filter ColumnsⅢ adsorption column and centrifuge at 12000rpm (13400×g) for 30s. Discard the adsorption column and collect the filtrate. Add 0.5 times the volume of the filtrate to the filtrate with anhydrous ethanol and mix thoroughly. Transfer all the mixed solution obtained in the previous step to the FastPure RNA ColumnsⅢ adsorption column, centrifuge at 12000rpm (13400×g) for 30s, and discard the filtrate. Add 700μL Buffer RW1 to the adsorption column, centrifuge at 12000rpm (13400×g) for 30s, and discard the filtrate. Add 700μL Buffer RW2 to the adsorption column, centrifuge at 12000rpm for 30s, and discard the filtrate. Add 500μL Buffer RW2 to the adsorption column, centrifuge at 12000rpm for 2min, discard the filtrate, put the adsorption column back into the collection tube, and centrifuge at 12000rpm for 1min. Transfer the adsorption column to a new RNase-free Collection Tubes1.5mL centrifuge tube, add 50μL RNase-free dd H2O to the center of the adsorption column, let stand at room temperature for 1min, centrifuge at 12000rpm for 1min to elute RNA. Detect the sample concentration using a spectrophotometer.

[0233] QPCR (using HiScript II One Step qRT-PCR SYBR Green Kit from Vazyme):

[0234] The reaction system for each well is shown in Table 2 below (20 μL):

[0235] Table 2

[0236]

[0237] Each sample was repeated three times, and the loaded Light Cycler 480 system 96-well plate was placed in the qPCR instrument, a. 50℃ reverse transcription for 3min, b. 95℃ pre-denaturation for 30s, c. 95℃ denaturation for 10s, d. 60℃ annealing and extension for 30s, and the fluorescence signal was collected after the extension. ec-d cycles were repeated 40 times, and f. the melting curve was collected during the extension process. The relative content of mRNA was calculated using the comparative Ct method and standardized to the control group as 1.

[0238] 2.3. Test results statistics

[0239] Table 3

[0240]

[0241] Example 11: Cytotoxicity assay of compounds

[0242] This example uses the following method to detect the cytotoxicity of the compounds of the present invention:

[0243] 1. The cytotoxicity of the compound was detected by the MTT (3-(4,5-dimethyl-2-thiazole)-2,5-dimethylbenzene tetrazolium bromide) method. The method is to expose cells in the exponential growth phase to the compound, remove the compound, and then allow the cells to proliferate for 2 to 3 population doubling times, so that the proliferating surviving cells can be distinguished from the non-proliferating surviving cells, and then the number of surviving cells is determined by the MTT dye reduction reaction. The MTT-formazan product is dissolved in an appropriate solvent and quantified by spectrophotometry.

[0244] The specific steps include: suspending human lens epithelial cells and adding samples to a 96-well plate for culture, diluting the compound in multiples by at least 5 concentration gradients with culture medium, adding the compound when the cells enter the exponential growth phase, and setting up a control group without the addition of the compound; after adding the compound, continue to culture the cells until the end of the growth phase, add fresh culture medium and MTT to each well, wrap the culture plate with aluminum foil and culture for 4h to 8h, add DMSO to each well to dissolve the residual MTT-formazan crystals, then add glycine buffer to each well containing DMSO, and record the absorbance at 570nm.

[0245] A curve was drawn with drug concentration as the horizontal axis (X axis) and absorbance value as the vertical axis (Y axis) to obtain the percentage inhibition curve.

[0246] 2. Inoculate HLE-B3 cells in good condition into 12-well plates with a cell density of 40% to 50%; culture for about 24 hours, and the cell density is about 80%, then the cells can be transfected with crystallin αA-Y118D, αB-R120G, βB2-V187E, γC-G129C and γD-W43R mutants, and an empty control group. The specific operation is according to the transfection reagent Lipofectamine TM 2000; after 4 hours of transfection, the culture medium was changed to fresh DMEM and cultured for 16 hours, at which time the crystallin mutants were already expressed in large quantities in the cells; after being digested and dispersed with 0.25% trypsin (EDTA), the cells were inoculated into a 96-well plate with 2000 cells per well and cultured for 12 hours; the cell culture medium was changed to opti-MEM, and the compound of the present invention was added, two concentration gradients were set, the final concentration was 5uM or 50nM, and the cells were incubated for 12 hours; 10μL CKK-8 was added, the cells were incubated for 1 hour, and the absorbance was measured at 450nm.

[0247] Statistical analysis by the above method shows that the compounds provided by the present invention have no cytotoxicity to normal lens epithelial cells and cell lines transfected with various lens protein mutants, but instead improve cell viability to a certain extent.

[0248] It can be seen from the experimental results that the compound provided by the present invention has no toxic side effects on lens cells and has good safety.

[0249] Example 12: Determination of water solubility of compounds

[0250] In this example, the water solubility of the compound was determined by the following method.

[0251] 1. Determination of intrinsic solubility

[0252] Intrinsic solubility refers to the concentration of a saturated solution formed when the drug does not contain any impurities, does not dissociate or associate, and does not interact in the solvent. It is one of the important physical parameters of drugs, especially for new compounds.

[0253] The specific steps include: in the case of measuring several supersaturated solutions of different degrees, the prepared solution is kept at a constant temperature and continuously oscillated to reach dissolution equilibrium, after centrifugation or filtration, the supernatant is taken out and appropriately diluted, and the concentration of the drug in the saturated solution is measured. The measured drug solution concentration is used as the ordinate and the ratio of drug mass to solvent volume is used as the abscissa to draw a graph, and the characteristic solubility of the drug is obtained by extrapolating the straight line to the point where the ratio is zero.

[0254] 2. Determination of equilibrium solubility

[0255] The specific steps include: taking several portions of the drug, preparing a series of solutions ranging from unsaturated solutions to saturated solutions, oscillating under constant temperature conditions until equilibrium is reached, filtering through a filter membrane, taking the filtrate for analysis, determining the actual concentration S of the drug in the solution, and plotting the concentration c of the prepared solution. The turning point of the curve is the equilibrium solubility of the drug.

[0256] For the detailed steps of the above solubility determination, please refer to the provisions of the Chinese Pharmacopoeia 2020 edition.

[0257] The experimental results show that the compound provided by the present invention has good water solubility, is easily absorbed by the body, and has a good clinical application prospect.

[0258] Although the present invention has been described in detail above by means of general description, specific implementation methods and tests, it is obvious to those skilled in the art that some modifications or improvements may be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A steroidal compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I): in: A is -C(=O)-, -C(=S)-, -OC(=O)-, -NR 4 C(=O)-, -OP(=O)R 5 -, or -NR 4 P(=O)R 5 -; X is aminoalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl-OC(=O)-CR 6 R 7 -, alkyl-C(=O)O-CR 6 R 7 -, arylalkyl, hydroxyalkyl, mercaptoalkyl, aminoC(=O)-alkyl, arylalkyl, heteroarylalkyl or Q is hydrogen, hydroxyl, amino, arylamino, halogen, alkyl, carboxyl, phosphate, aryl, heteroaryl, monosaccharide, polysaccharide, cycloalkyl, cycloalkylalkyl, aryl-C(=O)-, R 8 OP(=O)OR 9 -O-, G is O or S; n is 0, 1 or 2; q is 0, 1, or 2; R 1 is hydrogen, deuterium, halogen, hydroxyl or alkyl; R 2 is halogen, hydroxyl, amino, alkyl, carboxyl, phosphoric acid, sulfonic acid or alkoxy; Or, R 1 , R 2 Together with the atoms to which it is attached, it forms a 3-7 membered ring which may or may not contain heteroatoms; R 3 and R 3’ are each independently hydrogen, deuterium, hydroxy, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl; R 4 and R 9 Each is independently H, alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl or alkoxyalkyl; R 5 and R 8 Each is independently hydroxy, alkoxy, alkyl-C(=O)O-(CR 10 R 11 ) m O-, alkyl-OC(=O)-(CR 10 R 11 ) m -NR 12 - or alkyl-C(=O)S-(CR 10 R 11 ) m O-; or R 5 and R 8 Form a P-containing heterocyclic ring with P; R 6 , R 7 , R 10 and R 11 each independently represents H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; R 12 is H, alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl or alkoxyalkyl; m is 1, 2 or 3; The R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, X or Q group is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl or heteroaryl; R a , R b , R c , R d , R e , R f , R g , R h each independently represents alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkylthio, halo- or hydroxy-substituted alkylthio, alkylamino, halo- or hydroxy-substituted alkylthio, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl or alkynyl; The hydrogen atoms on ring a, ring b, ring c and ring d are unsubstituted or at least one hydrogen atom is substituted by deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halogenated or hydroxy-substituted alkoxyalkyl, alkoxy, halo-substituted or hydroxy-substituted alkoxy, alkoxyalkoxy, halo-substituted or hydroxy-substituted alkoxyalkoxy, alkylamino, halo-substituted or hydroxy-substituted alkylamino, alkylthio, halo-substituted or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy.

2. The compound according to claim 1, characterized in that The compound has a structure as shown in formula (II) or formula (III), or is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II) or formula (III): In formula (II) and formula (III), Q, X, A, R 1 , R 2 , R 3 , R 3’ , q, and n are defined as in formula (I).

3. The compound according to claim 1 or 2, characterized in that R 1 is hydrogen, deuterium, halogen, hydroxyl or C 1-6 Alkyl; preferably hydrogen, deuterium, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl; R 2 For halogen, hydroxyl, amino, C 1-6 Alkyl, carboxyl, phosphate, sulfonic acid or C 1-6 Alkoxy; preferably F, Cl, Br, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, carboxyl, phosphate, sulfonate or methoxy, ethoxy or tert-butoxy; Or, R 1 , R 2 It forms a 3-7 membered O-containing heterocyclic ring with the atoms connected to it. Preferably, R 1 and R 2 Each is independently halogen or hydroxyl; Preferably, R 1 , R 2 and the atoms to which it is attached 4. The compound according to any one of claims 1 to 3, characterized in that R 3 is hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 Halogenated alkoxy C 1-6 alkyl; Preferably, R 3 is hydrogen, deuterium, hydroxy, F, Cl, Br, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl; or R 3’ is hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 Halogenated alkoxy C 1-6 alkyl; Preferably, R 3’ is hydrogen, deuterium, hydroxy, F, Cl, Br, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl.

5. The compound according to any one of claims 1 to 4, characterized in that R 4 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 Alkyl; preferably, R 4 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl; Or, R 9 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 Alkyl; preferably, R 9 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl.

6. The compound according to any one of claims 1 to 5, wherein X is C 1-6 Aminoalkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 1-6 Alkyl-OC(=O)-CR 6 R 7 -、C 1-6 Alkyl-C(=O)O-CR 6 R 7 -、C 6-10 Aryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, aminoC(=O)-C 1-6 Alkyl, C 2-9 Heteroaryl C 1-9 Alkyl or Preferably, X is aminomethyl, aminoethyl, imidazolylmethyl, imidazolylethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3- -thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolinyl , isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, methyl-OC(=O)-CR 6 R 7 -, ethyl-OC(=O)-CR 6 R 7 -, tert-butyl-OC(=O)-CR 6 R 7 -, methyl-C(=O)O-CR 6 R 7 -, ethyl-C(=O)O-CR 6 R 7 -, tert-butyl-C(=O)O-CR 6 R 7 -, phenylmethyl, phenylethyl, phenylpropyl, phenyl tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl, mercaptoethyl, mercaptopropyl, aminoC(=O)-methyl, aminoC(=O)-ethyl, aminoC(=O)-propyl, indolylmethyl, isoxazolylmethyl or 7. The compound according to any one of claims 1 to 6, wherein Q is H, hydroxyl, amino, C 6-10 Arylamino, halogen, C 1-6 Alkyl, carboxyl, phosphate, C 6-10 Aryl, C 2-9 Heteroaryl, monosaccharide, polysaccharide, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl-C(=O)-, R 8 OP(=O)OR 5 -O-, Wherein, the G is O or S; Preferably, Q is hydrogen, hydroxyl, amino, phenylamino, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carboxyl, phosphate, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, isoxazolyl, monosaccharide, polysaccharide, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylpropyl, phenyl-C(=O)-, naphthyl-C(=O)-, R 8 OP(=O)OR 9 -O-, 8. The compound according to any one of claims 1 to 7, wherein R 5 and R 8 Each is independently hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)O-(CR 10 R 11 ) m O-、C 1-6 Alkyl-OC(=O)-(CR 10 R 11 ) m -NR 12 - or C 1-6 Alkyl-C(=O)S-(CR 10 R 11 ) m O-, preferably hydroxy, methoxy, ethoxy, tert-butoxy, methyl-C(=O)O-(CR 10 R 11 ) m O-, ethyl-C(=O)O-(CR 10 R 11 ) m O-, tert-butyl-C(=O)O-(CR 10 R 11 ) m O-, methyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, ethyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, tert-butyl-OC(=O)-(CR 10 R 11 ) m -NR 12 -, methyl-C(=O)S-(CR 10 R 11 ) m O-, ethyl-C(=O)S-(CR 10 R 11 ) m O- or tert-butyl-C(=O)S-(CR 10 R 11 ) m O-; Or, R 5 , R 8 It forms a P-containing heterocyclic ring with the P atom connected thereto, preferably a six-membered P-containing heterocyclic ring.

9. The compound according to any one of claims 1 to 8, wherein R 6 , R 7 , R 10 and R 11 Each is independent of H and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl or C 2-9 Heterocyclic group; Preferably, R 6 , R 7 , R 10 and R 11 Each is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl; Or, R 12 H, C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy C 1-6 Alkyl; preferably, R 12 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenylmethyl, phenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl or ethoxymethyl.

10. The compound according to any one of claims 1 to 9, characterized in that Group R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 A, X or Q are optionally replaced by 1, 2, 3 or 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, oxo, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 2-9 substituted by a substituent in a heteroaryl group; Preferably, the group R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, X or Q are optionally replaced by 1, 2, 3 or 4 selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, trifluoroethyl, difluoromethyl, deuterated methyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, trifluoromethoxymethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy yl, methoxymethoxy, ethoxymethoxy, methylamino, ethylamino, methylthio, ethylthio, chlorophenyl, phenyl, naphthyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl , diazepine, thiazepine, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl The invention may be substituted by a substituent in oxadiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazol[1,5-a]pyridinyl, pyrazol[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

11. The compound according to any one of claims 1 to 10, characterized in that QX- is selected from the following groups: Phenyl, selected from hydroxy, phosphoryl, C 1-6 Alkyl, halogen substituted phenyl, biphenyl, selected from hydroxy, phosphoryl, C 1-6 biphenyl substituted with an alkyl or halogen substituent, and / or A is -C(=O)-.

12. The compound according to any one of claims 1 to 11, characterized in that Having the structure shown below, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

13. A composition, characterized in that The invention comprises the compound according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

14. Use of the compound according to any one of claims 1 to 12 or the composition according to claim 13 in the preparation of a medicament for preventing, treating, curing or alleviating a metabolic disease in a patient; Preferably, the metabolic disease is type 2 diabetes, hyperlipidemia, fatty liver or atherosclerosis.

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