Substituted pyridine compounds, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are substituted pyridine compounds, a preparation method therefor, and the use thereof. Provided in the present invention is the use of compounds represented by formula I, and stereoisomers, isotopically-labelled compounds, solvates, pharmaceutically acceptable salts thereof or solvates of the pharmaceutically acceptable salts of the compounds in preparing drugs for preventing and / or treating diseases, the diseases including hyperlipidemia, hyperglycemia, diabetes, obesity, cardiovascular diseases or tissue and organ fibrosis. It is discovered in the present invention that the substituted pyridine compounds exhibit good effects in the prevention and control for hyperlipidemia and hyperglycemia, are expected to achieve breakthroughs and fill existing gaps in the treatment of cardiovascular diseases and obesity and further solve the current problems of cardiovascular disease and obesity treatment drugs, and therefore have significant value in clinical applications.

Description

A substituted pyridine compound, a preparation method thereof, and an application thereof

[0001] This application claims priority to Chinese Patent Application No. 202411130801X, filed on August 16, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to a substituted pyridine compound, a preparation method thereof, and an application thereof. BACKGROUND

[0003] Hyperlipidemia and hyperglycemia are two major risk factors for cardiovascular disease. Obesity and type 2 diabetes (T2D) are increasingly serious health challenges, and the treatment needs are not met. CN113773316A discloses that a series of compounds have a significant effect in treating colorectal cancer. Currently, there is no report on the application of such compounds in the field of hyperlipidemia and hyperglycemia. Developing new applications of such compounds will have important value. SUMMARY

[0004] The technical problem to be solved by the present application is that there are few types of drugs in the prior art for treating hyperlipidemia, hyperglycemia, obesity, and the like. To this end, the present application provides a substituted pyridine compound, a preparation method thereof, and an application thereof. The present application finds that the substituted pyridine compound has good effects in the prevention and control of hyperlipidemia and hyperglycemia, and is expected to make a breakthrough in the treatment of cardiovascular diseases, obesity, and the like, fill the gap, and solve the problems existing in current cardiovascular disease treatment drugs and obesity drugs, which has important clinical application value. Further, the substituted pyridine compound also has outstanding curative effects in the treatment of tissue and organ fibrosis. On the other hand, the present application provides a series of new substituted pyridine compounds which also have outstanding curative effects in the treatment of tumors.

[0005] The present application solves the above technical problems by adopting the following technical solutions.

[0006] The present application provides a use of a compound as shown in Formula I, a stereoisomer thereof, an isotopically labeled compound thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating a disease or a disorder, wherein the disease or the disorder is hyperlipidemia, hyperglycemia, diabetes, obesity, fatty liver, cardiovascular disease, or tissue and organ fibrosis,

[0007] wherein,

[0008] Ring A is C 6-10 aryl, 5-10 membered heteroaryl, substituted with one or more R f ​substituted C 6-10 aryl or aryl substituted with one or more R f substituted 5-10 membered heteroaryl;

[0009] Z 1 and Z 2 are independently CH or N, and Z 1 and Z 2 at least one of which is N;

[0010] each R 0 , R 1 , and R 2 are independently H, deuterium, -NH2, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-6 cycloalkyl, -O-C 1-6 alkyl, -O-deuterated C 1-6 alkyl, cyano,

[0011] each R f is independently halogen, nitro, cyano, -O-C 1-6 alkyl, C 1-6 alkyl, -O-halogenated C 1-6 alkyl, or halogenated C 1-6 alkyl;

[0012] or, R 1 , R 2 and the atom to which they are attached together form a 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl substituted with one or more R a substituted 5-6 membered heterocyclyl, or 5-6 membered heteroaryl substituted with one or more R a substituted 5-6 membered heteroaryl, the kind of heteroatom or heteroatom group in the 5-6 membered heterocyclyl being selected from one, two, or three of N, O, C(O), and S, the total number of heteroatoms and heteroatom groups being one, two, or three;

[0013] each R a is independently C 1-6 alkyl, C 3-6 cycloalkyl, halogen, -NH2, hydroxyl, -O-C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C(O)-C 1-6 alkyl, or -O-C(O)-C 1-6 alkyl;

[0014] R a1 and R a2 are independently C 1-6 alkyl;

[0015] Ring E and t satisfy condition (1) or (2):

[0016] Condition (1): Ring E is C 6-10 aryl, 5-10 membered heteroaryl, substituted with one or more R d substituted C 6- 10 aryl or 5-10 membered heteroaryl substituted with one or more R d substituted C 5 and L 1 ; t is 1,

[0017] Condition (2): Ring E is Ring B is attached to Ring D, and t is 0;

[0018] each Ring B and Ring C is independently C 6-10 aryl or 5-10 membered heteroaryl;

[0019] each R b and R c is independently halogen or halogenated C 1-4 alkyl, each m1 and m2 is independently 0, 1 or 2;

[0020] R d is -O-C 1-6 alkyl;

[0021] is a single or double bond;

[0022] X 1 is C(O), CH2, NR e or O;

[0023] X 1a and X 2 are independently C, CH, N or O;

[0024] X 3 is CH2, NR e or O;

[0025] X 4 is C(O), CH2 or O;

[0026] X 5 is N or CH;

[0027] X 5a is C, N or CH;

[0028] each R e is independently H or C 1-4 alkyl;

[0029] n is 0 or 1;

[0030] L 1 is a single bond, C(O) or

[0031] L 2 is a single bond or -(CH2) m3 m3 is 1, 2, 3, 4, 5 or 6;

[0032] ring F is C 6-10 aryl or 5-10 membered heteroaryl;

[0033] each R 3 is independently halogen, nitro, cyano, -O-C 1-3 alkyl, C 1-3 alkyl, -O-haloC 1-3 alkyl, haloC 1-3 alkyl, -C(O)O-C 1-3 alkyl or

[0034] s is 1, 2 or 3;

[0035] the heteroatom species in each 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heteroaryl is independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0036] In a certain preferred embodiment, in the use of the compound of formula I, a stereoisomer thereof, an isotopically-labeled material thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any of the embodiments of the present application (the content of this paragraph is hereinafter referred to as "in a certain preferred embodiment").

[0037] In a certain preferred embodiment, the halogen or halo(alkyl) is independently F, Cl or Br; for example F.

[0038] In a certain preferred embodiment, the C 1-4 alkyl, C 1-6 alkyl, haloC 1-4 alkyl, C 1-4 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, -O-haloC 1-6 alkyl, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkyl, -O-haloC 1-6 alkyl, C 1-6 alkyl, -C(O)-C 1-6 alkyl, C1-6 alkyl and -O-C(O)-C 1-6 C in alkyl 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl (C 1-4 alkyl, for example methyl or ethyl.

[0039] In a certain preferred embodiment, the C 1-3 alkyl, -O-C 1-3 C in alkyl 1-3 alkyl, -O- haloC 1-3 C in alkyl 1-3 alkyl and haloC 1-3 C in alkyl 1-3 alkyl is independently methyl, ethyl, n-propyl or i-propyl, for example methyl or ethyl.

[0040] In a certain preferred embodiment, the C 6-10 aryl is independently phenyl or naphthyl.

[0041] In a certain preferred embodiment, the heteroatom species in the 5-10 membered heteroaryl and 5-6 membered heteroaryl is N, the number of heteroatoms is independently 1 or 2.

[0042] In a certain preferred embodiment, the 5-10 membered heteroaryl and 5-6 membered heteroaryl is independently a 5-membered heteroaryl or a 6-membered heteroaryl.

[0043] In a certain preferred embodiment, the 5-10 membered heteroaryl is pyrrolyl, pyrazolyl or imidazolyl; the 6-membered heteroaryl can be pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; for example pyridinyl.

[0044] In a certain preferred embodiment, the C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0045] In a certain preferred embodiment, the heteroatom or heteroatom species in the 5-6 membered heterocyclyl is selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom species is 1 or 2; the 5-6 membered heterocyclyl is a partially saturated 5-6 membered heterocyclyl, the number of alkenyl bonds in the partially saturated 5-6 membered heterocyclyl is 1 or 2, for example 1; for example the partially saturated 5-6 membered heterocyclyl is In a certain preferred embodiment, the heteroatom or heteroatom species in the 5-6 membered heterocyclyl is selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom species is 1 or 2; the 5-6 membered heterocyclyl is a partially saturated 5-6 membered heterocyclyl, the number of alkenyl bonds in the partially saturated 5-6 membered heterocyclyl is 1 or 2, for example 1; for example the partially saturated 5-6 membered heterocyclyl is

[0046] In a preferred embodiment, For Ring A is 5-10 membered heteroaryl; preferably, Ring A is 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl being N, the number of heteroatoms being independently 1 or 2; preferably, For

[0047] In a preferred embodiment, R 0 is H, deuterium, or C 1-4 alkyl, for example H or C 1-4 alkyl; for example H.

[0048] In a preferred embodiment, R 1 and R 2 are independently H, deuterium, amino, or cyano.

[0049] In a preferred embodiment, R 1 is H, deuterium, or cyano, for example R 1 is H or cyano, or R 1 is H or deuterium; for example H.

[0050] In a preferred embodiment, R 2 is H, deuterium, or amino, for example R 2 is H or amino, or R 2 is H or deuterium; for example H.

[0051] In a preferred embodiment, R 1 , R 2 , and the atoms to which they are attached together form a 5-6 membered heterocyclyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl substituted with one R a , the kind of heteroatom or heteroatom group in the 5-6 membered heterocyclyl being selected from one or two of N, O, and C(O), the total number of heteroatoms and heteroatom groups being 1 or 2; the heteroatom in the 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2; preferably, R 1 , R 2 , and the atoms to which they are attached together form a 5-6 membered heteroaryl or 5-6 membered heteroaryl substituted with one R a , the heteroatom in the 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2; more preferably, R 1 , R 2 , and the atoms to which they are attached together form a 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2.

[0052] In a preferred embodiment, each R a is independently C 1-6 alkyl; for example C1-4 alkyl.

[0053] In a certain preferred solution, R a1 and R a2 Independently for C 1-4 alkyl.

[0054] In a preferred embodiment, in condition (1), ring E is phenyl. Or by an R d The substituted phenyl group has ring B as a phenyl or a 5-6 membered heteroaryl group, wherein the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is one or two. Ring B is connected to ring D. 5 With L 1 Connection; t is 1; preferably, ring E is Ring B is a phenyl or a 5-6-membered heteroaryl group, wherein the heteroatom of the 5-6-membered heteroaryl group is N, and the number of heteroatoms is one or two; more preferably, ring E is... Ring B is phenyl.

[0055] In a certain preferred solution, in condition (2), ring E is... Ring B is a 5-6 membered heteroaryl group, wherein the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; ring C is phenyl, ring B is connected to ring D, and t is 0.

[0056] In a certain preferred solution, X 1 It is C(O) or CH2, for example C(O).

[0057] In a certain preferred solution, X 1a The answer is C.

[0058] In a certain preferred solution, X 2 It can be C or N.

[0059] In a certain preferred solution, X 3 CH2, NR e Or O; for example, O.

[0060] In a certain preferred solution, X 4 It is C(O) or CH2, for example CH2.

[0061] In a certain preferred solution, X 5 Let N be the number of elements in the array.

[0062] In a certain preferred solution, X 5a The answer is C.

[0063] In a certain preferred solution, each R b and R c Halogens are independent of each other.

[0064] In a preferred embodiment, ml is 0 or 1.

[0065] In a preferred embodiment, m2 is 1.

[0066] In a preferred embodiment, L 1 is a single bond.

[0067] In a preferred embodiment, L 2 is -(CH2) m3 , and m3 is 1, 2, 3, 4, 5 or 6.

[0068] In a preferred embodiment, ring F is C 6-10 aromatic or 5-6 membered heteroaromatic, the heteroatoms of which are N, the number of which is 1 or 2; for example, ring F is phenyl.

[0069] In a preferred embodiment, each R 3 is independently halogen or halogenated C 1-3 alkyl; for example, halogen.

[0070] In a preferred embodiment, s is 1 or 2.

[0071] In a preferred embodiment, the compound of formula I is a compound of formula I-1:

[0072] In a preferred embodiment, the compound of formula I is a compound of formula I-2:

[0073] for example

[0074] In a preferred embodiment, the compound of formula I is a compound of formula I-3:

[0075] In a preferred embodiment, the compound of formula I is a compound of formula I-1:

[0076] Z 1 and Z 2 are independently CH or N, and at least one of Z 1 and Z 2 is N;

[0077] R 0 is H, deuterium or C 1-4 alkyl;

[0078] R 1 , R 2 and the atom to which they are attached together form a 5-6 membered heteroaromatic; and asubstituted 5-6 membered heteroaryl, the heteroatoms of which are N, the number of which is 1 or 2;

[0079] each R a independently C 1-6 alkyl;

[0080] ring B is phenyl or 5-6 membered heteroaryl, the heteroatoms of which are N, the number of which is 1 or 2;

[0081] X 1 is C(O);

[0082] X 2 is C or N;

[0083] X 3 is O;

[0084] X 4 is CH2;

[0085] X 5 is N;

[0086] R b is halogen;

[0087] m1 is 0 or 1;

[0088] n is 0 or 1;

[0089] L 2 is -(CH2) m3 , m3 is 1, 2, 3, 4, 5 or 6;

[0090] ring F is C 6-10 aryl or 5-6 membered heteroaryl, the heteroatoms of which are N, the number of which is 1 or 2;

[0091] each R 3 independently halogen or halogenated C 1-3 alkyl;

[0092] s is 1 or 2.

[0093] In a preferred embodiment, R 0 is H or methyl.

[0094] In a preferred embodiment, R 1 is H or cyano.

[0095] In a preferred embodiment, R 2 is H or amino.

[0096] In a preferred embodiment, R amethyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, halogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, glycidoxypropyl, acetyl, acetyloxy, propionyl, propionyloxy; for example methyl.

[0097] In a preferred embodiment, R 1 , R 2 and the atom to which they are attached form

[0098] In a preferred embodiment, R is for example

[0099] In a preferred embodiment, R is Preferably, R is

[0100] In a preferred embodiment, ring C is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, naphthyl, phenanthryl, quinolyl, isoquinolyl, indolyl, benzodiazolyl, benzotriazolyl, or purinyl; preferably, ring C is phenyl.

[0101] In a preferred embodiment, ring B is phenyl, pyridyl, pyrazolyl (1,2 diazole) or imidazolyl (1,3 diazole).

[0102] In a preferred embodiment, R c is F, Cl, Br, trifluoroethyl or difluoromethyl, for example F.

[0103] In a preferred embodiment, R b is F, Cl, Br, trifluoroethyl or difluoromethyl, for example F.

[0104] In a preferred embodiment, R is

[0105] In a preferred embodiment, ring E is

[0106] In a preferred embodiment, -L 1 -L 2- is a single bond, methylene,

[0107] In a certain preferred embodiment, R 3 independently F, CF3or

[0108] In a certain preferred embodiment, ring F is phenyl, naphthyl,

[0109] In a certain preferred embodiment, is for example

[0110] In a certain preferred embodiment, the compound of formula I is any one of the following compounds:

[0111] In a certain preferred embodiment, the disease or disorder is obesity.

[0112] In a certain preferred embodiment, the cardiovascular disease is a cardiovascular disease caused by hyperlipidemia or hyperglycemia.

[0113] In a certain preferred embodiment, the obesity is obesity caused by an increase in fat (e.g. abdominal fat) and / or an increase in body weight.

[0114] In a certain preferred embodiment, the diabetes is diabetes caused by hyperglycemia, for example type II diabetes.

[0115] In a certain preferred embodiment, the diabetes is hyperglycemic diabetes.

[0116] In a certain preferred embodiment, the tissue organ fibrosis is tissue organ fibrosis associated with an increase in fat.

[0117] In a certain preferred embodiment, the disease or disorder is hyperlipidemia, hyperglycemia or diabetes.

[0118] In a certain preferred embodiment, the disease or disorder is fatty liver, for example non-alcoholic fatty liver or alcoholic fatty liver.

[0119] The present application provides use of a compound of formula I, a stereoisomer thereof, an isotopically-labeled material thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, as described in any of the embodiments, in the manufacture of a medicament for treating and / or preventing a disease or disorder associated with dysregulation of lipid droplet autophagy.

[0120] In one embodiment, the disease or condition associated with the dysregulation of lipid droplet autophagy is hyperlipidemia, obesity, or fatty liver; preferably, the fatty liver is non-alcoholic fatty liver or alcoholic fatty liver.

[0121] In this invention, lipid droplet autophagy disorder refers to the inability of lipid droplets to maintain normal levels of lipid droplets due to autophagy, resulting in abnormal accumulation of lipid droplets within the cell.

[0122] This invention provides a compound as shown in Formula II, its stereoisomer, its isotope label, its solvate, its pharmaceutically acceptable salt, or a solvate of a pharmaceutically acceptable salt thereof.

[0123] The compound shown in Formula II satisfies any of the following conditions:

[0124] (1) for R 1 When it is cyano; and s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or

[0125] (2) for R 1 R 2 Together with the atoms connected to it, they form a group bounded by an R a When the substituted 5-6 heteroaryl group is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or

[0126] (3)R 0 For deuterium, -NH2, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -O-deuterated C 1-6 Alkyl, cyano,

[0127] (4) for Z 2 Let N be the number of people in the group.

[0128] (5) for R 1 R 2 Together with the atoms attached to it, they form 5-6 membered heterocyclic groups or are bound by an R a Substituted 5-6 membered heterocyclic groups;

[0129] (6) for When ring A is a 5-10 membered heteroaryl group and s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or

[0130] (7) for

[0131] (8) Ring E is m1 is 1 or 2;

[0132] (9) Ring E is Ring B is a 5-10 member heteroaryl group;

[0133] (10) Ring E is

[0134] (11)X 3 CH2 or NR e When s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or

[0135] (12)L 1 For C(O) or And when s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or

[0136] (13)L 2 -(CH2) m3 m3 can be 2, 3, 4, 5 or 6;

[0137] (14) s is 2 or 3;

[0138] (15) ring F is a naphthalene ring or a 5-10 membered heteroaryl group;

[0139] wherein ring D, ring E, ring F, L 1 , L 2 , R 3 , s and t are as defined in any of the aspects of the present application.

[0140] In a preferred aspect, R 1 is cyano, R 2 is amino.

[0141] In a preferred aspect, R 1 , R 2 and the atom(s) to which they are attached form a 5-6 membered heterocyclyl group, a 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group substituted with one R a , the heteroatom(s) in said 5-6 membered heterocyclyl group or 5-6 membered heteroaryl group being selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom groups being 1 or 2; the heteroatom(s) in said 5-6 membered heteroaryl group being N, the number of heteroatoms being independently 1 or 2;

[0142] Preferably, R 1 , R 2 and the atom(s) to which they are attached form a 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group substituted with one R a , the heteroatom(s) in said 5-6 membered heteroaryl group being N, the number of heteroatoms being independently 1 or 2;

[0143] Alternatively, R 1 , R 2 and the atom(s) to which they are attached form a partially saturated 5-6 membered heterocyclyl group or a partially saturated 5-6 membered heterocyclyl group substituted with one R a , the heteroatom(s) in said partially saturated 5-6 membered heterocyclyl group being selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom groups being 1 or 2.

[0144] In a preferred aspect, ring A is a 5-6 membered heteroaryl group, the heteroatom(s) in said 5-6 membered heteroaryl group being N, the number of heteroatoms being 1 or 2.​​​​​

[0145] In a preferred embodiment, For R1and R2are independently H or deuterium.

[0146] In a preferred embodiment, ring E is Ring B is 5-6 membered heteroaryl, the heteroatom species of which is N, and the number of heteroatoms is 1 or 2.

[0147] In a preferred embodiment, X 3 is CH2or O.

[0148] In a preferred embodiment, ring F is naphthyl or 5-6 membered heteroaryl, the heteroatom of which is N, and the number of heteroatoms is 1 or 2, preferably ring F is 5-6 membered heteroaryl, the heteroatom of which is N, and the number of heteroatoms is 1 or 2.

[0149] In a preferred embodiment, the compound of formula II is a compound of formula I-1:

[0150] Z 1 and Z 2 are independently CH or N, and at least one of Z 1 and Z 2 is N;

[0151] R 0 is H, deuterium or C 1-4 alkyl;

[0152] R 1 , R 2 and the atom to which they are attached together form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the heteroatom of which is N, and the number of heteroatoms is 1 or 2;

[0153] each R a is independently C 1-6 alkyl;

[0154] Ring B is 5-6 membered heteroaryl, the heteroatom species of which is N, and the number of heteroatoms is 1 or 2.

[0155] X 1 is C(O);

[0156] X 2 is C or N;

[0157] X 3 is CH2or O;

[0158] X 4 is CH2;

[0159] X 5 is N;

[0160] R b is halogen;

[0161] m1 is 0 or 1 ;

[0162] n is 0 or 1 ;

[0163] L 2 is -(CH2) m3 , m3 is 1, 2, 3, 4, 5 or 6;

[0164] Ring F is C 6-10 aryl or 5-6 membered heteroaryl, the heteroatoms of which are N, the number of which is 1 or 2;

[0165] each R 3 is independently halogen or halogen-C 1-3 alkyl;

[0166] s is 1 or 2.

[0167] In a preferred embodiment, the compound of formula II is a compound of formula I-1 :

[0168] Z 1 and Z 2 are independently CH or N, and at least one of Z 1 and Z 2 is N;

[0169] R 0 is H, deuterium or C 1-4 alkyl;

[0170] R 1 , R 2 and the atoms to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one R a , the heteroatoms of which are N, the number of which is 1 or 2;

[0171] each R a is independently C 1-6 alkyl;

[0172] Ring B is phenyl or 5-6 membered heteroaryl, the heteroatoms of which are N, the number of which is 1 or 2;

[0173] X 1 is C(O);

[0174] X 2 is C or N;

[0175] X 3 is CH2or O;

[0176] X 4 is CH2;

[0177] X 5 is N;

[0178] R b is halogen;

[0179] m1is 0 or 1;

[0180] n is 0 or 1;

[0181] L 2 is -(CH2) m3 m3is 1, 2, 3, 4, 5 or 6;

[0182] ring F is naphthyl or 5-6 membered heteroaryl, the heteroatom species in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2;

[0183] each R 3 is independently halogen or halogenated C 1-3 alkyl;

[0184] s is 1 or 2.

[0185] The present application provides a preparation method of a compound shown in formula II as described in any one of the present application, which is any one of the following methods:

[0186] Method I: the compound shown in formula II is prepared by the following general method:

[0187] (1) compound 1 is dissolved in an organic solvent, and then reacted with a base and compound 2 to obtain compound 3;

[0188] (2) compound 3 is reacted with compound 4 (for example, pinacol diboronic acid), a palladium catalyst and a base in a solvent, and the reaction is carried out under the protection of an inert atmosphere to obtain compound 5;

[0189] In step (1), the organic solvent is selected from tetrahydrofuran;

[0190] In step (1), the base is selected from sodium hydride or potassium carbonate;

[0191] In step (1), the molar ratio of compound 1, base and compound 2 is 1.0:2-4:1-1.2;

[0192] In step (2), the base is selected from potassium acetate;​​​​​​​​​​​​​​​​​​​​​​

[0193] In step (2), the palladium catalyst is selected from palladium acetate, [1,1"-bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1"-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex or tris(dibenzylideneacetone)dipalladium;

[0194] In step (2), the solvent is selected from anhydrous dioxane, toluene, DMF or acetonitrile;

[0195] In step (2), the molar ratio of compound 3, compound 4 and base is 1.0:3.0~3.5:3.0~3.5;

[0196] In step (2), the inert gas is argon;

[0197] In step (2), the temperature of the reaction is 90~110℃;

[0198] In step (2), the time of the reaction is 12~15h;

[0199] In step (2), the inert gas is argon.

[0200] or

[0201] Method two: the compound shown as formula II is prepared by the following general method:

[0202] Method three: the compound shown as formula II is prepared by the following general method:

[0203] The following intermediates or raw materials used in the application can be directly purchased or prepared by referring to the existing methods:

[0204] The application provides a pharmaceutical composition comprising the compound shown as formula II, the stereoisomer thereof, the isotopically labeled compound thereof, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to any one of the application, and a pharmaceutical excipient.

[0205] The application provides application of the compound shown as formula II, the stereoisomer thereof, the isotopically labeled compound thereof, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to any one of the application in preparation of a drug for preventing and / or treating diseases or conditions, wherein the diseases or conditions are tumors, hyperlipidemia, hyperglycemia, diabetes, obesity, fatty liver, cardiovascular diseases or tissue and organ fibrosis.

[0206] In a certain preferred embodiment, the tumor is lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer, breast cancer or acute myeloid leukemia.

[0207] Definitions of terms

[0208] In addition to the foregoing, the following terms have the following meanings as indicated below, and as used in the specification and claims of this application unless otherwise specifically indicated.

[0209] As will be understood by those skilled in the art, the use of means that the respective group is attached to other fragments, groups in the compound via this site.

[0210] Herein, a substituent group can be preceded by a single dash "-", indicating attachment to the parent moiety by a single bond.

[0211] If a linking group is represented as "single bond", the structure on both sides of the linking group is directly connected by a single bond, for example -A-B-C-, when B is absent, -A-B-C- is -A-C-.

[0212] The term "stereoisomer" includes conformational isomers (e.g. (Z), (E) conformational isomers) and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present application can exist in the form of stereoisomers, and therefore all possible stereoisomer forms are encompassed, including but not limited to cis-trans isomers (geometric isomers), enantiomers, diastereoisomers, atropisomers, etc., and the compounds described in the present application can also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomer, racemate, equimolar mixture of atropisomers, and the like, such as a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof.

[0213] When the compounds described in the present application contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.

[0214] The solvate described in the present application can be in the form of a hydrate.

[0215] The term "pharmaceutically acceptable" means that the salt, solvent, adjuvant, etc. is generally non-toxic, safe, and suitable for use with patients.

[0216] In this invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable salts of the substituted pyridine compounds represented by Formula I of this invention refer to salts formed by the basic groups of the compound with acids, specifically salts formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, and phosphoric acid; salts formed with lower alkyl sulfonic acids, such as methanesulfonic acid and trifluoromethanesulfonic acid; salts formed with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; and salts formed with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, citric acid, malic acid, or succinic acid.

[0217] The term "isotope label" refers to a compound in which the isotopic abundance of one or more atoms differs from its natural abundance. For example, one or more atoms in a compound are replaced by atoms with a lower mass number found in nature—a hydrogen atom in the compound is replaced by deuterium. For example, in the substituted pyridine compounds of Formula I of the present invention, the hydrogen atom bonded to carbon may be replaced by the hydrogen isotope deuterium. Preferably, the alkyl groups of the present invention are replaced by deuterated alkyl groups, the alkoxy groups by deuterated epoxy groups, the benzene rings by deuterated benzene rings, and the aromatic rings by deuterated aromatic rings.

[0218] When any variable (e.g., R) 3 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 3 Group substitution, meaning that the group can be replaced by up to 3 R groups. 3 Replace, the position R 3 Definition and other positions R 3 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0219] In this invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, especially F, Cl or Br.

[0220] In this application, as a group or part of other groups (e.g., in haloalkyl, deuteralkyl, etc. groups), the term "alkyl" refers to a group having a specified number of carbon atoms (C). 1-6 C 1-4 C 1-3, straight or branched chain alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, i-pentyl n-hexyl, and the like.

[0221] In the present application, the term "cycloalkyl" as a group or part of a group refers to a saturated monocyclic or polycyclic carbocyclic ring substituent, and which can be attached to the remainder of the molecule through a single bond via any suitable carbon atom; such as 3-6 membered cycloalkyl groups having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0222] In the present application, the term "heterocycloalkyl" as a group or part of a group refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), preferably monocyclic.

[0223] In the present application, the term "heterocyclyl" as a group or part of a group refers to a stable, saturated or partially saturated, monocyclic or polycyclic, non-aromatic ring system consisting of carbon atoms and 1, 2, 3, 4, 5, or 6 heteroatoms or atom groups selected from N, O, C(O), and S; most preferably 3-8 membered heterocyclyl groups containing 1 or 2 heteroatoms or atom groups selected from N, O, and C(O), preferably partially saturated 5-6 membered heterocyclyl groups. Exemplary partially saturated heterocycloalkyl groups:

[0224] In the present application, the term "aryl" as a group or part of a group refers to a cyclic group consisting only of carbon atoms having a specified number of carbon atoms (e.g., C 6- 10 ) which is monocyclic or polycyclic, and each ring is aromatic (complies with Huckel's rule). Aryl groups include, but are not limited to, phenyl and naphthyl groups, and the like.

[0225] In the present application, the term "heteroaryl" as a group or part of a group refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 5-10 membered, 5-6 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), which is monocyclic or bicyclic, and each ring is aromatic when bicyclic. The heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, naphthyl, phenanthryl, quinolyl, isoquinolyl, indolyl, benzodiazolyl, benzotriazolyl, or purinyl.

[0226] Lipophagy is a selective autophagy process that regulates lipid levels and energy balance in cells by wrapping lipids in autophagosomes and transporting them to lysosomes for degradation.

[0227] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner to obtain various preferred embodiments of the present application.

[0228] The reagents and raw materials used in the present application are commercially available.

[0229] The positive progress effect of the present application is that the substituted pyridine compounds are found to have good effects in the prevention and control of hyperlipidemia and hyperglycemia, and also have good effects in the control of abdominal fat and weight control, and are expected to make a breakthrough in the treatment of cardiovascular diseases, obesity and the like to fill the gap, and solve the problems existing in current cardiovascular disease treatment drugs and obesity drugs, and have important clinical application value; further, the substituted pyridine compounds also have outstanding curative effects in the treatment of tissue and organ fibrosis. On the other hand, the series of new substituted pyridine compounds provided by the present application also have outstanding curative effects in the treatment of tumors.

[0230] The substituted pyridine compounds provided by the present application have the advantages of simple structure, easy synthesis, strong implementation, novel structure, strong plasticity, great potential for future modification, small toxic and side effects, fast metabolism, and safety in the treatment of tissue and organ fibrosis or tumors, the treatment and / or prevention of cardiovascular diseases. BRIEF DESCRIPTION OF DRAWINGS

[0231] Figure 1 is a blood glucose column chart of mice in different groups at 0, 30, 60, 90 and 120 minutes in a glucose tolerance test (30 min, ****p<0.0001 (compound Ia 100 mg / kg vs metformin 150 mg / kg); 60 min, **p<0.01 (compound Ia 100 mg / kg vs metformin 150 mg / kg; 120 min, *p<0.05 (compound Ia 100 mg / kg vs metformin 150 mg / kg).

[0232] Figure 2 is an animal dissection diagram of the present application for controlling the growth of abdominal fat in hyperglycemic mice.

[0233] Figure 3 is a fluorescence staining diagram of HepG2 cells treated with 10 μM ZK23.5 for 24 or 36 hours in a HepG2 cell model.

[0234] Figure 4 is a dynamic diagram of lipids in the observation of the state of lipids and lysosomes.

[0235] Figure 5 is a flow cytometry analysis chart of HepG2 cells after 24 hours of action in 10% FBS normal culture medium (DMSO, 10 mM ZK23.5) and low sugar culture medium (DMSO, 10 mM ZK23.5).

[0236] Figure 6 is a fluorescence staining chart of HepG2 cells after 24 hours of action in complete culture medium (DMSO, 10 mM ZK23.5). DETAILED DESCRIPTION

[0237] The present application is further illustrated by the following examples without thereby limiting the present application to the examples described. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions, or according to the product instructions.

[0238] The raw materials and equipment used in the specific embodiments of the present application are known products, which are obtained by purchasing commercially available products.

[0239] The 4-(3-methoxybenzyl)-8-(1H-pyrrolo[2,3-b]pyridine-5-yl)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Compound Ia or Compound ZK23.5) used in the specific embodiments of the present application is purchased from Shanghai Mofu Pharmaceutical Technology Co., Ltd., and the structural formula of Compound Ia is as follows:

[0240] The (400 MHz, DMSO-d6) hydrogen spectrum nuclear magnetic data is consistent with the data disclosed in Journal of Medicinal Chemistry (2022), 65(3), 1786-1807.

[0241] Effect Example 1: Materials and methods of animal experiment

[0242] I. Materials and methods

[0243] 1. Animal experiment

[0244] We have modeled and experimented with hyperlipidemia and hyperglycemia by the following methods. C57BL / 6J male mice were used, all mice were raised in the SKL Experimental Animal Center of the University of Science and Technology of Macau, the light-dark cycle was 12 hours, the environmental temperature was 22-25℃, the humidity was 30-70%, and the specific pathogen-free.

[0245] Hyperlipidemia model: 35 five-week-old C57BL / 6J male mice were divided into control group (7), model group (7), positive drug group (lovastatin 30 mg / kg / d: Selleckchem S2061, 7), low-dose drug group (50 mg / kg / d, 7) and high-dose drug group (100 mg / kg / d, 7). The mice were fed for 1 week of adaptive feeding. After 1 week of adaptive feeding, the mice were transferred to a 60% high-fat diet (D12492) for 6 weeks, and the body weight was recorded daily and the drug was prevented once a day.

[0246] Hyperglycemia model: 40 five-week-old C57 male mice were divided into control group (8), model group (8), positive drug group (metformin 150 mg / kg / d: MedChemExpress HY-B0627, 8), low-dose drug group (50 mg / kg / d, 8) and high-dose drug group (100 mg / kg / d, 8). After 1 week of adaptive feeding, the mice were transferred to a 60% high-fat diet (D12492) for 6 weeks. After 4 weeks of high-fat diet, streptozotocin STZ (sodium citrate buffer, 0.1M, pH 4.5, 1% concentration) was injected intraperitoneally at 50 mg / kg per day for 5 consecutive days to destroy islet cells. A baseline measurement of fasting blood glucose levels was made before the first injection, and the first fasting blood glucose was recorded to ensure the accuracy and comparability of the experiment; and fasting blood glucose and oral glucose tolerance test (OGTT) were measured one week after injection to evaluate the effect of ZKlab23.5 (Compound Ia) on blood glucose control. Mice with fasting blood glucose levels higher than 11.6 mmol / L were considered successfully modeled.

[0247] During the experiment, the mice could freely eat and drink water. The body weight of the hyperlipidemia and hyperglycemia model mice was recorded once a day, and the drug was prevented once a day. In the sixth week, we took blood from the eyeballs of the mice (1 ml) and dissected the relevant tissues and organs (liver, kidney, spleen, heart, brain, lung) according to the standard procedure.

[0248] 2. Measurement of mouse body weight, water intake, and tissue and organ weight

[0249] The mice were weighed at 10 am every day, and then preventive treatment was performed. Food intake was weighed for 72 hours, and water intake was measured with a graduated cylinder for 72 hours and recorded. In the sixth week, we dissected the mice and weighed the relevant tissues and organs, weighed them with an electronic analytical balance and recorded them.

[0250] 3. Drug preparation method and administration cycle

[0251] In addition to the study drug itself, we selected lovastatin as the positive drug for the hyperlipidemia model group, and metformin as the positive drug for the hyperglycemia model. Due to poor drug solubility, we prepared a suspension according to the formula of 4% DMSO + 40% PEG400 + 5% Tween 80 + 51% normal saline. The positive drug group was administered by gavage, and the rest of the groups were injected intraperitoneally once a day for six weeks.

[0252] 4. Blood glucose and blood lipid measurement

[0253] In the blood glucose determination, the hyperglycemia group of mice was injected intraperitoneally with STZ for 5 consecutive days after 4 weeks of high-fat diet to destroy the islet cells. The fasting blood glucose was recorded before the first injection, and the fasting blood glucose measurement and OGTT were performed one week after the injection was completed. OGTT was measured by taking tail blood and using a blood glucose meter and matching test paper (Roche blood glucose meter: CZ3457, test paper: CZ0001). OGTT requires fasting for 12-16 hours, for example, fasting starts at 18:00 the day before, and fasting blood glucose is measured at 8:00 the next day, then 20% glucose solution (2g / kg) is administered by gavage. Blood glucose was measured at 30, 60 and 120 minutes after gavage.

[0254] In the blood lipid determination, we measured total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), very low-density lipoprotein cholesterol (VLDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, and blood lipid level tests were performed by using mouse serum and enzymatic assay kits (Applygen TC: E1005-250 TG: E1003-250 LDL VLDL-C: E1018 HDL-C: E1017).

[0255] 5. Tissue section

[0256] H&E staining: liver and kidney tissues were fixed with 4% paraformaldehyde, paraffin-embedded, cut into 4μm sections, and stained with hematoxylin and eosin (H&E).

[0257] 6. Statistical analysis

[0258] All data are expressed as mean ± standard error, and analyzed using GraphPad Prism 8 software. When comparing two groups of variables, if the data are normally distributed, a two-sided unpaired Student's t-test is used; if not, a two-sided Mann-Whitney test is used. Data from more than two groups are compared using one-way analysis of variance (ANOVA). p<0.05 is considered significant.

[0259] 7. Test results:

[0260] (1) The results of the blood glucose test are shown in Tables 1, 2, and Figure 1:

[0261] Table 1: Fasting blood glucose values (unit: mmol / L) before and after injection of STZ

[0262] Table 2: Blood glucose values (unit: mmol / L) at 30, 60 and 120 minutes after fasting and gavage of 20% glucose solution 7 days after injection of STZ

[0263] The experimental results show that after one week of STZ injection, mice treated with compound Ia exhibit significant improvement in blood glucose control. As shown in Table 1, compound Ia-treated mice show a significant decrease in fasting blood glucose levels compared to the control group, suggesting that compound Ia has the ability to regulate blood glucose homeostasis.

[0264] In the glucose tolerance test, we were particularly interested in the effects of compound Ia (doses of 50 mg / kg, 100 mg / kg) on the dynamic response of blood glucose in mice. As shown in Figure 1, compound Ia-treated mice showed a significantly reduced increase in blood glucose concentration after glucose intake compared to the control group, and the time to return to baseline levels was shortened. In Figure 1, there were significant differences between the high-dose group and metformin at 30, 60, and 120 minutes. All of the above indicate that compound Ia has a significant hypoglycemic effect and may improve insulin sensitivity.

[0265] Through these tests, we were able to clearly observe the significant inhibitory effect of compound Ia on blood glucose levels in mice. These results not only confirm the potential of compound Ia in improving blood glucose control, but also provide strong evidence for further research into its potential as a candidate drug for the treatment of diabetes.

[0266] (2) Body weight and fat control results are shown in Figure 2.

[0267] According to the analysis of the results of Figure 2, the experiments demonstrate that ZKalb23.5 (compound Ia) has a good therapeutic effect on hyperlipidemia in mice through the above experiments. We continue to explore the effect of compound Ia on hyperglycemia in mice. The present invention establishes five groups, namely the control group, the model group, the positive drug metformin 150 mg / kg group, the compound Ia 50 mg / kg group, and the compound Ia 100 mg / kg group. After 4 weeks, a high-fat diet is fed and the islet cells are destroyed by STZ to successfully establish a mouse hyperglycemia model. The drug is administered once a day for 6 consecutive weeks. After 6 weeks, compound Ia has a great inhibitory effect on the growth of abdominal fat in mice and has a great control effect on the growth of fat in mice. In summary, compound Ia has a good control effect on the body weight and abdominal fat of hyperlipidemia and hyperglycemia mice.

[0268] (3) The blood lipid test results are shown in Table 3.

[0269] Table 3: Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-C) content, and low-density lipoprotein (LDL-C) content of mice in each group (unit: μmol / L):

[0270] The experimental results show that the total cholesterol (TC) and triglyceride (TG) levels in the blood of mice treated with compound Ia have a significant downward trend compared with the control group and other experimental groups.

[0271] Further analysis shows that compound Ia not only reduces the level of low-density lipoprotein cholesterol (LDL-C) which is harmful to health, but also shows a positive effect in increasing the level of high-density lipoprotein cholesterol (HDL-C) which is beneficial. In the group of mice treated with compound Ia (dose of 100 mg / kg), the level of HDL-C is significantly higher than that of all other experimental groups, which indicates that compound Ia may enhance the reverse transport of cholesterol by promoting the synthesis or slowing down the decomposition of HDL-C, thereby helping to maintain the cholesterol homeostasis in the body.

[0272] We observed the improvement effect of compound Ia treatment on the blood lipid level of mice, which provides a new perspective for the treatment of hyperlipidemia. Compound Ia shows a positive effect on the blood lipid level of hyperlipidemic mice by regulating blood lipid components, which may help to prevent and treat related cardiovascular diseases. Based on the above results, we conclude that compound Ia has a significant blood lipid regulating effect on hyperlipidemic mice, which can reduce harmful blood lipid components while increasing beneficial blood lipid components, showing good therapeutic effect.

[0273] In Figures 1-2, * represents the range of p values in pairwise comparison, *p≤0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001. # represents the range of p values in pairwise comparison between each group and the Model group (the meaning is the same as *, no * means that there is no difference between this group and the Model group). The statistical data of the experimental results are represented by mean ± standard error (SEM), and all p values are generated by two-tailed Student’s t-test.

[0274] Effect Example 2: Degradation effect of compound Ia (compound ZK23.5) on lipid droplets

[0275] Table 4

[0276] 1. Cell experiment

[0277] We performed modeling and experiments of Huh7 cells and HepG2 by the following methods. Normal incubator and equivalent conditions were used.

[0278] Drug dissolution method: DMSO was used for dissolution, and dilution was performed to the required concentration.

[0279] (I) Huh7 + 200 μM OA model: DMSO as solvent control, DGAT1 inh, DGAT 2 inh (inhibit lipid droplet formation) and BFA (inhibit lipolysis under acidic conditions) as negative controls, evaluate the effect of compound ZK23.5 (10 μM and 20 μM) and positive control Aldometanib on the degradation of lipid droplets in Huh7 cells after adding 200 μM oleic acid (OA) overnight (0.1% DMSO, 5 μM DGAT1 inh, 5 μM DGAT 2 inh, 100 nM BFA, 10 μM ZK23.5, 20 μM ZK23.5 and 1 μM Aldometanib were added to the cells treated with 200 μM OA for 8 hours, respectively, and the cells were treated for 24 hours). High content microscopy was used for observation, and the number and volume of lipid droplets were obtained.

[0280] Objective: Using the oleic acid-induced Huh7 cell steatosis model, combined with controls (including negative controls for inhibiting lipid droplet synthesis and lipolysis, and positive controls), quantitatively evaluate the ability of compound ZK23.5 to promote or inhibit lipid droplet degradation and its dose effect.

[0281] (II) Huh7 without OA model: DMSO as solvent control, DGAT1 inh, DGAT 2 inh (inhibit lipid droplet formation) and BFA (inhibit lipolysis under acidic conditions) as negative controls, evaluate the effect of compound ZK23.5 (10 μM and 20 μM) and positive control Aldometanib on the degradation of lipid droplets in Huh7 cells (without OA treatment, directly adding 0.1% DMSO, 5 μM DGAT1 inh, 5 μM DGAT 2 inh, 100 nM BFA, 10 μM ZK23.5, 20 μM ZK23.5 and 1 μM Aldometanib to the cells for 24 hours). High content microscopy was used for observation, and the number and volume of lipid droplets were obtained.

[0282] Objective: Combined with controls (including negative controls for inhibiting lipid droplet synthesis and lipolysis, and positive controls), quantitatively evaluate the ability of compound ZK23.5 to promote or inhibit lipid droplet degradation and its dose effect.

[0283] (III) HepG2 cell model: HepG2 cells cultured under different conditions (10% FBS normal medium, 10% FBS low sugar medium, 10% FBS MCDM (methionine and choline deficient medium)) were treated with 10 μΜ ZK23.5 for 24 or 36 hours, followed by BODIPY / DAPI staining (BODIPY is a specific lipid droplet dye, DAPI is a nuclear dye), and then fast fluorescence imaging.

[0284] (IV) Observation of the state of lipid droplets and lysosomes: HepG2 cells were treated with 10 μΜ ZK23.5 compound for 4-6 h, and then treated with Lalistat 2 for 12 h. The state of lipid droplets and lysosomes was observed by BODIPY staining and lysosome tracker.

[0285] Objective: To verify whether ZK23.5 can selectively promote fat decomposition (autophagic lipolysis, i.e. Lipophagy) by activating the autophagy pathway, and to determine whether its effect is regulated by energy stress (low sugar conditions). If the lipid droplets in the lysosomes of the ZK23.5 compound group increase significantly, it can be shown that the compound can promote lipophagy.

[0286] BODIPY staining and lysosome tracker can indicate the state of lipid droplets and lysosomes. If the lipid droplets in the lysosomes of the ZK23.5 compound group increase significantly, it can be shown that the compound can promote lipophagy.

[0287] (V) Evaluation of the effect of ZK23.5 on fat phagocytosis: After treating HepG2 cells cultured in normal and low sugar medium with 10 μΜ ZK23.5 for 24 h, cell flow cytometry was performed on the cells using Lipodetector 405 (which can label autophagosomes in cells) and Lipodetector 561 (which can label lysosomes in cells). The effect of ZK23.5 on autophagic lipolysis was evaluated. At the same time, in order to reduce the influence of nutritional status, HepG2 cells were cultured only in 10% FBS normal medium and treated with 10 μΜ ZK23.5 for 24 hours, and then autophagosomes and lysosomes were detected by fluorescence imaging using the two fat detectors to evaluate the effect of ZK23.5 on fat phagocytosis.

[0288] Objective: To quantitatively analyze the effect of ZK23.5 on key indicators of lipophagy by dual-channel flow cytometry, and to determine whether its role in promoting lipid droplet degradation depends on the activation of the autophagy pathway.

[0289] 2. Methods

[0290] a. Method for staining cells using BODIPY 493 / 503 and Lyso-Tracker Red

[0291] For lipid droplet staining in fixed cells, cells were fixed in 4% paraformaldehyde for 20 minutes, rinsed 3 times with PBS buffer, and then stained with BODIPY 493 / 503 diluted in PBS (1:5000 from 1 mg / ml DMSO solution) for 30 minutes. Cells were rinsed twice with PBS and then mounted. To calculate the proportion of lipid droplets that enter lysosomes, BODIPY 493 / 503 staining of lipid droplets and Lyso-Tracker staining of lysosomes were performed in live cells. BODIPY 493 / 503 was diluted in culture medium (1:2000 from 1 mg / ml DMSO solution) and stained for 30 minutes in a cell incubator. The staining medium was replaced with Lyso-Tracker Red diluted in pre-warmed culture medium (1:15000, stained for 15 minutes) and stained in a cell incubator. After completion of staining, the staining medium was replaced with fresh culture medium without Lyso-Tracker and the cells were immediately imaged.

[0292] b. Flow cytometry and gating analysis

[0293] HepG2 cells stably expressing lipid droplet probes were treated as indicated in the figure legend. Cells were collected and analyzed with a Beckman CytoFlex S. Lipid droplet probes were double-excited with 405 nm laser line and 561 nm laser line. Emission signals of the two excitations were collected through 610 / 20 BP filters, respectively. Data were analyzed using CytExpert software. Emission signals of 405 nm excitation were labeled as Lipid Droplet Probe (405), and emission signals of 561 nm excitation were labeled as Lipid Droplet Probe (561). Approximately 10,000 cells were sorted. Single cells were gated based on Lipid Droplet Probe (405) and Lipid Droplet Probe (561). The drawn triangular gating box represents the population of acidified lipid droplet probes. The same gating parameters were applied to comparative samples in the same batch of experiments.

[0294] c. Confocal microscopy imaging of lipid droplet probes

[0295] Stable lipodetector expressing cells were cultured in glass bottom dishes and imaged using an Olympus FV3000 confocal microscope equipped with a 63x objective lens. Cells using mKeima were alternately excited at two different wavelengths, 405 nm and 561 nm. When excited by 405 nm laser, the emission spectrum of the sample was in the range of 600-620 nm, and when excited by 561 nm, the emission spectrum of the sample was in the range of 620-700 nm. The emitted light was separated into the respective signal collection heat sinks using an SDM400-620 dichroic mirror.

[0296] 3. Test results

[0297] (1) Huh7 + 200 mM OA model results as shown in Table 5

[0298] Table 5 Lipid droplet number test results for each experimental group

[0299] In high content analysis, we used dimethyl sulfoxide (DMSO) as a solvent control and DGAT1, DGAT2 inhibitors to inhibit lipid droplet formation and BFA to inhibit lipolysis under acidic conditions as negative controls to evaluate the effect of compound ZK23.5 (10 mM and 20 mM) and positive control Aldometanib on lipid droplet degradation in Huh7 cells treated with 200 mM oleic acid (OA). We observed a significant decrease in both the volume and number of lipid droplets within individual cells. The above results show that our drug has a very significant effect on the degradation of lipid droplets within cells.

[0300] (2) Huh7 no OA model results as shown in Table 6:

[0301] Table 6 Lipid droplet number test results for each experimental group

[0302] In high content screening, Huh7 cells were treated with ZK23.5 (10 mM and 20 mM) and control Aldometanib in the absence of oleic acid (OA) to evaluate their effect on lipid droplet (LD) degradation. We observed a significant decrease in the volume and number of LDs, and the above results show the efficacy of ZK23.5 in regulating lipid metabolism and reducing lipid accumulation within cells, with consistent results in the presence and absence of OA, indicating its potential in both normal and dyslipidemic states.

[0303] (3) HepG2 cell results as shown in Figure 3, Table 7:

[0304] Table 7

[0305] 10 μM ZK23.5 treated HepG2 cells for 24 or 36 hours under different nutritional conditions, and then BODIPY / DAPI staining was performed, which showed that ZK23.5 could widely regulate cellular mechanisms, positively affect cells under different metabolic backgrounds, and significantly enhance lipid droplet degradation, proving the reduction of average lipid droplet area per cell.

[0306] (4) The results of observing the state of lipid droplets and lysosomes are shown in Figure 4 and Table 8:

[0307] Table 8

[0308] HepG2 cells were treated with 10 μM ZK23.5 compound for 4-6 h, and then treated with lassata 2 for 12 h. Through BODIPY staining and lysosome tracker, we can clearly see the state of lipid droplets and lysosomes. The results can fully prove that the ZK23.5 compound group significantly increases the number of lipid droplets in lysosomes, which intuitively shows that the compound can promote autophagy of lipid droplets.

[0309] (5) The results of observing autophagic lipolysis are shown in Figure 5 and Table 9:

[0310] Table 9

[0311] We used fat detector 405 and 561 to detect the number of lysosome lipid droplets and autophagosome lipid droplets, and analyzed HepG2 cells treated with 10 μM ZK23.5 for 24 hours in normal and low-sugar medium by flow cytometry to evaluate the effect of ZK23.5 on autophagic lipolysis. The results of the above experiments show that the number of lysosome lipid droplets in ZK23.5 treated cells significantly increases, and the results are consistent in both types of culture medium, which fully shows that ZK23.5 promotes autophagic degradation of lipid droplets.

[0312] (6) The results of evaluating the effect of ZK23.5 on fat phagocytosis are shown in Figure 6 and Table 10:

[0313] Table 10

[0314] In order to reduce the influence of nutritional status, we used fat detector 405 and 561 to detect HepG2 cells treated with 10 μM ZK23.5 for 24 hours in 10% FBS normal medium. By analyzing the results of fluorescence imaging, it is shown that the fluorescence measurement at 561 nm and 405 nm is consistent with the results of flow cytometry analysis in normal and low-sugar medium, which further verifies that ZK23.5 enhances fat phagocytosis.

[0315] The above descriptions are only the preferable embodiments of the present application, which are only illustrative but not restrictive. It is understood by those skilled in the art that many changes, modifications, even equivalences can be made to the present application within the spirit and scope defined by the claims of the present application, and all of them will fall into the protection scope of the present application.

Claims

1. Use of a compound as shown in Formula I, a stereoisomer thereof, an isotopically-labeled material thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of a disease or a disorder, the disease or the disorder being hyperlipidemia, hyperglycemia, diabetes, obesity, fatty liver, cardiovascular disease, or tissue organ fibrosis, Formula I wherein For Ring A is C 6-10 aryl, 5-10 heteroaryl, with one or more R f Replacement C 6-10 aryl or aryl with one or more R f Substituted 5-10 heteroaryl groups; Z 1 and Z 2 is independently CH or N, and Z 1 and Z 2 at least one of which is N; each R 0 , R 1 , and R 2 are independently H, deuterium, -NH2, halogen, C 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, -O-C 1-6 alkyl, -O-deuterated C 1-6 alkyl, cyano, each R f independently halogen, nitro, cyano, -O-C 1-6 alkyl, C 1-6 alkyl, -O-haloC 1-6 alkyl or haloC 1-6 alkyl; Or, R 1 R 2 Together with the atoms attached to it, they form 5-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and are bonded by one or more R groups. a The substituted 5-6 membered heterocyclic group or the one or more R a The substituted 5-6 membered heteroaryl group, wherein the heteroatom or heterogroup in the 5-6 membered heterocyclic group is selected from one, two or three of N, O, C(O) and S, and the total number of heteroatoms and heterogroups is 1, 2 or 3. each R a independently C 1-6 alkyl, C 3-6 cycloalkyl, halogen, -NH2, hydroxy, -0-C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C(O)-C 1-6 alkyl or -0-C(O)-C 1-6 alkyl; R a1 and R a2 independently C 1-6 alkyl; the definitions of ring E and t satisfy condition (1) or (2): Condition (1): Ring E is C 6-10 aryl, 5-10 membered heteroaryl, by one or more R d Replacement C 6- 10 aryl or aryl with one or more R d Substituted 5-10 membered heteroaryl groups, ring B connected to ring D, X 5 With L 1 Connection; t is 1, Condition (2): ring E is ring B is connected to ring D, and t is 0; each ring B and ring C is independently C 6-10 aryl or 5-10 membered heteroaryl; each R b and R c independently halogen or haloC 1-4 alkyl, each m1 and m2 independently 0, 1 or 2; R d -O-C 1-6 alkyl; is a single bond or a double bond; X 1 is C(O), CH2, NR e or O; X 1a and X 2 is independently C, CH, N or O; X 3 is CH2, NR e or O; X 4 is C(O), CH2or O; X 5 is N or CH; X 5a is C, N or CH; each R is independently H or C e independently H or C 1-4 alkyl; n is 0 or 1; L 1 is a single bond, C(O) or L 2 is a single bond or -(CH2) m3 m3 is 1, 2, 3, 4, 5 or 6; Ring F is C 6-10 aryl or 5-10 membered heteroaryl; each R 3 independently halogen, nitro, cyano, -O-C 1-3 alkyl, C 1-3 alkyl, -O-haloC 1-3 alkyl, haloC 1-3 alkyl, -C(O)O-C 1-3 alkyl or s is 1, 2 or 3; the heteroatom species in each 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heteroaryl is independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

2. Use according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions: (1) the halogen or halo is independently F, Cl or Br; for example, F; (2) said C 1-4 alkyl, C 1-6 alkyl, haloC 1-4 alkyl, C 1-4 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, -O-haloC 1-6 alkyl, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkyl, -O-haloC 1-6 alkyl, C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 1-6 alkyl, and -O-C(O)-C 1-6 alkyl, C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl (C 1-4 alkyl), for example methyl or ethyl; (3) said C 1-3 alkyl, -O-C 1-3 alkyl, -O-C 1-3 alkyl, -O- haloC 1-3 alkyl, -O-C 1-3 alkyl, -O-C 1-3 alkyl, -O-C 1-3 alkyl is independently methyl, ethyl, n-propyl or i-propyl, for example methyl or ethyl; (4) the C 6-10 aryl is independently phenyl or naphthyl; (5) the heteroatom species in the 5-10 membered heteroaryl and 5-6 membered heteroaryl is N, and the number of heteroatoms is independently 1 or 2; (6) the 5-10 membered heteroaryl and 5-6 membered heteroaryl is independently a 5 membered heteroaryl or a 6 membered heteroaryl; (7) said C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (8) the kind of heteroatom or heteroatom group in the 5-6 membered heterocyclyl is selected from one or two of N, O, and C(O), the total number of heteroatoms and heteroatom groups is 1 or 2; the 5-6 membered heterocyclyl is a partially saturated 5-6 membered heterocyclyl, the number of alkenes in the partially saturated 5-6 membered heterocyclyl is 1 or 2, for example 1; for another example, the partially saturated 5-6 membered heterocyclyl is Preferably, in the compound of formula I, the 5-10 membered heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, naphthyl, phenanthryl, quinolyl, isoquinolyl, indolyl, benzodiazolyl, benzotriazolyl or purinyl; for example, the 5 membered heteroaryl is pyrrolyl, pyrazolyl or imidazolyl; the 6 membered heteroaryl can be pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl; for example, pyridyl.

3. The use according to claim 1, wherein satisfies one or more of the following conditions: (1) For Ring A is a 5-10 membered heteroaryl; preferably, ring A is a 5-6 membered heteroaryl, the heteroatom species in the 5-6 membered heteroaryl is N, and the number of heteroatoms is independently 1 or 2; preferably, For (2) R 0 is H, deuterium, or C 1-4 alkyl, for example H or C 1-4 alkyl; also for example H; (3) R 1 is H, deuterium, amino, or cyano; for example, R 1 is H, deuterium, or cyano, and further for example, R 1 is H or cyano, or R 1 is H or deuterium; and still further for example, H; (4) R is H, deuterium, amino or cyano, for example R 2 is H, deuterium, amino or cyano, for example R 2 is H, deuterium or amino, for example R 2 is H or amino, or R 2 is H or deuterium; again for example H; (5)R 1 (6)R 2 and the atoms to which they are attached form a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the 5-6 membered heterocyclyl having one or two heteroatoms selected from the group consisting of N, O and C(O), the 5-6 membered heteroaryl having one or two heteroatoms selected from N; preferably R 1 (7)R 2 and the atoms to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the 5-6 membered heteroaryl having one or two heteroatoms selected from N; more preferably R 1 (8)R 2 and the atoms to which they are attached form a 5-6 membered heteroaryl, the 5-6 membered heteroaryl having one or two heteroatoms selected from N. (6) each R a independently C 1-6 alkyl; for example C 1-4 alkyl; (7) R a1 and R a2 independently C 1-4 alkyl; (8) In condition (1), ring E is phenyl, or one R d substituted phenyl, ring B is phenyl or 5-6 membered heteroaryl, the heteroatom of said 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2, ring B being attached to ring D, X 5 and L 1 ; t is 1; preferably, ring E is Ring B is phenyl or 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from N, the heteroatoms of which are N; more preferably, ring E is ring B is phenyl; (9) In condition (2), ring E is ring B is 5-6 membered heteroaryl, the heteroatom species in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; ring C is phenyl, ring B is connected to ring D, and t is 0; (10) X 1 is C(O) or CH2, for example C(O); (11) X 1a is C; (12) X 2 is C or N; (13) X 3 is CH2, NR e or O; for example O; (14) X 4 is C(O) or CH2, for example CH2; (15) X 5 is N; (16) X 5a is C; (17) each R b and R c independently halogen; (18) m1 is 0 or 1; (19) m2 is 1; (20) L 1 is a single bond; (21) L 2 -(CH2) m3 m3 is 1, 2, 3, 4, 5 or 6; (22) Ring F is C 6-10 aryl or 5-6 membered heteroaryl, the heteroatom of which is N, the number of heteroatoms being 1 or 2; for example, ring F is phenyl; (23) each R 3 independently halogen or haloC 1-3 alkyl, for example halogen; (24) s is 1 or 2; (25) the cardiovascular disease is a cardiovascular disease caused by hyperlipidemia or hyperglycemia; (26) the obesity is obesity caused by fat increase and / or body weight increase; (27) the diabetes is a hyperglycemic diabetes, for example, type II diabetes; (28) the tissue organ fibrosis is a tissue organ fibrosis associated with fat increase; (29) the disease or condition is hyperlipidemia, hyperglycemia or diabetes (30) the disease or condition is fatty liver, for example, non-alcoholic fatty liver or alcoholic fatty liver.

4. The use according to claim 1, wherein The compound of Formula I is a compound of Formula I-1, I-2, or I-3: Preferably, the compound of Formula I-2 is a compound of Formula I-2a: Preferably, in the compound of formula I-1: Z 1 and Z 2 are independently CH or N, and Z 1 and Z 2 at least one of which is N; R 0 H, deuterium or C 1-4 alkyl; R 1 R 2 and together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the heteroatoms of said 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2; each R is independently C a independently C 1-6 alkyl; Ring E is ring B is phenyl or 5-6 membered heteroaryl, the heteroatom species in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; X 1 is C(O); X 2 is C or N; X 3 is O; X 4 is CH2; X 5 is N; R b R is halogen; m1 is 0 or 1; n is 0 or 1; L 2 -(CH2) m3 , m3 is 1, 2, 3, 4, 5 or 6; Ring F is C 6-10 aryl or 5-6 membered heteroaryl, the heteroatom of which is N, the number of heteroatoms being 1 or 2; each R is independently halogen or haloC 3 independently halogen or haloC 1-3 alkyl; s is 1 or 2.

5. The use according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions: (1) R 0 is H or methyl; (2) R 1 is H or cyano; (3) R 2 is H or amino; (4) R a is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, halogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, propyleneoxy, acetyl, acetyloxy, propionyl, propionyloxy; for example methyl; (5) R 1 (6) R 2 and together with the atom to which they are attached form (6) ring C is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, naphthyl, phenanthryl, quinolyl, isoquinolyl, indolyl, benzodiazolyl, benzotriazolyl or purinyl; preferably, ring C is phenyl; (7) ring B is phenyl, pyridyl, pyrazolyl (1,2 diazole) or imidazolyl (1,3 diazole); (8) R c F, Cl, Br, trifluoroethyl or difluoromethyl, for example F; (9) R b F, Cl, Br, trifluoroethyl or difluoromethyl, for example F; (10) -L 1 - L 2 - is a single bond, methylene, (11) R 3 independently F, CF3or (12) phenyl, naphthyl, (13) heteroaryl, and (14) heteroaralkyl. Preferably, the compound of formula I satisfies one or more of the following conditions: (1) For For example (2) For Preferably, For (3) For (4) For For example More preferably, the compound of Formula I is 6. The use according to claim 1, wherein The compound as shown in Formula I is any one of the following compounds:

7. A compound as represented by Formula II, a stereoisomer thereof, an isotopically-labeled material thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, Formula II. wherein, ring D, ring E, ring F, L 1 , L 2 , R 3 , s and t are as defined in claim 1, and the compound of formula II satisfies any one of the following conditions: (1) For R 1 is cyano; and s is 1, R 3 is halo, nitro, cyano, -C 1-3 alkyl, -O-haloC 1-3 alkyl, haloC 1-3 alkyl, -C(O)O-C 1-3 alkyl or (2) For R 1 R 2 and together with the atom to which they are attached form a 5-6 membered heteroaryl substituted with one R a R 3 halo, nitro, cyano, -C 1-3 alkyl, -O-haloC 1-3 alkyl, haloC 1-3 alkyl, -C(O)O-C 1-3 alkyl or (3) R 0 is deuterium, -NH2, halogen, C 1-4 alkyl, halogen-C 1-4 alkyl, C 3-6 cycloalkyl, -O-C 1-6 alkyl, -O-deuterated C 1-6 alkyl, cyano, (4) For Z 2 is N; (5) For R 1 R 2 and together with the atom to which they are attached form a 5-6 membered heterocyclyl or a 5-6 membered heterocyclyl substituted with one R a R (6) For When ring A is a 5-10 membered heteroaryl group and s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or (7) For (8) Ring E is m1 is 1 or 2; (9) Ring E is ring B is 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; (10) Ring E is (11) X 3 CH2or NR e , and when s is 1, R 3 halo, nitro, cyano, -C 1-3 alkyl, -O-haloC 1-3 alkyl, haloC 1-3 alkyl, -C(O)O-C 1-3 alkyl or (12) L 1 is C(O) or And when s is 1, R 3 Halogen, nitro, cyano, -C 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C(O)OC 1-3 alkyl or (13) L 2 -(CH2) m3 m3 is 2, 3, 4, 5 or 6; (14) s is 2 or 3; (15) ring F is naphthalene ring or 5-10 membered heteroaryl; Preferably, ring D, ring E, ring F, L 1 , L 2 , R 3 , s and t are as defined in any one of claims 2-6.

8. The compound of formula II as claimed in claim 7, its stereoisomers, its isotopic labels, its solvates, its pharmaceutically acceptable salts, or solvates of pharmaceutically acceptable salts thereof, characterized in that, Preferably, the compound of formula I satisfies one or more of the following conditions: (1) For R 1 is cyano, R 2 is amino; or, For R 1 , R 2 and together with the atom to which they are attached form a 5-6 membered heterocyclyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl substituted with one R a , the kind of heteroatom or heteroatom group in the 5-6 membered heterocyclyl is selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom groups is 1 or 2; the heteroatom of the 5-6 membered heteroaryl is N, the number of heteroatoms is 1 or 2; Preferably, For R 1 R 2 and together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the heteroatom species in said 5-6 membered heteroaryl being N, the number of heteroatoms being independently 1 or 2; or For R 1 R 2 and together with the atom to which they are attached form a partially saturated 5-6 membered heterocyclyl or a partially saturated 5-6 membered heterocyclyl substituted by one R a ; the kind of heteroatom or heteroatom group in the partially saturated 5-6 membered heterocyclyl is selected from one or two of N, O and C(O), the total number of heteroatoms and heteroatom groups being 1 or 2; (2) For ring A is 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; (3) For R1 and R2 are independently H or deuterium; (4) Ring E is ring B is 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; (5) X 3 CH2or O; (6) ring F is naphthyl or 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2, preferably, ring F is 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2.

9. The compound of formula II as claimed in claim 7, its stereoisomers, its isotopic labels, its solvates, its pharmaceutically acceptable salts, or solvates of pharmaceutically acceptable salts thereof, characterized in that, It is the following scheme 1 or scheme 2: Scheme 1: The compound as shown in formula II is a compound as shown in formula I-1: Z 1 and Z 2 is independently CH or N, and Z 1 and Z 2 at least one of which is N; R 0 H, deuterium or C 1-4 alkyl; R 1 R 2 and together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted with one R a , the heteroatoms of said 5-6 membered heteroaryl being N, the number of heteroatoms being 1 or 2; each R is independently C a independently C 1-6 alkyl; ring B is 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; X 1 is C(O); X 2 is C or N; X 3 CH2or O; X 4 is CH2; X 5 is N; R b is halogen; m1 is 0 or 1; n is 0 or 1; L 2 -(CH2) m3 , m3 is 1, 2, 3, 4, 5 or 6; Ring F is C 6-10 aryl or 5-6 membered heteroaryl, the heteroatom of which is N, the number of heteroatoms being 1 or 2; each R is independently halogen or haloC 3 independently halogen or haloC 1-3 alkyl; s is 1 or 2 Scheme 2: The compound of formula II is a compound of formula I-1: Z 1 and Z 2 is independently CH or N, and Z 1 and Z 2 at least one of which is N; R 0 H, deuterium or C 1-4 alkyl; R 1 , R 2 and together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one R a , the heteroatom of the 5-6 membered heteroaryl being N and the number of heteroatoms being 1 or 2; each R is independently C a independently C 1-6 alkyl; ring B is phenyl or 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; X 1 is C(O); X 2 is C or N; X 3 is CH2or O; X 4 is CH2; X 5 is N; R b is halogen; m1 is 0 or 1; n is 0 or 1; L 2 -(CH2) m3 , m3 is 1, 2, 3, 4, 5 or 6; ring F is naphthyl or 5-6 membered heteroaryl, the kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatom is 1 or 2; each R is independently halogen or haloC 3 independently halogen or haloC 1-3 alkyl; s is 1 or 2.

10. The compound of formula II as claimed in claim 7, its stereoisomers, its isotopic labels, its solvates, its pharmaceutically acceptable salts, or solvates of pharmaceutically acceptable salts thereof, characterized in that, The compound as shown in Formula II is any one of the following compounds:

11. A pharmaceutical composition comprising the compound of formula II, stereoisomer thereof, isotope-labeled compound thereof, solvate thereof, pharmaceutically acceptable salt thereof or solvate of the pharmaceutically acceptable salt thereof as claimed in any one of claims 7-10, and a pharmaceutical adjuvant.

12. Use of the compound of formula II, stereoisomer thereof, isotope-labeled compound thereof, solvate thereof, pharmaceutically acceptable salt thereof or solvate of the pharmaceutically acceptable salt thereof as claimed in any one of claims 7-10 in the preparation of a medicament for preventing and / or treating a disease or disorder, wherein the disease or disorder is a tumor, hyperlipidemia, hyperglycemia, diabetes, obesity, fatty liver, cardiovascular disease or tissue and organ fibrosis. The tumor can be lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer, breast cancer or acute myeloid leukemia. The cardiovascular disease can be a cardiovascular disease caused by hyperlipidemia or hyperglycemia. The obesity can be obesity caused by fat increase and / or weight gain. The diabetes can be hyperglycemic diabetes, such as type II diabetes. The fatty liver can be non-alcoholic fatty liver or alcoholic fatty liver. Preferably, the disease or disorder is hyperlipidemia, hyperglycemia, fatty liver or diabetes.

13. Use of a compound of Formula I, a stereoisomer thereof, an isotopically-labeled material thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder associated with dysregulation of lipophagic activity.

14. Use according to claim 13, wherein the compound is ###0002### The disease or disorder associated with dysregulation of lipophagic activity is hyperlipidemia, obesity, or fatty liver; preferably, the fatty liver is non-alcoholic fatty liver or alcoholic fatty liver.

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