Protein-drug conjugate and use thereof

Abstract

A compound having biological activity and use thereof. More specifically, provided is a protein-drug conjugate, which comprises a targeting moiety and a bioactive molecule moiety linked to the targeting moiety by means of a linking fragment. It can be used for treating and / or preventing liver diseases, glycolipid metabolic diseases, glycolipid metabolism-related cardiovascular and cerebrovascular diseases, and other disorders.

Description

Protein-drug conjugates and their uses

[0001] This application is based on and claims priority to the following applications: CN application number 202510293024.9 (filed March 12, 2025), CN application number 202510756875.2 (filed June 6, 2025), CN application number 202511220677.0 (filed August 28, 2025), and CN application number 202610274730.3 (filed March 6, 2026). The disclosures of the aforementioned applications are incorporated herein by reference in their entirety. Technical Field

[0002] This application belongs to the pharmaceutical field, specifically relating to a protein-drug conjugate and its uses. Background Technology

[0003] With the increasing prevalence of lifestyle habits such as staying up late, prolonged sitting, and high-calorie, high-fat, and high-sugar diets, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising globally. Metabolic associated steatohepatitis (MASH) is a chronic liver disease characterized by abnormal fat accumulation in the liver, closely related to metabolic dysfunction and associated with diabetes, overweight or obesity, and metabolic disorders. MASH can progress to liver fibrosis and cirrhosis, and can also lead to extrahepatic diseases such as cardiovascular and cerebrovascular diseases, significantly impacting patients' quality of life and seriously threatening their health.

[0004] Obesity is one of the major risk factors for motor atherosclerosis (MASH). Obesity caused by a high-calorie diet and a sedentary lifestyle increases the accumulation of fat in the liver, thus triggering MASH. Obesity not only increases the risk of MASH but also exacerbates existing MASH, making treatment more difficult. Diabetes, especially type 2 diabetes, is closely related to the development of MASH. High blood sugar levels prompt the body to produce more free fatty acids, which are transported to the liver and stored, thus exacerbating the accumulation of fat in the liver.

[0005] Therefore, there is an urgent need for drugs that can reduce weight, lower blood sugar, lower blood lipids, and are effective against MASH. Summary of the Invention

[0006] The KLB-FGFR signaling pathway is a key pathway regulating energy metabolism. This pathway uses β-Klotho (KLB) protein as its core co-receptor, mediating the specific binding of fibroblast growth factor (FGF19 / FGF21) to the FGFR1c / 4 receptor, activating downstream signaling cascades, thereby regulating hepatic glucose and lipid metabolism, insulin sensitivity, and energy expenditure. Activation of this pathway significantly promotes fatty acid oxidation, inhibits hepatic lipogenesis, and has significant effects on improving body weight, blood glucose, and blood lipid levels. Furthermore, selective thyroxine β-receptor agonists, by activating the hepatic-specific thyroid hormone pathway, directly enhance mitochondrial β-oxidation capacity and cholesterol metabolism efficiency, accelerating triglyceride hydrolysis and promoting LDL receptor expression to reduce circulating low-density lipoprotein.

[0007] This application provides a compound and its conjugates, and exemplarily discloses a method for conjugating a protein with the general formula P-(MLD) to a thyroxine receptor agonist (such as a thyroxine β receptor agonist). n The conjugate shown in the diagram conjugates an FGFR agonist and / or a KLB-binding molecule (e.g., a fusion protein containing FGF21 protein or a variant thereof, or an anti-KLB antibody) with a thyroxine receptor agonist. Results show that the conjugate exhibits good plasma stability, high enzymatic cleavage efficiency (e.g., liver lysosomal cleavage efficiency), liver targeting, and high safety. It effectively activates the cellular KLB-FGFR signaling pathway and demonstrates a good synergistic effect in the treatment of metabolic diseases or related conditions, such as effectively reducing weight, improving blood biochemistry, reducing liver indices, reducing the degree of liver fibrosis, reducing MASH scores, and alleviating fatty liver. Furthermore, the effect of conjugating the FGFR agonist and / or KLB-binding molecule with a thyroxine receptor agonist is superior to the effect of combining the FGFR agonist and / or KLB-binding molecule with a thyroxine receptor agonist.

[0008] This application also provides compositions comprising the said compounds and / or their conjugates, pharmaceutical compositions, cassette products, and their use in the treatment and / or prevention of liver diseases, glucose and lipid metabolism disorders, and cardiovascular, respiratory, and musculoskeletal disorders related to glucose and lipid metabolism.

[0009] compound

[0010] The first aspect of this application provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, M'-LD (I).

[0011] in,

[0012] M' is the connector;

[0013] D represents the bioactive molecule portion;

[0014] L is a structure connecting M' and D.

[0015] In some embodiments, the bioactive molecule is a thyroid hormone receptor (THR) agonist.

[0016] In some embodiments, the thyroid hormone receptor agonist is a thyroxine beta receptor (THRβ) agonist.

[0017] In some embodiments, the thyroid hormone β-receptor agonist is selected from compounds of formula (A”) or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs.

[0018] in,

[0019] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-12 membered heterocyclic;

[0020] X1 is selected from chemical bonds, -CONH-, -NHCO-, and -O-(CR). a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m - and -(CR a R b ) m -;

[0021] X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0022] Y1is selected from the group consisting of a bond, -0-(CR a R b ) m -, c -(CR a R b ) m -, a R b ) m -, a R b ) m -;

[0023] R e is each independently at each occurrence selected from the group consisting of H, halogen, -CN, -OH, -SH-, -NR c R d , oxo, -C 1- 6alkyl, -O-C 1-6 alkyl, -O-C 6-10 aryl, -O-(5-10 membered heteroaryl), -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10 membered heteroaryl), -(CR a R b ) m -(4-18 membered heterocycloalkyl), -CONH-(CR a R b ) m -(C 1-6 alkyl), -CONH-(CR a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR a R b ) m -(C 6-10 aryl), -CONH-(CR a R b ) m -(5-10 membered heteroaryl), -NHCO-(CR a R b ) m -(C 1-6 alkyl), -NHCO-(CR a R b )m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3- 6-cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1- 6-Hydroalkyl and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0024] R3, R4, R6, and R7 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0025] Alternatively, R4 and R6, along with the atoms they are bonded to, together form C. 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl;

[0026] R5 is selected from -OH, -COOH, -C(=O)-OC1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, --PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, -C 1-4 alkylene-, -C 2-6 alkenyl, -C 2-6 alkynyl group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C 2-6 alkenyl, -C 2-6 Substitution of alkynyl and 4-8 membered heterocyclic alkyl groups;

[0027] R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0028] R c and R dEach is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group;

[0029] m is independently selected from 0, 1, 2, 3, 4, 5 and 6;

[0030] q is independently selected from 0, 1, 2, 3, 4 and 5.

[0031] In some embodiments, ring A is phenyl, naphthyl (e.g.) ), pyridazinyl (e.g.) ), indole (e.g.) ), pyrrolopyridyl (e.g.) ), benzopyridazine (e.g.) ), In some implementations, ring A is a phenyl group.

[0032] In some implementation schemes, R e Each time it appears, it is independently selected from H, halogen, -OH, -NR. c R d , oxo group, -C 1-6 Alkyl, -OC 6-10 Aryl, -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(C 1-6 Alkyl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18Cycloalkyl groups, 4-18 membered heterocyclic alkyl groups, are optionally selected by one or more independently selected from halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Cycloalkyl groups are substituted.

[0033] In some implementation schemes, R e Each can be independently represented by H, I, Br, OH, methyl, isopropyl, amino, oxo, -NHCOCH3, phenyl. Methylthio,

[0034] In some implementations, equation (A”) is further shown as equation (Aa”):

[0035] Among them, X1, X2, Y1, R e R3, R4, R5, R6 and R7 are as defined in any embodiment of this application;

[0036] Y2 is selected from -O-, -N(R) c )- and -S-, the R c Selected from H, -CH3 and -CO-C 1-6 alkyl.

[0037] In some implementations, equation (A”) is further shown as equation (A’):

[0038] Wherein, X1, X2, Y1, Y2, R3, R4 and R5 are as defined in any embodiment of this application;

[0039] R1 and R2 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d , oxo group, -C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) aR b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 1-6 alkyl), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -CONH-(CR) a R b ) m -(5-10 grade heteroaryl groups), -NHCO-(CR) a R b ) m -(C 1-6 alkyl), -NHCO-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Cycloalkyl groups are substituted.

[0040] In some implementations, R1 and R2 are each independently selected from H, halogens, -OH, and -NR. c R d , oxo group, -C 1-6 Alkyl, -OC6-10 Aryl, -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(C 1-6 Alkyl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl groups, 4-18 membered heterocyclic alkyl groups, are optionally selected by one or more independently selected from halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Cycloalkyl groups are substituted.

[0041] In some embodiments, the thyroid hormone β-receptor agonist is selected from compounds of formula (A') or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0042] in,

[0043] X1 is selected from chemical bonds, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m-、-S-(CR a R b ) m - and -(CR a R b ) m -;

[0044] X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0045] Y1 is selected from -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m -, -C(=O)-, -S(=O)-, -S(O)2- and -(CR a R b ) m -;

[0046] Y2 is selected from -O-, -N(R) c )- and -S-;

[0047] R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0048] R5 is selected from -OH, -COOH, and -C. 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, C 6-10 Aryl and 5-10 heteroaryl, the -C 1-4 Alkylene-, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0049] R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0050] R c and R d Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group;

[0051] m is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0052] In some implementations, formula (A') is further shown as in Figure (A):

[0053] X, R1, R2, R3, R4 and R5 are as defined in any embodiment of this application.

[0054] In some embodiments of formula (A), X is selected from chemical bonds, -O-, -NH-, and -C. 1-3 Alkylene-, wherein the alkylene group is optionally substituted with one or more groups independently selected from -OH, -NH2 and halogens;

[0055] R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, and -C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more groups independently selected from -OH, -NH2 and halogens;

[0056] R5 is selected from -OH, -COOH, and -C. 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene -OH and -C(=O)-C 1-4 Alkylene -COOH, wherein the alkylene group is optionally composed of one or more elements independently selected from -OH, -NH2, and -NH(C) 1-6 Alkyl groups are substituted.

[0057] In some implementations, Y1 is selected from chemical bonds, -O-, NH and -(CR). a R b ) m -, R a R b And m is as defined in any embodiment of this application.

[0058] In some implementations, Y1 is selected from chemical bonds, -O-, and -CH2-.

[0059] In some embodiments, the Y1 is selected from -O-, -NH-, and -(CR-). a R b ) m -, R a R b And m is as defined in any embodiment of this application.

[0060] In some implementations, Y1 is selected from -O- and -CH2-.

[0061] In some implementations, Y2 is selected from -O-, -N(R)c )- and -S-, the R c Selected from H, -CH3, -COCH3 and -COCH(CH3)CH2CH3.

[0062] In some implementations, Y2 is selected from -O-, -N(R) c )- and -S-, the R c Selected from H, -CH3 and -COCH3.

[0063] In some implementations, Y2 is selected from -O-, -NH-, -(CH3CO)N-, and -N(COCH(CH3)CH2CH3)-.

[0064] In some embodiments, the Y2 is selected from -O-, -NH- and -(CH3CO)N-.

[0065] In some implementations, X1 is selected from chemical bonds, -CONH-, -NHCO-, -O-(CR a R b ) m -、-N(R c )-(CR a R b ) m - and -(CR) a R b ) m -

[0066] In some embodiments, X1 is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, and -CH2CH(NH2)-.

[0067] In some implementations, X1 is selected from -O-(CR a R b ) m -、-NR c - and -(CR a R b ) m -, R a R b R c And m is as defined in any embodiment of this application.

[0068] In some embodiments, X1 is selected from -O-, -NH-, -O-CH2-, -CH2-, -CH2CH2- and -CH2CH(NH2)-.

[0069] In some embodiments, X2 is selected from chemical bonds and -4-7-membered heterocyclic groups-, which contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(=O), P and P(=O).

[0070] In some embodiments, the X2 is selected from chemical bonds and

[0071] In some embodiments, -X1-X2- is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, -CH2CH(NH2)- and (For example ).

[0072] In some embodiments, -X1-X2- is selected from -O-, -O-CH2-, -NH-, -CH2-, -CH2CH2-, -CH2CH(NH2)- and

[0073] In some embodiments, -X1-X2- is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-#, -O-CH2-#, -CH2-, -CH2CH2-, -CH2CH(NH2)-#, and (For example ), where # is connected to R5.

[0074] In some embodiments, -X1-X2- is selected from -O-, -O-CH2-#, -NH-, -CH2-, -CH2CH2-, -CH2CH(NH2)-#, and The # terminal is connected to R5.

[0075] In some embodiments, X is selected from -O-, -NH-, methylene, and ethylene, wherein the methylene and ethylene are optionally substituted by one, two, or three independent groups selected from -OH and -NH2.

[0076] In some implementations, X is selected from -NH- and -CH2-.

[0077] In some embodiments, X is -CH2-. In some embodiments, R1, R2, R3, and R4 are each independently selected from H, halogens, and -C. 1-4 Alkyl, the -C 1-4 The alkyl group may be optionally substituted with one or more groups independently selected from -OH and -NH2.

[0078] In some embodiments, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, F, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

[0079] In some implementations, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, -CH3 and -CH(CH3)2.

[0080] In some implementations, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl and -CH(CH3)2.

[0081] In some implementations, R1 is H.

[0082] In some implementations, R2 is selected from I and -CH(CH3)2.

[0083] In some implementations, R2 is I.

[0084] In some implementations, R3 and R4 are each independently selected from I, Br, Cl and -CH3.

[0085] In some implementations, R3 and R4 are each independently selected from I, Br, and Cl.

[0086] In some implementations, R3 and R4 are each independently I.

[0087] In some implementations, R3, R4, R6, and R7 are each independently selected from H, halogens, and -C. 1-6 alkyl.

[0088] In some implementations, R3 and R4 are each independently selected from halogens and -C. 1-6 alkyl.

[0089] In some implementations, R6 and R7 are each independently selected from H.

[0090] In some implementations, R4 and R6, together with the atoms they are bonded to, form

[0091] In some implementations, R5 is selected from -COOH, -C(=O)-OC 1-4 Alkyl, -C 1-4 Alkylene groups -COOH, -PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C1-4 Alkyl, -C 1-4 Alkylene, 4-8 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C 2-6 alkenyl, -C 2-6 Substitution with alkynyl and 4-8 membered heterocyclic alkyl groups.

[0092] In some embodiments, R5 is selected from -COOH, -C(=O)-OCH2CH3, -CH2-COOH, -(CH2)2-COOH, -CH(NH2)-COOH-, -CH2CH(NH2)-COOH, -PO(OH)2, -CH2-PO(OH)2, -C(=O)-CH2-COOH,

[0093] In some embodiments, R5 is selected from -COOH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 alkylene-COOH and C 6-10 Aryl, the -C 1-4 Alkylene- and C 6-10 The aryl group is optionally surrounded by one, two, or three independently selected halogens, -OH, -NH2, and -NH(C). 1-4 Substitution of alkyl groups;

[0094] In some embodiments, R5 is selected from -COOH, -C 1-4 Alkylene-COOH and -C(=O)-C 1-4 Alkylene -COOH, wherein the alkylene group is optionally composed of one, two, or three independently selected from -OH, -NH2, and -NH(C) 1-4 Alkyl groups are substituted.

[0095] In some embodiments, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH and phenyl, wherein the CH2 and phenyl are optionally substituted by one, two or three groups independently selected from halogens, -OH and -NH2.

[0096] In some embodiments, R5 is selected from -COOH, -CH2COOH and -C(=O)CH2COOH, wherein -CH2COOH and -C(=O)CH2COOH are optionally substituted by one, two or three groups independently selected from -OH and -NH2.

[0097] In some embodiments, R5 is selected from -COOH, -C(=O)CH2COOH and -CH(NH2)COOH.

[0098] In some embodiments, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH, (For example )and

[0099] In some embodiments, R5 is selected from -COOH and (For example ).

[0100] In some embodiments, the thyroxine beta receptor agonist is selected from...

[0101] In some embodiments, the thyroxine beta receptor agonist is selected from...

[0102] In some embodiments, the thyroxine beta receptor agonist is selected from...

[0103] In some embodiments, the thyroxine beta receptor agonist is selected from...

[0104] In some embodiments, the thyroxine beta receptor agonist is selected from...

[0105] In some implementations, the thyroid hormone receptor agonist is linked to L via a -OH, -COOH, -SH, primary amino, secondary amino, or tertiary amino group.

[0106] In some implementations, the thyroid hormone receptor agonist is linked to L via a -OH, primary amino, secondary amino, or tertiary amino group.

[0107] In some embodiments, D is a monovalent structure obtained by losing an H from a -OH, -SH, -NH2, or secondary amine group on the thyroid hormone receptor agonist, or a monovalent structure obtained by losing an OH from a -COOH group on the thyroid hormone receptor agonist.

[0108] In some embodiments, D is a monovalent structure obtained by losing an H from the -OH, -NH2, or secondary amine group on the thyroid hormone receptor agonist, or a monovalent structure obtained by losing an OH from the -COOH group on the thyroid hormone receptor agonist.

[0109] In some embodiments, the structure of D is as shown in equation (A-1”), equation (Aa-1”), equation (A-1’), equation (A-2’), equation (A-3’), or equation (A-4’):

[0110] Among them, R 5a The structure obtained by losing a H group from the -OH, -NH2, or secondary amine group in R5 as defined in any embodiment of this application, or the structure obtained by losing an OH group from the -COOH group on R5;

[0111] Preferably, R 5a Selected from -O-, -C(=O)-, -C 1-4 Alkylene -O-, -C 1-4 Alkylene -C(=O)-, -C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 alkylene-C(=O)-, wherein the -C 1-4 Alkylenes are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0112] Ring A, q, X1, X2, Y1, Y2, R e , R1, R2, R3, R4, R5, R6, R7, R c and R d As defined in any embodiment of this application.

[0113] In some implementation schemes, R 5aThe structure obtained by losing an H from the -OH, -NH2, or secondary amine group in R5 as defined in any embodiment of this application, or the structure obtained by losing an OH from the -COOH group on R5.

[0114] In some embodiments, the structure of D is shown in equation (A-1), equation (A-2), or equation (A-3):

[0115] in,

[0116] X is selected from chemical bonds, -O-, -NH-, and -C. 1-3 Alkylene-, wherein the alkylene group is optionally substituted with one or more groups independently selected from -OH, -NH2 and halogens;

[0117] R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, and -C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more groups independently selected from -OH, -NH2 and halogens;

[0118] R5 is selected from -OH, -COOH, and -C. 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene -OH and -C(=O)-C 1-4 Alkylene -COOH, wherein the alkylene group is optionally composed of one or more elements independently selected from -OH, -NH2, and -NH(C) 1- (6-alkyl) group substitution.

[0119] In some implementations, the structure of D is as shown in formula (A-2-1):

[0120] R1, R2, R3 and R4 are defined as in any embodiment of this application.

[0121] In some implementations, the structure of D is as shown in formula (A-3-1):

[0122] R1, R2, R3 and R4 are defined as in any embodiment of this application.

[0123] In some implementations, D is selected from...

[0124] In some implementations, D is selected from...

[0125] In some implementations, D is selected from...

[0126] In some implementations, D is selected from...

[0127] In some implementations, M' is selected from:

[0128] Wherein, Lg is a leaving group or an addition group in a nucleophilic substitution reaction.

[0129] In some embodiments, the Lg is selected from halogens (e.g., F, Cl, Br, I) and halogenated C. 1-6 Alkyl, maleimide, halogenated maleimide, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 Alkyl sulfoxide, halophenoxy, -OH, -SH, -NH2, nitro, azide, cyano, C 2-6 alkenyl, C 2-6 Alkyne groups and C-containing groups 2-6 The structure of the alkynyl group, the halogenated C 1-6 Alkyl, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 The alkyl sulfoxide, halophenoxy, alkenyl, ynyl and ynyl-containing structures may optionally be replaced by one or more suitable substituents.

[0130] In some embodiments, the Lg is selected from halogens (e.g., F, Cl, Br, I) and halogenated C. 1-6 Alkyl, maleimide, halogenated maleimide, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 Alkyl sulfoxide, halophenoxy, -OH, -SH, -NH2, nitro, azide, cyano, C 2-6 alkenyl, C 2-6 Alkyne groups and C-containing groups 2-6 The structure of the acetylene group.

[0131] In some implementations, the Lg is selected from halogens, C 1-4 Alkyl sulfonyl, halophenoxy, -OH, -SH or -NH2.

[0132] In some embodiments, the Lg is selected from halogens, CH3S(=O)2-, halophenoxy groups, -OH, -SH, or -NH2.

[0133] In some implementations, M' is selected from...

[0134] In some implementations, M' is

[0135] In some implementations, the structure of L is -L1-L2-L3-.

[0136] L1 is selected from substituted or unsubstituted structures composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): natural amino acids or non-natural amino acids and their analogues (e.g., Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala), Lys(R'), Glu(R'), short peptides composed of amino acids (e.g., Gly-Lys, Ala-Ala, Ala-Lys, Ala-Lys(Ac), Ala-Pro, Gly-Glu, Gly-Gly, Phe-L ys, Phe-Lys(Ac), Val-Ala, Val-Cit, Val-Lys, Val-Lys(Ac), Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Gly, D-Leu-Ala-Glu, Gly-Gly-Arg, Gly -Glu-Gly, Gly-Gly-Gly, Gly-Ser-Lys, Glu-Val-Ala, Glu-Val-Cit, Ser-D-Ala-Pro, Val-Leu-Lys, Val-Lys-Ala, Val-Lys-Gly, Gly-Gly-Phe-Gly (GGFG, SEQ ID NO:7), Gly-Gly-Val-Ala (GGVA, SEQ ID NO:8), Gly-Phe-Leu-Gly (GFLG, SEQ ID NO:9), Glu-Ala-Ala-Ala (EAAA, SEQ ID NO:10), Gly-Gly-Gly-Gly-Gly (GGGGG, SEQ ID NO:11), Asp-Gly-Gly-Phe-Gly (DGGFG, SEQ ID NO:12), Glu-Gly-Gly-Phe-Gly (EGGFG, SEQ ID NO:13)), s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0137] L2 does not exist, or is selected from

[0138] L3 is absent, or is selected from the following substituted or unsubstituted structures: -NH-CH2-, t is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0139] R' is selected from a structure composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): hydrogen, -NHC 1-6 Alkylene-SO3H, -CH2NH-SO3H, -CH2N(C) 1- (6-alkyl)-SO3H,-CH2NHC 1-6 Alkylene -SO3H, -CH2N(C 1-6 Alkyl)C 1-6 Alkylene -SO3H, -CH2N(C 1-6 Alkylene (-SO3H)2, -CH2N + (C 1-6 Alkylene (-SO3H)3, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylene -SO3H, -CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkylene (SO3H)3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1- 6-alkylene-SO3H)3、-CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkyl group 3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)2-CH2CO2H, -CH2N(C1-6 alkyl)-C 1-6 Alkylenes -CO2H, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylene -CO2H, glucosyl, galactosyl, glucuronic acid, galacturonic acid, -CH2N(C 1-6 Alkyl)-C(=O)-(CH2CH2O) r -C 1-6 Alkyl group, -CH2N(C) 1-6 Alkyl)-C(=O)-(OCH2CH2) r -OC 1-6 Alkyl group, -(CH2N(Me)-C(=O)) r -C 1-6 Alkyl group, -(CH2CH2O) r -C 1-6 Alkyl groups, -DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid residues), -DOTAGA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-propionyl), -NOTA (1,4,7-triazacyclononane-N,N',N”-triacetic acid residues), -EDTA (ethylenediaminetetraacetic acid residues), -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and r is an integer from 1 to 20, such as 1-12, 3-12, 1-10, 1-8, 3-8, 1-6, 1-4, or 1-2, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0140] In some implementations, Lys is

[0141] In some implementations, Glu is

[0142] In some implementations, Lys(R') refers to the following structure

[0143] In some implementations, Glu(R') refers to the following structure

[0144] In some implementations, "-DOTA" refers to

[0145] In some implementations, "-DOTAGA" refers to

[0146] In some implementations, "-NOTA" refers to

[0147] In some implementations, "-EDTA" refers to

[0148] In some embodiments, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6, or 7) substituted or unsubstituted structures: Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala, Lys(R'). Where R' is selected from glucosyl, galactosyl, glucuronic acid, galacturonic acid, -DOTA, -DOTAGA, -NOTA, -EDTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0149] In some embodiments, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6, or 7) substituted or unsubstituted structures:

[0150] In some embodiments, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6, or 7) substituted or unsubstituted structures:

[0151] In some implementations, L1 is selected from...

[0152] In some implementations, L1 is selected from...

[0153] In some implementations, L2 is absent or selected from... R' is as described in any of the above.

[0154] In some implementations, L2 is absent or selected from... R' is selected from glucosyl, galactosyl, glucuronic acid, and galacturonic acid.

[0155] In some implementations, L2 is absent or selected from...

[0156] In some implementations, L3 is absent, or is selected from -NHCH2-,

[0157] In some implementations, L3 is absent or selected from...

[0158] In some implementations, -L1-L2- is selected from

[0159] In some implementations, -L1-L2- is selected from

[0160] In some implementations, -L1-L2- is selected from

[0161] In some implementation schemes, L is selected from

[0162] In some implementations, L is selected from...

[0163] In some implementations, L is selected from...

[0164] In some embodiments, the compound is selected from the structure shown in formula (I-1”) or formula (Ia-1”).

[0165] Among them, rings A, q, X1, X2, Y1, Y2, and R e R3, R4, R5, R 5a R6, R7, L1, L2, L3 and M' are as defined in any embodiment of this application.

[0166] In some embodiments, the compound is selected from the structures shown in formula (I-1'), formula (I-2'), formula (I-3'), or formula (I-4').

[0167] Among them, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R 5a L1, L2, L3 and M' are as defined in any embodiment of this application.

[0168] In some embodiments, the compound is selected from the structures shown in formula (I-1), formula (I-2), or formula (I-3).

[0169] Wherein, X, R1, R2, R3, R4, R5, L1, L2, L3, and M' are as defined in any embodiment of this application. In some embodiments, the compound is selected from the structure shown in formula (I-2-1).

[0170] R1, R2, R3, R4, L1, L2, L3 and M' are as defined in any embodiment of this application.

[0171] In some embodiments, the compound is selected from the structure shown in formula (I-3-1).

[0172] R1, R2, R3, R4, L1, L2, L3 and M' are as defined in any embodiment of this application.

[0173] In some embodiments, the compound is selected from...

[0174] 01： 04：

[0175] 05：

[0176] 06：

[0177] 07：

[0178] 08：

[0179] 10：

[0180] 11：

[0181] 12：

[0182] 13：

[0183] 14：

[0184] 15：

[0185] 16：

[0186] 17：

[0187] 18：

[0188] 19：

[0189] 20： 21：

[0190] 22：

[0191] 23：

[0192] 24：

[0193] 25：

[0194] 26：

[0195] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs can be used to prepare conjugates or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs.

[0196] Coupled

[0197] The second aspect of this application provides a conjugate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, wherein the conjugate comprises the compound of the first aspect or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof.

[0198] In some embodiments, the coupling is as shown in formula (II), P-(MLD) n (II)

[0199] in,

[0200] P represents the target moiety (e.g., small molecule ligands, proteins, peptides, non-protein reagents (e.g., sugars, RNA, or DNA));

[0201] M is a structure connecting P and L;

[0202] L and D are as defined in any embodiment of this application;

[0203] n is 1-10.

[0204] In some implementations, P is a protein.

[0205] In some implementations, P is a fusion protein or an antibody.

[0206] In some embodiments, P is a target molecule of receptor tyrosine kinase (RTK) and / or Klotho family proteins.

[0207] In some embodiments, P is a target molecule of FGFR (Fibroblast Growth Factor Receptor) and / or β-Klotho (KLB).

[0208] In some embodiments, the coupling is as shown in formula (II), P-(MLD) n (II)

[0209] in,

[0210] P is an FGFR (Fibroblast Growth Factor Receptor) agonist and / or a KLB (β-Klotho) binding molecule;

[0211] M is a structure connecting P and L;

[0212] L and D are as defined in any embodiment of this application;

[0213] n is 1-10.

[0214] In some embodiments, M is selected from the following substituted or unsubstituted structures:

[0215] In some embodiments, M is selected from the following substituted or unsubstituted structures:

[0216] In some embodiments, M is selected from the following substituted or unsubstituted structures:

[0217] In some embodiments, P is an FGF21R ​​agonist. In some embodiments, the FGF21R ​​agonist is a fusion protein.

[0218] In some embodiments, P is a fusion protein containing FGF21 or a mutant thereof.

[0219] In some embodiments, P is a fusion protein comprising wild-type FGF21 or a mutant thereof.

[0220] In some embodiments, the wild-type FGF21 comprises the amino acid sequence shown in SEQ ID NO:114.

[0221] In some embodiments, P is a fusion protein comprising wild-type FGF21, which does not contain a signal peptide. In some embodiments, the wild-type FGF21 has an amino acid sequence as shown in SEQ ID NO:125.

[0222] In some embodiments, the fusion protein comprises an FGF21 mutant. In some embodiments, the FGF21 mutant has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the wild-type FGF21, or the mutant has one or more amino acid substitutions, deletions, or additions (e.g., one, two, or three amino acid substitutions, deletions, or additions) compared to the wild-type FGF21, and is capable of activating the KLB-FGFR signaling pathway.

[0223] In some embodiments, the FGF21 mutant, relative to wild-type FGF21 without a signal peptide (e.g., wild-type FGF21 having the amino acid sequence shown in SEQ ID NO:125), contains one or more of the following mutations: L98R, P171G, A180E, Q27C, G120C, K122R, P130S, S167A, G174A.

[0224] In some embodiments, the FGF21 mutant contains the following mutations relative to wild-type FGF21 without the signal peptide (e.g., wild-type FGF21 having the amino acid sequence shown in SEQ ID NO:125): (1) L98R, P171G, and A180E; or (2) Q27C, G120C, K122R, P130S, S167A, P171G, and G174A.

[0225] In some embodiments, the wild-type FGF21 or its mutant is a truncated fragment with one, two, three, four, five, or six amino acid residues removed from its N-terminus or C-terminus. In some embodiments, the truncated fragment retains the activation ability of the wild-type FGF21 or its mutant on the KLB-FGFR signaling pathway.

[0226] In some embodiments, the wild-type FGF21 or its mutant is a truncated fragment with the four N-terminal amino acid residues removed.

[0227] In some embodiments, the FGF21 mutant is a truncated fragment with four amino acid residues removed from its N-terminus, and has the following amino acid mutations relative to the wild-type FGF21 (e.g., wild-type FGF21 without a signal peptide having the amino acid sequence shown in SEQ ID NO:125): Q27C, G120C, K122R, P130S, S167A, P171G, G174A.

[0228] In some embodiments, the FGF21 mutant comprises the sequence shown in SEQ ID NO:3 or 124.

[0229] In some embodiments, the FGF21 mutant, relative to the wild-type FGF21, contains one or more of the following mutations: L98R, P171G, and A180E.

[0230] In some embodiments, the FGF21 mutant comprises the amino acid sequence shown in SEQ ID NO:3.

[0231] In some embodiments, the amino acid sequence of the FGF21 mutant is shown in SEQ ID NO:3.

[0232] In some embodiments, the fusion protein further comprises an IgG constant domain or a fragment thereof. In some embodiments, the IgG constant domain or a fragment thereof is an Fc domain of IgG, such as the Fc domain of IgG1, IgG2, IgG3, or IgG4. In some embodiments, the IgG constant domain or a fragment thereof is the Fc domain of human IgG1.

[0233] In some embodiments, the Fc domain contained in the fusion protein has one or more amino acid substitutions relative to the Fc domain of wild-type human IgG1, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0234] In some embodiments, the Fc domain, compared to the wild-type Fc region, includes one or more mutations that alter (e.g., reduce) Fc-mediated effector function. For example, the Fc domain may include mutations that reduce or eliminate antibody-dependent cytotoxicity (ADCC) activity and / or complement-dependent cytotoxicity (CDC) activity. In some embodiments, according to the EU numbering scheme, the Fc domain may comprise: (i) E233A and L235A (EALA) amino acid substitutions; (ii) L234A and L235A (LALA) amino acid substitutions; (iii) L234A L235A D265S (LALADS) amino acid substitutions; (iv) L234A L235A P329G (LALAPG) amino acid substitutions; (v) L234A L235A P329A (LALAPA) amino acid substitutions; (vi) L235E (LE) amino acid substitutions; (vii) D265A (DS) amino acid substitutions; (viii) D265A N297G (DANG) amino acid substitutions; (ix) N297X amino acid substitutions, where X is an amino acid other than N; (x) L234AL235A G237A(LALAGA) amino acid substitution; or (xi)L234F / L235E / P331S amino acid substitution.

[0235] In some embodiments, the Fc domain has the following amino acid substitutions compared to the Fc domain of wild-type human IgG1: Leu234Ala, Leu235Ala (according to the EU numbering system). In some embodiments, the Fc domain has the following amino acid substitutions compared to the Fc domain of wild-type human IgG1: Leu234Ala, Leu235Ala, and Gly237Ala (according to the EU numbering system).

[0236] In some embodiments, the Fc domain, compared to the wild-type Fc region, contains one or more mutations that enhance pH-dependent FcRn binding activity, thereby prolonging the in vivo half-life. For example, the Fc region variants, according to the EU numbering system, may include N434A. As another example, the Fc region variants, according to the EU numbering system, may include M252Y, S254T, and T256E.

[0237] In some embodiments, the Fc domain may further include naturally occurring allotypes in different populations. For example, relative to the wild-type Fc sequence shown in SEQ ID NO:4 (which contains D356 and L358), an allotype variant of the Fc domain may include amino acid substitutions of D356E and L358M.

[0238] In some embodiments, the Fc domain of the human IgG1 contains the amino acid sequence shown in SEQ ID NO:4, 122, or 123.

[0239] In some embodiments, the Fc domain of the human IgG1 contains the amino acid sequence shown in SEQ ID NO:4.

[0240] In some embodiments, the FGF21 or a mutant thereof is fused with an IgG constant domain or a fragment thereof via a linker. In some embodiments, the linker comprises the amino acid sequence shown in SEQ ID NO:2.

[0241] In some implementations, the connector includes GS.

[0242] In some embodiments, the N-terminus of the adapter is fused to the C-terminus of the IgG constant domain or a fragment thereof, and the N-terminus of the FGF21 or a mutant thereof is fused to the C-terminus of the adapter.

[0243] In some embodiments, the N-terminus of the adapter is fused to the C-terminus of FGF21 or a mutant thereof, and the C-terminus of the adapter is fused to the N-terminus of an IgG constant domain or a fragment thereof (e.g., the Fc domain).

[0244] In some embodiments, the fusion protein comprises the amino acid sequence shown in SEQ ID NO:1, 120, or 121.

[0245] In some embodiments, the fusion protein comprises the amino acid sequence shown in SEQ ID NO:1.

[0246] In some embodiments, the fusion protein is in dimer form. Specifically, the fusion protein comprises a first polypeptide chain and a second polypeptide chain. In some embodiments, the first polypeptide chain and the second polypeptide chain maintain a stable dimer structure primarily through hydrophobic interactions, hydrogen bonds, and van der Waals forces.

[0247] In some embodiments, the first polypeptide chain and the second polypeptide chain have the same amino acid sequence. In some embodiments, the first polypeptide chain and the second polypeptide chain each contain the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:1, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:1. In some embodiments, the amino acid sequences of the first polypeptide chain and the second polypeptide chain are different.

[0248] In some embodiments, P is a KLB antibody. In some embodiments, the KLB antibody is Ab01, Ab02, MK-3655, RG7992, or mimAb1, or a variant of the aforementioned antibodies. In some embodiments, the KLB antibody is MK-3655, RG7992, or mimAb1.

[0249] In some embodiments, P is an antibody or antigen-binding fragment thereof capable of specifically binding to KLB, comprising:

[0250] (1) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:74, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:75; or

[0251] (2) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:93, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:94; or

[0252] (3) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:14, and / or the three complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) shown in SEQ ID NO:15.

[0253] In some implementations, the complementary determinant regions (CDRs) contained in the light chain variable region (VL) and the complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) described in (1), (2), and (3) are defined by the Kabat, Chothia, Abm, or IMGT numbering system.

[0254] In some implementations, P includes:

[0255] (1) The following VL and / or VH,

[0256] (1a) CDRs are defined according to the kabat numbering system:

[0257] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:81 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:85 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0258] (1b) CDRs are defined according to the Chothia numbering system:

[0259] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:82 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:86 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0260] (1c) CDRs are defined according to the Abm numbering system:

[0261] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:84 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:88 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0262] (1d) CDRs are defined according to the IMGT numbering system:

[0263] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:77 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:79 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:83 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:87 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:90 or a variant thereof;

[0264] Wherein, the variant described in any one of (1a), (1b), (1c), and (1d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0265] or

[0266] (2) The following VL and / or VH,

[0267] (2a) CDRs are defined according to the kabat numbering system:

[0268] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:100 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:104 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0269] (2b) CDRs are defined according to the Chothia numbering system:

[0270] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:101 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:105 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0271] (2c) CDRs are defined according to the Abm numbering system:

[0272] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:103 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:107 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0273] (2d) CDRs are defined according to the IMGT numbering system:

[0274] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:96 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:98 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:102 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:106 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:109 or a variant thereof;

[0275] Wherein, the variant described in any one of (2a), (2b), (2c), and (2d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0276] or

[0277] (3) The following VL and / or VH,

[0278] (3a) CDRs are defined according to the kabat numbering system:

[0279] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:21 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:25 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0280] (3b) CDRs are defined according to the Chothia numbering system:

[0281] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:22 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:26 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0282] (3c) CDRs are defined according to the Abm numbering system:

[0283] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:24 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:28 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0284] (3d)CDRs are defined according to the IMGT numbering system:

[0285] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:17 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:19 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:23 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:27 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:30 or a variant thereof;

[0286] Wherein, the variant described in any one of (3a), (3b), (3c), and (3d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0287] In some implementations, P includes:

[0288] (1) The following VL and VH,

[0289] (1a) CDRs are defined according to the kabat numbering system:

[0290] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:81, CDR-H2 with sequence SEQ ID NO:85, and CDR-H3 with sequence SEQ ID NO:89; or

[0291] (1b) CDRs are defined according to the Chothia numbering system:

[0292] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:82, CDR-H2 with sequence SEQ ID NO:86, and CDR-H3 with sequence SEQ ID NO:89; or

[0293] (1c) CDRs are defined according to the Abm numbering system:

[0294] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:84, CDR-H2 with sequence SEQ ID NO:88, and CDR-H3 with sequence SEQ ID NO:89; or

[0295] (1d) CDRs are defined according to the IMGT numbering system:

[0296] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:77, CDR-L2 with sequence SEQ ID NO:79, and CDR-L3 with sequence SEQ ID NO:80; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:83, CDR-H2 with sequence SEQ ID NO:87, and CDR-H3 with sequence SEQ ID NO:90;

[0297] or

[0298] (2) The following VL and VH,

[0299] (2a) CDRs are defined according to the kabat numbering system:

[0300] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:100, CDR-H2 with sequence SEQ ID NO:104, and CDR-H3 with sequence SEQ ID NO:108; or

[0301] (2b) CDRs are defined according to the Chothia numbering system:

[0302] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:101, CDR-H2 with sequence SEQ ID NO:105, and CDR-H3 with sequence SEQ ID NO:108; or

[0303] (2c) CDRs are defined according to the Abm numbering system:

[0304] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:103, CDR-H2 with sequence SEQ ID NO:107, and CDR-H3 with sequence SEQ ID NO:108; or

[0305] (2d) CDRs are defined according to the IMGT numbering system:

[0306] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:96, CDR-L2 with sequence SEQ ID NO:98, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:102, CDR-H2 with sequence SEQ ID NO:106, and CDR-H3 with sequence SEQ ID NO:109; or

[0307] (3) The following VL and VH,

[0308] (3a) CDRs are defined according to the kabat numbering system:

[0309] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:21, CDR-H2 with sequence SEQ ID NO:25, and CDR-H3 with sequence SEQ ID NO:29; or

[0310] (3b) CDRs are defined according to the Chothia numbering system:

[0311] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:22, CDR-H2 with sequence SEQ ID NO:26, and CDR-H3 with sequence SEQ ID NO:29; or

[0312] (3c) CDRs are defined according to the Abm numbering system:

[0313] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:24, CDR-H2 with sequence SEQ ID NO:28, and CDR-H3 with sequence SEQ ID NO:29; or

[0314] (3d)CDRs are defined according to the IMGT numbering system:

[0315] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:17, CDR-L2 with sequence SEQ ID NO:19, and CDR-L3 with sequence SEQ ID NO:20; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:23, CDR-H2 with sequence SEQ ID NO:27, and CDR-H3 with sequence SEQ ID NO:30.

[0316] In some implementations, P includes:

[0317] (1) VL or a variant thereof shown in SEQ ID NO:74, and / or VH or a variant thereof shown in SEQ ID NO:75; or

[0318] (2) VL or a variant thereof shown in SEQ ID NO:93, and / or VH or a variant thereof shown in SEQ ID NO:94; or

[0319] (3) VL or a variant thereof shown in SEQ ID NO:14, and / or VH or a variant thereof shown in SEQ ID NO:15;

[0320] Wherein, the variant described in any one of (1), (2), and (3) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0321] In some implementations, P includes:

[0322] (1) VL shown in SEQ ID NO:74 and VH shown in SEQ ID NO:75; or

[0323] (2) VL shown in SEQ ID NO:93 and VH shown in SEQ ID NO:94; or

[0324] (3) VL shown in SEQ ID NO:14 and VH shown in SEQ ID NO:15.

[0325] In some implementations, P further includes:

[0326] (a) The heavy chain constant region (CH) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions, or additions compared to its derived wild-type sequence (e.g., substitutions, deletions, or additions of up to 20, 15, 10, or 5 amino acids; e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids); and

[0327] (b) The light chain constant region (CL) of human immunoglobulin or a variant thereof, which has one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10 or up to 5 amino acids; e.g., substitutions, deletions or additions of 1, 2, 3, 4 or 5 amino acids).

[0328] In some embodiments, the heavy chain constant region is an IgG heavy chain constant region, such as the IgG1, IgG2, IgG3, or IgG4 heavy chain constant region, such as the human IgG1 heavy chain constant region or the human IgG4 heavy chain constant region.

[0329] In some embodiments, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:5.

[0330] In some embodiments, the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO:6 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:6.

[0331] In some embodiments, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 and a heavy chain constant region (CH) as shown in SEQ ID NO:6.

[0332] In some implementations, P includes:

[0333] (1) A light chain comprising the VL region of the sequence shown in SEQ ID NO:74 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:75 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or

[0334] (2) A light chain comprising the VL region of the sequence shown in SEQ ID NO:93 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:94 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or,

[0335] (3) A light chain comprising the VL of the sequence shown in SEQ ID NO:14 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH of the sequence shown in SEQ ID NO:15 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6.

[0336] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0337] (1) The light chain of the sequence shown in SEQ ID NO:91, and the heavy chain of the sequence shown in SEQ ID NO:92; or

[0338] (2) The light chain of the sequence shown in SEQ ID NO:110, and the heavy chain of the sequence shown in SEQ ID NO:101; or

[0339] (3) The light chain of the sequence shown in SEQ ID NO:31, and the heavy chain of the sequence shown in SEQ ID NO:32.

[0340] In some embodiments, P is a bispecific antibody or its antigen-binding fragment comprising a first antigen-binding domain that specifically binds to KLB and a second antigen-binding domain that specifically binds to FGFR1C; wherein the first antigen-binding domain comprises a first light chain variable region (VL) and a first heavy chain variable region (VH), the first VL and the first VH together forming a domain capable of specifically binding to KLB; the second antigen-binding domain comprises a second light chain variable region (VL) and a second heavy chain variable region (VH), the second VL and the second VH together forming a domain capable of specifically binding to FGFR1C.

[0341] In some implementations, the first antigen-binding domain and the second antigen-binding domain are each independently selected from scFv, Fab, and scFab.

[0342] In some implementations, the first antigen-binding domain and the second antigen-binding domain are Fab, and the Fab of the second antigen-binding domain contains domain exchanges of the form of CrossMab.

[0343] In some implementations, the CrossMab form of domain swapping involves swapping CH1 and CL in the Fab.

[0344] In some embodiments, the first VL contains three CDRs contained in the amino acid sequence shown in SEQ ID NO:33; and / or the first VH contains three CDRs contained in the amino acid sequence shown in SEQ ID NO:34.

[0345] In some implementations, the CDRs contained in the first VL and the CDRs contained in the first VH are defined by the Kabat, Chothia, Abm or IMGT numbering system.

[0346] In some implementations, the first VL includes:

[0347] (i) CDR-L1 with sequence SEQ ID NO:35 or a variant thereof, CDR-L2 with sequence SEQ ID NO:37 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or

[0348] (ii) CDR-L1 with sequence SEQ ID NO:36 or a variant thereof, CDR-L2 with sequence SEQ ID NO:38 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0349] and / or

[0350] The first VH includes:

[0351] (i) CDR-H1 with sequence SEQ ID NO:40 or a variant thereof, CDR-H2 with sequence SEQ ID NO:44 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or

[0352] (ii) CDR-H1 with sequence SEQ ID NO:41 or a variant thereof, CDR-H2 with sequence SEQ ID NO:45 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or

[0353] (iii) CDR-H1 with sequence SEQ ID NO:43 or a variant thereof, CDR-H2 with sequence SEQ ID NO:47 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or

[0354] (iv) CDR-H1 with sequence SEQ ID NO:42 or a variant thereof, CDR-H2 with sequence SEQ ID NO:46 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:49 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0355] The variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) with its source sequence. In some embodiments, the substitutions are conservative substitutions.

[0356] In some implementations, the first VL includes:

[0357] (i) CDR-L1 with sequence SEQ ID NO:35, CDR-L2 with sequence SEQ ID NO:37, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or

[0358] (ii) CDR-L1 with sequence SEQ ID NO:36, CDR-L2 with sequence SEQ ID NO:38, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the IMGT numbering system;

[0359] and / or

[0360] The first VH includes:

[0361] (i) CDR-H1 with sequence SEQ ID NO:40, CDR-H2 with sequence SEQ ID NO:44, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Kabat numbering system; or

[0362] (ii) CDR-H1 with sequence SEQ ID NO:41, CDR-H2 with sequence SEQ ID NO:45, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Chothia numbering system; or

[0363] (iii) CDR-H1 with sequence SEQ ID NO:43, CDR-H2 with sequence SEQ ID NO:47, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Abm numbering system; or

[0364] (iv) CDR-H1 with sequence SEQ ID NO:42, CDR-H2 with sequence SEQ ID NO:46, and CDR-H3 with sequence SEQ ID NO:49, wherein the CDRs are defined according to the IMGT numbering system.

[0365] In some embodiments, the first VL contains the amino acid sequence shown in SEQ ID NO:33 or a variant thereof, and the first VH contains the amino acid sequence shown in SEQ ID NO:34 or a variant thereof.

[0366] The variant has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence. In some embodiments, the substitutions are conservative substitutions.

[0367] In some embodiments, the first VL contains the amino acid sequence shown in SEQ ID NO:33, and the first VH contains the amino acid sequence shown in SEQ ID NO:34.

[0368] In some embodiments, the second VL contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:50; and / or the second VH contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:51.

[0369] In some implementations, the CDRs contained in the second VL and the CDRs contained in the second VH are defined by the Kabat, Chothia, Abm or IMGT numbering system.

[0370] In some implementations, the second VL includes:

[0371] (i) CDR-L1 with sequence SEQ ID NO:52 or a variant thereof, CDR-L2 with sequence SEQ ID NO:54 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or

[0372] (ii) CDR-L1 with sequence SEQ ID NO:53 or a variant thereof, CDR-L2 with sequence SEQ ID NO:55 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0373] and / or

[0374] The second VH includes:

[0375] (i) CDR-H1 with sequence SEQ ID NO:57 or a variant thereof, CDR-H2 with sequence SEQ ID NO:61 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or

[0376] (ii) CDR-H1 with sequence SEQ ID NO:58 or a variant thereof, CDR-H2 with sequence SEQ ID NO:62 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or

[0377] (iii) CDR-H1 with sequence SEQ ID NO:60 or a variant thereof, CDR-H2 with sequence SEQ ID NO:64 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or

[0378] (iv) CDR-H1 with sequence SEQ ID NO:59 or a variant thereof, CDR-H2 with sequence SEQ ID NO:63 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:66 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0379] The variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) with its source sequence. In some embodiments, the substitutions are conservative substitutions.

[0380] In some implementations, the second VL includes:

[0381] (i) CDR-L1 with sequence SEQ ID NO:52, CDR-L2 with sequence SEQ ID NO:54, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or

[0382] (ii) CDR-L1 with sequence SEQ ID NO:53, CDR-L2 with sequence SEQ ID NO:55, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the IMGT numbering system;

[0383] and / or

[0384] The second VH includes:

[0385] (i) CDR-H1 with sequence SEQ ID NO:57, CDR-H2 with sequence SEQ ID NO:61, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Kabat numbering system; or

[0386] (ii) CDR-H1 with sequence SEQ ID NO:58, CDR-H2 with sequence SEQ ID NO:62, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Chothia numbering system; or

[0387] (iii) CDR-H1 with sequence SEQ ID NO:60, CDR-H2 with sequence SEQ ID NO:64, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Abm numbering system; or

[0388] (iv) CDR-H1 with sequence SEQ ID NO:59, CDR-H2 with sequence SEQ ID NO:63, and CDR-H3 with sequence SEQ ID NO:66, wherein the CDRs are defined according to the IMGT numbering system.

[0389] In some embodiments, the second VL comprises the amino acid sequence shown in SEQ ID NO:50 or a variant thereof, and the second VH comprises the amino acid sequence shown in SEQ ID NO:51 or a variant thereof.

[0390] The variant has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence. In some embodiments, the substitutions are conservative substitutions.

[0391] In some embodiments, the second VL contains the amino acid sequence shown in SEQ ID NO:50, and the second VH contains the amino acid sequence shown in SEQ ID NO:51.

[0392] In some embodiments, the bispecific antibody comprises peptide chain IA, peptide chain IB, peptide chain IC, and peptide chain ID, wherein peptide chain IA comprises a first VL and a light chain constant region (CL), peptide chain IB comprises a first VH, a heavy chain CH1 region, and a first Fc domain monomer (or a second Fc domain monomer), peptide chain IC comprises a second VH, a light chain constant region (CL), and a second Fc domain monomer (or a first Fc domain monomer), and peptide chain ID comprises the second VL and a heavy chain CH1 region.

[0393] In some embodiments, the first Fc domain monomer and the second Fc domain monomer each independently contain one or more amino acid modifications that promote dimerization of the first Fc domain monomer and the second Fc domain monomer.

[0394] In some embodiments, the first Fc domain monomer contains an amino acid modification capable of forming a knob structure, and the second Fc domain monomer contains an amino acid modification capable of forming a hole structure, wherein the knob structure can pair with the hole structure to form a heterodimer.

[0395] In some embodiments, the first Fc domain monomer contains an amino acid sequence as shown in SEQ ID NO:112.

[0396] In some embodiments, the second Fc domain monomer contains an amino acid sequence as shown in SEQ ID NO:113.

[0397] In some embodiments, the heavy chain CH1 region contains an amino acid sequence as shown in SEQ ID NO:68.

[0398] In some embodiments, peptide chain IA includes the first VL and CL from the N-terminus to the C-terminus, peptide chain IB includes the first VH, the heavy chain CH1 region, and the first Fc domain monomer (or the second Fc domain monomer) from the N-terminus to the C-terminus, peptide chain IC includes the second VH, CL, and the second Fc domain monomer (or the first Fc domain monomer) from the N-terminus to the C-terminus, and peptide chain ID includes the second VL and the heavy chain CH1 region from the N-terminus to the C-terminus.

[0399] In some embodiments, adjacent domains of peptide chain IA are optionally connected by or without a connector, adjacent domains of peptide chain IB are optionally connected by or without a connector, adjacent domains of peptide chain IC are optionally connected by or without a connector, and / or adjacent domains of peptide chain ID are optionally connected by or without a connector.

[0400] In some implementations, the connectors are each independently the same or different peptide connectors (e.g., rigid peptide connectors or flexible peptide connectors).

[0401] In some embodiments, each peptide linker is independently selected from peptide linkers comprising one or more glycine (G) and / or serine (S), for example having the structure shown in (GGGGS)y, where y is an integer not less than 0, for example, y is 1, 2, 3, 4, 5, or 6. In some embodiments, each peptide linker independently comprises an amino acid sequence as shown in any one of SEQ ID NO:2 or SEQ ID NOs:115-119.

[0402] In some embodiments, peptide chain IA comprises an amino acid sequence as shown in SEQ ID NO:70, peptide chain IB comprises an amino acid sequence as shown in SEQ ID NO:71, peptide chain IC comprises an amino acid sequence as shown in SEQ ID NO:73, and / or peptide chain ID comprises an amino acid sequence as shown in SEQ ID NO:72.

[0403] In some implementations, n is 1-8, such as 3-5, 4-8, or 6-8, such as about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8.

[0404] In some implementations, n is 1-8, for example 3-5, such as about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8.

[0405] In some implementations, n is an integer.

[0406] In some embodiments, the coupling is as shown in formula (II-1”) or formula (IIa-1”):

[0407] Among them, rings A, q, X1, X2, Y1, Y2, and R e R3, R4, R5, R 5a R6, R7, L1, L2, L3, M, P and n are as defined in any embodiment of this application.

[0408] In some embodiments, the coupling is as shown in formula (II-1'), formula (II-2'), formula (II-3'), or formula (II-4').

[0409] Among them, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R 5a L1, L2, L3, M, P and n are as defined in any embodiment of this application.

[0410] In some embodiments, the coupling is as shown in formula (II-1), formula (II-2), or formula (II-3).

[0411] Wherein, X, R1, R2, R3, R4, R5, L1, L2, L3, M, P and n are as defined in any embodiment of this application.

[0412] In some embodiments, the coupling is as shown in formula (II-2-1).

[0413] Wherein, R1, R2, R3, R4, L1, L2, L3, M, P and n are as defined in any embodiment of this application.

[0414] In some embodiments, the coupling is as shown in formula (II-3-1).

[0415] Wherein, R1, R2, R3, R4, L1, L2, L3, M, P, and n are as defined in any embodiment of this application. In some embodiments, the coupling agent is selected from...

[0416] P-01:

[0417] P-04:

[0418] P-05:

[0419] P-06:

[0420] P-07:

[0421] P-08:

[0422] P-10:

[0423] P-11:

[0424] P-12:

[0425] P-13:

[0426] P-14:

[0427] P-15:

[0428] P-16:

[0429] P-17:

[0430] P-18:

[0431] P-19:

[0432] P-20:

[0433] P-21:

[0434] P-22:

[0435] P-23:

[0436] P-24:

[0437] P-25:

[0438] P-26:

[0439] Wherein, P and n are as defined in any embodiment of this application.

[0440] In some embodiments, P is linked to form a coupling via one or more thiol groups of cysteine ​​residues, one or more amino groups of lysine residues, one or more hydroxyl groups of threonine residues, or one or more hydroxyl groups of serine residues in the protein.

[0441] In some implementations, P is linked via one or more thiol groups of cysteine ​​residues in the protein to form a conjugate.

[0442] In some implementations, P is linked to one or more thiol groups of cysteine ​​residues in the Fc domain of IgG to form a conjugate.

[0443] In some embodiments, P is linked by n thiol groups of cysteine ​​residues, n amino groups of lysine residues, n hydroxyl groups of threonine residues, or n hydroxyl groups of serine residues in the protein to form a conjugate.

[0444] In some implementations, P is linked to n thiol groups of cysteine ​​residues in the Fc domain of IgG to form a conjugate.

[0445] In some embodiments, the coupling compound of the present invention may optionally be substituted with one or more suitable substituents.

[0446] Those skilled in the art will understand that the protein drug conjugates described in this application can be prepared in a modular manner. For example, a pre-conjugation form of the compound (which can be understood as M'-LD, where M' is the structural form of M before covalently linking with the protein) can be obtained first, and then covalently linked to the protein to obtain the protein drug conjugates described in this application. The pre-conjugation form of the compound can be a free form of the compound. Accordingly, in the pre-conjugation form of the compound, M' is linked to one or more thiol (-SH), amino (-NH2), or carboxyl (-COOH) groups on the protein through a substitution reaction (e.g., removal of the -SO2Me or -Br structure) or an addition reaction.

[0447] Composition

[0448] A third aspect of this application provides a composition comprising the conjugate described in the second aspect of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the drug-protein conjugation ratio of the composition is about 1-10, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 to 2, about 1 to 3, about 1 to 4, about 1 to 5, about 1 to 6, about 1 to 7, about 1 to 8. About 1 to 9, about 1 to 10, about 2 to 3, about 2 to 4, about 2 to 5, about 2 to 6, about 2 to 7, about 2 to 8, about 2 to 9, about 2 to 10, about 3 to 4, about 3 to 5, about 3 to 6, about 3 to 7, about 3 to 8, about 3 to 9, about 3 to 10, about 4 to 5, about 4 to 6, about 4 to 7, about 4 to 8, about 4 to 9, about 4 to 10, about 5 to 6, about 5 to 7, about 5 to 8, about 5 to 9, about 5 to 10, about 6 to 7, about 6 to 8, about 6 to 9, about 6 to 10, about 7 to 8, about 7 to 9, about 7 to 1 0, about 8 to 9, about 8 to 10, or about 9 to 10, or for example, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5 .3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.

[0449] In some embodiments, the composition is composed of, for example, P-(MLD). n The coupling composition is shown. In some embodiments, the P, M, L, D, and n of the individual couplings in the composition may be the same or different. In some embodiments, the P, M, L, and D of the individual couplings in the composition are the same, and the n may be the same or different.

[0450] Antibody

[0451] The fourth aspect of this application provides an antibody or antigen-binding fragment thereof capable of specifically binding to KLB, comprising:

[0452] (1) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:74, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:75; or

[0453] (2) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:93, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:94.

[0454] In some implementations, the complementary determinant regions (CDRs) contained in the light chain variable region (VL) and the complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) described in (1) and (2) are defined by the Kabat, Chothia, Abm or IMGT numbering system.

[0455] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0456] (1) The following VL and / or VH,

[0457] (1a) CDRs are defined according to the kabat numbering system:

[0458] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:81 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:85 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0459] (1b) CDRs are defined according to the Chothia numbering system:

[0460] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:82 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:86 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0461] (1c) CDRs are defined according to the Abm numbering system:

[0462] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:84 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:88 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0463] (1d) CDRs are defined according to the IMGT numbering system:

[0464] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:77 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:79 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:83 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:87 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:90 or a variant thereof;

[0465] Wherein, the variant described in any one of (1a), (1b), (1c), and (1d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0466] or

[0467] (2) The following VL and / or VH,

[0468] (2a) CDRs are defined according to the kabat numbering system:

[0469] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:100 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:104 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0470] (2b) CDRs are defined according to the Chothia numbering system:

[0471] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:101 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:105 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0472] (2c) CDRs are defined according to the Abm numbering system:

[0473] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:103 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:107 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0474] (2d) CDRs are defined according to the IMGT numbering system:

[0475] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:96 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:98 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:102 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:106 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:109 or a variant thereof;

[0476] Wherein, the variant described in any one of (2a), (2b), (2c), and (2d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0477] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0478] (1) The following VL and VH,

[0479] (1a) CDRs are defined according to the kabat numbering system:

[0480] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:81, CDR-H2 with sequence SEQ ID NO:85, and CDR-H3 with sequence SEQ ID NO:89; or

[0481] (1b) CDRs are defined according to the Chothia numbering system:

[0482] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:82, CDR-H2 with sequence SEQ ID NO:86, and CDR-H3 with sequence SEQ ID NO:89; or

[0483] (1c) CDRs are defined according to the Abm numbering system:

[0484] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:84, CDR-H2 with sequence SEQ ID NO:88, and CDR-H3 with sequence SEQ ID NO:89; or

[0485] (1d) CDRs are defined according to the IMGT numbering system:

[0486] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:77, CDR-L2 with sequence SEQ ID NO:79, and CDR-L3 with sequence SEQ ID NO:80; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:83, CDR-H2 with sequence SEQ ID NO:87, and CDR-H3 with sequence SEQ ID NO:90;

[0487] or

[0488] (2) The following VL and VH,

[0489] (2a) CDRs are defined according to the kabat numbering system:

[0490] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:100, CDR-H2 with sequence SEQ ID NO:104, and CDR-H3 with sequence SEQ ID NO:108; or

[0491] (2b) CDRs are defined according to the Chothia numbering system:

[0492] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:101, CDR-H2 with sequence SEQ ID NO:105, and CDR-H3 with sequence SEQ ID NO:108; or

[0493] (2c) CDRs are defined according to the Abm numbering system:

[0494] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:103, CDR-H2 with sequence SEQ ID NO:107, and CDR-H3 with sequence SEQ ID NO:108; or

[0495] (2d) CDRs are defined according to the IMGT numbering system:

[0496] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:96, CDR-L2 with sequence SEQ ID NO:98, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:102, CDR-H2 with sequence SEQ ID NO:106, and CDR-H3 with sequence SEQ ID NO:109.

[0497] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0498] (1) VL or a variant thereof shown in SEQ ID NO:74, and / or VH or a variant thereof shown in SEQ ID NO:75; or

[0499] (2) VL or a variant thereof shown in SEQ ID NO:93, and / or VH or a variant thereof shown in SEQ ID NO:94;

[0500] Wherein, the variant described in either (1) or (2) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0501] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0502] (1) VL shown in SEQ ID NO:74 and VH shown in SEQ ID NO:75; or

[0503] (2) VL shown in SEQ ID NO:93 and VH shown in SEQ ID NO:94.

[0504] In some embodiments, the antibody or its antigen-binding fragment further comprises:

[0505] (a) The heavy chain constant region (CH) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions, or additions compared to its derived wild-type sequence (e.g., substitutions, deletions, or additions of up to 20, 15, 10, or 5 amino acids; e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids); and

[0506] (b) The light chain constant region (CL) of human immunoglobulin or a variant thereof, which has one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10 or up to 5 amino acids; e.g., substitutions, deletions or additions of 1, 2, 3, 4 or 5 amino acids).

[0507] In some embodiments, the heavy chain constant region is an IgG heavy chain constant region, such as the IgG1, IgG2, IgG3, or IgG4 heavy chain constant region, such as the human IgG1 heavy chain constant region or the human IgG4 heavy chain constant region.

[0508] In some embodiments, the heavy chain constant region includes an Fc domain that, compared to the wild-type Fc region, contains one or more mutations that alter (e.g., reduce) effector function, such as reducing antibody-dependent cytotoxicity (ADCC) activity / complement-dependent cytotoxicity (CDC) activity, or eliminating ADCC activity / CDC activity.

[0509] In some embodiments, according to the EU numbering scheme, the Fc domain may comprise: (i) E233A and L235A (EALA) amino acid substitutions; (ii) L234A and L235A (LALA) amino acid substitutions; (iii) L234A L235A D265S (LALADS) amino acid substitutions; (iv) L234A L235A P329G (LALAPG) amino acid substitutions; (v) L234A L235AP329A (LALAPA) amino acid substitutions; (vi) L235E (LE) amino acid substitutions; (vii) D265A (DS) amino acid substitutions; (viii) D265A N297G (DANG) amino acid substitutions; (ix) N297X amino acid substitutions, where X is an amino acid other than N; (x) L234A L235A G237A(LALAGA) amino acid substitution; or (xi)L234F / L235E / P331S amino acid substitution.

[0510] In some embodiments, the Fc domain, compared to the wild-type Fc region, contains one or more mutations that enhance pH-dependent FcRn binding activity, thereby prolonging the in vivo half-life. For example, the Fc region variants, according to the EU numbering system, may include N434A. As another example, the Fc region variants, according to the EU numbering system, may include M252Y, S254T, and T256E.

[0511] In some embodiments, the Fc domain may further include naturally occurring allotypes in different populations. For example, relative to the wild-type Fc sequence shown in SEQ ID NO:4 (which includes D356 and L358), the allotype variants of the Fc domain may include D356E and L358M.

[0512] In some embodiments, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:5.

[0513] In some embodiments, the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO:6 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:6.

[0514] In some embodiments, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 and a heavy chain constant region (CH) as shown in SEQ ID NO:6.

[0515] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0516] (1) A light chain comprising the VL region of the sequence shown in SEQ ID NO:74 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:75 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or

[0517] (2) A light chain comprising the VL of the sequence shown in SEQ ID NO:93 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH of the sequence shown in SEQ ID NO:94 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6.

[0518] In some embodiments, the antibody or its antigen-binding fragment comprises:

[0519] (1) The light chain of the sequence shown in SEQ ID NO:91, and the heavy chain of the sequence shown in SEQ ID NO:92; or

[0520] (2) The light chain of the sequence shown in SEQ ID NO:110, and the heavy chain of the sequence shown in SEQ ID NO:101.

[0521] One aspect of this application also provides a chimeric antigen receptor comprising an antigen-binding domain, a spacer domain, a transmembrane domain, and an intracellular signal transduction domain, wherein the antigen-binding domain comprises an antibody or an antigen-binding fragment thereof as described in any embodiment of this application.

[0522] One aspect of this application also provides isolated nucleic acid molecules that encode the antibody or antigen-binding fragment thereof described in any embodiment of this application, its heavy chain and light chain, or its heavy chain variable region and light chain variable region.

[0523] One aspect of this application also provides isolated nucleic acid molecules that encode the chimeric antigen receptor described in any embodiment of this application.

[0524] This application also provides a vector comprising the isolated nucleic acid molecule described in any embodiment of this application. In some embodiments, the vector is a cloning vector or an expression vector.

[0525] One aspect of this application also provides a host cell containing the nucleic acid molecule described in any embodiment of this application or the vector described in any embodiment of this application.

[0526] One aspect of this application also provides a multispecific antibody comprising an antibody or antigen-binding fragment thereof that specifically binds to KLB as described in any embodiment of this application, as well as additional antibodies or antigen-binding fragments thereof. In some embodiments, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody.

[0527] Pharmaceutical Composition

[0528] The fifth aspect of this application provides a pharmaceutical composition comprising the compound described in the first aspect of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; the conjugate described in the second aspect of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; or the composition described in the third aspect of this application; or the antibody that specifically binds to KLB or its antigen-binding fragment described in the fourth aspect of this application; and one or more pharmaceutically acceptable carriers.

[0529] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, comprising a pharmaceutically active ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceuticalally acceptable carrier" refers to an excipient administered co-administered with the therapeutic agent, and which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0530] The above-described pharmaceutical compositions can act systemically and / or locally, which can be achieved through suitable dosage forms. These dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0531] The above-mentioned pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one of the compounds of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one conjugate of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one composition of this application.

[0532] This application also provides a method for preparing the above-mentioned pharmaceutical composition or its corresponding formulation, comprising combining a compound of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one conjugate of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one composition of this application with one or more pharmaceutically acceptable carriers.

[0533] Pillbox products

[0534] The sixth aspect of this application provides a medicine box product comprising:

[0535] a) at least one of the compounds described in the first aspect of this application or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof as a first therapeutic agent; conjugates described in the second aspect of this application or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof; or compositions described in the third aspect of this application; or antibodies that specifically bind to KLB or antigen-binding fragments thereof described in the fourth aspect of this application; or pharmaceutical compositions described in the fifth aspect of this application.

[0536] b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a composition comprising another therapeutic agent; and

[0537] c) Optional packaging and / or instructions.

[0538] The aforementioned kit product may contain 0.01 mg to 1000 mg of at least one of the compounds of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one conjugate of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one composition of this application.

[0539] This application also provides a method for preparing the aforementioned medicine box, comprising combining at least one compound of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one conjugate of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or at least one composition of this application with at least one other therapeutic agent optionally present or a composition containing other therapeutic agents, packaging and / or instructions.

[0540] Preparation and Use

[0541] The seventh aspect of this application provides the use of the compound described in the first aspect of this application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, in the preparation of the conjugate described in the second aspect of this application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof.

[0542] One aspect of this application also provides the use of the antibody or antigen-binding fragment thereof that specifically binds to KLB as described in the fourth aspect of this application in the preparation of the conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug as described in the second aspect of this application.

[0543] Medical Use

[0544] The eighth aspect of this application provides the use of the compounds described in the first aspect of this application or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, or the conjugates described in the second aspect of this application or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, or the compositions described in the third aspect of this application, or the antibodies that specifically bind to KLB or their antigen-binding fragments described in the fourth aspect of this application, or the pharmaceutical compositions described in the fifth aspect of this application, or the kit products described in the sixth aspect of this application, in the preparation of medicaments for treating and / or preventing diseases and / or conditions selected from liver diseases, glucose and lipid metabolism diseases and cardiovascular diseases, respiratory diseases, and musculoskeletal diseases related to glucose and lipid metabolism, and any combination of the aforementioned diseases and / or conditions.

[0545] The eighth aspect of this application also provides the compounds described in the first aspect of this application or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, or the conjugates described in the second aspect of this application or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, or the compositions described in the third aspect of this application, or the antibodies that specifically bind to KLB or their antigen-binding fragments described in the fourth aspect of this application, or the pharmaceutical compositions described in the fifth aspect of this application, or the kit products described in the sixth aspect of this application, which are used as medicines, for example for treating and / or preventing diseases and / or conditions selected from liver diseases, glucose and lipid metabolism diseases and cardiovascular diseases, respiratory diseases, and musculoskeletal diseases related to glucose and lipid metabolism, and any combination of the aforementioned diseases and / or conditions.

[0546] The eighth aspect of this application also provides a method for treating and / or preventing diseases and / or conditions, comprising administering to an individual in need an effective amount of the compound described in the first aspect of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a conjugate described in the second aspect of this application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a composition described in the third aspect of this application, or an antibody that specifically binds to KLB or an antigen-binding fragment thereof described in the fourth aspect of this application, or a pharmaceutical composition described in the fifth aspect of this application, or a kit product described in the sixth aspect of this application, wherein the disease and / or condition is selected from liver diseases, glucose and lipid metabolism diseases and cardiovascular diseases, respiratory diseases, and musculoskeletal diseases related to glucose and lipid metabolism, and any combination of the aforementioned diseases and / or conditions.

[0547] In some implementations, the liver disease is selected from fatty liver (e.g., steatohepatitis, metabolic-associated steatohepatitis (MASH)) and cirrhosis.

[0548] In some implementations, the glucose and lipid metabolism disorders are selected from diabetes (e.g., type 1 diabetes, type 2 diabetes), obesity, hyperlipidemia, and hyperglycemia.

[0549] In some implementations, the cardiovascular and cerebrovascular diseases related to glucose and lipid metabolism are selected from hypertension, coronary heart disease, cardiomyopathy, atherosclerosis, and heart failure.

[0550] In some implementations, the respiratory diseases and / or conditions related to glucose and lipid metabolism are selected from obstructive sleep apnea syndrome, dyspnea, and sleep apnea.

[0551] In some implementations, the skeletal joint disease related to glucose and lipid metabolism is selected from osteoarthritis and lumbar disc herniation.

[0552] intermediate

[0553] In some embodiments, this application provides the following compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotopically labeled compounds:

[0554] Each PG1 is independently protected by either an H or a carboxyl group, and the carboxyl group is, for example, a C. 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl;

[0555] Each PG2 group is independently protected by an H or amino group. The amino protecting group can be, for example, an alkoxycarbonyl group, such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), or methoxycarbonyl (or ethoxycarbonyl); an acyl group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; or an alkyl group, such as triphenylmethyl (Trt), C... 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn);

[0556] Each PG3 is independently protected by an H or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, or p-nitrobenzoyl.

[0557] Y1, R1, R2, R3, R4 and Lg are as described in any of the preceding implementation schemes.

[0558] In some embodiments, this application provides the following compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotopically labeled compounds:

[0559] In some embodiments, the aforementioned intermediate compound or its salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, or isotope-labeled compound can be used to prepare the compound described in the first aspect of this application or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug; or the conjugate described in the second aspect of this application or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug; or the composition described in the third aspect of this application.

[0560] Connection unit

[0561] In some embodiments, this application provides a linker unit of formula -ML-, wherein M and L are as described in any of the embodiments above. In some embodiments, the linker unit is used to link a protein and a drug to obtain a conjugate. In some embodiments, in the linker unit, L is a linker portion for linking the drug, and M is a connector for linking the protein. In some embodiments, in the linker unit, L is used for linking with D as described in any one of this application, and M is used for linking with P as described in any one of these applications.

[0562] In some implementations, the connection unit represented by -ML- is selected from the following structures:

[0563] In some implementations, the connection unit represented by -ML- is selected from the following structures:

[0564] In some implementations, the connection unit represented by -ML- is selected from the following structures:

[0565] In some implementations, the connection unit represented by -ML- is selected from the following structures:

[0566] In some embodiments, a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is provided, comprising a linker unit of the structure shown in -ML-.

[0567] In some embodiments, the present invention provides a linker unit of the formula M'-L-, wherein M' and L are as described in any of the embodiments above. In some embodiments, the linker unit is used to link a drug and a protein to obtain a conjugate. In some embodiments, in the linker unit, L is a linking portion for linking the drug, and M' is a structure capable of reacting with and linking to a protein. In some embodiments, in the linker unit, L is used to link with D as described in any one of the claims of this application, and M' is used to react with and link with P as described in any one of the claims herein.

[0568] In some embodiments, a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is provided, comprising a linking unit of the structure shown in M'-L-.

[0569] In some embodiments, this application provides a linker unit of formula -LD, wherein L and D are as described in any of the embodiments above. In some embodiments, the linker unit is used to link proteins via a adapter to obtain a conjugate.

[0570] In some embodiments, this application provides a linker unit of formula -MLD, wherein M, L, and D are as described in any of the above embodiments. In some embodiments, the linker unit is used to link proteins to obtain a conjugate.

[0571] In some embodiments, a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is provided, comprising a linker unit with a structure represented by -LD or -MLD.

[0572] All technical features disclosed in this specification, except for mutually exclusive features, can be combined in any way. This invention covers linking units, compounds, and couplings obtained by arbitrary combinations of various embodiments, wherein the linking units, compounds, and couplings of this invention can be optionally substituted with suitable substituents at suitable substitution positions.

[0573] This disclosure includes the following implementation schemes:

[0574] Implementation Scheme 1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, M'-LD (I)

[0575] in,

[0576] M' is the connector;

[0577] D represents the thyroid hormone receptor agonist portion;

[0578] L is a structure connecting M' and D.

[0579] Implementation Scheme 2. The compound described in Implementation Scheme 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein D is the thyroxine β-receptor agonist moiety;

[0580] Preferably, the thyroxine β-receptor agonist is selected from compounds of formula (A”) or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs.

[0581] in,

[0582] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-12 membered heterocyclic;

[0583] X1 is selected from chemical bonds, -CONH-, -NHCO-, and -O-(CR). a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m - and -(CR a R b ) m -;

[0584] X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0585] Y1 is selected from chemical bonds, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m -, -C(=O)-, -S(=O)-, -S(O)2- and -(CR a R b ) m -;

[0586] R e Each occurrence is independently selected from H, halogen, -CN, -OH, -SH-, -NR. c R d , oxo group, -C 1- 6-alkyl, -OC 1-6 Alkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), -(CR a R b ) m -(C 6-10aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 1-6 alkyl), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -CONH-(CR) a R b ) m -(5-10 grade heteroaryl groups), -NHCO-(CR) a R b ) m -(C 1-6 alkyl), -NHCO-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3- 6-cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1- 6-Hydroalkyl and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0587] R3, R4, R6, and R7 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0588] Alternatively, R4 and R6, along with the atoms they are bonded to, together form C. 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl;

[0589] R5 is selected from -OH, -COOH, -C(=O)-OC 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, --PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, -C 1-4 alkylene-, -C 2-6 alkenyl, -C 2-6 alkynyl group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C2-6 alkenyl, -C 2-6 Substitution of alkynyl and 4-8 membered heterocyclic alkyl groups;

[0590] R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0591] R c and R d Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group;

[0592] m is independently selected from 0, 1, 2, 3, 4, 5 and 6;

[0593] q is independently selected from 0, 1, 2, 3, 4 and 5;

[0594] Preferably, formula (A”) is further shown as formula (Aa”):

[0595] Among them, X1, X2, Y1, R e R3, R4, R5, R6, and R7 are as defined above; Y2 is selected from -O-, -N(R c )- and -S-, the R c Selected from H, -CH3 and -CO-C 1-6 alkyl;

[0596] Preferably, formula (A”) is further shown as formula (A’):

[0597] Among them, X1, X2, Y1, Y2, R3, R4 and R5 are as defined above;

[0598] R1 and R2 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d , oxo group, -C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 1-6 alkyl), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -CONH-(CR) a R b ) m -(5-10 grade heteroaryl groups), -NHCO-(CR) a R b ) m -(C 1-6 alkyl), -NHCO-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1-6 Halogenated alkyl groups and -C 3-6The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0599] More preferably, X1 is selected from chemical bonds, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m - and -(CR a R b ) m -;

[0600] X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0601] Y1 is selected from -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m -, -C(=O)-, -S(=O)-, -S(O)2- and -

[0602] (CR a R b ) m -;

[0603] Y2 is selected from -O-, -N(R)c )- and -S-;

[0604] R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group may optionally be selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0605] R5 is selected from -OH, -COOH, and -C. 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, C 6-10 Aryl and 5-10 heteroaryl, the -C 1-4 Alkylene-, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0606] R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0607] R c and R d Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group;

[0608] m is independently selected from 0, 1, 2, 3, 4, 5 and 6;

[0609] Preferably, the structure of D is as shown in equation (A-1”), equation (Aa-1”), equation (A-1’), equation (A-2’), equation (A-3’), or equation (A-4’):

[0610] Among them, R 5a The structure obtained by losing a H from the -OH, -NH2, or secondary amine group in R5 as defined above, or the structure obtained by losing an OH from the -COOH group on R5;

[0611] Preferably, R 5a Selected from -O-, -C(=O)-, -C 1-4 Alkylene -O-, -C 1-4 Alkylene -C(=O)-, -C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 alkylene-C(=O)-, wherein the -C 1-4 Alkylenes are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups;

[0612] Ring A, q, X1, X2, Y1, Y2, R e , R1, R2, R3, R4, R5, R6, R7, Rc and R d As defined above.

[0613] Implementation Scheme 3. The compound described in Implementation Scheme 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0614] The Y1 is selected from -O-, -NH- and -(CR). a R b ) m -, R a R b and m are as defined in implementation scheme 2;

[0615] Preferably, Y1 is selected from -O- and -CH2-;

[0616] Alternatively, Y1 can be selected from chemical bonds, -O-, NH, and -(CR). a R b ) m - Preferably, Y1 is selected from chemical bonds, -O- and -CH2-, R a R b And m is as defined in implementation scheme 2.

[0617] Implementation Scheme 4. The compound described in any one of Implementation Schemes 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0618] The Y2 is selected from -O-, -N(R) c )- and -S-, the R c Selected from H, -CH3, -COCH3 and -COCH(CH3)CH2CH3;

[0619] Preferably, Y2 is selected from -O-, -NH-, -(CH3CO)N-, and -N(COCH(CH3)CH2CH3)-;

[0620] Preferably, Y2 is selected from -O-, -NH- and -(CH3CO)N-.

[0621] Implementation Scheme 5. The compound described in any one of Implementation Schemes 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0622] X1 is selected from -O-(CR) a R b ) m-、-NR c - and -(CR a R b ) m -, R a R b R c and m are as defined in implementation scheme 2;

[0623] Preferably, X1 is selected from -O-, -NH-, -O-CH2-, -CH2-, -CH2CH2- and -CH2CH(NH2)-;

[0624] Alternatively, X1 can be selected from chemical bonds, -CONH-, -NHCO-, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m - and -(CR) a R b ) m -; Preferably, X1 is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, -CH2CH(NH2)-.

[0625] Implementation Scheme 6. The compound described in any one of Implementation Schemes 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0626] X2 is selected from chemical bonds and -4-7-membered heterocyclic groups-, wherein the -4-7-membered heterocyclic groups- contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(=O), P and P(=O);

[0627] Preferably, X2 is selected from chemical bonds and

[0628] Preferably, -X1-X2- is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, -CH2CH(NH2)- and (For example Preferred to be selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-#, -O-CH2-#, -CH2-, -CH2CH2-, -CH2CH(NH2)-# and (For example ), where the # end is connected to R5; for example, selected from -O-, -O-CH2-#, -NH-, -CH2-, -CH2CH2-, -CH2CH(NH2)-# and The # terminal is connected to R5.

[0629] Implementation Scheme 7. The compound described in any one of Implementation Schemes 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0630] R1, R2, R3, and R4 are each independently selected from H, halogens, and -C. 1-4 Alkyl, the -C 1-4 The alkyl group may optionally be substituted by one or more groups independently selected from -OH and -NH2;

[0631] Preferably, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, F, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2;

[0632] Preferably, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, -CH3 and -CH(CH3)2;

[0633] Preferably, R1 is H;

[0634] Preferably, R2 is selected from I and -CH(CH3)2;

[0635] Preferably, R3 and R4 are each independently selected from I, Br, Cl and -CH3.

[0636] Implementation Scheme 8. The compound described in any one of Implementation Schemes 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0637] R5 is selected from -COOH, -C(=O)-OC 1-4 Alkyl, -C 1-4 Alkylene groups -COOH, -PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, -C 1-4 Alkylene, 4-8 membered heterocyclic alkyl, C 6-10The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C 2-6 alkenyl, -C 2-6 Substitution of alkynyl and 4-8 membered heterocyclic alkyl groups;

[0638] Preferably, R5 is selected from -COOH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 alkylene-COOH and C 6-10 Aryl, the -C 1-4 Alkylene- and C 6-10 The aryl group is optionally surrounded by one, two, or three independently selected halogens, -OH, -NH2, and -NH(C). 1-4 Substitution of alkyl groups;

[0639] Preferably, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH and phenyl, wherein the CH2 and phenyl are optionally substituted by one, two or three groups independently selected from halogen, -OH and -NH2;

[0640] Preferably, R5 is selected from -COOH, -C(=O)-OCH2CH3, -CH2-COOH, -(CH2)2-COOH, -CH(NH2)-COOH-, -CH2CH(NH2)-COOH, -PO(OH)2, -CH2-PO(OH)2, -C(=O)-CH2-COOH,

[0641] Preferably, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH, (For example )and

[0642] Implementation Scheme 9. The compound described in any one of Implementation Schemes 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0643] The thyroxine β receptor agonist is selected from...

[0644] Preferably, the thyroxine β receptor agonist is selected from...

[0645] Preferably, the thyroxine β receptor agonist is selected from...

[0646] Preferably, D is selected from

[0647] Preferably, D is selected from

[0648] Implementation Scheme 10. The compound described in any one of Implementation Schemes 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0649] M' is selected from: Wherein, Lg is a leaving group or an addition group for nucleophilic substitution reactions;

[0650] Preferably, Lg is selected from halogens (e.g., F, Cl, Br, I) and halogenated C. 1-6 Alkyl, maleimide, halogenated maleimide, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 Alkyl sulfoxide, halophenoxy, -OH, -SH, -NH2, nitro, azide, cyano, C 2-6 alkenyl, C 2-6 Alkyne groups and C-containing groups 2-6 The structure of the alkynyl group, the halogenated C 1-6 Alkyl, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 Alkyl sulfoxide, halophenoxy, alkenyl, ynyl and ynyl-containing structures may optionally be substituted by one or more suitable substituents;

[0651] Preferably, Lg is selected from halogens (e.g., F, Cl, Br, I) and halogenated C. 1-6 Alkyl, maleimide, halogenated maleimide, C 1-6 Alkyl sulfonyl, halogenated C 1-6 Alkyl sulfonyl, halosulfonyl, C 1-6 Alkyl sulfonate group, halogenated C 1-6 Alkyl sulfonate group, C 1-6 Alkyl sulfinate group, C 1-6 Alkyl sulfoxide, halophenoxy, -OH, -SH, -NH2, nitro, azide, cyano, C 2-6 alkenyl, C 2-6 Alkyne groups and C-containing groups 2-6 The structure of the alkynyl group;

[0652] Preferably, Lg is selected from halogens, C 1-4 Alkyl sulfonyl, halophenoxy, -OH, -SH or -NH2;

[0653] Preferably, Lg is selected from halogens, CH3S(=O)2-, halophenoxy groups, -OH, -SH, or -NH2;

[0654] Preferably, M' is selected from

[0655] Preferably, M' is

[0656] Implementation Scheme 11. The compound described in any one of Implementation Schemes 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the structure of L is -L1-L2-L3-.

[0657] L1 is selected from substituted or unsubstituted structures composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): natural amino acids or non-natural amino acids and their analogues (e.g., Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala), Lys(R'), Glu(R'), short peptides composed of amino acids (e.g., Gly-Lys, Ala-Ala, Ala-Lys, Ala-Lys(Ac), Ala-Pro, Gly-Glu, Gly-Gly, Phe-L ys, Phe-Lys(Ac), Val-Ala, Val-Cit, Val-Lys, Val-Lys(Ac), Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Gly, D-Leu-Ala-Glu, Gly-Gly-Arg, Gly -Glu-Gly, Gly-Gly-Gly, Gly-Ser-Lys, Glu-Val-Ala, Glu-Val-Cit, Ser-D-Ala-Pro, Val-Leu-Lys, Val-Lys-Ala, Val-Lys-Gly, Gly-Gly-Phe-Gly (GGFG, SEQ ID NO:7), Gly-Gly-Val-Ala (GGVA, SEQ ID NO:8), Gly-Phe-Leu-Gly (GFLG, SEQ ID NO:9), Glu-Ala-Ala-Ala (EAAA, SEQ ID NO:10), Gly-Gly-Gly-Gly-Gly (GGGGG, SEQ ID NO:11), Asp-Gly-Gly-Phe-Gly (DGGFG, SEQ ID NO:12), Glu-Gly-Gly-Phe-Gly (EGGFG, SEQ ID NO:13)), s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0658] L2 does not exist, or is selected from

[0659] L3 is absent, or is selected from the following substituted or unsubstituted structures: -NH-CH2-, t is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0660] R' is selected from a structure composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): hydrogen, -NHC 1-6 Alkylene-SO3H, -CH2NH-SO3H, -CH2N(C) 1- (6-alkyl)-SO3H,-CH2NHC 1-6 Alkylene -SO3H, -CH2N(C 1-6 Alkyl)C 1-6 Alkylene -SO3H, -CH2N(C 1-6 Alkylene (-SO3H)2, -CH2N + (C 1-6 Alkylene (-SO3H)3, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylene -SO3H, -CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkylene (SO3H)3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1- 6-alkylene-SO3H)3、-CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkyl group 3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)2-CH2CO2H, -CH2N(C1-6 alkyl)-C 1-6 Alkylenes -CO2H, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylene -CO2H, glucosyl, galactosyl, glucuronic acid, galacturonic acid, -CH2N(C 1-6 Alkyl)-C(=O)-(CH2CH2O) r -C 1-6 Alkyl group, -CH2N(C) 1-6 Alkyl)-C(=O)-(OCH2CH2) r -OC 1-6 Alkyl group, -(CH2N(Me)-C(=O)) r -C 1-6 Alkyl group, -(CH2CH2O) r -C 1-6 Alkyl groups, -DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid residues), -DOTAGA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-propionyl), -NOTA (1,4,7-triazacyclononane-N,N',N”-triacetic acid residues), -EDTA (ethylenediaminetetraacetic acid residues), -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and r is selected from integers from 1 to 20, such as 1-12, 3-12, 1-10, 1-8, 3-8, 1-6, 1-4, and 1-2, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

[0661] Preferably, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6 or 7) substituted or unsubstituted structures: Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala, Lys(R'), Where R' is selected from glucosyl, galactosyl, glucuronic acid, galacturonic acid, -DOTA, -DOTAGA, -NOTA, -EDTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0662] Preferably, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6, or 7) substituted or unsubstituted structures:

[0663] Preferably, L1 is selected from

[0664] Preferably, L2 does not exist, or is selected from... R' is selected from glucosyl, galactosyl, glucuronic acid, and galacturonic acid.

[0665] Preferably, L2 does not exist, or is selected from...

[0666] Preferably, L3 is absent, or is selected from -NHCH2-,

[0667] Implementation Scheme 12. The compound described in any one of Implementation Schemes 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0668] -L1-L2- Selected from

[0669] Preferably, L is selected from

[0670] Implementation Scheme 13. The compound described in any one of Implementation Schemes 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the structure shown in Formula (I-1”), Formula (Ia-1”), Formula (I-1'), Formula (I-2'), Formula (I-3'), or Formula (I-4').

[0671] Among them, rings A, q, X1, X2, Y1, Y2, and R e R1, R2, R3, R4, R5, R 5a R6, R7, L1, L2, L3 and M' are as defined in any of the embodiments 1-12.

[0672] Implementation Scheme 14. The compound described in any one of Implementation Schemes 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from...

[0673] 01:

[0674] 04:

[0675] 05:

[0676] 06:

[0677] 07:

[0678] 08:

[0679] 10:

[0680] 11:

[0681] 12:

[0682] 13:

[0683] 14:

[0684] 15:

[0685] 16:

[0686] 17:

[0687] 18:

[0688] 19:

[0689] 20:

[0690] twenty one:

[0691] twenty two:

[0692] twenty three:

[0693] twenty four:

[0694] 25:

[0695] 26:

[0696] Implementation Scheme 15. A conjugate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, comprising the compound described in any one of Implementation Schemes 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof.

[0697] Implementation Scheme 16. The conjugate of Implementation Scheme 15 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein the conjugate is as shown in Formula (II), P-(MLD) n (II)

[0698] in,

[0699] P is an FGFR agonist and / or a KLB-binding molecule;

[0700] M is a structure connecting P and L;

[0701] L and D are as defined in any of Implementation Schemes 1-14;

[0702] n is 1-10.

[0703] Implementation Scheme 17. The conjugate described in Implementation Scheme 15 or 16 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein M is selected from the following substituted or unsubstituted structures:

[0704] Preferably, M is selected from the following substituted or unsubstituted structures:

[0705] Preferably, M is selected from the following substituted or unsubstituted structures:

[0706] Implementation Scheme 18. The conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 15-17, wherein P is an FGF21R ​​agonist;

[0707] Preferably, the FGF21R ​​agonist is a fusion protein.

[0708] Implementation Scheme 19. The conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 15-18, wherein P is a fusion protein comprising wild-type FGF21 or a mutant thereof;

[0709] Preferably, the wild-type FGF21 comprises the amino acid sequence shown in SEQ ID NO:114;

[0710] Preferably, the fusion protein comprises an FGF21 mutant; wherein the FGF21 mutant has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the wild-type FGF21, or the mutant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the wild-type FGF21, and is capable of activating the KLB-FGFR signaling pathway;

[0711] Preferably, the FGF21 mutant, relative to the wild-type FGF21, contains one or more of the following mutations: L98R, P171G, and A180E;

[0712] Preferably, the FGF21 mutant contains the amino acid sequence shown in SEQ ID NO:3.

[0713] Implementation Scheme 20. The conjugate described in Implementation Scheme 19 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the fusion protein further comprises an IgG constant domain or a fragment thereof.

[0714] Preferably, the constant domain of IgG or a fragment thereof is the Fc domain of IgG, such as the Fc domain of IgG1, IgG2, IgG3 or IgG4.

[0715] Preferably, the IgG constant domain or a fragment thereof is the Fc domain of human IgG1;

[0716] Preferably, the Fc domain of the human IgG1 contains the amino acid sequence shown in SEQ ID NO:4.

[0717] Implementation Scheme 21. The conjugate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 15-20, wherein the FGF21 or a mutant thereof is fused with the constant domain of IgG or a fragment thereof via a linker;

[0718] Preferably, the adapter comprises the amino acid sequence shown in SEQ ID NO:2.

[0719] Preferably, the N-terminus of the linker is fused to the C-terminus of the IgG constant domain or a fragment thereof, and the N-terminus of FGF21 or a mutant thereof is fused to the C-terminus of the linker;

[0720] Preferably, the fusion protein comprises the amino acid sequence shown in SEQ ID NO:1.

[0721] Implementation Scheme 22. The conjugate described in Implementation Scheme 16 or 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein P is a KLB antibody.

[0722] Implementation Scheme 23. The conjugate described in Implementation Scheme 22 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein the KLB antibody is Ab01, Ab02, MK-3655, RG7992 or mimAb1.

[0723] Implementation Scheme 24. The conjugate described in Implementation Scheme 16 or 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein P is an antibody or antigen-binding fragment thereof capable of specifically binding to KLB, comprising:

[0724] (1) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:74, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:75; or

[0725] (2) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:93, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:94; or

[0726] (3) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:14, and / or the three complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) shown in SEQ ID NO:15;

[0727] Preferably, the complementary determinant regions (CDRs) contained in the light chain variable region (VL) and the complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) in (1), (2), and (3) are defined by the Kabat, Chothia, Abm, or IMGT numbering system.

[0728] Implementation Scheme 25. The conjugate of Implementation Scheme 24 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein P comprises:

[0729] (1) The following VL and / or VH,

[0730] (1a) CDRs are defined according to the kabat numbering system:

[0731] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:81 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:85 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0732] (1b) CDRs are defined according to the Chothia numbering system:

[0733] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:82 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:86 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0734] (1c) CDRs are defined according to the Abm numbering system:

[0735] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:84 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:88 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0736] (1d) CDRs are defined according to the IMGT numbering system:

[0737] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:77 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:79 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:83 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:87 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:90 or a variant thereof;

[0738] Wherein, the variant described in any one of (1a), (1b), (1c), and (1d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0739] or

[0740] (2) The following VL and / or VH,

[0741] (2a) CDRs are defined according to the kabat numbering system:

[0742] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:100 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:104 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0743] (2b) CDRs are defined according to the Chothia numbering system:

[0744] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:101 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:105 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0745] (2c) CDRs are defined according to the Abm numbering system:

[0746] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:103 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:107 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0747] (2d) CDRs are defined according to the IMGT numbering system:

[0748] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:96 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:98 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:102 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:106 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:109 or a variant thereof;

[0749] Wherein, the variant described in any one of (2a), (2b), (2c), and (2d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0750] or

[0751] (3) The following VL and / or VH,

[0752] (3a) CDRs are defined according to the kabat numbering system:

[0753] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:21 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:25 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0754] (3b) CDRs are defined according to the Chothia numbering system:

[0755] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:22 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:26 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0756] (3c) CDRs are defined according to the Abm numbering system:

[0757] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:24 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:28 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or

[0758] (3d)CDRs are defined according to the IMGT numbering system:

[0759] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:17 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:19 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:23 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:27 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:30 or a variant thereof;

[0760] Wherein, the variant described in any one of (3a), (3b), (3c), and (3d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0761] Implementation Scheme 26. The conjugate of Implementation Scheme 24 or 25 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein P comprises:

[0762] (1) The following VL and VH,

[0763] (1a) CDRs are defined according to the kabat numbering system:

[0764] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:81, CDR-H2 with sequence SEQ ID NO:85, and CDR-H3 with sequence SEQ ID NO:89; or

[0765] (1b) CDRs are defined according to the Chothia numbering system:

[0766] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:82, CDR-H2 with sequence SEQ ID NO:86, and CDR-H3 with sequence SEQ ID NO:89; or

[0767] (1c) CDRs are defined according to the Abm numbering system:

[0768] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:84, CDR-H2 with sequence SEQ ID NO:88, and CDR-H3 with sequence SEQ ID NO:89; or

[0769] (1d) CDRs are defined according to the IMGT numbering system:

[0770] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:77, CDR-L2 with sequence SEQ ID NO:79, and CDR-L3 with sequence SEQ ID NO:80; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:83, CDR-H2 with sequence SEQ ID NO:87, and CDR-H3 with sequence SEQ ID NO:90;

[0771] or

[0772] (2) The following VL and VH,

[0773] (2a) CDRs are defined according to the kabat numbering system:

[0774] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:100, CDR-H2 with sequence SEQ ID NO:104, and CDR-H3 with sequence SEQ ID NO:108; or

[0775] (2b) CDRs are defined according to the Chothia numbering system:

[0776] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:101, CDR-H2 with sequence SEQ ID NO:105, and CDR-H3 with sequence SEQ ID NO:108; or

[0777] (2c) CDRs are defined according to the Abm numbering system:

[0778] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:103, CDR-H2 with sequence SEQ ID NO:107, and CDR-H3 with sequence SEQ ID NO:108; or

[0779] (2d) CDRs are defined according to the IMGT numbering system:

[0780] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:96, CDR-L2 with sequence SEQ ID NO:98, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:102, CDR-H2 with sequence SEQ ID NO:106, and CDR-H3 with sequence SEQ ID NO:109; or

[0781] (3) The following VL and VH,

[0782] (3a) CDRs are defined according to the kabat numbering system:

[0783] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:21, CDR-H2 with sequence SEQ ID NO:25, and CDR-H3 with sequence SEQ ID NO:29; or

[0784] (3b) CDRs are defined according to the Chothia numbering system:

[0785] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:22, CDR-H2 with sequence SEQ ID NO:26, and CDR-H3 with sequence SEQ ID NO:29; or

[0786] (3c) CDRs are defined according to the Abm numbering system:

[0787] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:24, CDR-H2 with sequence SEQ ID NO:28, and CDR-H3 with sequence SEQ ID NO:29; or

[0788] (3d)CDRs are defined according to the IMGT numbering system:

[0789] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:17, CDR-L2 with sequence SEQ ID NO:19, and CDR-L3 with sequence SEQ ID NO:20; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:23, CDR-H2 with sequence SEQ ID NO:27, and CDR-H3 with sequence SEQ ID NO:30.

[0790] Implementation Scheme 27. The conjugate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 24-26, wherein P comprises:

[0791] (1) VL or a variant thereof shown in SEQ ID NO:74, and / or VH or a variant thereof shown in SEQ ID NO:75; or

[0792] (2) VL or a variant thereof shown in SEQ ID NO:93, and / or VH or a variant thereof shown in SEQ ID NO:94; or

[0793] (3) VL or a variant thereof shown in SEQ ID NO:14, and / or VH or a variant thereof shown in SEQ ID NO:15;

[0794] Wherein, the variant described in any one of (1), (2), and (3) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0795] Preferably, it comprises:

[0796] (1) VL shown in SEQ ID NO:74 and VH shown in SEQ ID NO:75; or

[0797] (2) VL shown in SEQ ID NO:93 and VH shown in SEQ ID NO:94; or

[0798] (3) VL shown in SEQ ID NO:14 and VH shown in SEQ ID NO:15.

[0799] Implementation Scheme 28. The conjugate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 24-27, wherein P further comprises:

[0800] (a) The heavy chain constant region (CH) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions, or additions compared to its derived wild-type sequence (e.g., substitutions, deletions, or additions of up to 20, 15, 10, or 5 amino acids; e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids); and

[0801] (b) The light chain constant region (CL) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10 or up to 5 amino acids; e.g., substitutions, deletions or additions of 1, 2, 3, 4 or 5 amino acids).

[0802] Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as the IgG1, IgG2, IgG3 or IgG4 heavy chain constant region, such as the human IgG1 heavy chain constant region or the human IgG4 heavy chain constant region.

[0803] Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:5;

[0804] Preferably, the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO:6 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:6;

[0805] Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 and a heavy chain constant region (CH) as shown in SEQ ID NO:6.

[0806] Implementation Scheme 29. The conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 24-28, wherein P comprises:

[0807] (1) A light chain comprising the VL region of the sequence shown in SEQ ID NO:74 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:75 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or

[0808] (2) A light chain comprising the VL region of the sequence shown in SEQ ID NO:93 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:94 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or,

[0809] (3) A light chain comprising the VL of the sequence shown in SEQ ID NO:14 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH of the sequence shown in SEQ ID NO:15 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6;

[0810] Preferably, the antibody or its antigen-binding fragment comprises:

[0811] (1) The light chain of the sequence shown in SEQ ID NO:91, and the heavy chain of the sequence shown in SEQ ID NO:92; or

[0812] (2) The light chain of the sequence shown in SEQ ID NO:110, and the heavy chain of the sequence shown in SEQ ID NO:101; or

[0813] (3) The light chain of the sequence shown in SEQ ID NO:31, and the heavy chain of the sequence shown in SEQ ID NO:32.

[0814] Implementation Scheme 30. The conjugate described in Implementation Scheme 16 or 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein P is a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain specifically binding to KLB and a second antigen-binding domain specifically binding to FGFR1C; wherein the first antigen-binding domain comprises a first light chain variable region (VL) and a first heavy chain variable region (VH), the first VL and the first VH together forming a domain capable of specifically binding to KLB; the second antigen-binding domain comprises a second light chain variable region (VL) and a second heavy chain variable region (VH), the second VL and the second VH together forming a domain capable of specifically binding to FGFR1C.

[0815] Implementation Scheme 31. The conjugate described in Implementation Scheme 30 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein,

[0816] The first antigen-binding domain and the second antigen-binding domain are each independently selected from scFv, Fab, and scFab;

[0817] Preferably, the first antigen-binding domain and the second antigen-binding domain are Fab, and the Fab of the second antigen-binding domain contains domain exchanges of the form of CrossMab.

[0818] Preferably, the crossMab-form domain swapping involves the interchange of CH1 and CL in Fab.

[0819] Implementation Scheme 32. The conjugate described in Implementation Scheme 30 or 31, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,

[0820] The first VL contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:33; and / or the first VH contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:34;

[0821] Preferably, the CDRs contained in the first VL and the CDRs contained in the first VH are defined by the Kabat, Chothia, Abm or IMGT numbering system;

[0822] Preferably,

[0823] The first VL includes:

[0824] (i) CDR-L1 with sequence SEQ ID NO:35 or a variant thereof, CDR-L2 with sequence SEQ ID NO:37 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or

[0825] (ii) CDR-L1 with sequence SEQ ID NO:36 or a variant thereof, CDR-L2 with sequence SEQ ID NO:38 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0826] and / or

[0827] The first VH includes:

[0828] (i) CDR-H1 with sequence SEQ ID NO:40 or a variant thereof, CDR-H2 with sequence SEQ ID NO:44 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or

[0829] (ii) CDR-H1 with sequence SEQ ID NO:41 or a variant thereof, CDR-H2 with sequence SEQ ID NO:45 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or

[0830] (iii) CDR-H1 with sequence SEQ ID NO:43 or a variant thereof, CDR-H2 with sequence SEQ ID NO:47 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or

[0831] (iv) CDR-H1 with sequence SEQ ID NO:42 or a variant thereof, CDR-H2 with sequence SEQ ID NO:46 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:49 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0832] Wherein, the variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0833] Preferably,

[0834] The first VL includes:

[0835] (i) CDR-L1 with sequence SEQ ID NO:35, CDR-L2 with sequence SEQ ID NO:37, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or

[0836] (ii) CDR-L1 with sequence SEQ ID NO:36, CDR-L2 with sequence SEQ ID NO:38, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the IMGT numbering system;

[0837] and / or

[0838] The first VH includes:

[0839] (i) CDR-H1 with sequence SEQ ID NO:40, CDR-H2 with sequence SEQ ID NO:44, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Kabat numbering system; or

[0840] (ii) CDR-H1 with sequence SEQ ID NO:41, CDR-H2 with sequence SEQ ID NO:45, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Chothia numbering system; or

[0841] (iii) CDR-H1 with sequence SEQ ID NO:43, CDR-H2 with sequence SEQ ID NO:47, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Abm numbering system; or

[0842] (iv) CDR-H1 with sequence SEQ ID NO:42, CDR-H2 with sequence SEQ ID NO:46, and CDR-H3 with sequence SEQ ID NO:49, wherein the CDRs are defined according to the IMGT numbering system.

[0843] Implementation Scheme 33. The conjugate described in any one of Implementation Schemes 30-32 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein,

[0844] The first VL contains the amino acid sequence shown in SEQ ID NO:33 or a variant thereof, and the first VH contains the amino acid sequence shown in SEQ ID NO:34 or a variant thereof.

[0845] The variant has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence; preferably, the substitutions are conservative substitutions.

[0846] Preferably, the first VL contains the amino acid sequence shown in SEQ ID NO:33, and the first VH contains the amino acid sequence shown in SEQ ID NO:34.

[0847] Implementation Scheme 34. The conjugate described in any one of Implementation Schemes 30-33 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein,

[0848] The second VL contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:50; and / or the second VH contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:51;

[0849] Preferably, the CDRs contained in the second VL and the CDRs contained in the second VH are defined by the Kabat, Chothia, Abm or IMGT numbering system;

[0850] Preferably,

[0851] The second VL includes:

[0852] (i) CDR-L1 with sequence SEQ ID NO:52 or a variant thereof, CDR-L2 with sequence SEQ ID NO:54 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or

[0853] (ii) CDR-L1 with sequence SEQ ID NO:53 or a variant thereof, CDR-L2 with sequence SEQ ID NO:55 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0854] and / or

[0855] The second VH includes:

[0856] (i) CDR-H1 with sequence SEQ ID NO:57 or a variant thereof, CDR-H2 with sequence SEQ ID NO:61 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or

[0857] (ii) CDR-H1 with sequence SEQ ID NO:58 or a variant thereof, CDR-H2 with sequence SEQ ID NO:62 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or

[0858] (iii) CDR-H1 with sequence SEQ ID NO:60 or a variant thereof, CDR-H2 with sequence SEQ ID NO:64 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or

[0859] (iv) CDR-H1 with sequence SEQ ID NO:59 or a variant thereof, CDR-H2 with sequence SEQ ID NO:63 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:66 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system;

[0860] Wherein, the variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0861] Preferably,

[0862] The second VL includes:

[0863] (i) CDR-L1 with sequence SEQ ID NO:52, CDR-L2 with sequence SEQ ID NO:54, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or

[0864] (ii) CDR-L1 with sequence SEQ ID NO:53, CDR-L2 with sequence SEQ ID NO:55, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the IMGT numbering system;

[0865] and / or

[0866] The second VH includes:

[0867] (i) CDR-H1 with sequence SEQ ID NO:57, CDR-H2 with sequence SEQ ID NO:61, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Kabat numbering system; or

[0868] (ii) CDR-H1 with sequence SEQ ID NO:58, CDR-H2 with sequence SEQ ID NO:62, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Chothia numbering system; or

[0869] (iii) CDR-H1 with sequence SEQ ID NO:60, CDR-H2 with sequence SEQ ID NO:64, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Abm numbering system; or

[0870] (iv) CDR-H1 with sequence SEQ ID NO:59, CDR-H2 with sequence SEQ ID NO:63, and CDR-H3 with sequence SEQ ID NO:66, wherein the CDRs are defined according to the IMGT numbering system.

[0871] Implementation Scheme 35. The conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 30-34, wherein,

[0872] The second VL contains the amino acid sequence shown in SEQ ID NO:50 or a variant thereof, and the second VH contains the amino acid sequence shown in SEQ ID NO:51 or a variant thereof.

[0873] The variant has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence; preferably, the substitutions are conservative substitutions.

[0874] Preferably, the second VL contains the amino acid sequence shown in SEQ ID NO:50, and the second VH contains the amino acid sequence shown in SEQ ID NO:51.

[0875] Implementation Scheme 36. The conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 30-35, wherein,

[0876] The bispecific antibody comprises peptide chain IA, peptide chain IB, peptide chain IC, and peptide chain ID, wherein peptide chain IA comprises a first VL and a light chain constant region (CL), peptide chain IB comprises a first VH, a heavy chain CH1 region, and a first Fc domain monomer (or a second Fc domain monomer), peptide chain IC comprises a second VH, a light chain constant region (CL), and a second Fc domain monomer (or a first Fc domain monomer), and peptide chain ID comprises a second VL and a heavy chain CH1 region;

[0877] Preferably, the first Fc domain monomer and the second Fc domain monomer each independently contain one or more amino acid modifications, the modifications being able to promote the dimerization of the first Fc domain monomer and the second Fc domain monomer;

[0878] Preferably, the first Fc domain monomer contains an amino acid modification capable of forming a knot structure, and the second Fc domain monomer contains an amino acid modification capable of forming a hole structure, wherein the knot structure can pair with the hole structure to form a heterodimer;

[0879] Preferably, the first Fc domain monomer contains an amino acid sequence as shown in SEQ ID NO:112;

[0880] Preferably, the second Fc domain monomer contains the amino acid sequence shown in SEQ ID NO:113;

[0881] Preferably, the heavy chain CH1 region contains an amino acid sequence as shown in SEQ ID NO:68.

[0882] Implementation Scheme 37. The conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 30-36, wherein,

[0883] The peptide chain IA includes the first VL and CL from the N-terminus to the C-terminus, the peptide chain IB includes the first VH, the heavy chain CH1 region and the first Fc domain monomer (or the second Fc domain monomer) from the N-terminus to the C-terminus, the peptide chain IC includes the second VH, CL and the second Fc domain monomer (or the first Fc domain monomer) from the N-terminus to the C-terminus, and the peptide chain ID includes the second VL and the heavy chain CH1 region from the N-terminus to the C-terminus.

[0884] Implementation Scheme 38. The conjugate described in any one of Implementation Schemes 30-37 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein,

[0885] The adjacent domains of peptide chain IA are optionally connected by or without a connector, the adjacent domains of peptide chain IB are optionally connected by or without a connector, the adjacent domains of peptide chain IC are optionally connected by or without a connector, and / or the adjacent domains of peptide chain ID are optionally connected by or without a connector.

[0886] Preferably, each of the connectors is independently the same or different peptide connectors (e.g., rigid peptide connectors or flexible peptide connectors);

[0887] Preferably, each peptide linker is independently selected from peptide linkers containing one or more glycine (G) and / or serine (S), for example having the structure shown in (GGGGS)y, wherein y is an integer not less than 0, for example y is 1, 2, 3, 4, 5 or 6; preferably, each peptide linker independently contains an amino acid sequence as shown in any one of SEQ ID NO:2 or SEQ ID NOs:115-119.

[0888] Implementation Scheme 39. The conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as described in any one of Implementation Schemes 30-38, wherein,

[0889] The peptide chain IA contains the amino acid sequence shown in SEQ ID NO:70, the peptide chain IB contains the amino acid sequence shown in SEQ ID NO:71, the peptide chain IC contains the amino acid sequence shown in SEQ ID NO:73, and / or, the peptide chain ID contains the amino acid sequence shown in SEQ ID NO:72.

[0890] Implementation Scheme 40. The conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 15-39, wherein n is 1-8, for example 3-5, 4-8, or 6-8, for example about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8.

[0891] Implementation Scheme 41. The conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 15-40, wherein the conjugate is as shown in Formula (II-1”), Formula (IIa-1”), Formula (II-1'), Formula (II-2'), Formula (II-3') or Formula (II-4').

[0892] Among them, rings A, q, X1, X2, Y1, Y2, and R e R1, R2, R3, R4, R5, R 5a R6, R7, L1, L2, L3, M, P and n are as defined in any of the implementation schemes 15-40.

[0893] Implementation Scheme 42. The conjugate described in any one of Implementation Schemes 15-41, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the conjugate is selected from...

[0894] P-01:

[0895] P-04:

[0896] P-05:

[0897] P-06:

[0898] P-07:

[0899] P-08:

[0900] P-10:

[0901] P-11:

[0902] P-12:

[0903] P-13:

[0904] P-14:

[0905] P-15:

[0906] P-16:

[0907] P-17:

[0908] P-18:

[0909] P-19:

[0910] P-20:

[0911] P-21:

[0912] P-22:

[0913] P-23:

[0914] P-24:

[0915] P-25:

[0916] Wherein, P and n are as defined in any of embodiments 15-41.

[0917] Implementation Scheme 43. A composition comprising one or more conjugates described in any one of Implementation Schemes 15-42 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the drug-protein conjugation ratio of the composition is about 1-10, for example about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 to 2, about 1 to 3, about 1 to 4, about 1 to 5, about 1 to 6, about 1 to 7, about 1 to 8, about 1 to 9, about 1 to 10, about 2 to 3, about 2 to 4, about 2 to 5, about 2 to 6, about 2 to 7, about 2 to 8, about 2 to 9, about 2 to 10, about 3 to 4, about 3 to 5, about 3 to 6, about 3 to 7, about 3 to 8, about 3 to 9, about 3 to 10, about 4 to 5, about 4 to 6, about 4 to 7, about 4 to 8, about 4 to 9, about 4 to 10, about 5 to 6, about 5 to 7, about 5 to 8, about 5 to 9, about 5 to 10, about 6 to 7, about 6 to 8, about 6 to 9, about 6 to 10, about 7 to 8, about 7 to 9, about 7 To 10, about 8 to 9, about 8 to 10, or about 9 to 10, or for example, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.

[0918] Implementation Scheme 44. An antibody or its antigen-binding fragment capable of specifically binding to KLB, comprising:

[0919] (1) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:74, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:75; or

[0920] (2) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:93, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:94;

[0921] Preferably, the complementary determinant regions (CDRs) contained in the light chain variable region (VL) and the complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) are defined by the Kabat, Chothia, Abm or IMGT numbering system.

[0922] Implementation Scheme 45. The antibody or antigen-binding fragment thereof described in Implementation Scheme 44, comprising:

[0923] (1) The following VL and / or VH,

[0924] (1a) CDRs are defined according to the kabat numbering system:

[0925] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:81 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:85 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0926] (1b) CDRs are defined according to the Chothia numbering system:

[0927] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:82 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:86 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0928] (1c) CDRs are defined according to the Abm numbering system:

[0929] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:84 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:88 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or

[0930] (1d) CDRs are defined according to the IMGT numbering system:

[0931] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:77 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:79 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:83 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:87 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:90 or a variant thereof;

[0932] Wherein, the variant described in any one of (1a), (1b), (1c), and (1d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0933] or

[0934] (2) The following VL and / or VH,

[0935] (2a) CDRs are defined according to the kabat numbering system:

[0936] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:100 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:104 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0937] (2b) CDRs are defined according to the Chothia numbering system:

[0938] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:101 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:105 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0939] (2c) CDRs are defined according to the Abm numbering system:

[0940] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:103 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:107 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or

[0941] (2d) CDRs are defined according to the IMGT numbering system:

[0942] A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:96 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:98 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:102 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:106 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:109 or a variant thereof;

[0943] Wherein, the variant described in any one of (2a), (2b), (2c), and (2d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions.

[0944] Implementation Scheme 46. The antibody or antigen-binding fragment thereof described in Implementation Scheme 44 or 45, comprising:

[0945] (1) The following VL and VH,

[0946] (1a) CDRs are defined according to the kabat numbering system:

[0947] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:81, CDR-H2 with sequence SEQ ID NO:85, and CDR-H3 with sequence SEQ ID NO:89; or

[0948] (1b) CDRs are defined according to the Chothia numbering system:

[0949] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:82, CDR-H2 with sequence SEQ ID NO:86, and CDR-H3 with sequence SEQ ID NO:89; or

[0950] (1c) CDRs are defined according to the Abm numbering system:

[0951] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:84, CDR-H2 with sequence SEQ ID NO:88, and CDR-H3 with sequence SEQ ID NO:89; or

[0952] (1d) CDRs are defined according to the IMGT numbering system:

[0953] VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:77, CDR-L2 with sequence SEQ ID NO:79, and CDR-L3 with sequence SEQ ID NO:80; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:83, CDR-H2 with sequence SEQ ID NO:87, and CDR-H3 with sequence SEQ ID NO:90;

[0954] or

[0955] (2) The following VL and VH,

[0956] (2a) CDRs are defined according to the kabat numbering system:

[0957] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:100, CDR-H2 with sequence SEQ ID NO:104, and CDR-H3 with sequence SEQ ID NO:108; or

[0958] (2b) CDRs are defined according to the Chothia numbering system:

[0959] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:101, CDR-H2 with sequence SEQ ID NO:105, and CDR-H3 with sequence SEQ ID NO:108; or

[0960] (2c) CDRs are defined according to the Abm numbering system:

[0961] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:103, CDR-H2 with sequence SEQ ID NO:107, and CDR-H3 with sequence SEQ ID NO:108; or

[0962] (2d) CDRs are defined according to the IMGT numbering system:

[0963] A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:96, CDR-L2 with sequence SEQ ID NO:98, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:102, CDR-H2 with sequence SEQ ID NO:106, and CDR-H3 with sequence SEQ ID NO:109.

[0964] Implementation Scheme 47. The antibody or antigen-binding fragment thereof described in any one of Implementation Schemes 44-46, comprising:

[0965] (1) VL or a variant thereof shown in SEQ ID NO:74, and / or VH or a variant thereof shown in SEQ ID NO:75; or

[0966] (2) VL or a variant thereof shown in SEQ ID NO:93, and / or VH or a variant thereof shown in SEQ ID NO:94;

[0967] Wherein, the variant described in either (1) or (2) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions;

[0968] Preferably, it comprises:

[0969] (1) VL shown in SEQ ID NO:74 and VH shown in SEQ ID NO:75; or

[0970] (2) VL shown in SEQ ID NO:93 and VH shown in SEQ ID NO:94.

[0971] Implementation Scheme 48. The antibody or antigen-binding fragment thereof described in any one of Implementation Schemes 44-47, further comprising:

[0972] (a) The heavy chain constant region (CH) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions, or additions compared to its derived wild-type sequence (e.g., substitutions, deletions, or additions of up to 20, 15, 10, or 5 amino acids; e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids); and

[0973] (b) The light chain constant region (CL) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10 or up to 5 amino acids; e.g., substitutions, deletions or additions of 1, 2, 3, 4 or 5 amino acids).

[0974] Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as the IgG1, IgG2, IgG3 or IgG4 heavy chain constant region, such as the human IgG1 heavy chain constant region or the human IgG4 heavy chain constant region.

[0975] Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:5;

[0976] Preferably, the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO:6 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:6;

[0977] Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 and a heavy chain constant region (CH) as shown in SEQ ID NO:6.

[0978] Implementation Scheme 49. The antibody or antigen-binding fragment thereof described in any one of Implementation Schemes 44-48, comprising:

[0979] (1) A light chain comprising the VL region of the sequence shown in SEQ ID NO:74 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:75 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or

[0980] (2) A light chain comprising the VL of the sequence shown in SEQ ID NO:93 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH of the sequence shown in SEQ ID NO:94 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6;

[0981] Preferably, the antibody or its antigen-binding fragment comprises:

[0982] (1) The light chain of the sequence shown in SEQ ID NO:91, and the heavy chain of the sequence shown in SEQ ID NO:92; or

[0983] (2) The light chain of the sequence shown in SEQ ID NO:110, and the heavy chain of the sequence shown in SEQ ID NO:101.

[0984] Implementation Scheme 50. An isolated nucleic acid molecule encoding an antibody or antigen-binding fragment thereof described in any one of Implementation Schemes 44-49, its heavy chain and light chain, or its heavy chain variable region and light chain variable region.

[0985] Implementation Scheme 51. A vector comprising the isolated nucleic acid molecule described in Implementation Scheme 50;

[0986] Preferably, the vector is a cloning vector or an expression vector.

[0987] Implementation Scheme 52. A host cell comprising the nucleic acid molecule described in Implementation Scheme 50 or the vector described in Implementation Scheme 51.

[0988] Implementation Scheme 53. A chimeric antigen receptor comprising an antigen-binding domain, a spacer domain, a transmembrane domain, and an intracellular signal transduction domain, wherein the antigen-binding domain comprises an antibody or an antigen-binding fragment thereof as described in any one of Implementation Schemes 44-49.

[0989] Implementation scheme 54. An isolated nucleic acid molecule that encodes the chimeric antigen receptor described in implementation scheme 53.

[0990] Implementation Scheme 55. A vector comprising the isolated nucleic acid molecules described in Implementation Scheme 54;

[0991] Preferably, the vector is a cloning vector or an expression vector.

[0992] Implementation Scheme 56. A host cell comprising the nucleic acid molecule described in Implementation Scheme 54 or the vector described in Implementation Scheme 55.

[0993] Implementation Scheme 57. A multispecific antibody comprising an antibody or antigen-binding fragment thereof that specifically binds to KLB as described in any one of Implementation Schemes 44-49, and additional antibodies or antigen-binding fragments thereof;

[0994] Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody.

[0995] Implementation Scheme 58. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; or a conjugate of any one of Implementation Schemes 15-42 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; or a composition of Implementation Scheme 43; or an antibody that specifically binds to KLB or an antigen-binding fragment thereof of any one of Implementation Schemes 44-49; and one or more pharmaceutically acceptable carriers.

[0996] Implementation Scheme 59. A medicine box product comprising:

[0997] a) at least one compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug as a first therapeutic agent; or a conjugate of any one of embodiments 15-42, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug; or a composition of embodiment 43; or an antibody that specifically binds to KLB or an antigen-binding fragment thereof of any one of embodiments 44-49; or a pharmaceutical composition of embodiment 58.

[0998] b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a composition comprising another therapeutic agent; and

[0999] c) Optional packaging and / or instructions.

[1000] Implementation Scheme 60. Use of the compound of any one of Implementation Schemes 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof in the preparation of the conjugate of any one of Implementation Schemes 15-42 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof.

[1001] Implementation Scheme 61. Use of the antibody or antigen-binding fragment thereof that specifically binds to KLB as described in any one of Implementation Schemes 44-49 in the preparation of the conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug as described in any one of Implementation Schemes 15-42.

[1002] Implementation Scheme 62. The use of the compound described in any one of Implementation Schemes 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or the conjugate described in any one of Implementation Schemes 15-42 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or the composition described in Implementation Scheme 43, or the antibody specifically binding to KLB or an antigen-binding fragment thereof described in any one of Implementation Schemes 44-49, or the pharmaceutical composition described in Implementation Scheme 58, or the kit product described in Implementation Scheme 59, in the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions, wherein the diseases and / or conditions are selected from liver diseases, glucose and lipid metabolism diseases and cardiovascular diseases, respiratory diseases and / or conditions, and musculoskeletal diseases related to glucose and lipid metabolism, and any combination of the aforementioned diseases and / or conditions.

[1003] Preferably, the liver disease is selected from fatty liver (e.g., steatohepatitis, metabolic-associated steatohepatitis (MASH)) and cirrhosis;

[1004] Preferably, the glucose and lipid metabolism disorders are selected from diabetes (e.g., type 1 diabetes, type 2 diabetes), obesity, hyperlipidemia, and hyperglycemia;

[1005] Preferably, the cardiovascular and cerebrovascular diseases related to glucose and lipid metabolism are selected from hypertension, coronary heart disease, cardiomyopathy, atherosclerosis, and heart failure;

[1006] Preferably, the respiratory diseases and / or conditions related to glucose and lipid metabolism are selected from obstructive sleep apnea syndrome, dyspnea, and sleep apnea;

[1007] Preferably, the skeletal joint diseases related to glucose and lipid metabolism are selected from osteoarthritis and lumbar disc herniation.

[1008] Implementation Scheme 63. Use of the compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of any one of Implementation Schemes 1-14 in the preparation of a conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein the conjugate or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug is preferably as described in any one of Implementation Schemes 15-42.

[1009] Terminology Definition

[1010] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[1011] The twenty common amino acids discussed herein are written in accordance with conventional usage. See, for example, Immunology-ASynthesis (2nd Edition, E.S. Golub and D.G. Ren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In this invention, amino acids are generally represented by single-letter and three-letter abbreviations known in the art. For example, alanine can be represented as A or Ala.

[1012] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[1013] Unless otherwise specified herein or clearly contradicted by the context, the terms “an” and “a kind” as well as “the” and similar designations shall be interpreted to cover both the singular and the plural in the context of describing the invention (especially in the context of the following claims).

[1014] As used herein, the term “and / or” should be considered as a specific disclosure of each of two or more specified features or elements, and any combination of two or more features or elements. Therefore, the term “and / or” as used in phrases, such as “A and / or B” herein, is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone).

[1015] As used in this article, This indicates the location where the structure connects to other parts of the molecule.

[1016] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "alkyl" and "C" 1-4"alkyl" refers to a linear or branched group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl) having 1 to 6 carbon atoms and 1 to 4 carbon atoms respectively, which is optionally substituted by one or more (such as 1, 2, or 3) suitable substituents.

[1017] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond, including, for example, "C..." 2-6 "alkenyl", "C" 2-4 Examples of these include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, etc.

[1018] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond. This includes, for example, "C..." 2-6 "Alkyne", "C" 4-6 Examples of "alkynyl" include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1,3-butyrynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,4-hexadiynyl, etc.

[1019] The term "halogenated alkyl" refers to an alkyl group substituted with one or more (such as 1, 2, or 3) identical or different halogen atoms, wherein the alkyl group is defined as described above. For example, the term "C" as used in this invention... 1-6 "Halogenated alkyl" refers to an alkyl halogroup having 1 to 6 carbon atoms. Common alkyl halogroups include (but are not limited to) -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The alkyl halogroups in this invention are optionally substituted by one or more substituents described in this invention.

[1020] The term "alkanoyl" refers to an alkyl-C(=O)- group. For example, the term "C" as used in this disclosure... 1-6 "alkylyl" refers to C 1-6 Alkyl-C(=O)-.

[1021] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[1022] The term "aryl" refers to an unsaturated carbocyclic group having a conjugated π-electron system, such as "6-10 aryl", and specific examples include, but are not limited to, phenyl and naphthyl.

[1023] The term "heteroaryl" refers to an unsaturated group having a conjugated π-electron system, consisting of ring atoms, with at least one (e.g., 1, 2, 3, or 4) ring atoms being heteroatoms, such as N, O, and S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. Examples include "5-12-membered heteroaryl," "5-11-membered heteroaryl," "5-10-membered heteroaryl," "5-9-membered heteroaryl," and "5-6-membered heteroaryl." Specific examples include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indazoleyl, indolyl, quinolinyl, and isoquinolinyl. For example, non-limiting examples of 5-6-membered heteroaryl groups include: furanyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), thiazolyl (e.g., 1,2,4-thiazolyl or 1,3,4-thiazolyl), imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl (e.g., ... Triazine, etc. In addition to the aforementioned 5-6-membered heteroaryl groups, 5-10-membered heteroaryl groups also include phenyl-5-6-membered heteroaryl groups, or 5-6-membered heteroaryl-5-6-membered heteroaryl groups, non-limiting examples of which include: indole (e.g., ), indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thienophenyl, quinazolinyl, benzothiazolyl, carbazole, thienopyridyl, pyridothiaphene, pyrrolopyridyl (e.g. ), imidazopyrazinyl, imidazopyrazinyl, triazolopyrimidinyl, benzoxazolyl, benzopyrazolyl, benzopyrazinyl (e.g. )wait.

[1024] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl), which, for example, has 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) carbon atoms, i.e., C64. 3-18 Cycloalkyl groups. The cycloalkyl group is, for example, a cycloalkyl group having 3 to 6 carbon atoms (i.e., C16). 3-6 (Cycloalkyl). Non-limiting examples of the cycloalkyl group include: cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl. Non-limiting examples of the polycyclic cycloalkyl group include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. For example, a spirocycloalkyl group can be a group formed by losing a hydrogen atom from the following cycloalkanes: Where n1, n2, n3, and n4 are each independently 0, 1, 2, or 3, n1 and n2 are not simultaneously 0, and n3 and n4 are not simultaneously 0. The cycloalkane is, for example, [example of a cycloalkane]. Similarly, fused cycloalkyl groups can be the groups formed by the loss of hydrogen atoms from the following cycloalkanes: Where n1, n2, n3, and n4 are each independently 0, 1, 2, or 3, n1 and n2 are not simultaneously 0, and n3 and n4 are not simultaneously 0. The cycloalkane is, for example, [example of a cycloalkane]. Bridged cycloalkyl groups can be formed by the loss of hydrogen atoms from the following cycloalkanes: Where n1 and n3 are each independently 0, 1, 2, or 3, and n5 is selected from 1, 2, or 3. The cycloalkane is, for example, [example of cycloalkane].

[1025] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or partially unsaturated cyclic group consisting of ring atoms, with at least one (e.g., 1, 2, 3, 4, or 5 heteroatoms) being a heteroatom, such as N, O, S, and P, wherein the nitrogen atom is optionally quaternized, the nitrogen, sulfur, and phosphorus heteroatoms are optionally oxidized, and the carbon atom is optionally oxidized. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, such as 4-18-membered heterocyclic alkyl groups (e.g., 4-6-membered, 4-7-membered, 4-8-membered heterocyclic alkyl groups), and specific embodiments include, but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,4-tetrahydroquinolinyl, ethylene oxide, azahexacyclic butyl, oxohexacyclic butyl, thiohexacyclic butyl, dihydropyrrolidinyl, dihydropyrroloketyl, pyrrolidinyl... Alkyl group, imidazoalkyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, tetrahydropyranyl group, dihydroimidazoyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyridyl group, tetrahydropyridyl group, pyridinone group, dihydropyridinone group, tetrahydropyridinone group, tetrahydrotriazine group, 1,3-dioxocyclopentyl group, 2,2-difluoro-1,3-dioxocyclopentyl group, cyclopentanyl group, 2,2-difluorocyclopentanyl group, azirheptanyl group, oxacyclopentyl group, azirheptanyl group, benzodihydropyranyl group, wait.

[1026] As used herein, the term "alkylene" refers to a divalent group, for example, "alkylene" refers to a divalent group formed by the loss of a hydrogen atom from an "alkyl" group, where "alkyl" is as defined above; for example, "heterocyclic alkylene" refers to a divalent group formed by the loss of a hydrogen atom from a "heterocyclic" group, where "heterocyclic" is as defined above, where "heterocyclic" is as defined above, for example...

[1027] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[1028] If a functional group or structure is described as “substituted or unsubstituted”, then the functional group or structure may be (1) unsubstituted or (2) substituted, for example, substituted by a suitable substituent.

[1029] Those skilled in the art will understand that when the statement "R is selected from -C" is used... 1-3 Alkylene-, -OC 1-3 Alkylene-, -NH-C 1- 3-alkylene- and -NHC(=O)-C 1-3 alkylene-, the -C 1-3 When "alkylene group - optionally substituted with 1, 2 or 3 halogen groups" indicates -C 1-3 Alkylene- and -OC 1-3 Alkylene-, -NH-C 1-3 Alkylene- and -NHC(=O)-C 1-3 -C in alkylene 1-3 Alkylene groups are optionally substituted with halogens.

[1030] As used herein, the term "suitable substituent" refers to modifications of a compound that can be made by those skilled in the art to suit the needs of the compound's substituents. "Suitable substituents" include oxo (=O), halogen, cyano, and NR. 8 R 9 Carboxyl, thiol, hydroxyl, ester group (e.g., -C) 1-6 Alkylene-C(=O)-OC 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, benzyl, hydroxy-substituted benzyl, indolylmethylene and C 1-6 Haloalkoxy, R 8 R 9Each is independently selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, halogens, hydroxyl groups, carboxyl groups, and ester groups (e.g., -C) 1-6 Alkylene-C(=O)-OC 1-6 alkyl).

[1031] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms in a specified compound or structure by a substituent, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. For example, each substituent may independently consist of one or more of the following structures: NR 8 R 9 -O-, -S-, -NR'-, halogens, -CN, -OH, -SH, -NH2, -NO2, -C(O)-, -CN, =O, C 1-6 (alkylene) group, C 1-6 Halogenated (alkylene) group, C 1-6 Alkoxy, C 2-6 (imide)alkenyl, C 2-6 (Asyl) ynyl, C 3-8 (Hypo-cycloalkylene), 3-8 membered (hetero-cycloalkylene), C 6-10 (sub-)aryl and 5-10 quinone (sub-)heteroaryl, etc., among which R 8 R 9 R' is as defined above. For example, the substituent can be a suitable substituent as described above. If a substituent is described as being "independently selected" from a set of functional groups, then each substituent is selected independently of the others. Therefore, each substituent can be the same as or different from another (other) substituent.

[1032] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[1033] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[1034] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[1035] The term "isotope label" refers to the substitution of one or more atoms in a compound by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in this invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D or 123)). 2 H), tritium (T or 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); and isotopes of sulfur (e.g. 35 S).

[1036] Solid lines (—) and solid wedges may be used in this article. Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[1037] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[1038] It should also be understood that certain compounds of the present invention may exist in a free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above. The compounds of the present invention include, but are not limited to, the drug-linkers and protein-drug conjugates of the present invention.

[1039] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[1040] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts, including aspartate, fumarate, glucoheponicate, glucuronide, glucuronide, hexafluorophosphate, etc.

[1041] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts, including aluminum salts, arginine salts, choline salts, diethylamine salts, etc.

[1042] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[1043] The term "ester" refers to esters derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves be esters.

[1044] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[1045] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[1046] This invention further includes, within its scope, prodrugs of the compounds of the invention. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the desired therapeutically active compound. Therefore, in these cases, the term "administration" for the treatment methods of the invention should include treating various diseases or conditions with one or more prodrug forms of the claimed compounds, but after administration to an individual, the prodrug form is converted in vivo into the aforementioned compound. For example, conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design of Prodrug," ed. H. Bundgaard, Elsevier, 1985.

[1047] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[1048] The term "antibody" refers to an immunoglobulin molecule typically composed of two pairs of polypeptide chains (each pair consisting of one light chain (LC) and one heavy chain (HC)). Antibody light chains can be classified as κ (kappa) and λ (lambda) light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within both light and heavy chains, variable and constant regions are linked by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 3 or more amino acids. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. Constant domains do not directly participate in antibody-antigen binding but exhibit various effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can be further subdivided into highly degenerated regions (called complementarity-determining regions (CDRs)) interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy / light chain pair form antigen-binding sites. The amino acid distribution in each region or domain can follow various numbering systems known in the art.

[1049] The term "antibody" also includes embodiments in which the heavy chain constant region contains a C-terminal lysine, or lacks a C-terminal lysine, or a C-terminal glycine-lysine dipeptide. The term also includes embodiments in which the N-terminal amino acid of the antibody variable region has been cyclized into a pyroglutamate salt. Therefore, in compositions comprising the antibodies disclosed herein, various antibodies may independently contain a C-terminal lysine, lack a C-terminal lysine, lack a C-terminal glycine-lysine, and / or contain N-terminal glutamine or glutamate, or have an N-terminal amino acid cyclized into pyroglutamate.

[1050] The term "complementarity-determining region" or "CDR" refers to the amino acid residues in the variable region of an antibody that are responsible for antigen binding. Each of the heavy and light chain variable regions contains three CDRs, named CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al. (1989) Nature 342: 878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27: 55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86: 9268–9272). For a given antibody, those skilled in the art will readily identify the CDR as defined by each numbering system. Furthermore, the correspondence between different numbering systems is well known to those skilled in the art (see, for example, Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[1051] In this invention, the CDR contained in the antibody or its antigen-binding fragment can be determined according to various numbering systems known in the art, such as the Kabat, Chothia, IMGT, or AbM numbering systems. In some embodiments, the CDR contained in the antibody or its antigen-binding fragment is defined using the Chothia numbering system.

[1052] V H The complete amino acid sequence is typically numbered according to Kabat, while the three CDRs within the variable region can be defined according to any of the aforementioned numbering systems. In some embodiments, V H The amino acid sites in the sequence can be numbered sequentially starting from amino acid site 1 until the end of the sequence, or they can be numbered according to Kabat. Unless otherwise stated, the V mentioned herein... H and V L The amino acid sites in the sequence are defined according to their sequential numbering.

[1053] The amino acid sites in the heavy chain constant region can be numbered sequentially from amino acid site 1 to the end of the sequence, or they can be numbered according to Eu. The amino acid sequence of the IgG1 heavy chain constant region has 330 amino acids, numbered sequentially from 1 to 330. The corresponding sequence numbered according to Eu starts from site 118 and ends at site 447. Unless otherwise stated, the amino acid sites of the heavy and light chains described herein are defined according to sequential numbering.

[1054] The term "antibody" is not limited to any particular method of producing antibodies. For example, it includes recombinant antibodies, monoclonal antibodies, and polyclonal antibodies. Antibodies can be different isotypes of antibodies, such as IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[1055] The term "antigen-binding fragment" in antibody refers to a fragment of the antibody polypeptide, such as a fragment of the full-length antibody polypeptide, which retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen; it is also referred to as the "antigen-binding moiety". See also Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding fragments of antibodies can be generated by recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide-stabilized Fv proteins (“dsFv”), single-domain antibodies (sdAb, nanobodies), and peptides containing at least a portion of an antibody sufficient to confer specific antigen-binding ability to the peptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23:1126-1136.

[1056] The term “Fd” refers to an antibody fragment consisting of VH and CH1 domains; the term “dAb fragment” refers to an antibody fragment consisting of VH domains (Ward et al., Nature 341:544 546 (1989)); the term “Fab fragment” refers to an antibody fragment consisting of VL, VH, CL and CH1 domains, however, those skilled in the art will understand that Fab domains may be arranged according to the above natural orientations, but may also contain domain substitutions or exchanges that promote proper VH and VL pairing (e.g., crossmab-type domain exchanges); the term “F(ab')2 fragment” refers to an antibody fragment containing two Fab fragments connected by disulfide bridges on the hinge region; the term “Fab' fragment” refers to the fragment obtained by reducing the disulfide bonds connecting the two heavy chain fragments in the F(ab')2 fragment, consisting of a complete light chain and heavy chain Fd fragment (consisting of VH and CH1 domains).

[1057] The term "Fv" refers to an antibody fragment consisting of the VL and VH domains of a single arm of the antibody. Fv fragments are generally considered to be the smallest antibody fragment capable of forming a complete antigen-binding site. It is generally believed that six CDRs confer antigen-binding specificity to the antibody. However, even a variable region (such as the Fd fragment, which contains only three antigen-specific CDRs) can recognize and bind to the antigen, although its affinity may be lower than that of a complete binding site.

[1058] The term "Fc" refers to an antibody fragment formed by disulfide bonds connecting the second and third constant regions of the first heavy chain to the second and third constant regions of the second heavy chain. The Fc fragment of an antibody has various functions but does not participate in antigen binding.

[1059] The term "scFv" refers to a single polypeptide chain containing VL and VH domains linked by a linker (see, for example, Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Roseburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules may have a general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of a repeating GGGGS (SEQ ID NO:48) amino acid sequence or a variant thereof. For example, a linker having the amino acid sequence (GGGGS)4 (SEQ ID NO:49) can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers that can be used in this invention are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond may also exist between VH and VL of scFv. In some implementations, the VH and VL domains can be positioned relative to each other in any suitable arrangement. For example, domains containing NH2-VH-VH-COOH, NH 2- VL-VL-COOH of scFv.

[1060] Each of the above antibody fragments retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen.

[1061] In this article, unless the context clearly indicates otherwise, when referring to the term "antibody," it includes not only the complete antibody but also the antigen-binding fragment of the antibody.

[1062] Antigen-binding fragments (e.g., the antibody fragments described above) of a given antibody (e.g., the antibody provided in this invention) can be obtained using conventional techniques known to those skilled in the art (e.g., recombinant DNA techniques or enzymatic or chemical fragmentation methods), and the antigen-binding fragments of the antibody can be specifically screened in the same manner as those used for intact antibodies.

[1063] The term "bispecific antibody" refers to an antibody that has binding specificity to two different antigens (or epitopes). It comprises two antigen-binding domains with binding specificity to different antigens (or epitopes), thereby enabling it to bind to two different binding sites and / or target molecules. The individual antigen-binding domains of a bispecific antibody can be independently selected from full-length antibodies (e.g., IgG antibodies) or their antigen-binding fragments (e.g., Fv, Fab, scFab, scFv, F(ab')2, or SdAb), nanobodies, etc. In some cases, the individual antigen-binding domains are linked by peptide linkers.

[1064] The term "multispecific antibody" refers to an antibody that has binding specificity against at least two (e.g., three or four) different antigens (or epitopes). A multispecific antibody comprises multiple antigen-binding domains that have binding specificity against different antigens (or epitopes), thereby enabling it to bind to at least two different binding sites and / or target molecules. In some cases, the individual antigen-binding domains are linked by peptide linkers.

[1065] The term "humanized antibody" refers to a genetically engineered non-human antibody whose amino acid sequence has been modified to increase its homology with that of a human antibody. Typically, all or part of the CDR region of a humanized antibody is derived from a non-human antibody (donor antibody), and all or part of the non-CDR region (e.g., the variable region FR and / or constant region) is derived from a human immunoglobulin (receptor antibody). Humanized antibodies generally retain the intended properties of the donor antibody, including but not limited to antigen specificity, affinity, reactivity, ability to enhance immune cell activity, and ability to enhance the immune response. Donor antibodies can be mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibodies with the intended properties (e.g., antigen specificity, affinity, reactivity, ability to enhance immune cell activity, and / or ability to enhance the immune response).

[1066] The term "CrossMab" refers to a method for constructing bispecific antibodies that involves exchanging the heavy and light chain domains within the antigen-binding fragment (Fab) of half of the bispecific antibody, allowing the light chain to bind correctly to its homologous heavy chain. This "exchange" preserves the antigen-binding affinity but makes the two arms so different that light chain mismatches no longer occur. Three possible forms of "CrossMab" are: CrossMab Fab CrossMab refers to the crossover or exchange of all VH-CH1 and VL-CL domain positions in half of a bispecific antibody. VH-VL This refers to the crossover or exchange of only the VH and VL domain positions in half of a bispecific antibody; and CrossMab CH1-CL This refers to the crossover or exchange of the CH1 and CL domain positions within half of the Fab region of a bispecific antibody. CorssMab antibodies have been described or claimed in WO2009080252, WO2009080253, WO2009080251, WO2009080254, WO2010136172, WO2010145792 and WO2013026831. The term “CrossMab” antibody is recognized in the art; see, for example, Brinkmann and Kontennann, MAbs 9(2):182-212 (2017); Kontermann and Brinkmann, Drug Discovery Today 20(7):838-846 (2015); Schaefer et al., PNAS, 108 11187-1191 (2011); Kleinet et al., MAbs 8(6):1010-1020 (2016); and Klein et al., MAbs 4(6):653-663 (2012).

[1067] The term "specific binding" refers to a non-random binding reaction between two molecules, such as the reaction between an antibody and its target antigen. The strength or affinity of a specific binding interaction can be expressed by the equilibrium dissociation constant (K0) of that interaction. D or half-maximal effect concentration (EC50) 50 )express.

[1068] The specific binding properties between two molecules can be determined using methods known in the art. One method involves measuring the rate of antigen binding site / antigen complex formation and dissociation. The "binding rate constant" (k...) a or k on ) and "dissociation rate constant" (k dis or k offBoth can be calculated from concentration and the actual rates of association and dissociation (see Malmqvist M, Nature, 1993, 361: 186-187). dis / k on The ratio is equal to the dissociation constant KD (see Davies et al., Annual Rev Biochem, 1990; 59:439-473). KD and k can be measured by any effective method. on and k dis The dissociation constant can be measured using bioluminescence interferometry (e.g., the ForteBio Octet method) in some implementations. Alternatively, surface plasmon resonance techniques (e.g., Biacore) or Kinexa can be used.

[1069] The term "vector" refers to a nucleic acid delivery vehicle into which polynucleotides can be inserted. When a vector enables the expression of a protein encoded by the inserted polynucleotide, it is called an expression vector. Vectors can be introduced into host cells through transformation, transduction, or transfection, allowing the genetic material elements they carry to be expressed in the host cells. Vectors are well known to those skilled in the art and include, but are not limited to: plasmids; phage particles; Cos plasmids; artificial chromosomes, such as yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), or P1-derived artificial chromosomes (PAC); bacteriophages such as λ phage or M13 phage; and animal viruses. Animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (such as herpes simplex virus), poxviruses, baculoviruses, papillomaviruses, and polyomaviruses (such as SV40). A vector may contain multiple elements that control expression, including but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes. In addition, vectors may also contain replication initiation sites.

[1070] Expression and cloning vectors contain nucleic acid sequences that enable the vector to replicate in one or more selected host cells. Typically, in cloning vectors, this sequence is the one that enables the vector to replicate independently of the host chromosomal DNA, and it includes an origin of replication or an autonomous replication sequence. As used herein, the term "expression vector" refers to a vector containing recombinant polynucleotides that include expression regulatory sequences effectively linked to the nucleotide sequence to be expressed. Expression vectors contain sufficient cis-acting elements for expression; other elements for expression may be provided by the host cell or an in vitro expression system. Expression vectors include all those known in the art, such as entrapments, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses).

[1071] As used herein, the term "host cell" refers to cells that can be used to introduce a vector, including but not limited to prokaryotic cells such as Escherichia coli or Bacillus subtilis, fungal cells such as yeast cells or Aspergillus, insect cells such as S2 Drosophila cells or Sf9, or animal cells such as fibroblasts, NSO cells, Vero cells, HeLa cells, COS cells, CHO cells (e.g., CHO-K1, CHO-S, CHO DXB11, Expi CHO, CHO DG44 cells), Expi CHO cells, HEK293 cells, Expi293 cells, BHK cells, and MDCKII cells.

[1072] The term "identity" is used to refer to the sequence matching between two polypeptides or two nucleic acids. Two compared sequences are considered identical at that position when a position is occupied by the same base or amino acid monomer subunit (e.g., a position in each of two DNA molecules is occupied by adenine, or a position in each of two polypeptides is occupied by lysine). The "percentage identity" between two sequences is a function of the number of matching positions shared by the two sequences divided by the number of positions compared × 100. For example, if six out of ten positions in two sequences match, then the two sequences have 60% identity. For example, the DNA sequences CTGACT and CAGGTT have 50% identity (three out of six positions match). Typically, two sequences are compared to produce the maximum identity. Such comparisons can be made using methods conveniently performed, for example, by computer programs such as the Align program (DNAstar, Inc.) Needleman et al. (1970) J. Mol. Biol. 48: 443-453. The percentage identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl Biosci., 4:11-17 (1988)) integrated into the ALIGN program (version 2.0), which uses a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Alternatively, the percentage identity between two amino acid sequences can be determined using the Needleman and Wunsch algorithm (J MoI Biol. 48:444-453 (1970)) in the GAP program integrated into the GCG software package (available at www.gcg.com), which uses a Blossum 62 matrix or a PAM250 matrix, along with gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[1073] The term "conservative substitution" refers to an amino acid substitution that does not adversely affect or alter the intended properties of a protein / peptide containing an amino acid sequence. For example, conservative substitutions can be introduced using standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include substitutions of amino acid residues with amino acid residues having similar side chains, such as substitutions with residues that are physically or functionally similar to the corresponding amino acid residues (e.g., having similar size, shape, charge, chemical properties, including the ability to form covalent or hydrogen bonds). Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid and glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, and methionine), β-branched side chains (e.g., threonine, valine, and isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, and histidine). Therefore, it is preferable to replace the corresponding amino acid residue with another amino acid residue from the same side chain family. Methods for identifying conserved amino acid substitutions are well known in the art (see, for example, Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl Acad. Set USA 94:412-417 (1997), which are incorporated herein by reference).

[1074] The twenty common amino acids discussed herein are written in accordance with conventional usage. See, for example, Immunology-ASynthesis (2nd Edition, E.S. Golub and D.G. Ren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In this invention, amino acids are generally represented by single-letter and three-letter abbreviations known in the art. For example, alanine can be represented as A or Ala.

[1075] As used herein, the term "drug-protein conjugation ratio" refers to: (a) the number of linkers / drug moieties linked to the protein in a single protein-drug conjugate molecule, which is an integer from 0 to 10, such as an integer from 1 to 10; or (b) the average number of linkers / drug moieties linked to the protein in a composition comprising more than one protein-drug conjugate molecule, which is an integer or decimal from 0 to 10, such as an integer or decimal from 1 to 10. Methods for determining the drug-protein conjugation ratio are well known to those skilled in the art, including methods using reversed-phase chromatography or HPLC-MS.

[1076] Whether explicitly stated or not, all numerical values ​​in this application are modified by the term "about". The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated value.

[1077] The term "effective dose" refers to a dose that is sufficient to induce a biological or medical response in cells, tissues, organs, or organisms (e.g., individuals) and to achieve the desired preventive and / or therapeutic effects.

[1078] The dosing regimen can be adjusted to provide the optimal required response. For example, it can be administered as a single dose, divided into doses over time, or the dose can be reduced or increased proportionally as needed. It is understood that, for any given individual, the specific dosing regimen should be adjusted as required and with the professional judgment of the person administering the composition or supervising the administration of the composition.

[1079] The dosage of the protein-drug conjugate or drug linker of the present invention, or its pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof, will depend on individual circumstances, the severity of the disease or condition, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. Generally, the effective dose is about 0.001-10000 mg / kg body weight per day. Where appropriate, the effective dose is about 0.01-1000 mg / kg body weight per day. About 0.01-1000 mg / kg body weight can be administered daily, every two days, or every three days, typically about 0.1-500 mg / kg body weight. Exemplary dosing regimens are once or more daily, once or more weekly, or once or more monthly. With multiple administrations, the interval between single doses can typically be daily, weekly, monthly, or annually. Alternatively, it can be administered in the form of a sustained-release formulation, in which case a lower dosing frequency is required. The dosage and frequency of administration may vary depending on the half-life of the drug in the subject and may also vary depending on whether it is for prophylactic or therapeutic use. In prophylactic use, relatively low doses are administered at relatively low frequency intervals over a long period; in therapeutic use, relatively high doses are sometimes required at shorter intervals until disease progression is slowed or stopped, preferably until the individual shows partial or complete improvement in disease symptoms, after which prophylactic use can be adopted.

[1080] The term "treatment" refers to the reduction or elimination of a targeted disease or symptom. If a subject receives a therapeutic amount of the protein-drug conjugate of the present invention or its pharmaceutically acceptable salt, its stereoisomer, its isotopic label, or the composition or pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement, the subject is considered to have been successfully "treated." It is understood that treatment includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[1081] The term "administrate / administrating / administration" (or "drug administration") refers to the process of applying an active pharmaceutical ingredient (such as the protein-drug conjugate of the present invention or its pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof) or a pharmaceutical composition containing the active pharmaceutical ingredient (such as the pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc., so as to bring the active pharmaceutical ingredient or pharmaceutical composition into contact with the individual or its cells, tissues, organs, biological fluids, etc. Common methods of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, and vaginal administration.

[1082] The term "need" refers to the judgment of a physician or other caregiver regarding an individual's need for or potential benefit from prevention and / or treatment, based on various factors within the physician's or other caregiver's area of ​​expertise.

[1083] The term "individual" (or subject) refers to a human or non-human animal. Individuals in this invention include individuals suffering from diseases and / or conditions (patients) and healthy individuals. Non-human animals in this invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[1084] As used herein, the term “FGF21” refers to the FGF21 protein from any animal source, including mammals such as humans or mice. The term encompasses precursor or unprocessed FGF21, as well as any form of FGF21 produced by cellular processing. The term also covers naturally occurring variants of FGF21, such as splice variants or allelic variants. For example, “FGF21” encompasses the naturally occurring human FGF21 protein (without the signal peptide) with an L or P at position 146.

[1085] As used herein, the terms “wild,” “wild-type,” or “natural” are used interchangeably. When these terms are used to describe a nucleic acid molecule, polypeptide, or protein, they mean that the nucleic acid molecule, polypeptide, or protein is present in nature, found in nature, and has not been artificially modified or processed. As used herein, wild-type FGF21 means naturally occurring, biologically active FGF21. In some embodiments, wild-type FGF21 encompasses wild-type FGF21 molecules containing a signal peptide (e.g., having the amino acid sequence shown in SEQ ID NO: 114) or FGF21 molecules not containing a signal peptide (e.g., having the amino acid sequence shown in SEQ ID NO: 125). Attached Figure Description

[1086] Figure 1 is a schematic diagram of the structure of the bispecific antibody RG7992-crossmab;

[1087] Figure 2 shows the results of endocytic activity assays of Ab01 and its conjugates on cells overexpressing human KLB;

[1088] Figure 3 shows the results of endocytic activity assay of Ab01 and its conjugates in KLB-overexpressing mouse cells;

[1089] Figure 4 shows the results of endocytic activity assay of RG7992-crossmab and its conjugates in cells overexpressing human KLB;

[1090] Figure 5 shows the results of endocytic activity assay of RG7992-crossmab and its conjugates in KLB-overexpressing mouse cells;

[1091] Figure 6 shows the results of endocytic activity assays of Ab02 and its conjugates in KLB-overexpressing mouse cells;

[1092] Figure 7 shows the phosphorylation activity detection results of AbO2 and its conjugates;

[1093] Figure 8 shows the results of THRβ activation activity detection of FPA and its conjugates -1;

[1094] Figure 9 shows the results of THRβ activation activity detection of FPA and its conjugates -2;

[1095] Figure 10 shows the results of THRβ activation activity detection of FPA and its conjugates -3;

[1096] Figure 11 shows the results of THRβ activation activity assay of MK3655-Fc mutant and its conjugate in cells overexpressing human KLB;

[1097] Figure 12 shows the results of THRβ activation activity assay of Ab01 and its conjugates in cells overexpressing human KLB;

[1098] Figure 13 shows the results of THRβ activation activity assay of RG7992-crossmab and its conjugates in KLB-overexpressing mouse cells;

[1099] Figure 14 shows the results of THRβ activation activity assay of Ab02 and its conjugates in KLB-overexpressing mouse cells;

[1100] Figure 15 shows the changes in body weight of obese and MASH mouse models after administration of FPA-07, FPA-10, FPA-11 or saline.

[1101] Figure 16 shows the serum aspartate aminotransferase (AST) levels in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1102] Figure 17 shows the serum triglyceride (TG) content in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1103] Figure 18 shows the serum cholesterol (TC) levels in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1104] Figure 19 shows the serum glucose (GLU) levels in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1105] Figure 20 shows the liver index in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1106] Figure 21. Liver fibrosis scores in obese and MASH mouse models after 8 weeks of administration of FPA-07, FPA-10, FPA-11 or saline.

[1107] Figure 22 shows the changes in body weight of obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12 or saline.

[1108] Figure 23 shows the serum aspartate aminotransferase (AST) levels in obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12, or saline.

[1109] Figure 24 shows the serum alanine aminotransferase (ALT) levels in obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12, or saline.

[1110] Figure 25 shows the serum triglyceride (TG) levels in obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12, or saline.

[1111] Figure 26 shows the low-density lipoprotein cholesterol (LDL-C) levels in obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12, or saline.

[1112] Figure 27 shows the serum glucose (GLU) levels in obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12, or saline.

[1113] Figure 28 shows the liver index of obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12 or saline.

[1114] Figure 29 shows the MASH scores of obese and MASH mouse models after 8 weeks of administration of FPA-12, FPA-14, FPA, hIgG1-12 or saline.

[1115] Figure 30 shows the changes in body weight of obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19 or saline.

[1116] Figure 31 shows the serum alanine aminotransferase (ALT) levels in obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19, or saline.

[1117] Figure 32 shows the serum aspartate aminotransferase (AST) levels in obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19, or saline.

[1118] Figure 33 shows the serum triglyceride (TG) levels in obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19, or saline.

[1119] Figure 34 shows the low-density lipoprotein cholesterol (LDL-C) levels in obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19, or saline.

[1120] Figure 35 shows the liver index of mice in obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19 or saline.

[1121] Figure 36 shows the MASH scores of obese and MASH mouse models after 8 weeks of administration of FPA-18, FPA-19 or saline.

[1122] Figure 37 shows the liver fibrosis scores of obese and MASH mouse models after 8 weeks of administration of FPA-19 or saline.

[1123] Figure 38 shows the changes in body weight of obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1124] Figure 39 shows the serum alanine aminotransferase (ALT) levels in obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1125] Figure 40 shows the serum aspartate aminotransferase (AST) levels in obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1126] Figure 41 shows the serum triglyceride (TG) levels in obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1127] Figure 42 shows the low-density lipoprotein cholesterol (LDL-C) content in obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1128] Figure 43 shows the liver index of mice in obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1129] Figure 44 shows the liver fibrosis scores of obese and MASH mouse models after 8 weeks of administration of FPA-26 or saline.

[1130] Figure 45 shows the plasma stability of the conjugate of this disclosure in human or mouse plasma.

[1131] Note: In the above figures, * indicates P<0.05 compared with the saline group, ** indicates P<0.01 compared with the saline group; # indicates P<0.05 compared with the G4 group, and ## indicates P<0.01 compared with the G4 group.

[1132] Sequence information

[1133] The descriptions of the sequences involved in this application are provided in the table below. Detailed Implementation

[1134] The present invention will be further described below through specific embodiments, but this is not intended to limit the invention. Those skilled in the art can make various modifications or improvements based on the teachings of the present invention without departing from the basic ideas and scope of the invention. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments used without a specified manufacturer are all commercially available conventional products. In the following embodiments, Int A1 and Int-A1 represent the same structure, and Int A2 and Int-A2 represent the same structure.

[1135] Example 1: Preparation of Drug-Linker

[1136] The structures of the compounds described in the following examples were determined by NMR ( 1 It can be determined by 1H NMR or mass spectrometry (MS).

[1137] Nuclear magnetic resonance (NMR) 1 The H NMR measurements were performed using a Bruker 400MHz NMR spectrometer; the deuterated reagent was hexadeuterated dimethyl sulfoxide (DMSO-d6); and the internal standard was tetramethylsilane (TMS).

[1138] The abbreviations used in the nuclear magnetic resonance (NMR) spectra in the examples are shown below.

[1139] s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d6: deuterated dimethyl sulfoxide.

[1140] The δ value is expressed in ppm.

[1141] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[1142] Intermediate A3: 2-(3,5-Diiodo-4-(3-iodo-4-((methyl(2-(methylamino)ethyl)carbamoyl)oxy)phenoxy)phenyl)acetic acid (Int A3)

[1143] Step 1: Synthesis of methyl 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetate (Int A3-2)

[1144] Compound Triac (Int A3-1, 500 mg, 803.95 μmol), Tol (5 mL), and MeOH (2 mL) were added to a reaction flask. After stirring and dissolving, the mixture was cooled in an ice-water bath, and then TMSCHN2 (2 M, 522.57 μL) was added dropwise. Under nitrogen protection, the reaction was carried out at 0 °C for 3 hours. After the reaction was completed by TLC monitoring, a few drops of acetic acid were added to quench the reaction, and the mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with a mobile phase of EA:PE = 25:75. The product was collected and evaporated to dryness to obtain compound Int A3-2 (500 mg).

[1145] Step 2: Synthesis of methyl 2-(4-(4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)-3-iodophenoxy)-3,5-diiodophenyl)acetate (Int A3-3)

[1146] Compound Int A3-2 (500 mg, 786.22 μmol), DCM (8 mL), DIPEA (203.22 mg, 1.57 mmol), and triphosgene (116.65 mg, 393.11 μmol) were added to a reaction flask. After reacting for 20 min, N-methyl-N-[2-(methylamino)ethyl]carbamate tert-butyl ester (177.62 mg, 943.46 μmol) was added. The reaction was carried out under nitrogen protection at 25 °C for 1 h. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with EA:PE = 35:65 as the mobile phase. The collected product was evaporated to dryness to obtain compound Int A3-3 (550 mg). MS (ESI, m / z): 750.8 [M+H-Boc] + .

[1147] Step 3: Synthesis of 2-(4-(4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)-3-iodophenoxy)-3,5-diiodophenyl)acetic acid (Int A3-4)

[1148] Compound Int A3-3 (550 mg, 646.89 μmol) and THF (3 mL) were added to a reaction flask and dissolved. Then, a solution of LiOH·H2O (81.44 mg, 1.94 mmol) in H2O (0.5 mL) was added. The reaction was carried out under nitrogen protection at 25 °C for 5 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound Int A3-4. MS (ESI, m / z): 737.3 [M+H-Boc] + .

[1149] Step 4: Synthesis of 2-(3,5-diiodo-4-(3-iodo-4-((methyl(2-(methylamino)ethyl)carbamoyl)oxy)phenoxy)phenyl)acetic acid (Int A3)

[1150] Compound Int A3-4 (500 mg, 597.95 μmol), TFA (1 mL), and DCM (3 mL) were added to a reaction flask. The reaction was carried out under nitrogen protection at 25 °C for 1 hour. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography using acetonitrile:water (0.05% formic acid) as the mobile phase (30:70), and lyophilized to obtain compound Int A3 (275 mg). MS (ESI, m / z): 737.3 [M+H] + .

[1151] Intermediate 04-1: tert-butylN2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-5,6-diamino-6-oxohexyl)-L-glutamine

[1152] Step 1: Synthesis of (9H-fluorene-9-yl)methyl tert-butyl(6-amino-6-oxohexane-1,5-diyl)(S)-dicarbamate (compound 04-1-2)

[1153] Compound 04-1-1 (23.0 g, 49.1 mmol) was dissolved in CH2Cl2 (230 mL), and EDCI (14.1 g, 73.6 mmol), NH4Cl (5.25 g, 98.2 mmol), DIEA (19.0 g, 147 mmol, 25.7 mL), and HOBt (9.95 g, 73.6 mmol) were added. The mixture was reacted at 25 °C for 2 hours. The reaction was detected as complete by LC-MS and TLC (CH2Cl2 / MeOH = 10 / 1, Rf = 0.22). The reaction solution was extracted with H2O (500 mL) and CH2Cl2 (200 mL x 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 1 / 0-10 / 1) to obtain compound (04-1-2) (18.9 g). MS m / z (ESI): 468.1 [M+H] + .

[1154] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.6Hz,2H),7.73(d,J=6.4Hz,2H),7.39-7.45(m,2H),7.24-7.38(m,4H),6.96(s,1H),6.77(d, J=4.8Hz,1H),4.18-4.30(m,3H),3.81-3.95(m,1H),2.85-2.93(m,2H),1.42-1.65(m,3H),1.34-1.38(m,10H),1.17-1.30(m,2H).

[1155] Step 2: Synthesis of (9H-fluorene-9-yl)methyl(S)-(1,6-diamino-1-oxohexane-2-yl)carbamate (compound 04-1-3)

[1156] Compound 04-1-2 (18.9 g, 40.4 mmol) was dissolved in CH₂Cl₂ (180 mL), followed by the addition of HCl / 1,4-dioxane (4 M, 60 mL). The reaction was stirred at 25 °C for 0.5 hr. LC-MS analysis confirmed the reaction was complete, and the solution was directly concentrated to give compound 04-1-3 (16.3 g). MS m / z (ESI): 368.2 [M+H] + .

[1157] 1H NMR (400MHz, CD3OD) δ7.80(d,J=7.6Hz,2H),7.61-7.71(m,2H),7.27-7.42(m,4H),4.32-4.47(m,2H),4.23(t,J=6.4Hz ,1H),4.08(dd,J=8.8,4.8Hz,1H),2.91(t,J=6.4Hz,2H),1.77-1.91(m,1H),1.66(s,3H),1.44(dd,J=14.4,7.2Hz,2H).

[1158] Step 3: Synthesis of tert-butylN5-((S)-5-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-6-amino-6-oxohexyl)-N2-((benzyloxy)carbonyl)-L-glutamine (compound 04-1-5)

[1159] Compound 04-1-3 (16.3 g, 40.4 mmol) was dissolved in CH₂Cl₂ (160 mL), followed by the addition of EDCI (11.6 g, 60.5 mmol), compound 04-1-4 (16.3 g, 48.4 mmol), DIEA (15.7 g, 121 mmol, 21.1 mL), and HOBt (8.18 g, 60.5 mmol). The reaction was carried out at 25 °C for 2 hours. The reaction was confirmed by LC-MS. The mixture was directly filtered, and the filter cake was washed with CH₂Cl₂ (50 mL) and dried to obtain compound 04-1-5 (23.4 g). MS m / z (ESI): 687.5 [M+H] + .

[1160] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=7.6Hz,2H),7.77-7.82(m,1H),7.73(dd,J=7.2,2.4Hz,1H),7.50 -7.62(m,1H),7.37-7.45(m,2H),7.20-7.37(m,9H),6.97(s,1H),5.85-6.03(m,1H),4.95-5.11(m, 2H),4.18-4.30(m,3H),3.82-3.93(m,2H),3.00(d,J=5.6Hz,3H),2.14(t,J=7.4Hz,2H),1.91(d,J= 7.6Hz,1H),1.69-1.80(m,1H),1.60-1.65(m,1H),1.52(dd,J=9.2,4.8Hz,1H),1.38(s,9H),1.23(br s,4H)

[1161] Step 4: Synthesis of tert-butylN5-((S)-5-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-6-amino-6-oxohexyl)-L-glutamine (compound 04-1-6)

[1162] Compound 04-1-5 (13.0 g, 18.9 mmol) was dissolved in DMF (100 mL), and Pd / C (4.00 g, 10% purity) was added under a nitrogen atmosphere. After purging with hydrogen three times, the reaction was carried out at 25 °C for 4 hours under a H2 (15 Psi) atmosphere. The reaction was confirmed to be complete by TLC (CH2Cl2 / MeOH = 10 / 1, Rf = 0.24). After filtration, the solution was washed with DMF (50 mL × 2), and then concentrated directly to give compound 04-1-6 (1.89 g). MS m / z (ESI): 553.2 [M + H] + .

[1163] Step 5: Synthesis of tert-butylN2-((S)-2-((tert-butyloxycarbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-5,6-diamino-6-oxohexyl)-L-glutamine (compound 04-1)

[1164] Compound 04-1-6 (1.50 g, 2.00 mmol) was dissolved in DMF (15 mL), and EDCI (574 mg, 3.00 mmol), compound 04-1-7 (1.32 g, 2.40 mmol), DIEA (774 mg, 5.99 mmol, 1.04 mL), and HOBt (404 mg, 3.00 mmol) were added. The reaction was carried out at 25 °C for 12 h s. The reaction was confirmed to be complete by LCMS. The mixture was extracted with H2O (50 mL) and CH2Cl2 (20 mL x 3), and the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 28%-58%, 58 min) to obtain compound 04-1 (1.80 g). MS m / z (ESI): 1064.6 [M+H] + .

[1165] 1H NMR (400MHz, CD3OD) δ7.85 (s, 2H), 7.02 (d, J = 2.8Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 6.59(dd,J=8.8,2.4Hz,1H),4.59(s,3H),4.28-4.41(m,2H),3.52(d,J=6.6Hz,1H ),3.19(t,J=6.6Hz,2H),3.12(dd,J=13.2,4.4Hz,1H),2.33(t,J=7.6Hz,2H),1.9 8-2.12(m,1H),1.82-1.96(m,2H),1.66-1.75(m,1H),1.49(s,11H),1.41(s,9H).

[1166] Intermediate 04-1-7: (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid

[1167] (S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid (1.80 g, 2.77 mmol) was dissolved in 1,4-dioxane (20 mL) and H₂O (5 mL), and TEA (27.9 mg, 276 μmol, 38.5 μL) and (Boc)₂O (724 mg, 3.32 mmol, 762 μL) were added. The reaction was carried out at 25 °C for 16 hours. The reaction was confirmed to be complete by LC-MS and TLC (CH₂Cl₂ / MeOH = 20 / 1, Rf = 0.36). The mixture was extracted with H₂O (50 mL) and CH₂Cl₂ (20 mL x 3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 1 / 0-20 / 1) to obtain compound O₄-1-7 (1.86 g). MS m / z (ESI): 651.8 [M+H-Boc] + .

[1168] 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),9.99(s,1H),7.81(s,2H),7.19(d,J=8.8Hz,1H),6.96(d,J=3.2Hz,1H),6.79(d,J= 8.8Hz, 1H), 6.56 (dd, J=8.8, 3.2Hz, 1H), 4.12-4.19 (m, 1H), 3.04 (dd, J=13.6, 3.6Hz, 1H), 2.73-2.79 (m, 1H), 1.34 (s, 9H).

[1169] Intermediate A4: (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amido)-4-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Int-A4)

[1170] Step 1: Synthesis of (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amido)-4-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundecyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Int-A4-2)

[1171] Compound 06-2 (450 mg, 455.51 μmol), compound Int-A4-a (128.64 mg, 683.26 μmol), DIPEA (88.30 mg, 683.26 μmol), and DCM (15 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water and extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with DCM:MeOH = 96:4 as the mobile phase. The collected product was evaporated to dryness to obtain compound Int-A4-2 (385 mg). MS (ESI, m / z): 937.5 [M+H-Boc] + .

[1172] Step 2: Synthesis of (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amido)-4-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Int-A4)

[1173] Compound Int-A4-2 (385 mg, 371.24 μmol), DCM (5 mL), and TFA (1 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 3 hours under nitrogen protection. The reaction solution was directly concentrated and then passed through a reverse-phase chromatography system. The crude product was purified by reverse-phase chromatography using water (0.05% formic acid):acetonitrile = 60:40 as the mobile phase, and lyophilized to obtain compound Int-A4 (270 mg). MS (ESI, m / z): 937.4 [M+H] + .

[1174] Example 1.1: (2S,3S,4S,5R,6S)-6-(4-((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(2-(2-(6-(2-((methanesulfonyl)pyrimidin-5-yl)hex-5-yneamide)ethoxy)ethoxy)acetamido)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 01)

[1175] Step 1: Preparation of (2S,3R,4S,5S,6S)-2-(2-amino-4-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 01-2)

[1176] The starting material (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 01-1, 10 g, 20.6 mmol) was dissolved in ethyl acetate (200 mL), and platinum dioxide (1 g) was added. The mixture was stirred for 2 hours under hydrogen purging and protection. The product was clearly visible under LC-MS monitoring. After filtration, the filtrate was concentrated under reduced pressure to give compound 01-2 (9.16 g). MS m / z (ESI): 456.0 [M+H] + .

[1177] Step 2: Preparation of (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 01-3):

[1178] 2-(2-(2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy)ethoxy)acetic acid (10.16 g, 26.35 mmol) and (2S,3R,4S,5S,6S)-2-(2-amino-4-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (12 g, 26.35 mmol) were dissolved in dichloromethane (300 mL), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (13.03 g, 52.70 mmol) was added. The mixture was stirred for 2 hours. The product was clearly visible under LC-MS monitoring. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (elution: 5% methanol / dichloromethane) to give the title compound 01-3 (21 g). MS m / z (ESI): 823.2 [M+H] + .

[1179] Step 3: Preparation of (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 01-4):

[1180] (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (2 g, 2.43 mmol) and diisopropylethylamine (942.43 mg, 7.29 mmol) were dissolved in dry dichloromethane (50 mL), and a dichloromethane solution (5 mL) of (4-nitrophenyl)chloroformate (1.47 g, 7.29 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 15 hours. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (elution: 70% ethyl acetate / petroleum ether) to give the title compound 01-4 (960 mg).

[1181] Step 4: Preparation of (S)-2-((((3-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)oxy)carbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid (compound 01-5):

[1182] (2S,3R,4S,5S,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (75.88 mg, 76.81 μmol) and (2S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid (50 mg, 76.81 μmol) were dissolved in DMF (1 mL), and diisopropylethylamine (29.78 mg, 230.42 μmol) was added dropwise. The mixture was stirred for 1 hour. The product was clearly visible under LCMS monitoring. The reaction solution was directly used for the next reaction. MS m / z (ESI): 1500.2 [M+H] + .

[1183] Step 5: Preparation of (2S,3R,4S,5S,6S)-6-(2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-4-(((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 01-6):

[1184] A 0.5 mL solution of lithium hydroxide (19.31 mg, 460.07 μmol) in water was added dropwise to the reaction solution from step four, and stirring was continued for 1 hour. The product was clearly visible under LC-MS monitoring. After neutralizing the reaction solution with 3N hydrochloric acid, the product was purified by preparative high-performance liquid chromatography and then freeze-dried to obtain the title compound 01-6 (31 mg). MS m / z (ESI): 1138.0 [M+H] + .

[1185] Its preparation method is as follows:

[1186] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[1187] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[1188] Step 6: Preparation of (2S,3R,4S,5S,6S)-6-(4-((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(2-(2-(6-(2-((methanesulfonyl)pyrimidin-5-yl)hex-5-acetylamide)ethoxy)ethoxy)acetamyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 01):

[1189] (2,5-dioxopyrrolidone-1-yl)6-(2-methylsulfonylpyrimidin-5-yl)hex-5-acetylacetate (Int A1, 10.53 mg, 28.81 μmol) and (2S,3R,4S,5S,6S)-6-(2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-4-(((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (31 mg, 26.20 μmol) were dissolved in DMF (1 mL), and diisopropylethylamine (3.39 mg, 26.20 μmol) was added dropwise. The mixture was stirred for 1 hour. The product was clearly visible under LCMS monitoring. The reaction solution was purified by preparative high-performance liquid chromatography and then freeze-dried to give the title compound 1 (2.68 mg). MS m / z (ESI): 1387.6 [M+H] + .

[1190] Its preparation method is as follows:

[1191] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[1192] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[1193] Example 1.2: N2-((S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-6-amino-5-(6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynylamide)-6-oxohexyl)-L-glutamine (Compound 04)

[1194] Step 1: Synthesis of tert-butylN5-((S)-6-amino-5-(6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-acetylamide)-6-oxohexyl)-N2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-L-glutamine (compound 04-2)

[1195] Compound Int A1 (15.74 mg, 45.06 μmol), compound 04-1 (25 mg, 22.53 μmol), and DMF (1 mL) were added to a reaction flask and stirred until dissolved. Then, DIPEA (5.82 mg, 45.06 μmol) was added. The reaction was carried out under nitrogen protection at 25 °C for 4 hours. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 04-2 (25 mg). MS (ESI, m / z): 1314.0 [M+H] + .

[1196] Step 2: Synthesis of N2-((S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-6-amino-5-(6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-acetylamide)-6-oxohexyl)-L-glutamine (compound 04)

[1197] Compound 04-2 (35 mg, 26.64 μmol), DCM (1 mL), and TFA (1 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in DCM, and the pH was adjusted to weakly alkaline with TEA. The crude product was purified by pre-HPLC and lyophilized to obtain compound 04 (13 mg). MS (ESI, m / z): 1157.9 [M+H] + .

[1198] 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),9.12(s,2H),8.33–8.19(m,1H),8.03–7.95(m,1H),7.90(t,J=5.6Hz,1H),7.84(s,2 H),7.38(s,1H),7.03(d,J=2.8Hz,1H),6.96(s,1H),6.82(d,J=8.8Hz,1H),6.59(dd,J=8.8,2.8Hz,1H),4.20–4.13(m,1H) ,4.12–4.07(m,1H),3.60–3.56(m,2H),3.41(s,3H),3.04–2.92(m,4H),2.63–2.53(m,2H),2.35–2.28(m,3H),2.17–2.04( m,3H),1.98–1.89(m,1H),1.87–1.75(m,3H),1.66–1.56(m,1H),1.54–1.45(m,1H),1.41–1.32(m,2H),1.30–1.21(m,2H).

[1199] Example 1.3: N2-((S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-6-amino-5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamido)-6-oxohexyl)-L-glutamine (Compound 05)

[1200] Step 1: Synthesis of tert-butylN5-((R)-6-amino-5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamido)-6-oxohexyl)-N2-((R)-2-((tert-butyloxycarbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-D-glutamine (compound 05-2)

[1201] Compound Int A2 (40.57 mg, 131.59 μmol), compound 04-1 (73 mg, 65.79 μmol), DMF (2 mL), DIPEA (42.52 mg, 328.97 μmol), and HOBT (17.78 mg, 131.59 μmol) were added to a reaction flask. The mixture was reacted at 25 °C for 4 hours under nitrogen protection. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 05-2 (70 mg). MS (ESI, m / z): 1257.1 [M+H] + .

[1202] Step 2: Synthesis of N2-((S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionyl)-N5-((S)-6-amino-5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamido)-6-oxohexyl)-L-glutamine (compound 05)

[1203] Compound 05-2 (100 mg, 79.57 μmol), TFA (2 mL), and DCM (2 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 3 hours under nitrogen protection. The reaction solution was evaporated to dryness, neutralized with one drop of TEA, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-HPLC and lyophilized to give compound 05 (15.42 mg). MS (ESI, m / z): 1100.9 [M+H] + .

[1204] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.23–8.11(m,1H),7.92(t,J=5.2Hz,1H),7.81(s,2H),7.76(d,J=7 .2Hz,1H),7.45(s,1H),7.08–7.02(m,2H),7.00(s,2H),6.81(d,J=8.8Hz,1H),6.58(dd,J=8.8,2.8Hz,1H) ,4.26–4.17(m,1H),4.08–4.00(m,1H),3.68–3.62(m,1H),3.47–3.36(m,2H),3.08–2.90(m,3H),2.14–2. 03(m,5H),1.91–1.82(m,2H),1.77–1.58(m,3H),1.52–1.43(m,5H),1.41–1.34(m,2H),1.30–1.14(m,5H).

[1205] Example 1.4: (2S,3S,4S,5R,6S)-6-(4-((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(2-(2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamido)ethoxy)ethoxy)acetamido)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 06)

[1206] Step 1: Synthesis of (2S,3S,4S,5R,6S)-2-(2-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 06-2)

[1207] Compound 06-1 (500 mg, 607.68 μmol), DIPEA (235.61 mg, 1.82 mmol), and DCM (10 mL) were added to a reaction flask and stirred until homogeneous. Then, (4-nitrophenyl)chloroformate (367.46 mg, 1.82 mmol) was added. The mixture was reacted at 25 °C for 12 hours under nitrogen protection. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with a mobile phase of EA:PE = 20:80. The collected product was evaporated to dryness to obtain compound 06-2 (380 mg). MS (ESI, m / z): 988.3 [M+H] + .

[1208] Step 2: Synthesis of (S)-2-((((3-(1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-amide)-4-(((2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)oxy)carbonyl)amino)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid (compound 06-3)

[1209] Compound 06-2 (100 mg, 101.22 μmol), (2S)-2-amino-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)propionic acid (T3, 65.89 mg, 101.22 μmol), DMF (2 mL), and DIPEA (39.25 mg, 303.67 μmol) were added to a reaction flask. The mixture was reacted at 25 °C for 12 hours under nitrogen protection. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 06-3 (150 mg). MS (ESI, m / z): 1499.9 [M+H] + .

[1210] Step 3: Synthesis of (2R,3S,4S,5R,6S)-6-(2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-4-(((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 06-4)

[1211] Compound 06-3 (150 mg, 100.02 μmol), LiOH·H₂O (33.58 mg, 800.12 μmol), MeOH (5 mL), and H₂O (1 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 1 hour under nitrogen protection. After the reaction, the mixture was directly purified by reverse-phase chromatography using acetonitrile:water at a mobile phase of 40:60. The purified compound was lyophilized to obtain compound 06-4 (55 mg). MS (ESI, m / z): 1137.9 [M+H] + .

[1212] Step 4: Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((S)-1-carboxy-2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(2-(2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamido)ethoxy)ethoxy)acetamido)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 06)

[1213] Compound 06-4 (70 mg, 61.54 μmol), compound Int A2 (37.95 mg, 123.09 μmol), DIPEA (39.77 mg, 307.72 μmol), and DMF (2 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 16 hours under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-HPLC and lyophilized to obtain compound 06 (37.88 mg). MS (ESI, m / z): 1330.9 [M+H] + .

[1214] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.14(s,1H),8.19(d,J=2.0Hz,1H),7.87–7.80(m,3H),7.66(d,J=8.4Hz,1H),7.16(d,J=8.4 Hz,1H),7.06–6.97(m,4H),6.82(d,J=8.8Hz,1H),6.58–6.52(m,1H),5.52(s,1H),5.31(br,1H),4.98–4.92(m,2H),4.90–4.85(m, 1H),4.22–4.16(m,1H),4.15–4.05(m,3H),3.83–3.77(m,1H),3.71–3.67(m,2H),3.64–3.59(m,2H),3.43(t,J=6.0Hz,2H),3.39–3 .34(m,7H),3.22–3.17(m,2H),3.07–3.01(m,1H),2.82–2.74(m,1H),2.03(t,J=7.2Hz,2H),1.50–1.41(m,4H),1.20–1.11(m,2H).

[1215] Example 1.5: (S)-2-((((4-((S)-2-((S)-2-(6-(2,5-dio...

Claims

A conjugate or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The coupling is shown in formula (II). P-(M-L-D) n (II) in, P is an FGFR agonist and / or a KLB-binding molecule; M is a structure connecting P and L; L is the structure connecting M and D; D represents the thyroid hormone receptor agonist portion; n is 1-10. The conjugate of claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The D portion represents the β-receptor agonist portion of the thyroxine receptor. Preferably, the thyroxine β-receptor agonist is selected from compounds of formula (A”) or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs. in, Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-12 membered heterocyclic; X1 is selected from chemical bonds, -CONH-, -NHCO-, and -O-(CR). a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m - and -(CR a R b ) m -; X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; Y1 is selected from chemical bonds, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m -, -C(=O)-, -S(=O)-, -S(O)2- and -(CR a R b ) m -; R e Each occurrence is independently selected from H, halogen, -CN, -OH, -SH-, -NR. c R d , oxo group, -C 1- 6-alkyl, -OC 1-6 Alkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 1-6 alkyl), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -CONH-(CR) a R b ) m -(5-10 grade heteroaryl groups), -NHCO-(CR) a R b ) m -(C 1-6 alkyl), -NHCO-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3- 6-cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1- 6-Hydroalkyl and -C 3-6 The cycloalkyl group is optionally selected by one or more elements, each independently selected from halogen, -CN, -OH, -NR. c R d -C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; R3, R4, R6, and R7 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group is optionally selected by one or more elements, each independently selected from halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; Alternatively, R4 and R6, along with the atoms they are bonded to, together form C. 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; R5 is selected from -OH, -COOH, -C(=O)-OC 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, --PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, -C 1-4 alkylene-, -C 2-6 alkenyl, -C 2-6 alkynyl group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C 2-6 alkenyl, -C 2-6 Substitution of alkynyl and 4-8 membered heterocyclic alkyl groups; R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; R c and R d Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group; m is independently selected from 0, 1, 2, 3, 4, 5 and 6; q is independently selected from 0, 1, 2, 3, 4 and 5; Preferably, formula (A”) is further shown as formula (Aa”): Among them, X1, X2, Y1, R e R3, R4, R5, R6, and R7 are as defined above; Y2 is selected from -O-, -N(R c )- and -S-, the R c Selected from H, -CH3 and -CO-C 1-6 alkyl; Preferably, formula (A”) is further shown as formula (A’): Among them, X1, X2, Y1, Y2, R3, R4 and R5 are as defined above; R1 and R2 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d , oxo group, -C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), -(CR a R b ) m -(C 6-10 aryl), -(CR a R b ) m -(5-10% heteroaryl groups), -(CR) a R b ) m -(4-18 membered heterocyclic alkyl groups), -CONH-(CR) a R b ) m -(C 1-6 alkyl), -CONH-(CR) a R b ) m -(C 3-18 cycloalkyl), -CONH-(CR) a R b ) m -(C 6-10 aryl), -CONH-(CR) a R b ) m -(5-10 grade heteroaryl groups), -NHCO-(CR) a R b ) m -(C 1-6 alkyl), -NHCO-(CR) a R b ) m -(C 6-10 aryl), -NHCO-(CR a R b ) m -(5-10 membered heteroaryl), -C(O) (4-18 membered heterocyclic alkyl), -S(O)2 (4-18 membered heterocyclic alkyl), -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-18 Cycloalkyl, 4-18 membered heterocycloalkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group is optionally selected by one or more elements, each independently selected from halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; More preferably, X1 is selected from chemical bonds, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m -、-S-(CR a R b ) m - and -(CR a R b ) m -; X2 is selected from chemical bonds, -C 3-7 Cycloalkyl- and -4-7-membered heterocyclic-, said -C 3-7 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; Y1 is selected from -O-(CR a R b ) m -, -N(R c )-(CR a R b ) m -, -S-(CR a R b ) m -, -C(=O)-, -S(=O)-, -S(O)2- and -(CR a R b ) m -; Y2 is selected from -O-, -N(R) c )- and -S-; R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, -OH, and -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 The cycloalkyl group is optionally selected by one or more elements, each independently selected from halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; R5 is selected from -OH, -COOH, and -C. 1-4 alkylene -OH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-COOH, C 6-10 Aryl and 5-10 heteroaryl, the -C 1-4 Alkylene-, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; R a and R b Each is independently selected from H, halogen, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group may be optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; R c and R d Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Alkyl group; m is independently selected from 0, 1, 2, 3, 4, 5 and 6; Preferably, the structure of D is as shown in equation (A-1”), equation (Aa-1”), equation (A-1’), equation (A-2’), equation (A-3’), or equation (A-4’): Among them, R 5a The structure obtained by losing an H from the -OH, -NH2, or secondary amine group in R5 as defined above, or the structure obtained by losing an OH from the -COOH group on R5; Preferably, R 5a Selected from -O-, -C(=O)-, -C 1-4 Alkylene -O-, -C 1-4 Alkylene -C(=O)-, -C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 alkylene-C(=O)-, wherein the -C 1-4 Alkylenes are optionally selected independently from one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -C 3-6 Substitution of cycloalkyl groups; Ring A, q, X1, X2, Y1, Y2, R e , R1, R2, R3, R4, R5, R6, R7, R c and R d As defined above. The conjugate of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein, The Y1 is selected from -O-, -NH- and -(CR). a R b ) m -, R a R b and m as defined in claim 2; Preferably, Y1 is selected from -O- and -CH2-; Alternatively, Y1 can be selected from chemical bonds, -O-, NH, and -(CR). a R b ) m - Preferably, Y1 is selected from chemical bonds, -O- and -CH2-, R a R b and m as defined in claim 2. The conjugate of any one of claims 1-3 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The Y2 is selected from -O-, -N(R) c )- and -S-, the R c Selected from H, -CH3, -COCH3 and -COCH(CH3)CH2CH3; Preferably, Y2 is selected from -O-, -NH-, -(CH3CO)N-, and -N(COCH(CH3)CH2CH3)-; Preferably, Y2 is selected from -O-, -NH- and -(CH3CO)N-. The conjugate of any one of claims 1-4 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, X1 is selected from -O-(CR) a R b ) m -、-NR c - and -(CR a R b ) m -, R a R b R c and m as defined in claim 2; Preferably, X1 is selected from -O-, -NH-, -O-CH2-, -CH2-, -CH2CH2- and -CH2CH(NH2)-; Alternatively, X1 can be selected from chemical bonds, -CONH-, -NHCO-, -O-(CR) a R b ) m -、-N(R c )-(CR a R b ) m - and -(CR) a R b ) m -; Preferably, X1 is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, -CH2CH(NH2)-. The conjugate of any one of claims 1-5 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, X2 is selected from chemical bonds and -4-7-membered heterocyclic groups-, wherein the -4-7-membered heterocyclic groups- contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(=O), P and P(=O); Preferably, X2 is selected from chemical bonds and Preferably, -X1-X2- is selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-, -O-CH2-, -CH2-, -CH2CH2-, -CH2CH(NH2)- and (For example Preferred to be selected from chemical bonds, -CONH-, -NHCO-, -O-, -NH-, -O-CH(NH2)-#, -O-CH2-#, -CH2-, -CH2CH2-, -CH2CH(NH2)-# and (For example ), where the # end is connected to R5; for example, selected from -O-, -O-CH2-#, -NH-, -CH2-, -CH2CH2-, -CH2CH(NH2)-# and The # terminal is connected to R5. The conjugate of any one of claims 1-6 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, R1, R2, R3, and R4 are each independently selected from H, halogens, and -C. 1-4 Alkyl, the -C 1-4 The alkyl group may optionally be substituted by one or more groups independently selected from -OH and -NH2; Preferably, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, F, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2; Preferably, R1, R2, R3 and R4 are each independently selected from H, I, Br, Cl, -CH3 and -CH(CH3)2; Preferably, R1 is H; Preferably, R2 is selected from I and -CH(CH3)2; Preferably, R3 and R4 are each independently selected from I, Br, Cl and -CH3. The conjugate of any one of claims 1-7 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, R5 is selected from -COOH, -C(=O)-OC 1-4 Alkyl, -C 1-4 Alkylene groups -COOH, -PO(OH)2, -C 1-4 Alkylene -PO(OH)2, -C(=O)-C 1-4 Alkylene-COOH, 4-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, -C 1-4 Alkylene, 4-8 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally selected independently by one or more halogens, -CN, -OH, -NR. c R d -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 3-6 cycloalkyl, -C 2-6 alkenyl, -C 2-6 Substitution of alkynyl and 4-8 membered heterocyclic alkyl groups; Preferably, R5 is selected from -COOH, -C 1-4 Alkylene -COOH, -C(=O)-C 1-4 Alkylene-COOH and C 6-10 Aryl, the -C 1-4 Alkylene- and C 6-10 The aryl group is optionally surrounded by one, two, or three independently selected from halogens, -OH, -NH2, and -NH(C). 1-4 Substitution of alkyl groups; Preferably, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH and phenyl, wherein the CH2 and phenyl are optionally substituted by one, two or three groups independently selected from halogen, -OH and -NH2; Preferably, R5 is selected from -COOH, -C(=O)-OCH2CH3, -CH2-COOH, -(CH2)2-COOH, -CH(NH2)-COOH-, -CH2CH(NH2)-COOH, -PO(OH)2, -CH2-PO(OH)2, -C(=O)-CH2-COOH, Preferably, R5 is selected from -COOH, -CH2COOH, -C(=O)CH2COOH, (For example )and The conjugate of any one of claims 1-8 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The thyroxine β receptor agonist is selected from... Preferably, the thyroxine β receptor agonist is selected from... Preferably, the thyroxine β receptor agonist is selected from... Preferably, D is selected from Preferably, D is selected from The conjugate of any one of claims 1-9 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The structure of L is -L1-L2-L3-, L1 is selected from substituted or unsubstituted structures composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): natural amino acids or non-natural amino acids and their analogues (e.g., Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala), Lys(R'), Glu(R'), short peptides composed of amino acids (e.g., Gly-Lys, Ala-Ala, Ala-Lys, Ala-Lys(Ac), Ala-Pro, Gly-Glu, Gly-Gly, Phe-L ys, Phe-Lys(Ac), Val-Ala, Val-Cit, Val-Lys, Val-Lys(Ac), Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Gly, D-Leu-Ala-Glu, Gly-Gly-Arg, Gly -Glu-Gly, Gly-Gly-Gly, Gly-Ser-Lys, Glu-Val-Ala, Glu-Val-Cit, Ser-D-Ala-Pro, Val-Leu-Lys, Val-Lys-Ala, Val-Lys-Gly, Gly-Gly-Phe-Gly (GGFG, SEQ ID NO:7), Gly-Gly-Val-Ala (GGVA, SEQ ID NO:8), Gly-Phe-Leu-Gly (GFLG, SEQ ID NO:9), Glu-Ala-Ala-Ala (EAAA, SEQ ID NO:10), Gly-Gly-Gly-Gly-Gly (GGGGG, SEQ ID NO:11), Asp-Gly-Gly-Phe-Gly (DGGFG, SEQ ID NO:12), Glu-Gly-Gly-Phe-Gly (EGGFG, SEQ ID NO:13)), s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; L2 does not exist, or is selected from L3 is absent, or is selected from the following substituted or unsubstituted structures: -NH-CH2-, t is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R' is selected from a structure composed of one or more of the following groups (e.g., 1, 2, 3, 4, 5, 6, or 7): hydrogen, -NHC 1-6 Alkylene-SO3H, -CH2NH-SO3H, -CH2N(C) 1- (6-alkyl)-SO3H,-CH2NHC 1-6 Alkylenes -SO3H, -CH2N(C 1-6 Alkyl)C 1-6 Alkylenes -SO3H, -CH2N(C 1-6 Alkylene (-SO3H)2, -CH2N + (C 1-6 Alkylene (-SO3H)3, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylenes -SO3H, -CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkylene (SO3H)3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1- 6-alkylene-SO3H)3、-CH2N(C 1-6 alkyl)-C(=O)C 1-6 Alkylene-N + (C 1-6 Alkyl group 3, -CH2NH-C(=O)C 1-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)3、-CH2N(C 1-6 alkyl)-C(=O)OC 2-6 Alkylene-N + (C 1-6 alkyl)2-CH2CO2H, -CH2N(C 1-6 alkyl)-C 1-6 Alkylenes -CO2H, -CH2N + (C 1-6 (alkyl)2-C 1-6 Alkylene -CO2H, glucosyl, galactosyl, glucuronic acid, galacturonic acid, -CH2N(C 1-6 Alkyl)-C(=O)-(CH2CH2O) r -C 1-6 Alkyl group, -CH2N(C) 1-6 Alkyl)-C(=O)-(OCH2CH2) r -OC 1-6 Alkyl group, -(CH2N(Me)-C(=O)) r -C 1-6 Alkyl group, -(CH2CH2O) r -C 1-6 Alkyl groups, -DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid residues), -DOTAGA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-propionyl), -NOTA (1,4,7-triazacyclononane-N,N',N”-triacetic acid residues), -EDTA (ethylenediaminetetraacetic acid residues), -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and r is selected from integers from 1 to 20, such as 1-12, 3-12, 1-10, 1-8, 3-8, 1-6, 1-4, and 1-2, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; Preferably, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6 or 7) substituted or unsubstituted structures: Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala, Lys(R'), Where R' is selected from glucosyl, galactosyl, glucuronic acid, galacturonic acid, -DOTA, -DOTAGA, -NOTA, -EDTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-DOTAGA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-NOTA, -C 1-6 Alkylene-N(C) 1-6 Alkyl)-EDTA and s is selected from integers from 1 to 20, such as 1-15, 1-12, 3-12, 5-10, 8-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; Preferably, L1 is selected from one or more of the following (e.g., 1, 2, 3, 4, 5, 6, or 7) substituted or unsubstituted structures: Preferably, L1 is selected from Preferably, L2 does not exist, or is selected from... R' is selected from glucosyl, galactosyl, glucuronic acid, and galacturonic acid. Preferably, L2 does not exist, or is selected from... Preferably, L3 is absent, or is selected from -NHCH2-, The conjugate of any one of claims 1-10 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, -L1-L2- Selected from Preferably, L is selected from The conjugate of any one of claims 1-11 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, M is selected from the following substituted or unsubstituted structures: Preferably, M is selected from the following substituted or unsubstituted structures: Preferably, M is selected from the following substituted or unsubstituted structures: The conjugate of any one of claims 1-12 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P is an FGF21R ​​agonist; Preferably, the FGF21R ​​agonist is a fusion protein. The conjugate of any one of claims 1-13 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, P is a fusion protein containing wild-type FGF21 or its mutants; Preferably, P is a fusion protein containing wild-type FGF21, wherein the wild-type FGF21 does not contain a signal peptide; Preferably, the wild-type FGF21 comprises the amino acid sequence shown in SEQ ID NO:125; Preferably, the fusion protein comprises an FGF21 mutant; wherein the FGF21 mutant has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the wild-type FGF21, or the mutant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the wild-type FGF21, and is capable of activating the KLB-FGFR signaling pathway; Preferably, the FGF21 mutant, relative to wild-type FGF21 without a signal peptide (e.g., wild-type FGF21 having the amino acid sequence shown in SEQ ID NO: 125), contains one or more of the following mutations: L98R, P171G, A180E, Q27C, G120C, K122R, P130S, S167A, G174A; Preferably, the FGF21 mutant, relative to wild-type FGF21 without a signal peptide (e.g., wild-type FGF21 having the amino acid sequence shown in SEQ ID NO: 125), contains the following mutations: (1) L98R, P171G, and A180E; or (2) Q27C, G120C, K122R, P130S, S167A, P171G, and G174A; Preferably, the wild-type FGF21 or its mutant is a truncated fragment after removing one, two, three, four, five, or six amino acid residues from the N-terminus or C-terminus; preferably, the truncated fragment can retain the activation ability of the wild-type FGF21 or its mutant on the KLB-FGFR signaling pathway. Preferably, the wild-type FGF21 or its mutant is a truncated fragment with the four N-terminal amino acid residues removed; Preferably, the FGF21 mutant is a truncated fragment with four amino acid residues removed from the N-terminus, and has the following amino acid mutations relative to the wild-type FGF21 (e.g., wild-type FGF21 without a signal peptide having the amino acid sequence shown in SEQ ID NO:125): Q27C, G120C, K122R, P130S, S167A, P171G, G174A; Preferably, the FGF21 mutant contains the amino acid sequence shown in SEQ ID NO:3 or 124. The conjugate of claim 14 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The fusion protein also includes an IgG constant domain or a fragment thereof; Preferably, the constant domain of IgG or a fragment thereof is the Fc domain of IgG, such as the Fc domain of IgG1, IgG2, IgG3 or IgG4. Preferably, the IgG constant domain or a fragment thereof is the Fc domain of human IgG1; Preferably, the Fc domain has one or more amino acid substitutions relative to the Fc domain of wild-type human IgG1, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. Preferably, the Fc domain has the following amino acid substitutions compared to the Fc domain of wild-type human IgG1: Leu234Ala, Leu235Ala (according to the position in the EU numbering system); Preferably, the Fc domain has the following amino acid substitutions compared to the Fc domain of wild-type human IgG1: Leu234Ala, Leu235Ala, and Gly237Ala (according to their positions in the EU numbering system); Preferably, the Fc domain of the human IgG1 contains the amino acid sequence shown in SEQ ID NO:4, 122 or 123. The conjugate of any one of claims 1-15 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The FGF21 or its mutant is fused with the constant domain of IgG or a fragment thereof via a linker; Preferably, the connector comprises the amino acid sequence shown in SEQ ID NO:2, or comprises GS; Preferably, the N-terminus of the adapter is fused to the C-terminus of the IgG constant domain or a fragment thereof, and the N-terminus of FGF21 or a mutant thereof is fused to the C-terminus of the adapter; Preferably, the fusion protein comprises the amino acid sequence shown in SEQ ID NO:1, 120 or 121. The conjugate of any one of claims 1-12 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, P is a KLB antibody. The conjugate of claim 17 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The KLB antibody is Ab01, Ab02, MK-3655, RG7992 or mimAb1. The conjugate of any one of claims 1-12 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P is an antibody or its antigen-binding fragment capable of specifically binding to KLB, comprising: (1) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:74, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:75; or (2) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:93, and / or the three CDRs contained in the heavy chain variable region (VH) shown in SEQ ID NO:94; or (3) The three complementary determinant regions (CDRs) contained in the light chain variable region (VL) shown in SEQ ID NO:14, and / or the three complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) shown in SEQ ID NO:15; Preferably, the complementary determinant regions (CDRs) contained in the light chain variable region (VL) and the complementary determinant regions (CDRs) contained in the heavy chain variable region (VH) in (1), (2), and (3) are defined by the Kabat, Chothia, Abm, or IMGT numbering system. The conjugate of claim 19 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The P includes: (1) The following VL and / or VH, (1a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:81 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:85 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or (1b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:82 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:86 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or (1c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:76 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:78 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:84 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:88 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:89 or a variant thereof; or (1d) CDRs are defined according to the IMGT numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:77 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:79 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:80 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:83 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:87 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:90 or a variant thereof; Wherein, the variant described in any one of (1a), (1b), (1c), and (1d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions; or (2) The following VL and / or VH, (2a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:100 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:104 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or (2b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:101 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:105 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or (2c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:95 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:97 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:103 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:107 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:108 or a variant thereof; or (2d) CDRs are defined according to the IMGT numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:96 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:98 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:99 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:102 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:106 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:109 or a variant thereof; Wherein, the variant described in any one of (2a), (2b), (2c), and (2d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions; or (3) The following VL and / or VH, (3a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:21 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:25 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or (3b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:22 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:26 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or (3c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:16 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:18 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or, a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:24 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:28 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:29 or a variant thereof; or (3d)CDRs are defined according to the IMGT numbering system: A VL containing the following three CDRs: CDR-L1 with the sequence SEQ ID NO:17 or a variant thereof, CDR-L2 with the sequence SEQ ID NO:19 or a variant thereof, and CDR-L3 with the sequence SEQ ID NO:20 or a variant thereof; and / or a VH containing the following three CDRs: CDR-H1 with the sequence SEQ ID NO:23 or a variant thereof, CDR-H2 with the sequence SEQ ID NO:27 or a variant thereof, and CDR-H3 with the sequence SEQ ID NO:30 or a variant thereof; Wherein, the variant described in any one of (3a), (3b), (3c), and (3d) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions. The conjugate of claim 19 or 20 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The P includes: (1) The following VL and VH, (1a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:81, CDR-H2 with sequence SEQ ID NO:85, and CDR-H3 with sequence SEQ ID NO:89; or (1b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:82, CDR-H2 with sequence SEQ ID NO:86, and CDR-H3 with sequence SEQ ID NO:89; or (1c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:76, CDR-L2 with sequence SEQ ID NO:78, and CDR-L3 with sequence SEQ ID NO:80; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:84, CDR-H2 with sequence SEQ ID NO:88, and CDR-H3 with sequence SEQ ID NO:89; or (1d) CDRs are defined according to the IMGT numbering system: VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:77, CDR-L2 with sequence SEQ ID NO:79, and CDR-L3 with sequence SEQ ID NO:80; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:83, CDR-H2 with sequence SEQ ID NO:87, and CDR-H3 with sequence SEQ ID NO:90; or (2) The following VL and VH, (2a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:100, CDR-H2 with sequence SEQ ID NO:104, and CDR-H3 with sequence SEQ ID NO:108; or (2b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:101, CDR-H2 with sequence SEQ ID NO:105, and CDR-H3 with sequence SEQ ID NO:108; or (2c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:95, CDR-L2 with sequence SEQ ID NO:97, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:103, CDR-H2 with sequence SEQ ID NO:107, and CDR-H3 with sequence SEQ ID NO:108; or (2d) CDRs are defined according to the IMGT numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:96, CDR-L2 with sequence SEQ ID NO:98, and CDR-L3 with sequence SEQ ID NO:99; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:102, CDR-H2 with sequence SEQ ID NO:106, and CDR-H3 with sequence SEQ ID NO:109; or (3) The following VL and VH, (3a) CDRs are defined according to the kabat numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:21, CDR-H2 with sequence SEQ ID NO:25, and CDR-H3 with sequence SEQ ID NO:29; or (3b) CDRs are defined according to the Chothia numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:22, CDR-H2 with sequence SEQ ID NO:26, and CDR-H3 with sequence SEQ ID NO:29; or (3c) CDRs are defined according to the Abm numbering system: A VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:16, CDR-L2 with sequence SEQ ID NO:18, and CDR-L3 with sequence SEQ ID NO:20; and a VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:24, CDR-H2 with sequence SEQ ID NO:28, and CDR-H3 with sequence SEQ ID NO:29; or (3d)CDRs are defined according to the IMGT numbering system: VL containing the following three CDRs: CDR-L1 with sequence SEQ ID NO:17, CDR-L2 with sequence SEQ ID NO:19, and CDR-L3 with sequence SEQ ID NO:20; and VH containing the following three CDRs: CDR-H1 with sequence SEQ ID NO:23, CDR-H2 with sequence SEQ ID NO:27, and CDR-H3 with sequence SEQ ID NO:

30. The conjugate of any one of claims 19-21 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P includes: (1) VL or a variant thereof shown in SEQ ID NO:74, and / or VH or a variant thereof shown in SEQ ID NO:75; or (2) VL or a variant thereof shown in SEQ ID NO:93, and / or VH or a variant thereof shown in SEQ ID NO:94; or (3) VL or a variant thereof shown in SEQ ID NO:14, and / or VH or a variant thereof shown in SEQ ID NO:15; Wherein, the variant described in any one of (1), (2), and (3) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions; Preferably, it comprises: (1) VL shown in SEQ ID NO:74 and VH shown in SEQ ID NO:75; or (2) VL shown in SEQ ID NO:93 and VH shown in SEQ ID NO:94; or (3) VL shown in SEQ ID NO:14 and VH shown in SEQ ID NO:

15. The conjugate of any one of claims 19-22 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P also includes: (a) The heavy chain constant region (CH) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions, or additions compared to its derived wild-type sequence (e.g., substitutions, deletions, or additions of up to 20, 15, 10, or 5 amino acids; e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids); and (b) The light chain constant region (CL) of human immunoglobulin or a variant thereof, said variant having one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10 or up to 5 amino acids; e.g., substitutions, deletions or additions of 1, 2, 3, 4 or 5 amino acids). Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as the IgG1, IgG2, IgG3 or IgG4 heavy chain constant region, such as the human IgG1 heavy chain constant region or the human IgG4 heavy chain constant region. Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:5; Preferably, the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO:6 or a variant thereof, the variant having up to 20 conserved substitutions (e.g., up to 15, up to 10, or up to 5 amino acid substitutions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions) compared to SEQ ID NO:6; Preferably, the antibody or its antigen-binding fragment comprises a light chain constant region (CL) as shown in SEQ ID NO:5 and a heavy chain constant region (CH) as shown in SEQ ID NO:

6. The conjugate of any one of claims 19-23 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P includes: (1) A light chain comprising the VL region of the sequence shown in SEQ ID NO:74 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:75 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or (2) A light chain comprising the VL region of the sequence shown in SEQ ID NO:93 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH region of the sequence shown in SEQ ID NO:94 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; or, (3) A light chain comprising the VL of the sequence shown in SEQ ID NO:14 and the light chain constant region (CL) of the sequence shown in SEQ ID NO:5, and a heavy chain comprising the VH of the sequence shown in SEQ ID NO:15 and the heavy chain constant region (CH) of the sequence shown in SEQ ID NO:6; Preferably, the antibody or its antigen-binding fragment comprises: (1) The light chain of the sequence shown in SEQ ID NO:91, and the heavy chain of the sequence shown in SEQ ID NO:92; or (2) The light chain of the sequence shown in SEQ ID NO:110, and the heavy chain of the sequence shown in SEQ ID NO:101; or (3) The light chain of the sequence shown in SEQ ID NO:31, and the heavy chain of the sequence shown in SEQ ID NO:

32. The conjugate of any one of claims 1-12 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The P is a bispecific antibody or its antigen-binding fragment comprising a first antigen-binding domain that specifically binds to KLB and a second antigen-binding domain that specifically binds to FGFR1C; wherein, the first antigen-binding domain comprises a first light chain variable region (VL) and a first heavy chain variable region (VH), the first VL and the first VH together forming a domain capable of specifically binding to KLB; the second antigen-binding domain comprises a second light chain variable region (VL) and a second heavy chain variable region (VH), the second VL and the second VH together forming a domain capable of specifically binding to FGFR1C. The conjugate of claim 25 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The first antigen-binding domain and the second antigen-binding domain are each independently selected from scFv, Fab, and scFab; Preferably, the first antigen-binding domain and the second antigen-binding domain are Fab, and the Fab of the second antigen-binding domain contains domain exchanges of the form of CrossMab. Preferably, the crossMab-form domain swapping involves the interchange of CH1 and CL in Fab. The conjugate of claim 25 or 26 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, The first VL contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:33; and / or the first VH contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:34; Preferably, the CDRs contained in the first VL and the CDRs contained in the first VH are defined by the Kabat, Chothia, Abm or IMGT numbering system; Preferably, The first VL includes: (i) CDR-L1 with sequence SEQ ID NO:35 or a variant thereof, CDR-L2 with sequence SEQ ID NO:37 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or (ii) CDR-L1 with sequence SEQ ID NO:36 or a variant thereof, CDR-L2 with sequence SEQ ID NO:38 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:39 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system; and / or The first VH includes: (i) CDR-H1 with sequence SEQ ID NO:40 or a variant thereof, CDR-H2 with sequence SEQ ID NO:44 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or (ii) CDR-H1 with sequence SEQ ID NO:41 or a variant thereof, CDR-H2 with sequence SEQ ID NO:45 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or (iii) CDR-H1 with sequence SEQ ID NO:43 or a variant thereof, CDR-H2 with sequence SEQ ID NO:47 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:48 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or (iv) CDR-H1 with sequence SEQ ID NO:42 or a variant thereof, CDR-H2 with sequence SEQ ID NO:46 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:49 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system; Wherein, the variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions; Preferably, The first VL includes: (i) CDR-L1 with sequence SEQ ID NO:35, CDR-L2 with sequence SEQ ID NO:37, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or (ii) CDR-L1 with sequence SEQ ID NO:36, CDR-L2 with sequence SEQ ID NO:38, and CDR-L3 with sequence SEQ ID NO:39, wherein the CDRs are defined according to the IMGT numbering system; and / or The first VH includes: (i) CDR-H1 with sequence SEQ ID NO:40, CDR-H2 with sequence SEQ ID NO:44, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Kabat numbering system; or (ii) CDR-H1 with sequence SEQ ID NO:41, CDR-H2 with sequence SEQ ID NO:45, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Chothia numbering system; or (iii) CDR-H1 with sequence SEQ ID NO:43, CDR-H2 with sequence SEQ ID NO:47, and CDR-H3 with sequence SEQ ID NO:48, wherein the CDRs are defined according to the Abm numbering system; or (iv) CDR-H1 with sequence SEQ ID NO:42, CDR-H2 with sequence SEQ ID NO:46, and CDR-H3 with sequence SEQ ID NO:49, wherein the CDRs are defined according to the IMGT numbering system. The conjugate of any one of claims 25-27 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The first VL contains the amino acid sequence shown in SEQ ID NO:33 or a variant thereof, and the first VH contains the amino acid sequence shown in SEQ ID NO:34 or a variant thereof. The variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence; preferably, the substitutions are conservative substitutions; Preferably, the first VL contains the amino acid sequence shown in SEQ ID NO:33, and the first VH contains the amino acid sequence shown in SEQ ID NO:

34. The conjugate of any one of claims 25-28 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The second VL contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:50; and / or the second VH contains the three CDRs contained in the amino acid sequence shown in SEQ ID NO:51; Preferably, the CDRs contained in the second VL and the CDRs contained in the second VH are defined by the Kabat, Chothia, Abm or IMGT numbering system; Preferably, The second VL includes: (i) CDR-L1 with sequence SEQ ID NO:52 or a variant thereof, CDR-L2 with sequence SEQ ID NO:54 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the kabat, Chothia or Abm numbering system; or (ii) CDR-L1 with sequence SEQ ID NO:53 or a variant thereof, CDR-L2 with sequence SEQ ID NO:55 or a variant thereof, and CDR-L3 with sequence SEQ ID NO:56 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system; and / or The second VH includes: (i) CDR-H1 with sequence SEQ ID NO:57 or a variant thereof, CDR-H2 with sequence SEQ ID NO:61 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Kabat numbering system; or (ii) CDR-H1 with sequence SEQ ID NO:58 or a variant thereof, CDR-H2 with sequence SEQ ID NO:62 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Chothia numbering system; or (iii) CDR-H1 with sequence SEQ ID NO:60 or a variant thereof, CDR-H2 with sequence SEQ ID NO:64 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:65 or a variant thereof, wherein the CDRs are defined according to the Abm numbering system; or (iv) CDR-H1 with sequence SEQ ID NO:59 or a variant thereof, CDR-H2 with sequence SEQ ID NO:63 or a variant thereof, and CDR-H3 with sequence SEQ ID NO:66 or a variant thereof, wherein the CDRs are defined according to the IMGT numbering system; Wherein, the variant described in any one of (i), (ii), (iii), and (iv) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with respect to the sequence from which it originates, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to the sequence from which it originates; preferably, the substitutions are conservative substitutions; Preferably, The second VL includes: (i) CDR-L1 with sequence SEQ ID NO:52, CDR-L2 with sequence SEQ ID NO:54, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the kabat, Chothia, or Abm numbering system; or (ii) CDR-L1 with sequence SEQ ID NO:53, CDR-L2 with sequence SEQ ID NO:55, and CDR-L3 with sequence SEQ ID NO:56, wherein the CDRs are defined according to the IMGT numbering system; and / or The second VH includes: (i) CDR-H1 with sequence SEQ ID NO:57, CDR-H2 with sequence SEQ ID NO:61, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Kabat numbering system; or (ii) CDR-H1 with sequence SEQ ID NO:58, CDR-H2 with sequence SEQ ID NO:62, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Chothia numbering system; or (iii) CDR-H1 with sequence SEQ ID NO:60, CDR-H2 with sequence SEQ ID NO:64, and CDR-H3 with sequence SEQ ID NO:65, wherein the CDRs are defined according to the Abm numbering system; or (iv) CDR-H1 with sequence SEQ ID NO:59, CDR-H2 with sequence SEQ ID NO:63, and CDR-H3 with sequence SEQ ID NO:66, wherein the CDRs are defined according to the IMGT numbering system. The conjugate of any one of claims 25-29 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The second VL contains the amino acid sequence shown in SEQ ID NO:50 or a variant thereof, and the second VH contains the amino acid sequence shown in SEQ ID NO:51 or a variant thereof. The variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with its source sequence, or the variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, or 3 amino acids) compared to its source sequence; preferably, the substitutions are conservative substitutions; Preferably, the second VL contains the amino acid sequence shown in SEQ ID NO:50, and the second VH contains the amino acid sequence shown in SEQ ID NO:

51. The conjugate of any one of claims 25-30 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The bispecific antibody comprises peptide chain IA, peptide chain IB, peptide chain IC, and peptide chain ID, wherein peptide chain IA comprises a first VL and a light chain constant region (CL), peptide chain IB comprises a first VH, a heavy chain CH1 region, and a first Fc domain monomer (or a second Fc domain monomer), peptide chain IC comprises a second VH, a light chain constant region (CL), and a second Fc domain monomer (or a first Fc domain monomer), and peptide chain ID comprises a second VL and a heavy chain CH1 region; Preferably, the first Fc domain monomer and the second Fc domain monomer each independently contain one or more amino acid modifications, the modifications being able to promote the dimerization of the first Fc domain monomer and the second Fc domain monomer; Preferably, the first Fc domain monomer contains an amino acid modification capable of forming a knot structure, and the second Fc domain monomer contains an amino acid modification capable of forming a hole structure, wherein the knot structure can pair with the hole structure to form a heterodimer; Preferably, the first Fc domain monomer contains an amino acid sequence as shown in SEQ ID NO:112; Preferably, the second Fc domain monomer contains the amino acid sequence shown in SEQ ID NO:113; Preferably, the heavy chain CH1 region contains an amino acid sequence as shown in SEQ ID NO:

68. The conjugate of any one of claims 25-31 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The peptide chain IA includes the first VL and CL from the N-terminus to the C-terminus, the peptide chain IB includes the first VH, the heavy chain CH1 region and the first Fc domain monomer (or the second Fc domain monomer) from the N-terminus to the C-terminus, the peptide chain IC includes the second VH, CL and the second Fc domain monomer (or the first Fc domain monomer) from the N-terminus to the C-terminus, and the peptide chain ID includes the second VL and the heavy chain CH1 region from the N-terminus to the C-terminus. The conjugate of any one of claims 25-32 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The adjacent domains of peptide chain IA are optionally connected by or without a connector, the adjacent domains of peptide chain IB are optionally connected by or without a connector, the adjacent domains of peptide chain IC are optionally connected by or without a connector, and / or the adjacent domains of peptide chain ID are optionally connected by or without a connector. Preferably, each of the connectors is independently the same or different peptide connectors (e.g., rigid peptide connectors or flexible peptide connectors); Preferably, each peptide linker is independently selected from peptide linkers containing one or more glycine (G) and / or serine (S), for example having the structure shown in (GGGGS)y, wherein y is an integer not less than 0, for example y is 1, 2, 3, 4, 5 or 6; preferably, each peptide linker independently contains an amino acid sequence as shown in any one of SEQ ID NO:2 or SEQ ID NOs:115-119. The conjugate of any one of claims 25-33 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The peptide chain IA contains the amino acid sequence shown in SEQ ID NO:70, the peptide chain IB contains the amino acid sequence shown in SEQ ID NO:71, the peptide chain IC contains the amino acid sequence shown in SEQ ID NO:73, and / or, the peptide chain ID contains the amino acid sequence shown in SEQ ID NO:

72. The conjugate of any one of claims 1-34 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, wherein, n is 1-8, for example 3-5, 4-8, or 6-8, for example about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8. The conjugate of any one of claims 1-35 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The coupling is as shown in formula (II-1”), formula (IIa-1”), formula (II-1’), formula (II-2’), formula (II-3’) or formula (II-4’). Among them, rings A, q, X1, X2, Y1, Y2, and R e R1, R2, R3, R4, R5, R 5a R6, R7, L1, L2, L3, M, P and n are as defined in any one of claims 1-35. The conjugate of any one of claims 1-36 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, wherein, The coupling agent is selected from P-01: P-04: P-05: P-06: P-07: P-08: P-10: P-11: P-12: P-13: P-14: P-15: P-16: P-17: P-18: P-19: P-20: P-21: P-22: P-23: P-24: P-25： P-26: Wherein, P and n are as defined in any one of claims 1-36. Composition comprising one or more conjugates as described in any one of claims 1-37 or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, wherein the drug-protein conjugation ratio of the composition is about 1-10, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 to 2, about 1 to 3, about 1 to 4, about 1 to 5, about 1 to 6, about 1 to 7, about 1 to 8, about 1 to 1 9. About 1 to 10, About 2 to 3, About 2 to 4, About 2 to 5, About 2 to 6, About 2 to 7, About 2 to 8, About 2 to 9, About 2 to 10, About 3 to 4, About 3 to 5, About 3 to 6, About 3 to 7, About 3 to 8, About 3 to 9, About 3 to 10, About 4 to 5, About 4 to 6, About 4 to 7, About 4 to 8, About 4 to 9, About 4 to 10, About 5 to 6, About 5 to 7, About 5 to 8, About 5 to 9, About 5 to 10, About 6 to 7, About 6 to 8, About 6 to 9, About 6 to 10, About 7 to 8, About 7 to 9, About 7 to 10, Approximately 8 to 9, approximately 8 to 10, or approximately 9 to 10, or for example, approximately 2.1, approximately 2.2, approximately 2.3, approximately 2.4, approximately 2.5, approximately 2.6, approximately 2.7, approximately 2.8, approximately 2.9, approximately 3, approximately 3.1, approximately 3.2, approximately 3.3, approximately 3.4, approximately 3.5, approximately 3.6, approximately 3.7, approximately 3.8, approximately 3.9, approximately 4, approximately 4.1, approximately 4.2, approximately 4.3, approximately 4.4, approximately 4.5, approximately 4.6, approximately 4.7, approximately 4.8, approximately 4.9, approximately 5, approximately 5.1, approximately 5.2, approximately 5. 3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9. A pharmaceutical composition comprising the conjugate of any one of claims 1-37 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the composition of claim 38, and one or more pharmaceutically acceptable carriers. A medicine box product comprising: a) at least one conjugate of any one of claims 1-37 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug as a first therapeutic agent, or the composition of claim 38, or the pharmaceutical composition of claim 39. b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a composition comprising another therapeutic agent; and c) Optional packaging and / or instructions. The use of the conjugate of any one of claims 1-37 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the composition of claim 38, or the pharmaceutical composition of claim 39, or the kit product of claim 40 in the preparation of a medicament for treating and / or preventing diseases and / or conditions, wherein the diseases and / or conditions are selected from liver diseases, glucose and lipid metabolism diseases and cardiovascular diseases, respiratory diseases and / or conditions and musculoskeletal diseases related to glucose and lipid metabolism, and any combination of the aforementioned diseases and / or conditions. Preferably, the liver disease is selected from fatty liver (e.g., steatohepatitis, metabolic-associated steatohepatitis (MASH)) and cirrhosis; Preferably, the glucose and lipid metabolism disorders are selected from diabetes (e.g., type 1 diabetes, type 2 diabetes), obesity, hyperlipidemia, and hyperglycemia; Preferably, the cardiovascular and cerebrovascular diseases related to glucose and lipid metabolism are selected from hypertension, coronary heart disease, cardiomyopathy, atherosclerosis, and heart failure; Preferably, the respiratory diseases and / or conditions related to glucose and lipid metabolism are selected from obstructive sleep apnea syndrome, dyspnea, and sleep apnea; Preferably, the skeletal joint diseases related to glucose and lipid metabolism are selected from osteoarthritis and lumbar disc herniation.

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