CN117843621A - Novel pyridazine compound, and pharmaceutical composition and application thereof - Google Patents

Abstract

The invention discloses aNovel pyridazine compounds, and pharmaceutical compositions and uses thereof; specifically, one relates to formula (I ₀ -1) or (I) ₀ -2) compounds, solvates, stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts, pharmaceutical compositions comprising these compounds and the use thereof in the prevention and/or treatment of thyroid hormone receptor related diseases.

Description

A novel pyridazine compound and its pharmaceutical composition and use

This application claims priority to Chinese patent applications filed in China on December 31, 2022, with application number 202211737025.0, and invention name “A novel pyridazine compound, its pharmaceutical composition and use”, filed in China on April 28, 2023, with application number 2023104791877, and invention name “A novel pyridazine compound, its pharmaceutical composition and use”, filed in China on May 17, 2023, with application number 2023105515446, and invention name “A novel pyridazine compound, its pharmaceutical composition and use”, and filed in China on August 1, 2023, with application number 2023109585946, and invention name “A novel pyridazine compound, its pharmaceutical composition and use”, the contents of which should be understood as being incorporated into this application by reference.

Technical Field

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

Background Art

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

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

Summary of the invention

In one aspect, the present invention provides a novel pyridazine compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₀ -1) or (I ₀ -2):

In formula (I ₀ -1) and/or formula (I ₀ -2),

L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

Y ₁ , Y ₂ and Y ₃ are independently selected from O and S;

R ₁ is selected from hydrogen, cyano, C1-C6 alkyl which may be substituted by one or more substituents, or C3-C6 cycloalkyl which may be substituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen;

R ₇ is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl which may be substituted by one or more substituents, or C3-C6 cycloalkyl which may be substituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl, deuterium and C1-C6 alkoxy;

_R8 and _R9 are independently selected from hydrogen, It is also stipulated that when Y ₁ , Y ₂ and Y ₃ are all O, R ₈ and R ₉ cannot be hydrogen at the same time;

The above n ₁ is selected from 1, 2 and 3;

_W1 is O or S;

_Ra1 , _Ra2 , _Ra3 and _Ra4 are independently selected from hydrogen, deuterium, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium, halogen, hydroxyl and C1-C6 alkoxy;

R _b0 is selected from amino, in,

The above n ₂ is selected from 1, 2, 3, 4, 5 and 6;

_Rd1 and _Rd2 are independently selected from hydrogen, C1-C6 alkyl which may be substituted or unsubstituted by one or more substituents, or C3-C6 cycloalkyl which may be substituted or unsubstituted by one or more substituents selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _e1 and R _e2 are independently selected from hydrogen, in,

R _h1 and R _h2 are independently selected from hydrogen, C1-C6 alkyl which is substituted or unsubstituted by one or more substituents, wherein the substituents are selected from C1-C6 alkyl, guanidino, carboxyl, amide, thiol, hydroxyl, C1-C6 alkylthiol, imidazolyl, hydroxyphenyl and phenyl;

_Rf is selected from the group consisting of R _i , -OR _i and -NR _i R _j ; wherein,

The above R _i and R _j are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C10 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C10 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, and the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether and thioether;

R _b1 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, The substituent is deuterium or fluorine; wherein,

The above n ₂ is selected from 1, 2, 3, 4, 5 and 6;

R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl;

R _c3 and R _c4 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or R _c3 and R _c4 and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

_Rd1 and _Rd2 are independently selected from hydrogen, C1-C6 alkyl which may be substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl which may be substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _d3 is selected from in,

The above _W2 and _W3 are independently selected from O and S;

R _c5 , R _c6 , R _c7 and R _c8 are independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R c5 and R c6 and the carbon atoms to which they are connected are linked together to form a ring, or, R c7 and R c8 are independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R _c5 and R _c6 and the carbon atoms to which _{they c8} and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

R _e3 and R _f1 are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

_Rg is selected from hydroxyl, C1-C6 alkyl-O- which is substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl and C1-C6 alkoxy;

R _b2 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and the substituent is deuterium or fluorine;

And stipulates that

When L is O, _R8 and _R9 are independently selected from Wherein Ra ₁ and Ra ₂ are both hydrogen, and R _b1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, then one or more hydrogen in the C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl must be substituted with deuterium or fluorine;

When L is O, _R8 and _R9 are independently selected from Wherein Ra ₃ and Ra ₄ are both hydrogen, and R _b2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, then one or more hydrogen in the C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl must be substituted with deuterium or fluorine;

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₀ -3):

The definition of the substituent in formula (I ₀ -3) is the same as that in formula (I ₀ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₀ -4):

The definition of the substituent in formula (I ₀ -4) is the same as that in formula (I ₀ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₀ -5):

The substituents in formula (I ₀ -5) are as defined in formula (I ₀ -2).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotopic derivative or a pharmaceutically acceptable salt thereof of formula (I ₀ -1) or (I ₀ -2), wherein:

Y ₁ , Y ₂ and Y ₃ are all O, and R ₈ and R ₉ are not hydrogen at the same time;

_R8 and _R9 are independently selected from hydrogen,

The above n ₁ is 1;

W ₁ is O;

R _a1 and R _a2 are both hydrogen and deuterium;

R _a3 and R _a4 are both hydrogen and deuterium;

R _b1 is selected from C1-C6 alkyl substituted by one or more substituents, C3-C6 cycloalkyl substituted by one or more substituents, C3-C8 heterocycloalkyl substituted by one or more substituents, C6-C20 aryl substituted by one or more substituents, C6-C20 arylalkyl substituted by one or more substituents, C6-C20 heteroaryl substituted by one or more substituents, and C6-C20 heteroarylalkyl substituted by one or more substituents, wherein the substituent is deuterium or fluorine;

R _b2 is selected from C1-C6 alkyl substituted by one or more substituents, C3-C6 cycloalkyl substituted by one or more substituents, C3-C8 heterocycloalkyl substituted by one or more substituents, C6-C20 aryl substituted by one or more substituents, C6-C20 arylalkyl substituted by one or more substituents, C6-C20 heteroaryl substituted by one or more substituents, C6-C20 heteroarylalkyl substituted by one or more substituents, and the substituent is deuterium or fluorine;

The other substituents are as defined in formula (I ₀ -1) and/or (I ₀ -2) in claim 1.

In some embodiments, in the above formulas (I ₀ -1) to (I ₀ -5), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; preferably, L is O, S, or Se.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), Y ₁ is selected from O, and S.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), Y ₂ is selected from O, and S.

In some embodiments, in the above formulae (I ₀ -1), (I ₀ -3), and (I ₀ -4), Y ₃ is selected from O, and S.

In some embodiments, in the above formulas (I ₀ -1)-(I ₀ -5), R ₁ is selected from hydrogen, cyano, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents, and the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R ₁ is selected from hydrogen, cyano, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R ₁ is selected from cyano.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), R ₂ is selected from hydrogen, deuterium, and halogen; preferably, R ₂ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), R ₃ is selected from hydrogen, deuterium, and halogen; preferably, R ₃ is selected from halogen; more preferably, R ₃ is selected from Cl.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), R ₄ is selected from hydrogen, deuterium, and halogen; preferably, R ₄ is selected from halogen; more preferably, R ₄ is selected from Cl.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), R ₅ is selected from hydrogen, deuterium, and halogen; preferably, R ₅ is selected from hydrogen, and deuterium.

In some embodiments, in the above formulae (I ₀ -1)-(I ₀ -5), R ₆ is selected from hydrogen, deuterium, and halogen; preferably, R ₆ is selected from hydrogen and deuterium.

In some embodiments, in the above formula (I ₀ -1)-(I ₀ -5), R ₇ is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium, or C1-C6 alkoxy groups; preferably, R ₇ is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium, or C1-C6 alkoxy groups; more preferably, R ₇ is C1-C6 alkyl, or C1-C6 alkyl substituted by deuterium; most preferably, R ₇ is isopropyl, or isopropyl in which any hydrogen atom is deuterated;

In some embodiments, in the above formula (I ₀ -1) and/or (I ₀ -3), R ₈ is hydrogen;

In some embodiments, in the above formula (I ₀ -1)-(I ₀ -2) and/or (I ₀ -4)-(I ₀ -5), R ₈ is selected from It is stipulated that when Y ₁ , Y ₂ and Y ₃ are all O, R ₈ and R ₉ cannot be hydrogen at the same time; wherein,

The above _n1 is selected from 1, 2, and 3; preferably, _n1 is selected from 1, and 2; more preferably, _n1 is 1;

_W is selected from O, and S;

_Ra1 and _Ra2 are independently selected from hydrogen, deuterium, C1-C6 alkyl which may be substituted or unsubstituted by one or more substituents, or C3-C6 cycloalkyl which may be substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _Ra1 and _Ra2 are independently selected from hydrogen, deuterium, C1-C6 alkyl and C3-C6 cycloalkyl groups; more preferably, _Ra1 and _Ra2 are both hydrogen, _Ra1 and _Ra2 are both deuterium, either _Ra1 or _Ra2 is hydrogen, and the other is methyl;

R _a3 and R _a4 are independently selected from hydrogen, deuterium, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, and the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R _a3 and R _a4 are independently selected from hydrogen, deuterium, C1-C6 alkyl substituted or unsubstituted by one or more halogen atoms, C3-C6 cycloalkyl groups; more preferably, R _a3 and R _a4 are both hydrogen, R _a3 and R _a4 are both deuterium, any one of R _a3 and R _a4 is hydrogen and the other is methyl, or any one of R _a3 and R _a4 is hydrogen and the other is trifluoromethyl;

R _b0 is selected from amino, in,

The above n ₂ is selected from 1, 2, 3, 4, 5, or 6; preferably, n ₂ is selected from 1, 2, and 3;

R _d1 and R _d2 are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R _d1 and R _d2 are independently selected from hydrogen, C1-C6 alkyl groups and C3-C6 cycloalkyl groups; more preferably, R _d1 and R _d2 are both hydrogen;

R _e1 and R _e2 are independently selected from hydrogen, in,

The above R _h1 and R _h2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is selected from C1-C6 alkyl, guanidino, carboxyl, amide, thiol, hydroxyl, C1-C6 alkylthiol, imidazolyl, hydroxyphenyl, phenyl; preferably, R _h1 and R _h2 are both hydrogen, or any one of R _h1 and R _h2 is hydrogen and the other is methyl, isopropyl, isobutyl, or benzyl;

_Rf is selected from the group consisting of R _i , -OR _i , and -NR _i R _j ; wherein,

The above R _i and R _j are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C10 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C10 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, thioether; preferably, R _i and R j are independently selected from hydrogen, ... _j are independently selected from hydrogen, C1-C6 alkyl which is substituted or unsubstituted by one or more substituents, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, thioether; more preferably, R _f is hydroxyl;

R _b1 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, The substituent is deuterium or fluorine; preferably, R _b1 is selected from trifluoromethyl, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, or substituted or unsubstituted with one or more substituents The substituent is deuterium or fluorine; wherein,

The above n ₂ is selected from 1, 2, 3, 4, 5, and 6; preferably, n ₂ is selected from 1, 2, and 3;

R _d1 and R _d2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R _d1 and R _d2 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R _d1 and R _d2 are both hydrogen;

_Rg is selected from hydroxyl, C1-C6 alkyl-O- which is substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl and C1-C6 alkoxy; preferably, _Rg is selected from hydroxyl, or -O-C1-C6 alkyl-O-;

R _c3 and R _c4 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R _c3 and R _c4 and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, R _c3 and R _c4 are both hydrogen, any one of R _c3 and R _c4 is hydrogen and the other is methyl, or any one of R _c3 and R _c4 is hydrogen and the other is isopropyl;

R _d3 is selected from in,

The above W ₂ is selected from O, or S;

W ₃ is selected from O, or S;

_Rc5 and _Rc6 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, Rc5 and Rc6 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, _C6 -C20 heteroaryl substituted or unsubstituted by one or more substituents, or _c6 and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, any one of R _c5 and R _c6 is hydrogen, and the other is selected from benzyl, 1-methylpropyl, isopropyl, deuterated 1-methylpropyl, or deuterated isopropyl;

R _c7 and R _c8 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R _c7 and R _c8 and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, any one of R _c7 and R _c8 is hydrogen, and the other is selected from methyl or deuterated methyl;

R _e3 is selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, R _e3 is hydrogen;

_Rf1 is selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, _Rf1 is hydrogen;

R _b2 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, and the substituent is deuterium or fluorine; preferably, R _b2 is selected from methyl, deuterated methyl, trifluoromethyl, ethyl, deuterated ethyl, propyl, deuterated propyl, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl.

In some embodiments, in the above formula (I ₀ -1) and/or (I ₀ -4)-(I ₀ -5), R ₉ is hydrogen;

In some embodiments, in the above formula (I ₀ -1)-(I ₀ -3), R ₉ is selected from It is stipulated that when Y ₁ , Y ₂ and Y ₃ are all O, R ₈ and R ₉ cannot be hydrogen at the same time; wherein,

The above n ₁ , _{n 2} , _Ra1 , _Ra2 , Ra3 , _Ra4 , W ₁ , R _b0 , R _b1 and R _b2 are as defined above, respectively.

In some embodiments, a novel pyridazine compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₁ -1) is provided:

In formula (I ₁ -1),

L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

Y ₁ , Y ₂ and Y ₃ are independently selected from O and S;

R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl and C1-C6 alkoxy;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen;

R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium, or C1-C6 alkoxy;

_R8 and _R9 are independently selected from hydrogen, It is also stipulated that when Y ₁ , Y ₂ and Y ₃ are all O, R ₈ and R ₉ cannot be hydrogen at the same time;

The above n ₁ is selected from 1, 2 and 3;

R _a1 and R _a2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _b is selected from amino,

R _c is selected from in,

The above n ₂ is selected from 1, 2, 3, 4, 5 and 6;

R _d1 and R _d2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _e1 and R _e2 are independently selected from hydrogen,

R _f is selected from R _i , -OR _i and -NR _i R _j ;

_Rg is selected from hydroxyl, substituted or unsubstituted C1-C6 alkyl-O-, and the substituent is selected from halogen atoms, hydroxyl and C1-C6 alkoxy; wherein,

The above R _h1 and R _h2 are independently selected from hydrogen, or substituted or unsubstituted C1-C6 alkyl, and the substituent is selected from C1-C6 alkyl, guanidino, carboxyl, amide, thiol, hydroxyl, C1-C6 alkylthiol, imidazolyl, hydroxyphenyl and phenyl;

R _i and R _j are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C6-C20 arylalkyl, substituted or unsubstituted C6-C20 heteroaryl, substituted or unsubstituted C6-C20 heteroarylalkyl, and the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether and thioether.

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₁ -2):

The substituents in formula (I ₁ -2) are as defined in formula (I ₁ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₁ -3):

The substituents in formula (I ₁ -3) are as defined in formula (I ₁ -1).

In some embodiments, in the above formula (I ₁ -1), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, L is O;

In some embodiments, in the above formulae (I ₁ -2)-(I ₁ -3), L is O.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), Y ₁ is selected from O, and S.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), Y ₂ is selected from O, and S.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), Y ₃ is selected from O, and S.

In some embodiments, in the above formulas ( _I1-1 )-( _I1-3 ), _R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _R1 is selected from hydrogen, cyano, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, _R1 is selected from cyano, or C1-C6 alkyl.

In some embodiments, in the above formulae (I ₁ -1) to (I ₁ -3), R ₂ is selected from hydrogen, deuterium, or halogen; preferably, R ₂ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), R ₃ is selected from hydrogen, deuterium, or halogen; preferably, R ₃ is selected from halogen; more preferably, R ₃ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), R ₄ is selected from hydrogen, deuterium, or halogen; preferably, R ₄ is selected from halogen; more preferably, R ₄ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₁ -1)-(I ₁ -3), R ₅ is selected from hydrogen, deuterium, or halogen; preferably, R ₅ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₁ -1) to (I ₁ -3), R ₆ is selected from hydrogen, deuterium, or halogen; preferably, R ₆ is selected from hydrogen and deuterium.

In some embodiments, in the above formulas ( _I1-1 )-( _I1-3 ), _R7 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, or C1-C6 alkoxy; preferably, _R7 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, C1-C6 alkoxy; more preferably, _R7 is deuterated C1-C6 alkyl; most preferably, _R7 is isopropyl in which any hydrogen atom is deuterated;

In some embodiments, in the above formula (I ₁ -1)-(I ₁ -2), R ₈ is hydrogen;

In some embodiments, in the above formula (I ₁ -1) and/or (I ₁ -3), R ₈ is selected from in,

The above _n1 is selected from 1, 2, or 3; preferably, _n1 is selected from 1, or 2; more preferably, _n1 is 1;

_Ra1 and _Ra2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _Ra1 and _Ra2 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; more preferably, _Ra1 and _Ra2 are both hydrogen;

R _b is selected from amino,

R _c is selected from in,

The above n ₂ is selected from 1, 2, 3, 4, 5, or 6; preferably, n ₂ is selected from 1, 2, and 3;

R _d1 and R _d2 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R _d1 and R _d2 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R _d1 and R _d2 are both hydrogen;

R _e1 and R _e2 are independently selected from hydrogen,

R _f is selected from R _i , -OR _i , or -NR _i R _j ;

_Rg is selected from hydroxyl, or -O-substituted or unsubstituted C1-C6 alkyl-, wherein the substituent is selected from halogen atoms, hydroxyl and C1-C6 alkoxy; preferably, _Rg is selected from hydroxyl, -O-C1-C6 alkyl-;

in,

The above R _h1 and R _h2 are independently selected from hydrogen, or substituted or unsubstituted C1-C6 alkyl, and the substituent is selected from C1-C6 alkyl, guanidino, carboxyl, amide, thiol, hydroxyl, C1-C6 alkylthiol, imidazolyl, hydroxyphenyl, phenyl;

R _i and R _j are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C6-C20 arylalkyl, substituted or unsubstituted C6-C20 heteroaryl, substituted or unsubstituted C6-C20 heteroarylalkyl, and the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether and thioether; preferably, R _i and R _j are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether and thioether.

In some embodiments, in the above formula (I ₁ -1) and/or (I ₁ -3), R ₉ is hydrogen;

In some embodiments, in the above formula (I ₁ -1)-(I ₁ -2), R ₉ is selected from in,

The above n ₁ , _Ra1 , _Ra2 , R _b and R _c are as defined above.

In some embodiments, a novel pyridazine compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₂ -1) or (I ₂ -2) is provided:

In formula (I ₂ -1) or (I ₂ -2),

L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

Y ₁ , Y ₂ and Y ₃ are independently selected from O and S;

R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl and C1-C6 alkoxy;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen;

R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium and C1-C6 alkoxy;

_R8 and _R9 are independently selected from hydrogen, It is also stipulated that R ₈ and R ₉ cannot be hydrogen at the same time; wherein,

The above n ₁ is selected from 1, 2 and 3;

R _a1 and R _a2 are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _b1 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, The substituent is deuterium or fluorine; wherein,

The above R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl;

R _b2 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, wherein the substituent is deuterium or fluorine;

And stipulates that

When L is O, R _b1 is selected from the group consisting of: or the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

When L is O, R _b2 is selected from the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl.

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₂ -3):

The substituents in formula (I ₂ -3) are as defined in formula (I ₂ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₂ -4):

The substituents in formula (I ₂ -4) are as defined in formula (I ₂ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₂ -5):

The substituents in formula (I ₂ -5) are as defined in formula (I ₂ -2).

In some embodiments, in the above formulas (I ₂ -1)-(I ₂ -5), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, L is O, S, and Se.

In some embodiments, in the above formulae (I ₂ -1) to (I ₂ -5), Y ₁ is selected from O or S; preferably, Y ₁ is O.

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -5), Y ₂ is selected from O, or S; preferably, Y ₂ is O.

In some embodiments, in the above formulae (I ₂ -1), (I ₂ -3)-(I ₂ -4), Y ₃ is selected from O or S; preferably, Y ₃ is O.

In some embodiments, in the above formulas (I ₂ -1)-(I ₂ -5), R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R ₁ is selected from hydrogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl groups; more preferably, R ₁ is selected from cyano, C1-C6 alkyl groups.

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -5), R ₂ is selected from hydrogen, deuterium, and halogen; preferably, R ₂ is selected from hydrogen, and deuterium.

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -5), R ₃ is selected from hydrogen, deuterium, and halogen; preferably, R ₃ is selected from halogen; more preferably, R ₃ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -5), R ₄ is selected from hydrogen, deuterium, and halogen; preferably, R ₄ is selected from halogen; more preferably, R ₄ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -5), R ₅ is selected from hydrogen, deuterium, and halogen; preferably, R ₅ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₂ -1) to (I ₂ -5), R ₆ is selected from hydrogen, deuterium, and halogen; preferably, R ₆ is selected from hydrogen and deuterium.

In some embodiments, in the above formulas (I ₂ -1)-(I ₂ -5), R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; preferably, R ₇ is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, or C1-C6 alkoxy; more preferably, R ₇ is C1-C6 alkyl, deuterated C1-C6 alkyl; most preferably, R ₇ is isopropyl, and isopropyl in which any hydrogen atom is deuterated;

In some embodiments, in the above formula (I ₂ -1) and/or (I ₂ -3), R ₈ is hydrogen;

In some embodiments, in the above formulae (I ₂ -1)-(I ₂ -2) and/or (I ₂ -4)-(I ₂ -5), R ₈ is selected from in,

The above _n1 is selected from 1, 2, and 3; preferably, _n1 is selected from 1, and 2; more preferably, _n1 is 1;

_Ra1 and _Ra2 are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _Ra1 and _Ra2 are independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; more preferably, _Ra1 and _Ra2 are both hydrogen, and _Ra1 and _Ra2 are both deuterium;

R _b1 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, The substituent is deuterium or fluorine; preferably, R _b1 is selected from C1-C6 alkyl substituted or unsubstituted by deuterium or fluorine, Wherein, the above R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl, preferably, R _c1 and R _c2 are both hydrogen;

R _b2 is selected from the following groups which are substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, and the substituent is deuterium or fluorine; preferably, R _b2 is selected from C1-C6 alkyl which is substituted or unsubstituted by deuterium or fluorine.

Regulation,

When L is O, R _b1 is selected from the group consisting of: or the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

When L is O, R _b2 is selected from the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

In some embodiments, a novel pyridazine compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₃ -1) or (I ₃ -2) is provided:

In formula (I ₃ -1) or (I ₃ -2),

L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

Y ₁ , Y ₂ and Y ₃ are independently selected from O and S;

_R1 is selected from hydrogen, cyano, C1-C6 alkyl substituted or unsubstituted by one or more substituents, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen;

R ₇ is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl which may be substituted by one or more substituents, C3-C6 cycloalkyl which may be substituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl, deuterium, or C1-C6 alkoxy;

_R8 and _R9 are independently selected from hydrogen, It is also stipulated that R ₈ and R ₉ cannot be hydrogen at the same time; wherein,

The above n ₁ is selected from 1, 2 and 3;

_W1 is O or S;

R _a1 and R _a2 are independently selected from hydrogen, deuterium, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium, halogen, hydroxyl and C1-C6 alkoxy;

R _a3 and R _a4 are independently selected from C1-C6 alkyl substituted or unsubstituted by one or more halogen atoms, C3-C6 cycloalkyl substituted or unsubstituted by one or more halogen atoms;

R _b1 is selected from in,

The above R _c1 and R _c2 are independently selected from the following groups which are independently hydrogen, deuterium, halogen, cyano, trifluoromethyl, or substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl; or, R _c1 and R _c2 and the carbon atoms to which they are connected are linked together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

R _d is selected from in,

The above _W2 and _W3 are independently selected from O and S;

R _c3 , R _c4 , R _c5 and R _c6 are independently selected from the following groups which are independently hydrogen, deuterium, halogen, cyano, trifluoromethyl, or substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or, R _c3 and R _c4 and the carbon atoms to which they are connected are linked together to form a ring, or, R _c5 and R _c6 and the carbon atoms to which they are linked together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

R _e and R _f are independently selected from hydrogen, the following groups which are substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

R _b2 is selected from the following groups which are substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, wherein the substituent is deuterium or fluorine;

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₃ -3):

The substituents in formula (I ₃ -3) are as defined in formula (I ₃ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₃ -4):

The substituents in formula (I ₃ -4) are as defined in formula (I ₃ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₃ -5):

The substituents in formula (I ₃ -5) are as defined in formula (I ₃ -2).

In some embodiments, in the above formulas (I ₃ -1) to (I ₃ -5), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, L is O, S, and Se.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), Y ₁ is selected from O, and S; preferably, Y ₁ is O.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), Y ₂ is selected from O, and S; preferably, Y ₂ is O.

In some embodiments, in the above formulae (I ₃ -1), (I ₃ -3) to (I ₃ -4), Y ₃ is selected from O, and S; preferably, Y ₃ is O.

In some embodiments, in the above formulas (I ₃ -1)-(I ₃ -5), R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R ₁ is selected from hydrogen, cyano, C1-C6 alkyl, and C3-C6 cycloalkyl groups; more preferably, R ₁ is selected from cyano, and C1-C6 alkyl groups.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), R ₂ is selected from hydrogen, deuterium, and halogen; preferably, R ₂ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), R ₃ is selected from hydrogen, deuterium, and halogen; preferably, R ₃ is selected from halogen; more preferably, R ₃ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), R ₄ is selected from hydrogen, deuterium, and halogen; preferably, R ₄ is selected from halogen; more preferably, R ₄ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), R ₅ is selected from hydrogen, deuterium, and halogen; preferably, R ₅ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₃ -1) to (I ₃ -5), R ₆ is selected from hydrogen, deuterium, and halogen; preferably, R ₆ is selected from hydrogen and deuterium.

In some embodiments, in the above formulas (I ₃ -1) to (I ₃ -5), R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; preferably, R ₇ is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; more preferably, R ₇ is C1-C6 alkyl, and deuterated C1-C6 alkyl; most preferably, R ₇ is isopropyl, and isopropyl in which any hydrogen atom is deuterated;

In some embodiments, in the above formula (I ₃ -1) and/or (I ₃ -3), R ₈ is hydrogen;

In some embodiments, in the above formulae (I ₃ -1)-(I ₃ -2) and/or (I ₃ -4)-(I ₃ -5), R ₈ is selected from in,

The above _n1 is selected from 1, 2, and 3; preferably, _n1 is selected from 1, and 2; more preferably, _n1 is 1;

_W is selected from O, and S;

_Ra1 and _Ra2 are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _Ra1 and _Ra2 are independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; more preferably, _Ra1 and _Ra2 are both hydrogen, and _Ra1 and _Ra2 are both deuterium;

R _a3 and R _a4 are independently selected from C1-C6 alkyl substituted or unsubstituted by one or more halogen atoms, C3-C6 cycloalkyl substituted or unsubstituted by one or more halogen atoms; preferably, any one of R _a3 and R _a4 is hydrogen, and the other is trifluoromethyl;

R _b1 in,

The above R _c1 and R _c2 are independently selected from the following groups which are independently hydrogen, deuterium, halogen, cyano, trifluoromethyl, or substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl; or, R _c1 and R _c2 and the carbon atoms to which they are connected are linked together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R _c1 and R c2 are independently hydrogen, ... _c2 are independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl substituted by one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl; more preferably, R _c1 and R _c2 are independently selected from hydrogen, methyl, isopropyl;

R _d is selected from in,

The above W ₂ is selected from O, or S;

W ₃ is selected from O, or S;

R _c3 and R _c4 are independently selected from the following groups which are independently hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or, R c3 and R c4 and the carbon atoms to which they are connected are linked together to form a ring, and the substituent is hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R _c3 and R _c4 are independently selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or, R c3 and R c4 and the carbon atoms to which they are linked are linked together to form a ring, and the substituent is hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, _aryl , heteroaryl; preferably, _c4 are independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl substituted by one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, phenyl; More preferably, R _c3 and R _c4 are independently selected from hydrogen, benzyl, isopropyl, isobutyl, deuterated isopropyl, deuterated isobutyl;

_Rc5 and _Rc6 are independently selected from the following groups which are independently hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or, _Rc5 and _Rc6 and the carbon atoms to which they are connected are linked together to form a ring, and the substituent is hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, _Rc5 and Rc6 are selected from the following groups which are independently ... _c6 are independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl substituted by one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, phenyl; More preferably, R _c5 and R _c6 are independently selected from hydrogen, methyl, deuterated methyl;

R _e is selected from hydrogen, the following groups which are substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, wherein the substituents are hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R _e is hydrogen;

_Rf is selected from hydrogen, the following groups which are substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, wherein the substituents are hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, _Rf is hydrogen;

R _b2 is selected from the following groups which are substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, and the substituent is deuterium or fluorine; preferably, R _b2 is selected from methyl, ethyl, deuterated methyl, and deuterated ethyl.

In some embodiments, in the above formula (I ₃ -1) and/or (I ₃ -4)-(I ₃ -5), R ₉ is hydrogen;

In some embodiments, in the above formula (I ₃ -1)-(I ₃ -3), R ₉ is selected from in,

The above n ₁ , n ₂ , _Ra1 , _Ra2 , _Ra3 , _Ra4 , W ₁ , R _b1 and R _b2 are as defined above, respectively.

In some embodiments, a novel pyridazine compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₄ -1) or (I ₄ -2) is provided:

In formula (I ₄ -1) or (I ₄ -2),

L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

Y ₁ , Y ₂ and Y ₃ are independently selected from O and S;

R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl and C1-C6 alkoxy;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen;

R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium and C1-C6 alkoxy;

_R8 and _R9 are independently selected from hydrogen, In particular, R ₈ and R ₉ cannot be hydrogen at the same time; wherein,

The above n ₁ is selected from 1, 2 and 3;

R _a1 and R _a2 are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

R _b1 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, The substituent is deuterium or fluorine; wherein,

The above R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl;

R _b2 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, wherein the substituent is deuterium or fluorine;

And stipulates that

When L is O, R _b1 is selected from the group consisting of: or the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

When L is O, R _b2 is selected from the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl.

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₄ -3):

The substituents in formula (I ₄ -3) are as defined in formula (I ₄ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₄ -4):

The substituents in formula (I ₄ -4) are as defined in formula (I ₄ -1).

In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₄ -5):

The substituents in formula (I ₄ -5) are as defined in formula (I ₄ -2).

In some embodiments, in the above formulas (I ₄ -1)-(I ₄ -5), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, L is O, S, and Se.

In some embodiments, in the above formulae (I ₄ -1) to (I ₄ -5), Y ₁ is selected from O, and S; preferably, Y ₁ is O.

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -5), Y ₂ is selected from O, and S; preferably, Y ₂ is O.

In some embodiments, in the above formulae (I ₄ -1), (I ₄ -3)-(I ₄ -4), Y ₃ is selected from O, and S; preferably, Y ₃ is O.

In some embodiments, in the above formulas (I ₄ -1)-(I ₄ -5), R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R ₁ is selected from hydrogen, cyano, C1-C6 alkyl, or C3-C6 cycloalkyl groups; more preferably, R ₁ is selected from cyano, and C1-C6 alkyl groups.

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -5), R ₂ is selected from hydrogen, deuterium, and halogen; preferably, R ₂ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -5), R ₃ is selected from hydrogen, deuterium, and halogen; preferably, R ₃ is selected from halogen; more preferably, R ₃ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -5), R ₄ is selected from hydrogen, deuterium, and halogen; preferably, R ₄ is selected from halogen; more preferably, R ₄ is selected from Cl, and Br.

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -5), R ₅ is selected from hydrogen, deuterium, and halogen; preferably, R ₅ is selected from hydrogen and deuterium.

In some embodiments, in the above formulae (I ₄ -1) to (I ₄ -5), R ₆ is selected from hydrogen, deuterium, and halogen; preferably, R ₆ is selected from hydrogen and deuterium.

In some embodiments, in the above formulas (I ₄ -1)-(I ₄ -5), R ₇ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; preferably, R ₇ is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; more preferably, R ₇ is C1-C6 alkyl, deuterated C1-C6 alkyl; most preferably, R ₇ is isopropyl, and isopropyl in which any hydrogen atom is deuterated;

In some embodiments, in the above formula (I ₄ -1) and/or (I ₄ -3), R ₈ is hydrogen;

In some embodiments, in the above formulae (I ₄ -1)-(I ₄ -2) and/or (I ₄ -4)-(I ₄ -5), R ₈ is selected from in,

The above _n1 is selected from 1, 2, and 3; preferably, _n1 is selected from 1, and 2; more preferably, _n1 is 1;

_Ra1 and _Ra2 are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, and the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, _Ra1 and _Ra2 are independently selected from hydrogen, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, _Ra1 and _Ra2 are both hydrogen, or _Ra1 and _Ra2 are both deuterium;

R _b1 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, The substituents are deuterium, and fluorine; preferably, R _b1 is selected from C1-C6 alkyl substituted or unsubstituted by deuterium, fluorine, and Wherein, the above R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl, preferably, R _c1 and R _c2 are both hydrogen;

R _b2 is selected from the following groups which are substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, and the substituent is deuterium or fluorine; preferably, R _b2 is selected from C1-C6 alkyl which is substituted or unsubstituted by deuterium or fluorine.

Regulation,

When L is O, R _b1 is selected from the group consisting of: or the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

When L is O, R _b2 is selected from the following groups substituted by one or more deuterium or fluorine: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

In some embodiments, the novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof provided by the present invention is selected from the following compounds:

In another aspect, the present invention provides a pharmaceutical composition comprising the novel pyridazine compound, its tautomer, stereoisomer, isotopic derivative or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides use of the above-mentioned novel pyridazine compounds, tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions for preparing drugs for preventing or treating thyroid hormone receptor-related diseases.

In another aspect, the present invention provides the above-mentioned novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use in preventing or treating thyroid hormone receptor-related diseases.

In another aspect, the present invention provides a method for preventing or treating thyroid hormone receptor-related diseases, comprising administering a therapeutically effective amount of the novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual in need thereof.

The present invention provides the use or method of the above-mentioned pharmaceutical composition for preparing a drug for preventing or treating thyroid hormone receptor-related diseases, wherein the thyroid hormone receptor-related diseases prevented or treated are obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia, and fatty liver lesions.

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

The compounds disclosed in the present invention have better and highly selective THRβ agonistic effect.

The compounds disclosed in the present invention have better pharmacokinetic properties. When administered by oral gavage, the half-life is extended by about 1.5 times, the peak time is shortened by about 1.5 times, the exposure amount is increased by more than 2 times, the residence time is extended by more than 1.6 times, the bioavailability is increased by more than 1.5 times, and there are obvious enterohepatic circulation characteristics.

The compounds disclosed in the present invention show more excellent efficacy in reducing liver index, reducing liver TC and TG, reducing liver fibrosis ratio, and reducing NAS score in the NASH mouse model.

definition:

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

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

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

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

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

The term "alkenyl" refers to an aliphatic hydrocarbon group containing an unsaturated carbon-carbon double bond, including straight-chain and branched groups. The alkyl group may be substituted or unsubstituted. The carbon-carbon double bond may be one or more.

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

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two.

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

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

The term "hydroxy" refers to the -OH group.

The term "amino" refers to a _-NH2 group.

The term "carboxy" refers to a -COOH group.

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

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

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

Numeric ranges mentioned in this application, such as "C1-C6", mean that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the drug administration curve after intragastric administration.

Figure 2 shows the results of liver TC.

Figure 3 shows the results of liver TG.

Figure 4 shows the NAS scoring results.

FIG5 shows the results of fibrosis evaluation.

DETAILED DESCRIPTION

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

Example 1: Synthesis of ZJT1 in Compound

Reaction:

Preparation method:

Step 1: Preparation of compound ZJT1-03:

Under nitrogen protection, at room temperature, 3,6-dichloro-4-isopropylpyridazine (3.82g, 0.02mol) was dissolved in dimethyl sulfoxide (25mL), and then 2,6-dichloro-4-aminophenol (3.56g, 0.02mol), anhydrous potassium carbonate (13.8g, 0.1mol) and cuprous iodide (3.81g, 0.02mol) were added to the above system in sequence. The reaction mixture was reacted at 90°C for 24 hours, then cooled to room temperature and poured into water (750mL). The pH was adjusted to 7-8 with 1N dilute hydrochloric acid, and then ethyl acetate was added and stirred thoroughly. The system was filtered with diatomite, and the filter cake was washed with ethyl acetate. The filtrate was refined and separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate twice again, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound ZJT1-03 (3.15g) with a yield of 47.4%. ESI-MS (+): m/z = 332.03.

Step 2: Preparation of compound ZJT1-02:

Add glacial acetic acid (100 mL) to the reaction bottle, then add compound ZJT1-03 (3.0 g, 9.0 mmol) and sodium acetate (2.21 g, 27.0 mmol) in sequence under stirring at room temperature. After the addition is complete, heat the system to 100 ° C for 24 h, then cool to room temperature for 2 days. Concentrate the system, dilute the residue with water, and then adjust the pH of the system to 9 with 1N sodium hydroxide. Extract the system twice with ethyl acetate, adjust the pH of the aqueous phase to 5 with concentrated hydrochloric acid, and then extract it again with ethyl acetate twice. Combine all the layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was diluted with methanol, 1N sodium hydroxide (63 mL, 63 mmol) was added, heated to 120°C for 24 hours, then cooled and concentrated, an appropriate amount of purified water was added to the residue, extracted twice with ethyl acetate, the organic phases were combined, washed twice with dilute hydrochloric acid aqueous solution and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column to obtain compound ZJT1-02 (1.29 g), with a yield of 45.6%. ESI-MS (+): m/z = 314.08.

Step 3: Preparation of compound ZJT1-01:

Compound ZJT1-02 (1.2 g, 3.82 mmol) was added to water (65 mL), and then concentrated hydrochloric acid (25 mL) was added. The reaction mixture was cooled to 0 ° C, and an aqueous solution (2.5 mL) containing sodium nitrite (0.34 g, 4.97 mmol) was slowly added, and then the above system was stirred at 0 ° C for 30 minutes. Then the above reaction solution was quickly filtered and the filtrate was quickly added to a mixed solution of N-cyanoacetylurea (0.66 g, 4.23 mmol), water (100 mL) and pyridine (25 mL) precooled to 0 ° C. After the addition was completed, it was stirred at 0 ° C for 30 minutes, filtered, and the filter cake was rinsed with water and petroleum ether in turn, and purified by column to obtain compound ZJT1-01 (0.85 g) with a yield of 46.2%. ESI-MS (+): m/z = 481.10.

Step 4: Preparation of compound ZJT1:

At room temperature, compound ZJT1-01 (0.70 g, 1.45 mmol) was added to glacial acetic acid (15 mL), and then sodium acetate (0.6 g, 7.25 mmol) was added. The reaction mixture was heated to 120 ° C and maintained for 1.5 hours, and then cooled to 0 ° C. The system was diluted with water and stirred for 30 minutes. Filtered, the filter cake was dissolved in hot acetonitrile and decolorized with activated carbon, filtered with diatomaceous earth, rinsed, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixed solution of water and acetonitrile, filtered, and dried to obtain compound ZJT1 (0.35 g), with a yield of 55.5%. ESI-MS (+): m/z = 435.08. ¹ H NMR (400MHz, DMSO-d6) δ 13.206 (brs, 1H), 12.255 (s, 1H), 7.786 (s, 2H), 7.461 (s, 1H), 3.067 (m, 1H), 1.185 (d, J = 6.91Hz, 6H).

Example 2: Synthesis of compound ZJT2

Reaction:

Preparation method:

Under nitrogen protection, compound ZJT1 (0.87 g, 2.0 mmol) was dissolved in tetrahydrofuran (50 mL), potassium carbonate (1.38 g, 10 mmol) was added, and then formaldehyde aqueous solution (35-40%, 1.0 g) was slowly added, and the temperature was raised to 55°C for 8 h. The reaction was complete when detected by TLC. The system was concentrated, water and dichloromethane were added, shaken, separated, the aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified and separated by column to obtain compound ZJT2 (0.33 g) with a yield of 35.4%. ESI-MS (+): m/z=465.07.

Example 3: Synthesis of compound ZJT3

Reaction:

Preparation method:

Step 1: Preparation of compound ZJT3-01

In a reaction flask, ZJT1 (0.87 g, 2.0 mmol), p-toluenesulfonic acid pyridinium salt (70 mg, 0.28 mmol) and 3,4-dihydro-2H-pyran were added to 1,4-dioxane (20 mL) in sequence. After the addition was completed, the temperature was raised to 65°C for reaction for 16 hours, and then concentrated under reduced pressure. The residue was separated by liquid phase preparation to obtain compound ZJT3-01 (0.53 g) with a yield of 51.0%. ESI-MS (+): m/z = 519.14.

Step 2: Preparation of compound ZJT3

The compound ZJT3 (0.24 g) was obtained by referring to the operation procedure of Example 2 with a yield of 30.1%. ESI-MS (+): m/z = 549.15.

Example 4: Synthesis of Compound NASH161-01

Reaction:

Preparation method:

In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added to dichloromethane (10 mL) in sequence, and then a dichloromethane (5 mL) solution of NASH161-01-SM (0.16 g, 1 mmol) was added dropwise at 0°C, and the temperature was maintained and stirred for 5 hours. The system was concentrated under reduced pressure, and the residue was purified by column to obtain compound NASH161-01 (0.18 g) with a yield of 30.7%. ESI-MS (+): m/z = 586.10.

Example 5: Synthesis of Compound NASH161-02

Reaction:

Preparation method:

Step 1: Preparation of compound NASH161-0201

Toluene (10 mL), NASH161-02-SM (0.29 g, 1.2 mmol) and 2 drops of N,N-dimethylformamide were added to the reaction flask in sequence, and then thionyl chloride (0.22 g, 1.8 mmol) was added dropwise at room temperature. After the addition was completed, the reaction was carried out at 70 ° C for 1 hour, the system was cooled and concentrated under reduced pressure. Toluene was added to the residue again and the residue was concentrated under reduced pressure to remove excess thionyl chloride. The residue was compound NASH161-0201, which was used directly in the next step without treatment.

Step 2: Preparation of compound NASH161-02

In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added to dichloromethane (10 mL) in sequence, and then a dichloromethane (5 mL) solution containing NASH161-0201 (1.2 mmol, the yield in the previous step was 100%) was added dropwise at 0°C, and the reaction was stirred for 5 hours while maintaining the temperature. The system was concentrated under reduced pressure, and the residue was purified by column to obtain compound NASH161-02 (0.19 g) with a yield of 27.7%. ESI-MS (+): m/z = 685.17.

Example 6: Synthesis of Compound NASH161-03

Reaction:

Preparation method:

Referring to the operating procedure of Example 4, NASH161-03-SM was used to replace NASH161-01-SM to prepare compound NASH161-03 (0.21 g) with a yield of 32.8%. ESI-MS (+): m/z = 601.05.

Example 7: Synthesis of Compound NASH161-04

Reaction:

Preparation method:

Step 1: Preparation of compound NASH161-0401

Toluene (10 mL), 3-sulfopropionic acid (0.19 g, 1.2 mmol) and 2 drops of N,N-dimethylformamide were added to the reaction flask in sequence, and then thionyl chloride (0.22 g, 1.8 mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 55 °C for 30 minutes, the system was cooled and concentrated under reduced pressure. Toluene was added to the residue again and the mixture was concentrated under reduced pressure to remove excess thionyl chloride. The residue was compound NASH161-0401, which was used directly in the next step without further treatment.

Step 2: Preparation of compound NASH161-04

In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added to dichloromethane (10 mL) in sequence, and then a dichloromethane (5 mL) solution of NASH161-0401 (1.2 mmol, the yield of the previous step was 100%) was added dropwise at 0°C, and the temperature was maintained and stirred for 6 hours. The system was concentrated under reduced pressure, and the residue was purified by column to obtain compound NASH161-04 (0.14 g) with a yield of 23.3%. ESI-MS (+): m/z = 601.07.

Example 8: Synthesis of Compound NASH161-09

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-0906

At room temperature, acetonitrile (10 mL), sulfolane (30 mL), water (60 mL), 3,6-dichloropyridazine (4.4 g, 29.7 mmol), isobutyric acid-D6 deuterated (2.8 g, 29.7 mmol) and silver nitrate (2.53 g, 14.9 mmol) were added to the reaction bottle in sequence. After the addition was completed, the temperature was raised to 55°C, and a solution of concentrated sulfuric acid (4.8 mL) in water (15 mL) was added, and then a solution of ammonium persulfate (10.2 g, 44.6 mmol) in water (15 mL) was added dropwise over 40 minutes. After the addition was completed, the temperature was raised to 70°C for reaction for 20 minutes, and then the temperature was lowered to room temperature, and the reaction was stirred at room temperature for 24 hours. The system was cooled to 0°C, the pH was adjusted to 8 with aqueous ammonia, the solution was diluted with water and filtered, the filter cake was rinsed with ethyl acetate, the filtrate was allowed to stand to separate the organic phase, and then extracted twice with ethyl acetate, the organic phases were combined, washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column to obtain compound NASH161-0906 (3.98 g), with a yield of 68.0%. ESI-MS (+): m/z = 197.08.

Step 2-Step 5 were prepared by referring to the operating procedures of Example 1 to obtain compound NASH161-0902 (0.48 g) with an overall yield of 6.2%. ESI-MS (+): m/z=441.11.

Example 9: Synthesis of Compound NASH161-13

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-1301

Referring to the operation procedure of Example 4, ZJT3 was used to replace ZJT2 to prepare compound NASH161-1301 (0.76 g) with a yield of 31.7%. ESI-MS (+): m/z = 670.18.

Step 2: Synthesis of compound NASH161-13

Compound NASH161-1301 (0.67 g, 1.0 mmol) and dichloromethane (50 mL) were added to the reaction flask in sequence, and trifluoroacetic acid (7 mL) was then added dropwise to the above solution. After the addition, the reaction solution was reacted at room temperature for 6 hours, then quenched and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain the target compound NASH161-13 (0.21 g) with a yield of 35.8%. ESI-MS (+): m/z = 586.11.

Example 10: Synthesis of Compound NASH161-14

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-1401

Referring to the operation procedure of step 2 in Example 5, ZJT3 was used to replace ZJT2 to prepare compound NASH161-1401 (0.54 g) with a yield of 28.8%. ESI-MS (+): m/z = 769.24.

Step 2: Synthesis of compound NASH161-14

Referring to the operation procedure of step 2 in Example 9, NASH161-1401 was used to replace NASH161-1301 to prepare compound NASH161-14 (0.16 g) with a yield of 38.2%. ESI-MS (+): m/z = 685.19.

Example 11: Synthesis of Compound NASH161-15

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-1501

Referring to the operation procedure in Example 6, ZJT3 was used to replace ZJT2 to prepare compound NASH161-1501 (0.43 g) with a yield of 26.7%. ESI-MS (+): m/z = 685.11.

Step 2: Synthesis of compound NASH161-15

Referring to the operation procedure of step 2 in Example 9, NASH161-1501 was used to replace NASH161-1301 to prepare compound NASH161-15 (0.22 g) with a yield of 36.5%. ESI-MS (+): m/z = 601.08.

Example 12: Synthesis of Compound NASH161-16

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-1601

Referring to the operation procedure of step 2 in Example 7, ZJT3 was used to replace ZJT2 to prepare compound NASH161-1601 (0.43 g) with a yield of 26.7%. ESI-MS (+): m/z=685.11.

Step 2: Synthesis of compound NASH161-16

Referring to the operation procedure of step 2 in Example 9, NASH161-1601 was used to replace NASH161-1301 to prepare compound NASH161-16 (0.36 g) with a yield of 32.8%. ESI-MS (+): m/z=601.05.

Example 13: Synthesis of Compound NASH161-26

Reaction:

Preparation method:

Under argon protection, Lawesson's reagent (14.2 g, 35 mmol) was added to a solution of ZJT1 (4.35 g, 10 mmol) in anhydrous toluene (200 mL) at room temperature, and the reaction was heated to 110°C for 5 hours. The reaction was completed by TLC tracking, and the reaction was cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was separated and purified by a silica gel column to obtain compound NASH161-26 (2.7 g) with a yield of 55.9%. ESI-MS (+): m/z = 482.99.

Example 14: Synthesis of Compound NASH161-29

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH161-2901

Referring to the operation procedure in Example 2, NASH161-26 was used to replace ZJT2 to prepare compound NASH161-2901 (0.61 g) with a yield of 30.1%. ESI-MS (+): m/z = 512.91.

Step 2: Synthesis of compound NASH161-29

Referring to the operation procedure of step 2 in Example 5, NASH161-2901 was used to replace ZJT2 to prepare compound NASH161-29 (0.21 g) with a yield of 25.2%. ESI-MS (+): m/z = 733.11.

Example 15: Synthesis of Compound NASH161-36

Reaction:

Preparation method:

Step 1-Step 2: Preparation of compound NASH161-3602

Referring to the operation procedure of Example 3, NASH161-29 was used to replace ZJT1 to prepare compound NASH161-3602 (0.98 g) with a total yield of 17.3%. ESI-MS (+): m/z = 597.09.

Step 3: Preparation of compound NASH161-3601

Referring to the operation procedure of step 2 in Example 5, ZNASH161-3602 was used to replace ZJT2 to prepare compound NASH161-3601 (0.46 g) with a yield of 25.7%. ESI-MS (+): m/z=817.16.

Step 4: Preparation of compound NASH161-36

Referring to the operation procedure of step 2 in Example 9, NASH161-3601 was used to replace NASH161-1301 to prepare compound NASH161-36 (0.37 g) with a yield of 33.3%. ESI-MS (+): m/z = 733.11. The yield was 40.8%.

ESI-MS (+): m/z = 287.15.

Example 16: Synthesis of ZJT1 in Compound

Reaction:

Preparation method:

Step 1: Preparation of compound ZJT1-03:

Under nitrogen protection, at room temperature, 3,6-dichloro-4-isopropylpyridazine (3.82g, 0.02mol) was dissolved in dimethyl sulfoxide (25mL), and then 2,6-dichloro-4-aminophenol (3.56g, 0.02mol), anhydrous potassium carbonate (13.8g, 0.1mol) and cuprous iodide (3.81g, 0.02mol) were added to the above system in sequence. The reaction mixture was reacted at 90°C for 24 hours, then cooled to room temperature and poured into water (750mL). The pH was adjusted to 7-8 with 1N dilute hydrochloric acid, and then ethyl acetate was added and stirred thoroughly. The system was filtered with diatomite, and the filter cake was washed with ethyl acetate. The filtrate was refined and separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate twice again, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound ZJT1-03 (3.37g) with a yield of 50.7%. ESI-MS (+): m/z = 332.08.

Step 2: Preparation of compound ZJT1-02:

Add glacial acetic acid (100 mL) to the reaction bottle, then add compound ZJT1-03 (3.3 g, 9.9 mmol) and sodium acetate (2.43 g, 29.7 mmol) in sequence under stirring at room temperature. After the addition is complete, the system is heated to 100 ° C for 24 hours, and then cooled to room temperature for 2 days. The system is concentrated, the residue is diluted with water, and then the pH of the system is adjusted to 9 with 1N sodium hydroxide. The system is extracted with ethyl acetate twice, the aqueous phase is adjusted to pH 5 with concentrated hydrochloric acid, and then extracted with ethyl acetate twice again, all organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol, 1N sodium hydroxide (63 mL, 65 mmol) was added, heated to 120°C for 24 hours, then cooled and concentrated, an appropriate amount of purified water was added to the residue, extracted twice with ethyl acetate, the organic phases were combined, washed twice with dilute hydrochloric acid aqueous solution and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column to obtain compound ZJT1-02 (1.62 g), with a yield of 52.0%. ESI-MS (+): m/z = 314.11.

Step 3: Preparation of compound ZJT1-01:

Compound ZJT1-02 (1.6 g, 5.08 mmol) was added to water (90 mL), and then concentrated hydrochloric acid (35 mL) was added. The reaction mixture was cooled to 0 ° C, and an aqueous solution (3.5 mL) containing sodium nitrite (0.45 g, 6.61 mmol) was slowly added, and then the above system was stirred at 0 ° C for 30 minutes. Then the above reaction solution was quickly filtered and the filtrate was quickly added to a mixed solution of N-cyanoacetylurea (0.88 g, 5.63 mmol), water (130 mL) and pyridine (35 mL) precooled to 0 ° C. After the addition was completed, it was stirred at 0 ° C for 30 minutes, filtered, and the filter cake was washed with water and petroleum ether in turn, and purified by column to obtain compound ZJT1-01 (1.16 g) with a yield of 47.3%. ESI-MS (+): m/z = 481.12.

Step 4: Preparation of compound ZJT1:

At room temperature, compound ZJT1-01 (1.10 g, 2.28 mmol) was added to glacial acetic acid (25 mL), and then sodium acetate (0.94 g, 11.38 mmol) was added. The reaction mixture was heated to 120 ° C and maintained for 1.5 hours, and then cooled to 0 ° C. The system was diluted with water and stirred for 30 minutes. Filtered, the filter cake was dissolved in hot acetonitrile and decolorized with activated carbon, filtered with diatomaceous earth, rinsed, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixed solution of water and acetonitrile, filtered, and dried to obtain compound ZJT1 (0.58 g), with a yield of 58.3%. ESI-MS (+): m/z = 435.06. ¹ H NMR (400MHz, DMSO-d6) δ 13.210 (brs, 1H), 12.283 (s, 1H), 7.825 (s, 2H), 7.502 (s, 1H), 3.106 (m, 1H), 1.226 (d, J = 6.91Hz, 6H).

Example 17: Synthesis of Compound ZJT2A

Reaction:

Preparation method:

Under nitrogen protection, compound ZJT1 (1.74 g, 4.0 mmol) was dissolved in tetrahydrofuran (100 mL), cesium carbonate (6.52 g, 20 mmol) was added, and then formaldehyde aqueous solution (35-40%, 2.0 g) was slowly added, and the temperature was raised to 55°C for 8 h. The reaction was complete by TLC detection, and the system was concentrated, water and dichloromethane were added, shaken, and separated. The aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated by liquid preparation to obtain compound ZJT2A (0.89 g) with a yield of 47.8%. ESI-MS (+): m/z = 465.11.

Example 18: Synthesis of Compound NASH179-01

Reaction:

Preparation method:

Step 1: Preparation of chloromethyl (methyl-d3) carbonate

In a reaction flask, deuterated methanol (1.75 g, 50.0 mol) and triethylamine (6.1 g, 60 mmol) were added to dichloromethane (50 mL), the solution was cooled to 0°C, and then chloromethyl chloroformate (6.4 g, 50 mmol) was slowly added dropwise to the above solution, and then reacted at room temperature for 3 h. After the reaction was complete, water (12 mL) was quenched, and dichloromethane (25 mL) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target product (4.6 g) with a yield of 72.1%.

Step 2: Preparation of compound NASH179-0102

Compound ZJT1 (0.60 g, 1.38 mmol), 4-methylbenzenesulfonic acid pyridinium salt (PPTs, 50.3 mmol, 0.20 mmol), 3,4-dihydropyran (DHP, 0.47 g, 5.59 mmol) and 1,4-dioxane (10 mL) were added to the Schlenk tube in sequence. After the addition was completed, the reaction solution was heated to 65°C and reacted at this temperature for 18 hours. The temperature was lowered and the mixture was concentrated under reduced pressure. The residue was purified by liquid phase preparation to obtain compound NASH179-0102 (0.37 g) with a yield of 51.7%. ESI-MS (+): m/z = 519.16.

Step 3: Preparation of compound NASH179-0101

Compound NASH179-0102 (0.35 g, 0.67 mmol) and N,N-dimethylformamide (15 mL) were added to the reaction flask, followed by sodium hydride (0.04 g, 1.67 mmol). The resulting mixture was stirred for 10 minutes and then chloromethyl (methyl-d3) carbonate (0.13 g, 1.00 mmol) was added dropwise. After the addition, the reaction solution was heated to 55 ° C and maintained at the temperature for 18 hours. The system was quenched with water and then purified by preparative liquid phase to obtain compound NASH179-0101 (156 mg) with a yield of 38.0%. ESI-MS (+): m/z = 610.17.

Step 4: Preparation of compound NASH179-01

Compound NASH179-0101 (155 mg, 0.25 mmol) and dichloromethane (15 mL) were added to the reaction flask, followed by dropwise addition of trifluoroacetic acid (TFA, 1.5 mL). After addition, the reaction was continued for 5 hours. After the system was quenched, it was concentrated under reduced pressure, and the residue was purified by preparative liquid phase to obtain compound NASH179-01 (37.9 mg) with a yield of 28.8%. ESI-MS (+): m/z = 526.22.

Example 19: Synthesis of compounds NASH179-03 and NASH179-05

Reaction:

Preparation method:

Compound ZJT1 (0.60 g, 1.38 mmol), cesium carbonate (0.88 g, 2.70 mmol), chloromethyl (methyl-d3) carbonate (0.35 g, 2.70 mmol) and N, N-dimethylformamide (30 mL) were added to the reaction bottle in sequence, and the reaction solution was reacted at room temperature for 23 hours. The crude product was purified by preparative liquid phase to obtain two compounds: compound NASH179-03 (23 mg, 31.7%), ESI-MS (+): m/z = 526.13; compound NASH179-05 (21 mg, 28.9%), ESI-MS (+): m/z = 526.18.

Example 20: Synthesis of Compound NASH179-13

Reaction:

Preparation method:

Step 1: Preparation of deuterated isobutyryl chloride-D6

Isobutyric acid-D6 deuterated (0.13 g, 1.38 mmol) was added to dichloromethane (10 mL), and then thionyl chloride (0.33 g, 2.76 mmol) was slowly dropped in. After the addition was complete, the mixture was reacted at room temperature for 2 hours, and concentrated under reduced pressure. The residue was used directly.

Step 2: Preparation of compound NASH179-13

Into the reaction flask, dichloromethane (20 mL), compound ZJT2 (0.64 g, 1.38 mmol), triethylamine (0.88 g, 2.70 mmol) were added in sequence, and then a dichloromethane solution (5 mL) containing deuterated isobutyryl chloride-D6 (0.16 g, 1.38 mmol, the yield in the previous step is 100%) was added dropwise at 0°C. The temperature was maintained and stirred for 5 hours. The system was concentrated under reduced pressure and the residue was purified by column to obtain compound NASH179-13 (0.20 g, 26.9%), ESI-MS (+): m/z = 541.19.

Example 21: Synthesis of Compound NASH179-19

Reaction:

Preparation method:

Step 1: Preparation of trimethylacetyl chloride-D9

Add trimethylacetic acid-D9 (0.15 g, 1.38 mmol) to dichloromethane (10 mL), and then slowly drop thionyl chloride (0.33 g, 2.76 mmol). After the addition is complete, react at room temperature for 2 hours, concentrate under reduced pressure, and use the residue directly.

Step 2: Preparation of compound NASH179-19

Into the reaction flask, dichloromethane (20 mL), compound ZJT2 (0.64 g, 1.38 mmol), triethylamine (0.88 g, 2.70 mmol) were added in sequence, and then a dichloromethane solution (5 mL) containing trimethylacetyl chloride-D9 (1.38 mmol, the yield in the previous step is 100%) was added dropwise at 0°C. The temperature was maintained and stirred for 5 hours. The system was concentrated under reduced pressure and the residue was purified by column to obtain compound NASH179-19 (0.23 g, 29.8%), ESI-MS (+): m/z = 558.25.

Example 22: Synthesis of Compound NASH179-24

Reaction:

Preparation method:

Step 1: Preparation of compound NASH179-2407

At room temperature, the starting material NASH179-24-SM1 (4.5 g, 0.03 mol) was added to a mixed solution of acetonitrile (7 mL), sulfolane (21 mL) and water (49 mL), and then isobutyric acid (2.8 g, 0.03 mol) and silver nitrate (2.6 g,

0.0153mol). The system was heated to 55°C, and a solution of concentrated sulfuric acid (4.8mL) in water (15mL) was added, followed by a solution of ammonium persulfate (10.4g, 0.044mol) in water (15mL), which was added dropwise within 30 minutes. The system was heated to 70°C, reacted for 15 minutes, then cooled to room temperature, and continued to react at room temperature for 24 hours. The system was then cooled to 0°C, and the pH was slowly adjusted to 8 with aqueous ammonia (20mL). The resulting mixture was diluted with water (100mL) and filtered. The filter cake was washed with ethyl acetate (100mL). The organic phase was collected, and the aqueous phase was extracted twice with ethyl acetate (100mL). The organic phases were combined, washed with water (40mL) and saturated brine (40mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound (1.758g) with a yield of 62%. ESI-MS (+): m/z = 191.21.

Step 2: Preparation of compound NASH179-2406

At 25°C, 4-amino-2,6-dichloro-benzenethiol (1.5 g, 7.8 mmol) was added to N,N-dimethylformamide, and then compound NASH179-2407 (1.485 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol) were added. The system was heated to 90°C and reacted for 18 hours. Subsequently, the system was cooled to 25°C, poured into a mixture of ice water and 1N aqueous hydrochloric acid solution (15 mL), and then adjusted to pH = 7 with 1N aqueous hydrochloric acid solution, and then extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound NASH179-2406 (1.74 g) with a yield of 65%. ESI-MS (+): m/z = 347.91.

Step 3: Preparation of compound NASH179-2405

Compound NASH179-2406 (1.476 g, 4.2 mmol) was added to glacial acetic acid (40 mL), followed by sodium acetate (1.2 g, 14.7 mmol). The system was heated to 95 ° C and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, poured into water (150 mL), and neutralized with 3N sodium hydroxide aqueous solution. Then it was extracted twice with ethyl acetate (150 mL). The combined organic matter was washed with saturated sodium chloride aqueous solution (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH179-2405 (1.51 g) with a yield of 96%. It was an off-white solid and was used directly in the next step without further purification. ESI-MS (+): m/z = 372.15.

Step 4: Preparation of compound NASH179-2404

Compound NASH179-2405 (1.0 g, 2.675 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), and powdered sodium hydroxide (0.535 g, 13.375 mmol) was added. The system was then heated to reflux and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH179-2404 (0.857 g) with a yield of 97%, as a light brown solid. The compound was used directly in the next step without further purification. ESI-MS (+): m/z = 330.23.

Step 5: Preparation of compound NASH179-2403

Concentrated hydrochloric acid (8.4 mL) was added to a suspension of compound NASH179-2404 (402 mg, 1.26 mmol) in water (16 mL). The system was then cooled to 0°C, and a solution of sodium nitrite (109.5 mg, 1.587 mmol) in water (3 mL) was added. The system was then stirred at 0°C for 30 minutes, filtered, and quickly added to a mixed solution of N-cyanoacetylurea (216 mg, 1.38 mmol), water (30 mL), and pyridine (10 mL) pre-cooled to 0°C. The resulting suspension was stirred at 0°C for 30 minutes and then filtered. The filter cake was washed with water and petroleum ether in turn. The target product (311 mg) was obtained by vacuum drying at 80°C for 12 h, with a yield of 51%. ESI-MS (+): m/z = 497.23.

Step 6: Preparation of compound NASH179-2402

At room temperature, compound NASH179-2403 (300 mg, 0.604 mmol) was added to glacial acetic acid (5 mL) solution, and then sodium acetate (0.25 g, 3 mmol) was added. The system was then heated to 120°C and reacted for 1.5 hours. The system was then cooled to 0°C, diluted with water (20 mL), and stirred for 30 minutes. After filtering, the filter cake was washed with water and petroleum ether in turn, and then placed in a forced air drying oven. After drying for 60 minutes, it was slurried with a mixed solution of acetonitrile and water to obtain the target product (0.138 g) with a yield of 51%. ESI-MS (+): m/z = 451.34.

Step 7: Preparation of compound NASH179-2401

Compound NASH179-2402 (1.0 g, 2.3 mmol) was added to methanol (20 mL), and then 37% formaldehyde aqueous solution (3.75 mL, 50.36 mmol) was added. Subsequently, the system was heated to 100 ° C and reacted for 18 hours. Then, the system was cooled to 25 ° C and poured into water (20 ml). The precipitate was precipitated, filtered and collected, the filter cake was washed with water, and placed in a vacuum drying oven to obtain compound NASH179-2401 (952 mg) with a yield of 89%, as a light yellow solid. ESI-MS (+): m/z = 481.25.

Step 8: Preparation of compound NASH179-24

Compound NASH179-2401 (100 mg, 0.225 mmol) was added to dichloromethane (5 mL), followed by N,N-diisopropylethylamine (0.115 mL, 0.645 mmol) and 4-N,N-dimethylaminopyridine (12.9 mg, 0.105 mmol), and then the system was cooled to 0°C, and methyl chloroformate-D3 (23.98 mg, 0.245 mmol) was added. The system was slowly heated to 25°C and reacted for 3.5 hours. Then the system was heated to 40°C and stirred overnight. Subsequently, the system was cooled to 25°C, poured into water (100 mL), extracted with dichloromethane (100 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 ml), washed with water (100 ml), washed with saturated sodium chloride (100 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound NASH179-24 (35.3 mg) with a yield of 29%. It was a yellow solid. ESI-MS (+): m/z = 542.33.

Example 23: Synthesis of Compounds NASH179-38 and NASH179-39

Reaction:

Preparation method:

NASH179-2402 (120 mg, 0.266 mmol) was added to N, N-dimethylformamide (8 mL), followed by cesium carbonate (173 mg, 0.532 mmol) and dimethyl chloromethyl carbonate (36.4 mg, 0.292 mmol). The system was reacted at room temperature for 20 hours. The crude product was separated by preparative liquid phase to obtain two compounds: compound NASH179-38 (32.5 mg), yield 23%, ESI-MS (+): m/z = 539.34; NASH179-39 (17 mg), yield 12%, ESI-MS (+): m/z = 539.23.

Example 24: Synthesis of Compound NASH179-47

Reaction:

Preparation method:

Compound NASH179-2401 (150 mg, 0.311 mmol) was added to dichloromethane (8 mL), followed by N,N-diisopropylethylamine (0.166 mL, 0.933 mmol) and 4-N,N-dimethylaminopyridine (19 mg, 0.155 mmol), then the system was cooled to 0°C, and trifluoroacetyl chloride (45.3 mg, 0.342 mmol) was added. The system was slowly heated to 25°C and reacted for 3.5 hours. Then the system was heated to 40°C and stirred overnight. Subsequently, the system was cooled to 25°C, poured into water (30 mL), extracted with dichloromethane (30 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (30 mL), washed with water (30 mL), washed with saturated sodium chloride (30 mL), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound NASH179-47 (48.3 mg) with a yield of 27%. ESI-MS (+): m/z = 577.18.

Example 25: Synthesis of Compounds NASH179-50 and NASH179-51

Reaction:

Preparation method:

NASH179-2402 (200 mg, 0.46 mmol) was added to N, N-dimethylformamide (10 mL), followed by cesium carbonate (186 mg, 0.575 mmol) and 1-chloroethyl isopropyl carbonate (72 mg, 0.43 mmol). The system was reacted at room temperature for 20 hours. The crude product was separated by preparative liquid phase to obtain two compounds: compound NASH179-50 (48.6 mg), yield 19%, ESI-MS (+): m/z = 581.36; NASH179-51 (31.8 mg), yield 12%, ESI-MS (+): m/z = 581.27.

Example 26: Synthesis of Compound NASH179-52

Reaction:

Preparation method:

Compound ZJT1 (0.44 g, 1.0 mmol) (0.35 g, 0.67 mmol) and N, N-dimethylformamide (15 mL) were added to the reaction flask. After dissolution, sodium hydride (0.06 g, 2.50 mmol) (0.04 g, 1.67 mmol) was added. The resulting mixture was stirred for 15 minutes and then chloromethyl (methyl-d3) carbonate (0.26 g, 2.00 mmol) was added dropwise. After the addition, the reaction solution was heated to 60 ° C and maintained at the temperature for 24 hours. The system was quenched with water and then purified by preparative liquid phase to obtain compound NASH179-52 (157 mg) with a yield of 25%. ESI-MS (+): m/z = 617.38.

Example 27: Synthesis of Compound NASH179-55

Reaction:

Preparation method:

Step 1: Preparation of compound NASH179-5504

In a reaction flask, NASH179-55-SM1 (1.39 g, 6.0 mmol) and NASH179-55-SM2 (1.33 g, 6.0 mmol) were dissolved in tetrahydrofuran (THF, 20 mL), N-methylmorpholine (NMM, 0.73 g, 7.2 mmol) was added, stirred and cooled to about 0°C in an ice-water bath, N-hydroxysuccinimide (HOSu, 0.69 g, 6.0 mmol) and N, N'-dicyclohexylcarbodiimide (DCC, 1.24 g, 6.0 mmol) were added, and stirring and ice-water bath were continued at 0°C for 3 hours, then the ice bath was removed and stirred overnight. The THF solvent was removed by rotary evaporation, ethyl acetate (EA, 15 mL) was added to dissolve the turbid oil, and the white insoluble matter was removed by filtration. The EA solution was washed with 10% citric acid solution, saturated brine, 4% NaHCO3 solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue, compound NASH179-5504, was used directly without further treatment.

Step 2: Preparation of compound NASH179-5503

The above-mentioned reserve compound NASH179-5504 was dissolved in dichloromethane (20 mL), acetic acid (1.0 mL) and 10% palladium carbon (1.0 g) were added, and hydrogen was introduced. The reduction reaction was carried out at room temperature for 1.5 hours, the system was filtered through diatomaceous earth, a large amount of dichloromethane was eluted, the filtrate was evaporated to dryness under reduced pressure, and the residue was passed through a column to obtain compound NASH179-5503 (1.2 g), with a yield of 58%. ESI-MS (-): m/z = 344.21.

Step 3: Preparation of compound NASH179-5502

Under nitrogen protection, compound NASH179-0102 (2.08 g, 4.0 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (0.48 g, 20 mmol) was added, and then formaldehyde aqueous solution (35-40%, 2.0 g) was slowly added, and the temperature was raised to 55°C for reaction for 8 h. The reaction was complete by TLC detection, and the system was concentrated, water and dichloromethane were added, shaken, separated, and the aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column to obtain compound NASH179-5502 (1.0 g), with a yield of 45.5%. ESI-MS (+): m/z=549.36.

Step 4: Preparation of compound NASH179-5501

In a reaction flask, compound NASH179-5502 (1.0 g, 1.83 mmol) and compound NASH179-5503 (0.63 g, 1.83 mmol) were added to THF (20 mL), NMM (0.22 g, 2.2 mmol) was added, stirred and cooled to about 0°C in an ice-water bath, HOSu (0.21 g, 1.83 mmol) and DCC (0.38 g, 1.83 mmol) were added, stirring and ice-water bath were continued for 3 hours, then the ice bath was removed and stirred overnight. The THF solvent was removed by rotary evaporation, ethyl acetate was added, and the mixture was washed with 10% citric acid solution, saturated brine, 4% NaHCO3 solution and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was the crude product of compound NASH179-5501, which was directly used without treatment.

Step 5: Preparation of compound NASH179-55

The crude compound NASH179-5501 was added to trifluoroacetic acid (TFA, 10 mL), stirred at room temperature for 0.5 hours, evaporated to dryness under reduced pressure, and the residue was purified by column to obtain compound NASH179-55 (0.46 g) with a yield of 36.3%. ESI-MS (+): m/z=692.56.

Example 28: Synthesis of Compound NASH179-56

Reaction:

Preparation method:

Step 1: Preparation of compound NASH179-5601

In a reaction flask, compound ZJT2 (1.3 g, 2.8 mmol) and compound NASH179-5503 (0.97 g, 2.8 mmol) were added to THF (50 mL), and NMM (0.43 g, 4.2 mmol) was added. After stirring and cooling to about 0°C in an ice-water bath, HOSu (0.32 g, 2.8 mmol) and DCC (0.58 g, 1.83 mmol) were added. After continuing to stir and react in an ice-water bath at 0°C for 3 hours, the ice bath was removed and stirred overnight. The THF solvent was removed by rotary evaporation, ethyl acetate was added, and the mixture was washed with 10% citric acid solution, saturated brine, 4% NaHCO3 solution and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was the crude product of compound NASH179-5601, which was directly used without treatment.

Step 2:

The crude compound NASH179-5601 was added to trifluoroacetic acid (TFA, 15 mL), stirred at room temperature for 0.5 hours, evaporated to dryness under reduced pressure, and the residue was purified by column to obtain compound NASH179-56 (0.63 g) with a yield of 32.5%. ESI-MS (+): m/z=692.44.

Example 29: Preparation of Compound PY-50

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-0101

Compound tiopronin (11.0 g, 67.5 mmol), water (300 mL), dichloromethane (300 mL), tetrabutylammonium hydrogen sulfate (2.3 g, 6.75 mmol) and sodium bicarbonate (22.7 g, 270 mmol) were placed in a three-necked flask. Chloromethyl chlorosulfonate (13.5 g, 81.7 mmol) was added dropwise at room temperature, and the reaction was stirred at room temperature overnight. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The organic phases were combined, dried, concentrated, and purified by column (0 to 5% ethyl acetate/hexane gradient elution) to obtain compound NASH181-0101 (10.5 g) with a yield of 73.5%. ESI-MS (+): m/z = 212.33.

Step 2: Preparation of compounds NASH181-01 and NASH181-02

Compound ZJT1 (1.20 g, 2.76 mmol), cesium carbonate (1.76 g, 5.40 mmol), NASH181-0101 (1.14 g, 5.40 mmol) and N,N-dimethylformamide (50 mL) were added to the reaction flask in sequence, and the reaction solution was reacted at room temperature for 24 hours. The crude product was purified by preparative liquid phase to obtain two compounds: compound NASH181-01 (62 mg, 3.7%), ESI-MS (+): m/z = 610.29; compound NASH181-02 (55 mg, 3.3%), ESI-MS (+): m/z = 610.36.

Example 30: Synthesis of Compound NASH181-03

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-0303

Compound ZJT1 (1.20 g, 2.76 mmol), 4-methylbenzenesulfonic acid pyridinium salt (PPTs, 100.6 mg, 0.40 mmol), 3,4-dihydropyran (DHP, 0.94 g, 11.18 mmol) and 1,4-dioxane (20 mL) were added to the Schlenk tube in sequence. After the addition was completed, the reaction solution was heated to 65°C and reacted at this temperature for 18 hours. The temperature was lowered and the mixture was concentrated under reduced pressure. The residue was purified by liquid phase preparation to obtain compound NASH181-0303 (0.76 g) with a yield of 53.1%. ESI-MS (+): m/z = 519.23.

Step 2: Preparation of compound NASH181-0302

Under nitrogen protection, compound NASH181-0303 (1.04 g, 2.0 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydrogen (0.24 g, 10 mmol) was added, and then formaldehyde aqueous solution (35-40%, 1.0 g) was slowly added, and the temperature was raised to 55°C for reaction for 8 h. The reaction was complete when detected by TLC. The system was concentrated, water and dichloromethane were added, shaken, separated, the aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column to obtain compound NASH181-0302 (0.49 g) with a yield of 44.5%. ESI-MS (+): m/z=549.43.

Step 3: Preparation of compound NASH181-0301

In the reaction bottle, compound NASH181-0302 (1.0 g, 1.83 mmol) and thiopronin (0.30 g, 1.83 mmol) were added to THF (20 mL), N-methylmorpholine (NMM, 0.22 g, 2.2 mmol) was added, stirred and cooled to about 0°C in an ice-water bath, N-hydroxysuccinimide (HOSu, 0.21 g, 1.83 mmol) and N, N'-dicyclohexylcarbodiimide (DCC, 0.38 g, 1.83 mmol) were added, stirring and ice-water bath at 0°C were continued for 3 hours, then the ice bath was removed and stirred overnight. The THF solvent was removed by rotary evaporation, ethyl acetate was added, and the mixture was washed with 10% citric acid solution, saturated brine, 4% NaHCO ₃ solution and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was the crude product of compound NASH181-0301, which was directly used without treatment.

Step 3: Preparation of compound NASH181-03

The crude compound NASH181-0301 was added to trifluoroacetic acid (TFA, 10 mL), stirred at room temperature for 0.5 hours, evaporated to dryness under reduced pressure, and the residue was purified by column to obtain compound NASH181-03 (0.52 g) with a yield of 46.6%. ESI-MS (+): m/z=610.46.

Example 31: Synthesis of Compound NASH181-04

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-0402

Tiopronin (0.45 g, 2.76 mmol) was added to dichloromethane (20 mL), and then thionyl chloride (0.66 g, 5.52 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 hours, and concentrated under reduced pressure. The residue was directly used for later use.

Step 2: Preparation of compound NASH181-0401

Under nitrogen protection, compound ZJT1 (1.74 g, 4.0 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (0.72 g, 30 mmol) was added, and then formaldehyde aqueous solution (35-40%, 4.0 g) was slowly added, and the temperature was raised to 55°C for 8 h. The reaction was complete by TLC detection, and the system was concentrated, water and dichloromethane were added, shaken, separated, and the aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column to obtain compound NASH181-0401 (0.76 g) with a yield of 38.3%. ESI-MS (+): m/z=495.41.

Step 3: Preparation of compound NASH181-04

In the reaction flask, dichloromethane (20 mL), compound NASH181-0401 (0.68 g, 1.38 mmol), triethylamine (0.88 g, 2.70 mmol) were added in sequence, and then a dichloromethane solution (10 mL) containing NASH181-0402 (0.50 g, 2.76 mmol, the yield in the previous step is 100%) was added dropwise at 0°C. The temperature was maintained and stirred for 5 hours. The system was concentrated under reduced pressure, and the residue was purified by column to obtain compound NASH181-04 (0.35 g, 32.3%), ESI-MS (+): m/z = 785.46.

Example 32: Synthesis of Compound NASH181-07

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-0704

In a reaction flask, N-Boc-L-phenylalanine (4.80 g, 18.0 mmol) and L-alanine benzyl ester (3.3 g, 18.0 mmol) were dissolved in tetrahydrofuran (THF, 60 mL), N-methylmorpholine (NMM, 2.19 g, 21.6 mmol) was added, stirred and cooled to about 0°C in an ice-water bath, N-hydroxysuccinimide (HOSu, 2.07 g, 18.0 mmol) and N,N'-dicyclohexylcarbodiimide (DCC, 3.72 g, 18.0 mmol) were added, stirring and ice-water bath were continued at 0°C for 3 hours, then the ice bath was removed and stirred overnight. The THF solvent was removed by rotary evaporation, and ethyl acetate (EA, 45 mL) was added to dissolve the turbid oil and filtered. The EA solution was washed with 10% citric acid solution, saturated brine, 4% NaHCO ₃ solution and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was dissolved in dichloromethane (60 mL), acetic acid (3.0 mL) and 10% palladium carbon (3.0 g) were added, hydrogen was introduced, and the reduction reaction was carried out at room temperature for 1.5 hours, the system was filtered through diatomaceous earth, washed with a large amount of dichloromethane, the filtrate was evaporated to dryness under reduced pressure, and the residue was passed through a column to obtain compound NASH181-0704 (3.70 g), with a yield of 61.1%. ESI-MS (-): m/z = 335.21.

Step 2: Preparation of compound NASH181-0703

Under nitrogen protection, compound NASH181-0704 (3.36 g, 10.0 mmol) was added to acetonitrile (100 mL), phosphorus oxychloride (4.60 g, 30.0 mmol) and thiourea (0.76 g, 10.0 mmol) were slowly added under ice bath, heated to reflux for 16 hours, cooled, adjusted to alkalinity with triethylamine, filtered, concentrated the filtrate, and the residue was separated by column chromatography to obtain compound NASH181-0703 (0.85 g), with a yield of 24.1%. ESI-MS (-): m/z = 351.26.

Step 3: Preparation of compound NASH181-0702

Under nitrogen protection, compound ZJT1 (2.61 g, 6.0 mmol) was dissolved in tetrahydrofuran (150 mL), cesium carbonate (9.78 g, 30 mmol) was added, and then formaldehyde aqueous solution (35-40%, 3.0 g) was slowly added, and the temperature was raised to 55°C for 8 h. The reaction was complete after TLC detection. The system was concentrated, water and dichloromethane were added, shaken, separated, the aqueous phase was extracted with dichloromethane again, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was prepared for liquid phase separation to obtain compound NASH181-0702 (1.26 g) with a yield of 45.0%. ESI-MS (+): m/z=465.22.

Step 3: Preparation of compound NASH181-0701

Under nitrogen protection, compound NASH181-0703 (0.80 g, 2.27 mmol) was added to acetonitrile (50 mL), and 1-hydroxybenzotriazole (0.31 g, 2.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 0.35 g, 2.27 mmol) were slowly added under ice bath, and triethylamine (0.46 g, 4.54 mmol) was slowly added. After stirring at room temperature for 1 hour, compound NASH181-0702 (1.06 g, 2.27 mmol) was slowly added, and stirring at room temperature was continued for 16 hours. The mixture was filtered, and the filtrate was evaporated to remove the acetonitrile solvent. Ethyl acetate was added, and the mixture was washed with 10% citric acid solution, saturated brine, 4% NaHCO3 solution and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was the crude product of compound NASH181-0701, which was directly used without treatment.

Step 4: Preparation of compound NASH181-07

The crude compound NASH181-0701 was added to trifluoroacetic acid (TFA, 10 mL), stirred at room temperature for 0.5 hours, evaporated to dryness under reduced pressure, and the residue was purified by column to obtain compound NASH181-07 (0.43 g) with a yield of 27.1%. ESI-MS (+): m/z=699.56.

Example 33: Synthesis of Compound NASH181-08

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-0801

Under nitrogen protection, compound NASH181-0703 (1.06 g, 3.0 mmol) was added to acetonitrile (50 mL), 1-hydroxybenzotriazole (0.31 g, 2.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 0.47 g, 3.0 mmol) were slowly added under ice bath, triethylamine (0.61 g, 6.0 mmol) was slowly added, and after stirring at room temperature for 1 hour, compound NASH181-0302 (1.65 g, 3.0 mmol) was slowly added, and stirring at room temperature was continued for 16 hours, filtered, and the filtrate was evaporated to remove the acetonitrile solvent, ethyl acetate was added, and the mixture was washed with 10% citric acid solution, saturated brine, 4% NaHCO ₃ solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was the crude product of compound NASH181-0801, which was directly used without treatment.

Step 2: Preparation of compound NASH181-08

The crude compound NASH181-0801 was added to trifluoroacetic acid (TFA, 12 mL), stirred at room temperature for 0.5 hours, evaporated to dryness under reduced pressure, and the residue was purified by column to obtain compound NASH181-08 (0.53 g) with a yield of 25.2%. ESI-MS (+): m/z=699.42.

Example 34: Synthesis of Compound NASH181-11

Reaction:

Preparation method:

Under argon protection, at room temperature, compound NASH181-07 (1.12 g, 1.6 mmol) was added to anhydrous toluene (100 mL), and Lawesson's reagent (0.81 g, 2.0 mmol) was added under ice-water bath, and the temperature was raised to 110°C for 5 hours. The reaction was completed by TLC tracking, and the mixture was cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was separated and purified by a silica gel column to obtain compound NASH181-11 (0.60 g) with a yield of 52.4%. ESI-MS (+): m/z = 715.28.

The yield was 52.4%. ESI-MS (+): m/z = 715.28.

Example 35: Synthesis of Compounds NASH181-31 and NASH181-32

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-3101

Trifluoroacetaldehyde (58.0 g, 0.5 mol) and anhydrous zinc chloride (13.6 g, 0.1 mol) were added to the reaction flask, cooled to 0-5°C, and then ethyl chloroformate (54.3 g, 0.5 mol) was added dropwise within 1 hour. After the addition was completed, the temperature was raised to room temperature, and then continued to rise to 50-55°C, and the reaction was carried out for 8-10 hours. The reaction mixture was vacuum distilled to obtain the target NASH181-3101 (44.0 g) with a yield of 42.6%.

Step 2: Preparation of Compounds NASH181-31 and NASH181-32

ZJT1 (231.6 mg, 0.532 mmol) was added to N, N-dimethylformamide (20 mL), followed by cesium carbonate (346 mg, 1.064 mmol) and compound NASH181-3101 (120.6 mg, 0.584 mmol). The system was reacted at room temperature for 20 hours. The crude product was separated by preparative liquid phase to obtain two compounds: compound NASH181-31 (67 mg), yield 20.8%, ESI-MS (+): m/z = 605.67; NASH181-32 (57 mg), yield 17.7%, ESI-MS (+): m/z = 605.52.

Example 36: Synthesis of Compound NASH181-33

Reaction:

Preparation method:

Step 1: Preparation of compound NASH181-3301

Compound NASH181-0302 (0.56 g, 1.01 mmol) and N,N-dimethylformamide (30 mL) were added to the reaction flask, followed by sodium hydride (0.06 g, 2.51 mmol). The resulting mixture was stirred for 10 minutes and then NASH181-3101 (0.32 g, 1.50 mmol) was added dropwise. After the addition, the reaction solution was heated to 55°C and maintained at the temperature for 18 hours. The system was quenched with water and then purified by preparative liquid phase to obtain compound NASH181-3301 (293 mg) with a yield of 42.1%. ESI-MS (+): m/z = 689.57.

Step 2: Preparation of compound NASH181-33

Compound NASH181-3301 (290 mg, 0.42 mmol) and dichloromethane (30 mL) were added to the reaction flask, followed by dropwise addition of trifluoroacetic acid (TFA, 3.0 mL). After addition, the reaction was continued for 5 hours. After the system was quenched, it was concentrated under reduced pressure, and the residue was purified by preparative liquid phase to obtain compound NASH181-33 (92 mg) with a yield of 36.2%. ESI-MS (+): m/z=605.64.

Example 37: Synthesis of Compound NASH181-34

Reaction:

Preparation method:

Compound ZJT1 (0.44 g, 1.0 mmol) and N,N-dimethylformamide (20 mL) were added to the reaction flask, and after dissolution, sodium hydride (0.06 g, 2.50 mmol) was added. The resulting mixture was stirred for 15 minutes and then compound NASH181-3101 (0.41 g, 2.00 mmol) was added dropwise. After the addition, the reaction solution was heated to 60°C and maintained at the temperature for 24 hours. The system was quenched with water and then purified by preparative liquid phase to obtain compound NASH181-34 (239 mg) with a yield of 30.8%. ESI-MS (+): m/z = 775.48.

Example 38: Synthesis of compounds NASH192-05 and NASH192-06

Reaction:

Preparation method:

Step 1: Preparation of compound NASH192-L01-7:

At room temperature, the starting material NASH192-L01-SM (4.5 g, 0.03 mol) was added to a mixed solution of acetonitrile (7 mL), sulfolane (21 mL) and water (49 mL), and then isobutyric acid-D6 deuterated (2.82 g, 0.03 mol) and silver nitrate (2.6 g, 0.0153 mol) were added. The system was heated to 55°C, and a solution of concentrated sulfuric acid (4.8 mL) in water (15 mL) was added, followed by a solution of ammonium persulfate (10.4 g, 0.044 mol) in water (15 mL) which was added dropwise within 30 minutes. The system was heated to 70°C, reacted for 15 minutes, then cooled to room temperature, and continued to react at room temperature for 24 hours. The system was then cooled to 0°C, and the pH was slowly adjusted to 8 with aqueous ammonia (20 mL). The resulting mixture was diluted with water (100 mL) and filtered. The filter cake was washed with ethyl acetate (100 mL). The organic phase was collected, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound (3.49 g, yield 59.1%). ESI-MS (+): m/z = 197.08.

Step 2: Preparation of compound NASH192-L01-6:

At 25°C, 2,6-dichloro-4-aminophenol (1.38 g, 7.8 mmol) was added to N, N-dimethylformamide, and then compound NASH192-L01-7 (1.54 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol) were added. The system was heated to 90°C and reacted for 18 hours. Subsequently, the system was cooled to 25°C, poured into a mixture of ice water and 1N aqueous hydrochloric acid solution (15 mL), and then adjusted to pH = 7 with 1N aqueous hydrochloric acid solution, and then extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound NASH192-L01-6 (1.69 g, 64.2%). ESI-MS (+): m/z = 338.51.

Step 3: Preparation of compound NASH192-L01-5:

Compound NASH192-L01-6 (1.422 g, 4.2 mmol) was added to glacial acetic acid (40 mL), followed by sodium acetate (1.2 g, 14.7 mmol). The system was heated to 95 ° C and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, poured into water (150 mL), and neutralized with 3N sodium hydroxide aqueous solution. Then it was extracted twice with ethyl acetate (150 mL). The combined organic matter was washed with saturated sodium chloride aqueous solution (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH192-L01-5 (1.36 g, 90.1%) as an off-white solid, which was used directly in the next step without further purification. ESI-MS (+): m/z = 362.22.

Step 4: Preparation of compound NASH192-L01-4:

Compound NASH192-L01-5 (0.968 g, 2.675 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), and powdered sodium hydroxide (0.535 g, 13.375 mmol) was added. The system was then heated to reflux and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH192-L01-4 (0.819 g, 95.7%) as a light brown solid. The compound was used directly in the next step without further purification. ESI-MS (+): m/z = 320.21.

Step 5: Preparation of compound NASH192-L01-3

Concentrated hydrochloric acid (8.4 mL) was added to a suspension of compound NASH192-L01-4 (403 mg, 1.26 mmol) in water (16 mL). The system was then cooled to 0°C, and a solution of sodium nitrite (109.5 mg, 1.587 mmol) in water (3 mL) was added. The system was then stirred at 0°C for 30 minutes, filtered and quickly added to a mixed solution of N-cyanoacetylurea (216 mg, 1.38 mmol), water (30 mL) and pyridine (10 mL) pre-cooled to 0°C. The resulting suspension was stirred at 0°C for 30 minutes and then filtered. The filter cake was washed with water and petroleum ether in turn. The target product (370 mg, yield 60.2%) was obtained by vacuum drying at 80°C for 12 h. ESI-MS (+): m/z = 487.33.

Step 6: Preparation of compound NASH192-L01-2

At room temperature, compound NASH192-L01-3 (294 mg, 0.604 mmol) was added to glacial acetic acid (5 mL) solution, and then sodium acetate (0.25 g, 3 mmol) was added, and then the system was heated to 120 ° C and reacted for 1.5 hours, and then the system was cooled to 0 ° C, diluted with water (20 mL), and stirred for 30 minutes. Filter, the filter cake was washed with water and petroleum ether in turn, and then placed in a blast drying oven, dried for 60 minutes, and then slurried with a mixed solution of acetonitrile and water to obtain the target product (0.153 g, yield 57.4%). ESI-MS (+): m/z = 441.26.

Step 7: Preparation of compound NASH192-L01-1

NASH192-L01-SM2 (180 mg, 1.395 mmol) was added to dichloromethane (10 ml), and then the system was cooled to -15 °C, and triethylamine (155 mg, 1.534 mmol) was slowly added dropwise, and the temperature in the system was controlled not to exceed -5 °C. After the addition was completed, the system was cooled to -15 °C again, and deuterated ethanol (79.93 mg, 1.534 mmol) was added dropwise, and the temperature in the temperature control system was controlled not to exceed -5 °C, and the addition was completed. Slowly warmed to room temperature, and the reaction was continued for 3 hours. The system was quenched in water, and the aqueous phase was extracted with dichloromethane (100 ml), and then the organic phase was washed with saturated sodium chloride (100 ml), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil (178.0 mg, yield 88.9%). ESI-MS (+): m/z = 144.52.

Step 8: Preparation of compounds NASH192-05 and NASH192-06

Compound NASH192-L01-2 (106 mg, 0.240 mmol) was added to dichloromethane (5 mL), followed by N,N-diisopropylethylamine (0.107 mL, 0.645 mmol) and 4-N,N-dimethylaminopyridine (12.9 mg, 0.105 mmol), then the system was cooled to 0°C, and NASH192-L01-1 (34.4 mg, 0.240 mmol) was added. The system was slowly heated to 25°C and reacted for 3.5 hours. The system was then heated to 40°C and stirred overnight. Subsequently, the system was cooled to 25°C, poured into water (100 mL), extracted with dichloromethane (100 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 ml), washed with water (100 ml), washed with saturated sodium chloride (100 ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain two target compounds: NASH192-05 (41.4 mg, 31.5%) and NASH192-06 (29.9 mg, 22.8%). NASH192-05: ESI-MS (+): m/z = 548.31; NASH192-06: ESI-MS (+): m/z = 548.11.

Example 39: Synthesis of Compound NASH192-04

Reaction:

Preparation method:

NASH192-L01-2 (117 mg, 0.266 mmol) was added to THF (8 mL), and then 4M n-butyl lithium (67 μL, 0.266 mmol) was added. The system was then cooled to -25 °C, and NASH192-L01-1 (38.17 mg, 0.266 mmol) was added. The system was slowly raised to 25 °C and reacted for 3.5 h. The system was then raised to 40 °C and stirred overnight. Subsequently, the system was cooled to 25 °C, poured into water (100 mL), extracted with dichloromethane (100 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 ml), washed with water (100 ml), washed with saturated sodium chloride (100 ml), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain the target compound: NASH192-04 (49.5 mg, 34.1%). ESI-MS (+): m/z = 548.43.

Example 40: Synthesis of compounds NASH192-07 and NASH192-08

Reaction:

Preparation method:

Step 1: Preparation of compound NASH192-L02-7

At room temperature, the starting material NASH192-L01-SM (4.5 g, 0.03 mol) was added to a mixed solution of acetonitrile (7 mL), sulfolane (21 mL) and water (49 mL), and then 2-methylpropionic acid-D7 (2.85 g, 0.03 mol) and silver nitrate (2.6 g, 0.0153 mol) were added. The system was heated to 55 ° C, and a solution of concentrated sulfuric acid (4.8 mL) in water (15 mL) was added, followed by a solution of ammonium persulfate (10.4 g, 0,044 mol) in water (15 mL) was added dropwise, and the solution was completed within 30 minutes. The system was heated to 70 ° C, reacted for 15 minutes, then cooled to room temperature, and continued to react at room temperature for 24 hours. The system was then cooled to 0 ° C, and the pH was slowly adjusted to 8 with ammonia water (20 mL). The resulting mixture was diluted with water (100 mL) and filtered. The filter cake was washed with ethyl acetate (100 mL). The organic phase was collected, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound (3.38 g, yield 57.3%). ESI-MS (+): m/z = 198.17.

Step 2: Preparation of compound NASH192-L02-6

At 25°C, 2,6-dichloro-4-aminophenol (1.5 g, 7.8 mmol) was added to N,N-dimethylformamide, and then compound NASH192-L02-7 (1.544 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol) were added. The system was heated to 90°C and reacted for 18 hours. Subsequently, the system was cooled to 25°C, poured into a mixture of ice water and 1N aqueous hydrochloric acid solution (15 mL), and then adjusted to pH = 7 with 1N aqueous hydrochloric acid solution, and then extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound, NASH192-L02-6 (1.64 g, 62.3%), as an off-white foam. ESI-MS (+): m/z = 339.61.

Step 3: Preparation of compound NASH192-L02-5

Compound NASH192-L02-6 (1.426 g, 4.2 mmol) was added to glacial acetic acid (40 mL), followed by sodium acetate (1.2 g, 14.7 mmol). The system was heated to 95 ° C and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, poured into water (150 mL), and neutralized with 3N sodium hydroxide aqueous solution. Then it was extracted twice with ethyl acetate (150 mL). The combined organic matter was washed with saturated sodium chloride aqueous solution (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH192-L02-5 (1.4, 92.7%) as an off-white solid, which was used directly in the next step without further purification. ESI-MS (+): m/z = 363.22.

Step 4: Preparation of compound NASH192-L02-4

Compound NASH192-L02-5 (971 mg, 2.675 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), and powdered sodium hydroxide (0.535 g, 13.375 mmol) was added. The system was then heated to reflux and reacted for 18 h. Subsequently, the system was cooled to 25 ° C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound NASH192-L02-4 (0.802 g, 93.8%) as a light brown solid. The compound was used directly in the next step without further purification. ESI-MS (+): m/z = 321.21.

Step 5: Preparation of compound NASH192-L02-3

Concentrated hydrochloric acid (8.4 mL) was added to a suspension of compound NASH192-L02-4 (405 mg, 1.26 mmol) in water (16 mL). The system was then cooled to 0°C, and a solution of sodium nitrite (109.5 mg, 1.587 mmol) in water (3 mL) was added. The system was then stirred at 0°C for 30 minutes, filtered and quickly added to a mixed solution of N-cyanoacetylurea (216 mg, 1.38 mmol), water (30 mL) and pyridine (10 mL) pre-cooled to 0°C. The resulting suspension was stirred at 0°C for 30 minutes and then filtered. The filter cake was washed with water and petroleum ether in turn. The target product (386 mg, yield 62.9%) was obtained by vacuum drying at 80°C for 12 h. ESI-MS (+): m/z = 488.34.

Step 6: Preparation of compound NASH192-L02-2

At room temperature, compound NASH192-L02-3 (295 mg, 0.604 mmol) was added to glacial acetic acid (5 mL) solution, and then sodium acetate (0.25 g, 3 mmol) was added. The system was then heated to 120°C and reacted for 1.5 hours. The system was then cooled to 0°C, diluted with water (20 mL), and stirred for 30 minutes. After filtration, the filter cake was washed with water and petroleum ether in turn, and then placed in a forced air drying oven. After drying for 60 minutes, it was slurried with a mixed solution of acetonitrile and water to obtain the target product (0.145 g, yield 54.7%). ESI-MS (+): m/z = 442.26.

Step 7: Preparation of compounds NASH192-07 and NASH192-08

Compound NASH192-L02-2 (106 mg, 0.240 mmol) was added to dichloromethane (5 mL), followed by N,N-diisopropylethylamine (0.107 mL, 0.645 mmol) and 4-N,N-dimethylaminopyridine (12.9 mg, 0.105 mmol), then the system was cooled to 0°C, and NASH192-L01-1 (34.4 mg, 0.240 mmol) was added. The system was slowly heated to 25°C and reacted for 3.5 hours. Then the system was heated to 40°C and stirred overnight. Subsequently, the system was cooled to 25°C, poured into water (100 mL), extracted with dichloromethane (100 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 ml), washed with water (100 ml), washed with saturated sodium chloride (100 ml), dried with magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative liquid phase to obtain two compounds: compound NASH192-07 (16.7 mg, yield 12.7%) and NASH192-08 (28.2 mg, yield 21.4%). NASH192-07: ESI-MS (+): m/z = 549.32; NASH192-08: ESI-MS (+): m/z = 549.43.

Example 41: Synthesis of Compound NASH192-09

Reaction:

Preparation method:

NASH192-L02-2 (117 mg, 0.266 mmol) was added to THF (8 mL), and then 4M n-butyl lithium (67 μL, 0.266 mmol) was added. The system was then cooled to -25 °C, and NASH192-L01-1 (38, 17 mg, 0.266 mmol) was added. The system was slowly raised to 25 °C and reacted for 3.5 h. The system was then raised to 40 °C and stirred overnight. Subsequently, the system was cooled to 25 °C, poured into water (100 mL), extracted with dichloromethane (100 mL), and then the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 ml), washed with water (100 ml), washed with saturated sodium chloride (100 ml), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain the target compound: NASH192-09 (47.6 mg, yield 32.6%). ESI-MS (+): m/z = 549.52.

Example 42: Synthesis of Compound NASH179-43

Reaction:

Preparation method:

Step 1: Synthesis of compound NASH179-4301

Chloromethyl chloroformate (9g, 69.8mmol) was added to dichloromethane (90ml), and then the system was cooled to -5°C, and triethylamine (7.77g, 76.76mmol) was slowly added dropwise, and the internal temperature was controlled not to exceed 0°C. After the low dropwise addition was completed, the system was lowered to -5°C again, and deuterated ethanol (4g, 76.76mmol) was added dropwise, and the temperature of the temperature control system did not exceed 0°C, and solids gradually precipitated. The dropwise addition was completed. Slowly warmed to room temperature and continued to react for 3 hours. TLC showed no raw material. The system was poured into water for quenching, separated, and the aqueous phase was extracted with dichloromethane. The organic phase was combined, and then the organic phase was washed with saturated sodium chloride, dried with sodium sulfate, filtered, concentrated under reduced pressure, and passed through a column. A yellow liquid, NASH179-4301 (2.5g), was obtained with a yield of 25%. ESI-MS (+): m/z = 144.12.

Step 2: Synthesis of compound NASH179-43

ZJT1 (3 g, 6.89 mmol) was added to DMF (30 mL), and then cesium carbonate (4.49 g, 13.79 mmol) was added. The system was then cooled to -5 °C, and NASH179-4301 (1.99 g, 13.79 mmol) was added. The system was slowly raised to 25 °C and reacted for 3 h. TLC showed no raw material. The system was then poured into water, separated, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried with sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column (DCM: MeOH = 5: 1) to obtain compound NASH179-43 (650 mg), yield: 17%. ESI-MS (+): m/z = 542.31. ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.81 (s, 2H), 7.56 (s, 1H), 5.74 (s, 2H), 3.10 (p, J = 6.9 Hz, 1H), 1.23 (d, J = 6.9 Hz, 6H).

Example 43: Synthesis of Compound NASH192-05

Reaction:

Preparation method:

Step 1: Preparation of M01

SM01 (7.3 g, 0.05 mol), isobutyric acid-D6 deuterated (6.5 g, 0.073 mol), trifluoroacetic acid (5 mL), silver nitrate (0.8 g, 0.005 mol), and water (150 mL) were added to the reaction bottle in sequence, heated to 70°C, and an aqueous solution (50 nL) dissolved with ammonium persulfate (16.7 g, 0.07 mol) was added dropwise, and the temperature was maintained to continue the reaction for about 1 hour. The reaction was completed by TLC detection. The temperature was lowered, extracted with ethyl acetate, separated, concentrated, and the residue was separated by column to obtain M01 (2.4 g), with a yield of 24.4%. ESI-MS (+): m/z = 197.23.

Step 2: Preparation of M02

M01 (3.5 g, 18 mmol) was added to dimethyl sulfoxide (DMSO, 50 mL), followed by SM02 (3.17 g, 18 mmol), potassium carbonate (K2CO3, 9.8 g, 71 mmol), and iodine ketone (CuI, 3.0 g, 16 mmol); after addition, the mixture was heated to 100°C and reacted for 8 hours. The reaction was complete when detected by TLC, and the mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (180 mL×3), concentrated, and subjected to column chromatography to obtain a brown solid (1.6 g). The yield was 26.6%. ESI-MS (+): m/z=338.32.

Step 3: Preparation of M03

M02 (1.6 g, 4.7 mmol) and sodium acetate (0.8 g, 9.8 mmol) were added to acetic acid (60 mL) in sequence, heated to 110°C and refluxed for reaction for about 10 hours. The reaction was complete when detected by TLC. Water (50 mL) was added, and ethyl acetate was extracted (40 mL×3). The oil was concentrated to obtain an oil (1.4 g). The crude product was directly used in the next step. ESI-MS (+): m/z=362.16.

Step 4: Preparation of M04

1M strong sodium hydroxide aqueous solution (40mL) was added to methanol (40mL) and mixed evenly, then M03 (1.4g) obtained in step 3 was added to the above system, the temperature was raised to 100°C, and the reaction was completed by TLC spot plate. Methanol was removed by concentration, 3M hydrochloric acid was added to adjust the pH value to 5-6, ethyl acetate was extracted, concentrated, and the residue was separated by column to obtain a brown-gray solid (700mg), with a yield of 565%. ESI-MS (+): m/z = 320.24.

Step 5: Preparation of M05

A: Dissolve MO4 (700 mg, 2.2 mmol) in aqueous hydrochloric acid (10 mL hydrochloric acid + 30 mL water), add sodium nitrite (0.43 g, 6.2 mmol) in batches under ice bath, and stir at room temperature for 1 hour after addition;

B: SM03 (0.3 g, 1.9 mmol) was dissolved in a mixed solution of pyridine (10 mL) and water (10 mL), stirred in an ice-water bath for 30 minutes, and then reacted in an ice-water bath for 30 minutes;

A was quickly poured into the reaction bottle of B and reacted in an ice-water bath for 1 hour. The reaction was completed by TLC detection, and extracted with 25 ml of ethyl acetate (25 mL×3). The organic phase was then washed with water, washed with salt, dried, filtered, and concentrated to obtain a brown-red solid (2.3 g) which was directly used in the next step. ESI-MS (+): m/z=487.36.

Step 6: Preparation of M06

The above M05 (2.3g, 4.72mmol) and sodium acetate (2.3g, 28mmol) were added to acetic acid (40mL) in sequence, and the temperature was raised to reflux for 5 hours. The reaction was complete by TLC detection. The reaction solution was directly spin-dried, and then water (80mL) was added, extracted with ethyl acetate, and the organic phase was dried and spin-dried to obtain a crude product of 1.4g, which was added to acetonitrile (50mL), and then activated carbon (1.4g) was added, and refluxed for 2 hours. The mother liquor was collected by suction filtration, and the mother liquor was spin-dried to obtain a crude product of 540mg, which was then separated by preparing a large plate of dichloromethane/methanol (10:1) to obtain M06 (210mg), with a yield of 10.1%. ESI-MS (+): m/z=441.31.

Step 7: Preparation of NASH192-05

M06 (200 mg, 0.45 mmol), N,N-diisopropylethylamine (DIEA, 175.3 mg, 1.36 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.25 mmol) were added to dichloromethane (50 mL), then nitrogen was protected, the temperature was lowered to 0 ° C, and a dichloro solution (10 mL) of isobutyric acid-D6 deuterated (94.2 mg, 0.66 mmol) was added dropwise, and the reaction was carried out in an ice-water bath for 2 hours, and the reaction was stirred at room temperature for 24 hours. The reaction was complete after TLC detection. The reaction solution was directly spin-dried, and the residue was separated by column D/M (10:1) to obtain NASH192-05 (17 mg), with a yield of 6.9%. ESI-MS (+): m/z = 548.36. H-NMR (400MHz, DMSO-d6) δ7.79(s,2H),7.53(s,1H),5.72(s,2H),3.04(s,1H).

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

Example 44: In vitro TRα or TRβ agonism assay

Agonism of TRα or TRβ was performed using a time-resolved fluorescence resonance energy transfer coactivator peptide recruitment assay. The assay used Europium-anti-GST antibody (Cisbio, 6IGSTKLB), biotin-SRC2-2 coactivator peptide (angon Biotech), streptavidin-d2 (Cisbio, 610SADAB), RXRα (Pharmacon), and GST-tagged RXRα-LBD (invitrogen, PV4762) or TRβ-LBD (Invitrogen, PV4764). Europium-anti-GST antibody indirectly labeled RXRα-LBD or TRβ-LBD by binding to the GST tag. Streptavidin-d2 (Cisbio, 610SADAB) indirectly labeled the SRC2-2 coactivator peptide by binding to the biotin tag. In the presence of RXRα, TRα-LBD or TRβ-LBD can form heterodimers TRα-LBD/RXRα or TRβ-LBD/RXRα with it, respectively. Agonists bind to TRα-LBD/RXRα or TRβ-LBD/RXRα and cause changes in the conformation of TRα-LBD or TRβ-LBD, thereby increasing the ability of heterodimers to recruit SRC2-2 coactivator peptides. At the same time, the distance between the d2-labeled SRC2-2 coactivator peptide and the Europium-anti-GST antibody caused by this decreases, increasing the TR-FRET signal. According to the effect of different concentrations of compounds on TRα or TRβ activity, the agonist ability of the compound can be evaluated.

The structures of the positive compound (ie, ZJT1), comparative compound 1 (ie, NASH192-L01-2), comparative compound 2, comparative compound 3, and comparative compound 4 are as follows:

Among them, comparative compound 2 was synthesized with reference to the relevant synthesis method of CN101801960B; comparative compound 3 was synthesized with reference to the relevant synthesis method of CN112707892A; comparative compound 4 was synthesized with reference to the synthesis method of NASH192-05 in Example 38 of the present invention.

Specific method:

Dimethyl sulfoxide (DMSO) was used to prepare 6 mM solutions of positive compound (ZJT1) and test compound (100×, comparative compound 1, comparative compound 2, comparative compound 3, comparative compound 4 and the compounds disclosed in the present invention), and the negative control was 100% DMSO; the positive compound or test compound was diluted 1:3 from 6 mM (100×) with 100% DMSO, for a total of 10 concentrations, and transferred into a 96-well plate; 1× reaction buffer (50 mM HEPES (pH 7.0), 50 mM KF, 1 mM DTT, 0.05% NP-40, 0.2% BSA) to prepare 4X compound after concentration gradient dilution; add 5 μL of 4X compound after concentration gradient dilution to 384-well assay plate; prepare 4×TRβ-LBD and 4×RXRβ with 1× reaction buffer; add 5 μL of 4×TRβ-LBD and 4×RXRβ to 384-well assay plate; prepare 2×biotin-SRC2-2, 2×Europium-anti-GST and 2×streptavidin-d2 mixture with 1× reaction buffer, add 10 μL of 2× mixture to 384-well assay plate; centrifuge at 1000 rpm for 1 min and incubate at room temperature and in the dark for 4 hours. Read the 665nm and 615nm fluorescence signal values on EnVision 2104 (PerkinElmer) microplate reader.

Data calculation:

The relative ratio of each well is calculated as follows: Ratio = 665nm fluorescence signal value / 615nm fluorescence signal value;

Agonist activity (%) = (Ratio test compound - Ratio negative control) / (Ratio positive compound - Ratio negative control) × 100%, and then Graphpad8.0 was used to fit the relationship between agonist activity (%) and the logarithmic concentration of the compound by nonlinear regression method to calculate the THR-β EC50 (nM) of each test compound.

The THR-α EC50 (nM) of the test compound was measured and calculated using a similar method as described above.

THR-β agonist selectivity (SI) THR-β/THR-α=THR-αEC50/THR-βEC50.

Test results The results are shown in Table 1.

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

The data of comparative compounds 1 to 4 and positive compounds show that simply deuterating the parent core, esterifying the parent core with carboxylic acid derivatives through hydroxymethyl, and the parent core being deuterated and the carboxylic acid derivative side chain being esterified through hydroxymethyl does not significantly improve the agonist activity and selectivity for THR-β; however, the dipeptide derivatives, tripeptide derivatives, thiol-containing glycine derivatives, sulfonic acid derivatives and deuterated carboxylic acid derivatives in the present invention, after esterifying with the parent core through hydroxymethyl, all show higher agonist activity and agonist selectivity for THR-β than the positive compounds and comparative compounds 1 to 4, regardless of whether the parent core is deuterated. Unexpectedly, when there is deuteration in the parent core structure and at the same time there is deuteration in the carboxylic acid derivative that is esterified with the parent core through hydroxymethyl, this series of compounds all show extremely superior agonist activity and agonist selectivity for THR-β.

Example 45: Pharmacokinetic Study

Experimental animals: 54 male SD rats, weighing 200±20g, with free access to food and water, were adaptively raised for 3 days at room temperature of 20-26°C, humidity of 40-70%, and light illumination: dark = 12h: 12h. The experimental animals began to fast at 8 pm the day before administration, fasted for 12-13h before administration, and continued to fast for 4h after administration, for a total of 16-17h. No water was allowed during the entire experiment.

Preparation of oral administration samples: Weigh appropriate amounts of the test samples and place them in reagent bottles, add appropriate amounts of 2% Klucel LF and 0.1% Tween 80 mixed solution to prepare the administration solution. Prepare and use immediately.

Preparation of intravenous injection samples: Weigh appropriate amounts of the test samples, place them in reagent bottles, add appropriate amounts of mixed solvent (10% DMSO: 30% PEG400: 60% saline for injection). Prepare dosing solutions of corresponding concentrations, filter with a microporous filter membrane on a sterile bench before use (if there is a transfer bottle, pay attention to sterility), and use it immediately after preparation.

Experimental grouping and administration method: The experimental rats were divided into 18 groups, 3 rats in each group, with a total of 9 test articles. Each test article was administered by oral gavage and intravenous injection, respectively, for a single dose, as shown in Table 2.

Table 2 Dosage regimen for pharmacokinetic study

Blood sampling after intragastric administration: Blood was collected within 0.5h before intragastric administration (0h), and 0.5h, 1.5h, 3.0h, 4.5h, 6.0h, 8.0h, 10.0h, and 24.0h after administration. Animals were fed 4h after administration, and water was not allowed during the whole process.

Blood sampling for intravenous injection: Blood was collected within 0.5h (0h) before single intravenous injection, and 0.15h, 0.5h, 1.0h, 3.0h, 5.0h, 8.0h, 10.0h, and 24.0h after administration. Animals were fed 4h after administration, and water was not allowed during the whole process.

Plasma sample processing and detection: Blood sample collection and processing: At each blood collection time point, about 300 μL of blood was collected from the rat's orbital vein, added to a centrifuge tube with sodium heparin pre-cooled in ice water, and placed in an ice bath. After standing, centrifuge (4000rpm, 10min), take the plasma and divide it into 50 μL units, place it in a sterile EP tube, and store it at -80℃ for later use. Determine the concentration of the target analyte in plasma as soon as possible. Analyte information: NASH192-05 and comparative compound 4 detect NASH192-L01-2, and comparative compounds 3, NASH161-24, NASH179-43, NASH179-56, NASH181-01 and NASH181-07 detect ZJT1.

The pharmacokinetic parameters of injection administration are shown in Table 3, the pharmacokinetic parameters of oral administration are shown in Table 4, and the pharmacokinetic curve of oral administration pharmacokinetic test is shown in Figure 1.

Table 3 Pharmacokinetic parameters of injection

Table 4 Pharmacokinetic parameters of oral administration

The data of comparative compound 3, comparative compound 4 and positive compound showed that the carboxylic acid derivatives connected to the positive compound (i.e., the parent core) through the hydroxymethyl group, when not deuterated, had no significant difference in exposure (AUC _Inf ), peak plasma concentration (C _max ), half-life (T _1/2 ), residence time (MRT) and bioavailability did not show obvious differences, but when the parent nucleus was esterified with the side chains of the dipeptide derivatives, tripeptide derivatives, thiol-containing glycine derivatives, sulfonic acid derivatives and deuterated carboxylic acid derivatives of the present invention through hydroxymethyl, regardless of whether there was deuteration in the parent nucleus, it showed better effects in terms of exposure, half-life, peak blood drug concentration and bioavailability. Among them, compared with the positive compound, comparative compound 3 and comparative compound 4, the compound NASH192-05 was administered by oral gavage. The half-life was extended by about 1.5 times, the peak time was shortened by about 1.5 times, the exposure was increased by more than 2 times, the residence time was extended by more than 1.6 times, and the bioavailability was increased by more than 1.5 times. And the drug-time curve of oral gavage showed that the compound NASH192-05 had more obvious enterohepatic circulation characteristics compared with the positive compound, comparative compound 3, comparative compound 4 and NASH179-43.

Example 46: Efficacy experiment on HFD-induced NASH model in mice

Test compounds: Comparative compound 3, Comparative compound 4, NASH179-43, and NASH192-05.

Preparation of test compounds: Weigh appropriate amounts of test compounds, place in reagent bottles, add 2% Klucel LF and 0.1% Tween 80 mixed solution, stir evenly, and set aside. Prepare and vortex evenly before administration every day.

Experimental method: 80 C57BL/6J mice (Liaoning Changsheng Biotechnology Co., Ltd.), male, SPF grade, 6 weeks old, weighing 18g-20g, were randomly divided into a normal group (n=10) and a NASH modeling group (n=70) after 7 days of adaptive feeding. The normal group was fed with normal feed (Beijing Huafukang Biotechnology Co., Ltd., crude protein %≥20.0% and crude fat %≥4.0% in the main nutrients), and the NASH modeling group was fed with a high-fat feed (Beijing Huafukang Biotechnology Co., Ltd., crude fat %≥60%, crude protein %≥10%, and calories (carbohydrate or sugar) %≥25%). From the end of adaptive feeding, after 8 weeks of feeding, blood biochemical indicators and body weight were measured, mice with obvious abnormal indicators were eliminated, and mice with uniform indicators were selected for the experiment. Eight mice fed with normal diet were randomly selected from the normal group; 56 mice fed with high-fat diet were randomly selected from the NASH modeling group and randomly divided into 7 groups, 8 mice in each group, namely the model group, the comparison compound group 3, the comparison compound group 4, the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group, and the NASH192-05 high-dose group. The drug was administered by gavage once a day for 6 consecutive weeks. The dosing schedule is shown in Table 5.

Table 5 Dosage regimen for efficacy test

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

Observation, sample processing, and testing indicators:

1) General clinical symptom observation and body weight measurement

The general clinical symptoms of the experimental animals were observed before administration every day (10 a.m.), and the body weight was measured once on Monday and Thursday, each measurement was at 8 a.m.

Weigh the wet weight of the liver and calculate the liver index, liver index = liver weight (g) / body weight (g) × 100.

2) Determination of triglyceride (TG) and total cholesterol (TC) content in liver:

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

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

3) Histopathological analysis

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

Table 6 NAS scoring evaluation method

Lesion assessment criteria:

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

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

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

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

Statistical analysis:

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

Test results:

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

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

Note: Compared with the normal group *P<0.05, **P<0.01; compared with the model group ^# P<0.05, ^## P<0.01;

Compared with the normal group, the body weight, liver wet weight and liver index of the model group mice increased significantly after 14 weeks of HFD diet induction. Compared with the model group, the body weight, liver wet weight and liver index of the control compound 3 group, the control compound 4 group, the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group and the NASH192-05 high-dose group decreased; compared with the control compound 3 and the control compound 4, the body weight, liver wet weight and liver index of the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group and the NASH192-05 high-dose group decreased, among which the NASH192-05 medium-dose group and the NASH192-05 high-dose group decreased most significantly, and the NASH192-05 low-dose group (5 mg/kg) was equivalent to the NASH179-43 group (10 mg/kg).

Figures 2 and 3 show the results of TC and TG levels in the liver of mice after administration. Compared with the normal control group, the TC and TG levels in the liver tissue of the mice in the model group increased. Compared with the model group, the TC and TG levels in the comparison compound 3 group, the comparison compound 4 group, the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group and the NASH192-05 high-dose group all showed a downward trend. Compared with the comparison compound 3 and the comparison compound 4, the TC and TG levels of the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group and the NASH192-05 high-dose group decreased significantly, among which the NASH192-05 medium-dose group and the NASH192-05 high-dose group decreased most significantly, and the NASH192-05 low-dose group (5 mg/kg) was equivalent to the NASH179-43 group (10 mg/kg).

Figure 4 shows the results of NAS score, and the NAS score on the vertical axis is the sum of the scores of hepatocyte ballooning, intralobular inflammation, and fatty degeneration. Compared with the model group, the comparison compound group 3, and the comparison compound group 4, the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group, and the NASH192-05 high-dose group all achieved a significant reduction in the score, among which the scores of the NASH192-05 medium-dose group and the NASH192-05 high-dose group were extremely significantly reduced, and NASH192-05 was dose-related; at the same time, the NASH192-05 low-dose group (5 mg/kg) had equivalent efficacy to the NASH179-43 group (10 mg/kg).

Figure 5 shows the results of fibrosis evaluation. Compared with the model group, the comparison compound 3 group and the comparison compound 4 group, the NASH179-43 group, the NASH192-05 low-dose group, the NASH192-05 medium-dose group and the NASH192-05 high-dose group all achieved a significant decrease in the proportion of fibrosis, among which the scores of the NASH192-05 medium-dose group and the NASH192-05 high-dose group were significantly reduced, and the NASH192-05 was dose-related; at the same time, the NASH192-05 low-dose group (5 mg/kg) had comparable and slightly better efficacy than the NASH179-43 group (10 mg/kg).

Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art may make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be based on the definition of the claims.

Claims (9)

1. A novel pyridazine compound, tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I ₀ -1) and/or formula (I ₀ -2): In formula (I ₀ -1) and/or formula (I ₀ -2), L is selected from alkylene, O, S, Se, S(O) and S(O) ₂ ; wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; Y ₁ , Y ₂ and Y ₃ are independently selected from O and S; R ₁ is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium and halogen; R ₇ is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl which may be substituted by one or more substituents, and C3-C6 cycloalkyl which may be substituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl, deuterium and C1-C6 alkoxy; _R8 and _R9 are independently selected from hydrogen, It is also stipulated that when Y ₁ , Y ₂ and Y ₃ are all O, R ₈ and R ₉ cannot be hydrogen at the same time; The above n ₁ is selected from 1, 2 and 3; _W1 is O or S; _Ra1 , _Ra2 , _Ra3 and _Ra4 are independently selected from hydrogen, deuterium, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium, halogen, hydroxyl and C1-C6 alkoxy; R _b0 is selected from amino, in, The above n ₂ is selected from 1, 2, 3, 4, 5 and 6; _Rd1 and _Rd2 are independently selected from hydrogen, C1-C6 alkyl which may be substituted by one or more substituents, and C3-C6 cycloalkyl which may be substituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; R _e1 and R _e2 are independently selected from hydrogen, in, R _h1 and R _h2 are independently selected from hydrogen and C1-C6 alkyl which is unsubstituted or substituted by one or more substituents, wherein the substituents are selected from C1-C6 alkyl, guanidino, carboxyl, amide, thiol, hydroxyl, C1-C6 alkylthiol, imidazolyl, hydroxyphenyl and phenyl; _Rf is selected from the group consisting of R _i , -OR _i and -NR _i R _j ; wherein, The above R _i and R _j are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C10 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C10 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, and the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, thioether; R _b1 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, The substituent is deuterium or fluorine; wherein, The above n ₂ is selected from 1, 2, 3, 4, 5 and 6; R _c1 and R _c2 are independently selected from hydrogen and C1-C6 alkyl; R _c3 and R _c4 are each independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R _c3 and R _c4 and the carbon atom to which it is connected are connected together to form a ring, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; _Rd1 and _Rd2 are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; R _d3 is selected from in, The above _W2 and _W3 are independently selected from O and S; R _c5 , R _c6 , R _c7 and R _c8 are independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted by one or more substituents, or, R c5 and R c6 and the carbon atoms to which they are connected are linked together to form a ring, or, R c7 and R c8 are independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, _C3 - _C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, _C6 -C20 aryl _c8 and the carbon atom to which it is connected are connected together to form a ring, and the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R _e3 and R _f1 are independently selected from hydrogen, C1-C6 alkyl substituted or unsubstituted by one or more substituents, C1-C6 alkoxy substituted or unsubstituted by one or more substituents, C1-C6 alkylamino substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, wherein the substituent is deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; _Rg is selected from hydroxyl, C1-C6 alkyl-O- which is substituted or unsubstituted by one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl and C1-C6 alkoxy; R _b2 is selected from C1-C6 alkyl substituted or unsubstituted by one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted by one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted by one or more substituents, C6-C20 aryl substituted or unsubstituted by one or more substituents, C6-C20 arylalkyl substituted or unsubstituted by one or more substituents, C6-C20 heteroaryl substituted or unsubstituted by one or more substituents, and the substituent is deuterium or fluorine; And stipulates that When L is O, _R8 and _R9 are independently selected from Wherein Ra ₁ and Ra ₂ are both hydrogen, and R _b1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, then one or more hydrogen in the C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl must be substituted with deuterium or fluorine; When L is O, _R8 and _R9 are independently selected from Wherein _Ra3 and _Ra4 are both hydrogen, and _Rb2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, then one or more hydrogen in the C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl must be substituted by deuterium or fluorine. 2. The novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in formula (I ₀ -3): The substituents in formula (I ₀ -3) are as defined in formula (I ₀ -1) in claim 1. 3. The novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in formula (I ₀ -4): The substituents in formula (I ₀ -4) are as defined in formula (I ₀ -1) in claim 1. 4. The novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in formula (I ₀ -5): The substituents in formula (I ₀ -5) are as defined in formula (I ₀ -2) in claim 1. 5. The novel pyridazine compound, tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in formula (I ₀ -1) and/or (I ₀ -2), wherein: Y ₁ , Y ₂ and Y ₃ are all O, and R ₈ and R ₉ are not hydrogen at the same time; _R8 and _R9 are independently selected from hydrogen, The above n ₁ is 1; W ₁ is O; R _a1 and R _a2 are both hydrogen and deuterium; R _a3 and R _a4 are both hydrogen and deuterium; R _b1 is selected from C1-C6 alkyl substituted by one or more substituents, C3-C6 cycloalkyl substituted by one or more substituents, C3-C8 heterocycloalkyl substituted by one or more substituents, C6-C20 aryl substituted by one or more substituents, C6-C20 arylalkyl substituted by one or more substituents, C6-C20 heteroaryl substituted by one or more substituents, and C6-C20 heteroarylalkyl substituted by one or more substituents, wherein the substituent is deuterium or fluorine; R _b2 is selected from C1-C6 alkyl substituted by one or more substituents, C3-C6 cycloalkyl substituted by one or more substituents, C3-C8 heterocycloalkyl substituted by one or more substituents, C6-C20 aryl substituted by one or more substituents, C6-C20 arylalkyl substituted by one or more substituents, C6-C20 heteroaryl substituted by one or more substituents, C6-C20 heteroarylalkyl substituted by one or more substituents, and the substituent is deuterium or fluorine; The other substituents are as defined in formula (I ₀ -1) and/or (I ₀ -2) in claim 1. 6. The novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound includes but is not limited to the following compounds: 7. A pharmaceutical composition comprising the novel pyridazine compound, solvate, stereoisomer, tautomer, isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. 8. Use of the novel pyridazine compound, solvate, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 7 in the preparation of a drug for preventing or treating thyroid hormone receptor-related diseases. 9. The use of claim 8, wherein the thyroid hormone receptor-related disease is one or more of obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia and liver fatty disease.