A pyridazine compound, pharmaceutical composition thereof and use thereof

Abstract

The application discloses a novel pyridazine compound and a pharmaceutical composition and application thereof, and particularly relates to a compound, a solvate, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt of formula (I0-1) or (I0-2), a pharmaceutical composition containing the compound and an application in preventing and / or treating a thyroid hormone receptor related disease.

Description

[0001] This application claims priority to the following Chinese patent applications filed on December 31, 2022, with application number 202211737025.0, entitled "A Novel Pyridazine Compound and Pharmaceutical Composition and Use Thereof", filed on April 28, 2023, with application number 2023104791877, entitled "A Novel Pyridazine Compound and Pharmaceutical Composition and Use Thereof", filed on May 17, 2023, with application number 2023105515446, entitled "A Novel Pyridazine Compound and Pharmaceutical Composition and Use Thereof", and filed on August 1, 2023, with application number 2023109585946, entitled "A Novel Pyridazine Compound and Pharmaceutical Composition and Use Thereof", the contents of which are to be construed as incorporated herein by reference. Technical Field

[0002] This invention relates to, but is not limited to, the field of pharmaceutical chemistry, and particularly to a novel pyridazine compound, its pharmaceutical composition, and its uses. Background Technology

[0003] Thyroid hormones (TH) are thyroid-stimulating hormones secreted in response to the pituitary gland. Thyroid hormones play a crucial role in growth, development, metabolism, and homeostasis. There are two main types of thyroid hormones: 3,5,3'-triiodothyronine (T3) and thyroxine (T4). T3 (triiodothyronine) is an important component of thyroid hormones. The human body primarily secretes T4. In peripheral organs, T4 is converted into the more active T3 by deiodinases. 20% of T3 is produced by the thyroid gland itself, while the remaining 80% is converted from total serum thyroxine in peripheral tissues.

[0004] Studies have shown that the effects of thyroid hormone T3 on the heart, especially on heart rate, are mediated by thyroid receptor α (THRα). The effects of T3 on the liver, muscles, and other tissues are primarily mediated by thyroid receptor β (THRβ). Therefore, selective THRβ agonists should be able to treat obesity, hyperlipidemia, thyroid disease, and non-alcoholic steatohepatitis without affecting heart rate and rhythm. Thus, the search for a highly effective selective THRβ agonist drug has significant social and economic value. Summary of the Invention

[0005] In one aspect, this invention provides a novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I0-1) or (I0-2):

[0006]

[0007] In equation (I0-1) and / or equation (I0-2),

[0008] 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0009] Y1, Y2, and Y3 are independently selected from O and S, respectively;

[0010] R1 is selected from hydrogen, cyano, C1-C6 alkyl substituted or unsubstituted with one or more substituents, or C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0011] R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, and halogens;

[0012] R7 is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl substituted or unsubstituted with one or more substituents, or C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium and C1-C6 alkoxy groups;

[0013] R8 and R9 are independently selected from hydrogen, It is stipulated that when Y1, Y2, and Y3 are all O, R8 and R9 cannot both be hydrogen; among them,

[0014] The n1 mentioned above is selected from 1, 2, and 3;

[0015] W1 is either O or S;

[0016] R a1 R a2 R a3 and R a4 The substituents are independently selected from hydrogen, deuterium, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium, halogens, hydroxyl groups and C1-C6 alkoxy groups;

[0017] R b0 Selected from amino, in,

[0018] The n² above is selected from 1, 2, 3, 4, 5, and 6;

[0019] Rd1 and R d2 Each of the following is independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, or C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0020] R e1 and R e2 Selected independently from hydrogen, in,

[0021] The above R h1 and R h2 Each is independently selected from hydrogen, C1-C6 alkyl groups substituted with one or more substituents or unsubstituted, wherein the substituents are selected from C1-C6 alkyl, guanidinyl, carboxyl, amide, mercapto, hydroxyl, C1-C6 alkyl mercapto, imidazolyl, hydroxyphenyl and phenyl;

[0022] R f Selected from R i -OR i and -NR i R j ;in,

[0023] The above R i and R j The substituents are independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C3-C10 cycloalkyl groups substituted or unsubstituted with one or more substituents, C3-C10 heterocycloalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 aryl groups substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl groups substituted or unsubstituted with one or more substituents, and C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether groups;

[0024] R b1 Selected from C1-C6 alkyl groups substituted or unsubstituted with one or more substituents; C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents; C3-C8 heterocycloalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 aryl groups substituted or unsubstituted with one or more substituents; C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents. The substituent is deuterium or fluorine; wherein...

[0025] The n² above is selected from 1, 2, 3, 4, 5, and 6;

[0026] R c1 and R c2 They are independently selected from hydrogen and C1-C6 alkyl groups, respectively;

[0027] R c3 and R c4 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted with one or more substituents, C1-C6 alkoxy substituted or unsubstituted with one or more substituents, C1-C6 alkylamine substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted with one or more substituents, C6-C20 aryl substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl substituted or unsubstituted with one or more substituents, C6-C20 heteroarylalkyl substituted or unsubstituted with one or more substituents, or R c3 and R c4 The carbon atoms connected to it are linked together to form a ring, and the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0028] R d1 and R d2 Each of the following is independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0029] R d3 Selected from in,

[0030] The above W2 and W3 are independently selected from O and S, respectively;

[0031] R c5 R c6 R c7 and R c8Each is independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted with one or more substituents, C1-C6 alkoxy substituted or unsubstituted with one or more substituents, C1-C6 alkylamine substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted with one or more substituents, C6-C20 aryl substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl substituted or unsubstituted with one or more substituents, or R c5 and R c6 And the carbon atoms they are connected to form a ring, or, R c7 and R c8 The carbon atoms connected to it are linked together to form a ring, and the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

[0032] R e3 and R f1 The components are independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C1-C6 alkoxy groups substituted or unsubstituted with one or more substituents, C1-C6 alkylamino groups substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, and C3-C8 heterocyclic alkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0033] R g Selected from hydroxyl groups, C1-C6 alkyl-O- groups substituted with or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0034] R b2The substituent is selected from C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 aryl groups substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl groups substituted or unsubstituted with one or more substituents, and C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituent is deuterium or fluorine;

[0035] And stipulates that,

[0036] When L is 0, R8 and R9 are independently selected from... Where Ra1 and Ra2 are both hydrogen, and R b1 When selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, and C6-C20 heteroarylalkyl, one or more hydrogen atoms in C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, and C6-C20 heteroarylalkyl must be substituted with deuterium or fluorine.

[0037] When L is 0, R8 and R9 are independently selected from... Both Ra3 and Ra4 are hydrogen, and R b2 When selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, and C6-C20 heteroarylalkyl, one or more hydrogen atoms in C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, and C6-C20 heteroarylalkyl must be substituted with deuterium or fluorine.

[0038] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I0-3):

[0039]

[0040] The substituents in equation (I0-3) are defined as defined in equation (I0-1).

[0041] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I0-4):

[0042]

[0043] The substituents in equation (I0-4) are defined as defined in equation (I0-1).

[0044] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I0-5):

[0045]

[0046] The substituents in equation (I0-5) are defined as defined in equation (I0-2).

[0047] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof of formula (I0-1) or (I0-2), wherein,

[0048] Y1, Y2 and Y3 are all O, and R8 and R9 are not both hydrogen at the same time;

[0049] R8 and R9 are independently selected from hydrogen,

[0050] The above n1 is 1;

[0051] W1 is 0;

[0052] R a1 and R a2 Both are hydrogen and deuterium;

[0053] R a3 and R a4 Both are hydrogen and deuterium;

[0054] R b1 The substituent is selected from C1-C6 alkyl groups substituted with one or more substituents, C3-C6 cycloalkyl groups substituted with one or more substituents, C3-C8 heterocycloalkyl groups substituted with one or more substituents, C6-C20 aryl groups substituted with one or more substituents, C6-C20 arylalkyl groups substituted with one or more substituents, C6-C20 heteroaryl groups substituted with one or more substituents, and C6-C20 heteroarylalkyl groups substituted with one or more substituents, wherein the substituent is deuterium or fluorine;

[0055] R b2The substituent is selected from C1-C6 alkyl groups substituted with one or more substituents, C3-C6 cycloalkyl groups substituted with one or more substituents, C3-C8 heterocycloalkyl groups substituted with one or more substituents, C6-C20 aryl groups substituted with one or more substituents, C6-C20 arylalkyl groups substituted with one or more substituents, C6-C20 heteroaryl groups substituted with one or more substituents, and C6-C20 heteroarylalkyl groups substituted with one or more substituents, wherein the substituent is deuterium or fluorine;

[0056] Other substituents are defined as those defined in formulas (I0-1) and / or (I0-2) of claim 1.

[0057] In some embodiments, in the above formulas (I0-1)-(I0-5), 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; preferably, L is O, S, or Se.

[0058] In some implementations, Y1 in the above formulas (I0-1)-(I0-5) is selected from O and S.

[0059] In some implementations, Y2 in the above formulas (I0-1)-(I0-5) is selected from O and S.

[0060] In some implementations, Y3 in the above formulas (I0-1), (I0-3), and (I0-4) is selected from O and S.

[0061] In some embodiments, in the above formulas (I0-1)-(I0-5), R1 is selected from hydrogen, cyano, C1-C6 alkyl substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituents are 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.

[0062] In some embodiments, in the above formulas (I0-1)-(I0-5), R2 is selected from hydrogen, deuterium, and halogen; preferably, R2 is selected from hydrogen and deuterium.

[0063] In some embodiments, in the above formulas (I0-1)-(I0-5), R3 is selected from hydrogen, deuterium, and halogens; preferably, R3 is selected from halogens; more preferably, R3 is selected from Cl.

[0064] In some embodiments, in the above formulas (I0-1)-(I0-5), R4 is selected from hydrogen, deuterium, and halogens; preferably, R4 is selected from halogens; more preferably, R4 is selected from Cl.

[0065] In some embodiments, in the above formulas (I0-1)-(I0-5), R5 is selected from hydrogen, deuterium, and halogen; preferably, R5 is selected from hydrogen and deuterium.

[0066] In some embodiments, in the above formulas (I0-1)-(I0-5), R6 is selected from hydrogen, deuterium, and halogen; preferably, R6 is selected from hydrogen and deuterium.

[0067] In some embodiments, in formulas (I0-1)-(I0-5) above, R7 is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium, or C1-C6 alkoxy groups; preferably, R7 is selected from C1-C6 alkyl substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium, or C1-C6 alkoxy groups; more preferably, R7 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with deuterium; most preferably, R7 is isopropyl or isopropyl with any hydrogen atom deuterated.

[0068] In some implementations, R8 is hydrogen in the above formulas (I0-1) and / or (I0-3);

[0069] In some implementations, in the above formulas (I0-1)-(I0-2) and / or (I0-4)-(I0-5), R8 is selected from... The rule stipulates that when Y1, Y2, and Y3 are all O, R8 and R9 cannot both be hydrogen; among them,

[0070] The n1 mentioned above is selected from 1, 2, and 3; preferably, n1 is selected from 1 and 2; more preferably, n1 is 1;

[0071] W1 is selected from O, and S;

[0072] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, or C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a1 and R a2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl; more preferably, R a1 and Ra2 Both are hydrogen, R a1 and R a2 All are deuterium, R a1 and R a2 One of them is hydrogen, and the other is methyl;

[0073] R a3 and R a4 The components are independently selected from hydrogen, deuterium, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a3 and R a4 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl groups substituted or unsubstituted with one or more halogen atoms, and C3-C6 cycloalkyl groups; more preferably, R a3 and R a4 Both are hydrogen, R a3 and R a4 All are deuterium, R a3 and R a4 One of them is hydrogen, and the other is methyl, or R a3 and R a4 One of them is hydrogen, and the other is trifluoromethyl;

[0074] R b0 Selected from amino, in,

[0075] The above n2 is selected from 1, 2, 3, 4, 5, or 6; preferably, n2 is selected from 1, 2, and 3;

[0076] R d1 and R d2 Each of the following is independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted with 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 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; more preferably, R d1 and R d2 All are hydrogen;

[0077] R e1 and R e2 Selected independently from hydrogen, in,

[0078] The above R h1 and R h2Each group is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C1-C6 alkyl, guanidinyl, carboxyl, amide, mercapto, hydroxyl, C1-C6 alkyl mercapto, imidazolyl, hydroxyphenyl, and phenyl; preferably, R h1 and R h2 All are hydrogen, or R h1 and R h2 One of them is hydrogen, and the other is methyl, isopropyl, isobutyl, or benzyl;

[0079] R f Selected from R i -OR i , and -NR i R j ;in,

[0080] The above R i and R j The groups are independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C3-C10 cycloalkyl groups substituted or unsubstituted with one or more substituents, C3-C10 heterocycloalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 aryl groups substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents, and C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether groups; preferably, R i and R j Each is independently selected from hydrogen, C1-C6 alkyl groups substituted with one or more substituents or unsubstituted, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether groups; more preferably, R f It is a hydroxyl group;

[0081] R b1 Selected from C1-C6 alkyl groups substituted or unsubstituted with one or more substituents; C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents; C3-C8 heterocycloalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 aryl groups substituted or unsubstituted with one or more substituents; C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents; C6-C20 heteroarylalkyl groups substituted or unsubstituted with one or more substituents. The substituent is deuterium or fluorine; preferably, Rb1 Selected from Trifluoromethyl, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, or substituted with one or more substituents or unsubstituted. The substituent is deuterium or fluorine; wherein...

[0082] The n2 mentioned above is selected from 1, 2, 3, 4, 5, and 6; preferably, n2 is selected from 1, 2, and 3;

[0083] R d1 and R d2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R d1 and R d2 Each is independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R d1 and R d2 All are hydrogen;

[0084] R g Selected from hydroxyl groups, C1-C6 alkyl-O- groups substituted with one or more substituents or unsubstituted groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R g Selected from hydroxyl, or -O-C1-C6 alkyl-O-;

[0085] R c3 and R c4 Each is independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted with one or more substituents, C1-C6 alkoxy substituted or unsubstituted with one or more substituents, C1-C6 alkylamine substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted with one or more substituents, C6-C20 aryl substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl substituted or unsubstituted with one or more substituents, or R c3 and R c4 The carbon atoms connected to it are linked together to form a ring, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, R c3 and R c4 All are hydrogen, R c3 and Rc4 One of them is hydrogen, and the other is methyl or R. c3 and R c4 One of them is hydrogen, and the other is isopropyl;

[0086] R d3 Selected from in,

[0087] The above W2 is selected from O or S;

[0088] W3 is selected from O or S;

[0089] R c5 and R c6 Each is independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted with one or more substituents, C1-C6 alkoxy substituted or unsubstituted with one or more substituents, C1-C6 alkylamine substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted with one or more substituents, C6-C20 aryl substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl substituted or unsubstituted with one or more substituents, or R c5 and R c6 The carbon atoms connected to it are linked together to form a ring, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, R c5 and R c6 One of them is hydrogen, and the other is selected from benzyl, 1-methylpropyl, isopropyl, deuterated 1-methylpropyl, or deuterated isopropyl;

[0090] R c7 and R c8Each is independently selected from hydrogen, deuterium, halogen, cyano, trifluoromethyl, C1-C6 alkyl substituted or unsubstituted with one or more substituents, C1-C6 alkoxy substituted or unsubstituted with one or more substituents, C1-C6 alkylamine substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl substituted or unsubstituted with one or more substituents, C6-C20 aryl substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl substituted or unsubstituted with one or more substituents, C6-C20 heteroaryl substituted or unsubstituted with one or more substituents, or R c7 and R c8 The carbon atoms connected to it are linked together to form a ring, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; preferably, R c7 and R c8 One of them is hydrogen, and the other is selected from methyl or deuterated methyl;

[0091] R e3 The group is selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C1-C6 alkoxy groups substituted or unsubstituted with one or more substituents, C1-C6 alkylamino groups substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, and C3-C8 heterocyclic alkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl; preferably, R e3 It is hydrogen;

[0092] R f1 The group is selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C1-C6 alkoxy groups substituted or unsubstituted with one or more substituents, C1-C6 alkylamino groups substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, and C3-C8 heterocyclic alkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl; preferably, R f1 It is hydrogen;

[0093] R b2 Selected from C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, C3-C8 heterocycloalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 aryl groups substituted or unsubstituted with one or more substituents, C6-C20 arylalkyl groups substituted or unsubstituted with one or more substituents, C6-C20 heteroarylyl groups substituted or unsubstituted with one or more substituents, wherein the substituent is deuterium or fluorine; preferably, R b2 Selected from methyl, deuterated methyl, trifluoromethyl, ethyl, deuterated ethyl, propyl, deuterated propyl, isopropyl, deuterated isopropyl, tert-butyl, and deuterated tert-butyl.

[0094] In some implementations, R9 is hydrogen in the above formulas (I0-1) and / or (I0-4)-(I0-5);

[0095] In some implementations, R9 in the above formulas (I0-1)-(I0-3) is selected from... The rule stipulates that when Y1, Y2, and Y3 are all O, R8 and R9 cannot both be hydrogen; among them,

[0096] The above n1, n2, R a1 R a2 R a3 R a4 W1, R b0 R b1 and R b2 As defined above.

[0097] In some embodiments, a novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I1-1) is provided.

[0098]

[0099] In equation (I1-1),

[0100] 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0101] Y1, Y2, and Y3 are independently selected from O and S, respectively;

[0102] R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0103] R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, and halogens;

[0104] R7 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 atom, hydroxyl, deuterium, or C1-C6 alkoxy.

[0105] R8 and R9 are independently selected from hydrogen, It is stipulated that when Y1, Y2, and Y3 are all O, R8 and R9 cannot both be hydrogen; among them,

[0106] The n1 mentioned above is selected from 1, 2, and 3;

[0107] R a1 and R a2 The substituents are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0108] R b Selected from amino,

[0109] R c Selected from in,

[0110] The n² above is selected from 1, 2, 3, 4, 5, and 6;

[0111] R d1 and R d2 The substituents are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0112] R e1 and R e2 Selected independently from hydrogen,

[0113] R f Selected from R i -OR i and -NR i R j ;

[0114] R gSelected from hydroxyl, substituted or unsubstituted C1-C6 alkyl-O-, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; wherein,

[0115] The above R h1 and R h2 Each is independently selected from hydrogen, or from substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C1-C6 alkyl, guanidinyl, carboxyl, amide, mercapto, hydroxyl, C1-C6 alkyl mercapto, imidazolyl, hydroxyphenyl and phenyl;

[0116] R i and R j The substituents 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, and substituted or unsubstituted C6-C20 heteroarylalkyl, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether.

[0117] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I1-2):

[0118]

[0119] The substituents in equation (I1-2) are defined as defined in equation (I1-1).

[0120] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I1-3):

[0121]

[0122] The substituents in equation (I1-3) are defined as defined in equation (I1-1).

[0123] In some embodiments, in the above formula (I1-1), 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, L is O;

[0124] In some implementations, L is 0 in the above formulas (I1-2)-(I1-3).

[0125] In some implementations, Y1 in the above formulas (I1-1)-(I1-3) is selected from O and S.

[0126] In some implementations, Y2 in the above formulas (I1-1)-(I1-3) is selected from O and S.

[0127] In some implementations, Y3 in the above formulas (I1-1)-(I1-3) is selected from O and S.

[0128] 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, wherein 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.

[0129] In some embodiments, in the above formulas (I1-1)-(I1-3), R2 is selected from hydrogen, deuterium, or halogen; preferably, R2 is selected from hydrogen and deuterium.

[0130] In some embodiments, in the above formulas (I1-1)-(I1-3), R3 is selected from hydrogen, deuterium, or halogen; preferably, R3 is selected from halogen; more preferably, R3 is selected from Cl and Br.

[0131] In some embodiments, in the above formulas (I1-1)-(I1-3), R4 is selected from hydrogen, deuterium, or halogen; preferably, R4 is selected from halogen; more preferably, R4 is selected from Cl and Br.

[0132] In some embodiments, in the above formulas (I1-1)-(I1-3), R5 is selected from hydrogen, deuterium, or halogen; preferably, R5 is selected from hydrogen and deuterium.

[0133] In some embodiments, in the above formulas (I1-1)-(I1-3), R6 is selected from hydrogen, deuterium, or halogen; preferably, R6 is selected from hydrogen and deuterium.

[0134] In some embodiments, in formulas (I1-1)-(I1-3) above, R7 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 atom, hydroxyl, deuterium, or C1-C6 alkoxy; preferably, R7 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atom, hydroxyl, deuterium, or C1-C6 alkoxy; more preferably, R7 is deuterated C1-C6 alkyl; most preferably, R7 is isopropyl with any hydrogen atom deuterated.

[0135] In some implementations, R8 in the above formulas (I1-1)-(I1-2) is hydrogen;

[0136] In some implementations, in formulas (I1-1) and / or (I1-3) above, R8 is selected from... in,

[0137] The n1 mentioned above is selected from 1, 2, or 3; preferably, n1 is selected from 1 or 2; more preferably, n1 is 1;

[0138] R a1 and R a2 The substituents are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a1 and R a2 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; more preferably, R a1 and R a2 All are hydrogen;

[0139] R b Selected from amino,

[0140] R c Selected from in,

[0141] The above n2 is selected from 1, 2, 3, 4, 5, or 6; preferably, n2 is selected from 1, 2, and 3;

[0142] R d1 and R d2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R d1 and R d2 Each is independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R d1and R d2 All are hydrogen;

[0143] R e1 and R e2 Selected independently from hydrogen,

[0144] R f Selected from R i -OR i , or -NR i R j ;

[0145] R g Selected from hydroxyl groups, or -O-substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R g Selected from hydroxyl, -O-C1-C6 alkyl-;

[0146] in,

[0147] The above R h1 and R h2 Each is independently selected from hydrogen, or from substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C1-C6 alkyl, guanidinyl, carboxyl, amide, mercapto, hydroxyl, C1-C6 alkyl mercapto, imidazolyl, hydroxyphenyl, and phenyl.

[0148] R i and R j The groups 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, and substituted or unsubstituted C6-C20 heteroarylalkyl, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether; preferably, R i and R j Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, cyano, ether, and thioether groups.

[0149] In some implementations, R9 is hydrogen in the above formulas (I1-1) and / or (I1-3);

[0150] In some implementations, R9 in the above formulas (I1-1)-(I1-2) is selected from... in,

[0151] The above n1, R a1 R a2 R b and R c As defined above.

[0152] In some embodiments, a novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof, as shown in formula (I2-1) or (I2-2), is provided:

[0153]

[0154] In formula (I2-1) or (I2-2),

[0155] 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0156] Y1, Y2, and Y3 are independently selected from O and S, respectively;

[0157] R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0158] R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, and halogens;

[0159] R7 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 groups, deuterium and C1-C6 alkoxy groups;

[0160] R8 and R9 are independently selected from hydrogen, It is stipulated that R8 and R9 cannot both be hydrogen; among them,

[0161] The n1 mentioned above is selected from 1, 2, and 3;

[0162] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0163] R b1Selected from the following groups, whether substituted or unsubstituted: 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...

[0164] The above R c1 and R c2 They are independently selected from hydrogen and C1-C6 alkyl groups, respectively;

[0165] R b2 The substituent is selected from the following groups, whether substituted or unsubstituted: 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;

[0166] And stipulates that,

[0167] When L is 0, R b1 Selected from those substituted with or unsubstituted with one or more deuterium or fluorine atoms. The following groups, or those substituted with 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;

[0168] When L is 0, R b2 Selected from the following groups substituted with 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.

[0169] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I2-3):

[0170]

[0171] The substituents in equation (I2-3) are defined as defined in equation (I2-1).

[0172] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I2-4):

[0173]

[0174] The substituents in equation (I2-4) are defined as defined in equation (I2-1).

[0175] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I2-5):

[0176]

[0177] The substituents in equation (I2-5) are defined as defined in equation (I2-2).

[0178] In some embodiments, in the above formulas (I2-1)-(I2-5), 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, L is O, S and Se.

[0179] In some implementations, in the above formulas (I2-1)-(I2-5), Y1 is selected from O or S; preferably, Y1 is O.

[0180] In some implementations, in the above formulas (I2-1)-(I2-5), Y2 is selected from O or S; preferably, Y2 is O.

[0181] In some implementations, in the above formulas (I2-1), (I2-3)-(I2-4), Y3 is selected from O or S; preferably, Y3 is O.

[0182] In some embodiments, in the above formulas (I2-1)-(I2-5), R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R1 is selected from hydrogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; more preferably, R1 is selected from cyano and C1-C6 alkyl.

[0183] In some embodiments, in the above formulas (I2-1)-(I2-5), R2 is selected from hydrogen, deuterium, and halogen; preferably, R2 is selected from hydrogen and deuterium.

[0184] In some embodiments, in the above formulas (I2-1)-(I2-5), R3 is selected from hydrogen, deuterium, and halogens; preferably, R3 is selected from halogens; more preferably, R3 is selected from Cl and Br.

[0185] In some embodiments, in the above formulas (I2-1)-(I2-5), R4 is selected from hydrogen, deuterium, and halogens; preferably, R4 is selected from halogens; more preferably, R4 is selected from Cl and Br.

[0186] In some embodiments, in the above formulas (I2-1)-(I2-5), R5 is selected from hydrogen, deuterium, and halogen; preferably, R5 is selected from hydrogen and deuterium.

[0187] In some embodiments, in the above formulas (I2-1)-(I2-5), R6 is selected from hydrogen, deuterium, and halogen; preferably, R6 is selected from hydrogen and deuterium.

[0188] In some embodiments, in formulas (I2-1)-(I2-5) above, R7 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 atom, hydroxyl, deuterium, or C1-C6 alkoxy; preferably, R7 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atom, hydroxyl, deuterium, or C1-C6 alkoxy; more preferably, R7 is C1-C6 alkyl or deuterated C1-C6 alkyl; most preferably, R7 is isopropyl or isopropyl with any hydrogen atom deuterated.

[0189] In some implementations, R8 is hydrogen in the above formulas (I2-1) and / or (I2-3);

[0190] In some implementations, in the above formulas (I2-1)-(I2-2) and / or (I2-4)-(I2-5), R8 is selected from... in,

[0191] The n1 mentioned above is selected from 1, 2, and 3; preferably, n1 is selected from 1 and 2; more preferably, n1 is 1;

[0192] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a1 and R a2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl; more preferably, R a1 and R a2 All are hydrogen, R a1 and R a2 All are deuterium;

[0193] R b1Selected from the following groups, whether substituted or unsubstituted: 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 Selected from C1-C6 alkyl groups substituted with or unsubstituted with deuterium or fluorine. Among them, the above R c1 and R c2 Each is independently selected from hydrogen and C1-C6 alkyl groups, preferably R. c1 and R c2 All are hydrogen;

[0194] R b2 Selected from the following groups, whether substituted or unsubstituted: 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; preferably, R b2 Selected from C1-C6 alkyl groups that are substituted with deuterium, fluorine, or unsubstituted.

[0195] Regulation,

[0196] When L is 0, R b1 Selected from those substituted with or unsubstituted with one or more deuterium or fluorine atoms. The following groups, or those substituted with 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;

[0197] When L is 0, R b2 Selected from the following groups substituted with one or more deuterium or fluorine groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

[0198] In some embodiments, a novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof, as shown in formula (I3-1) or (I3-2), is provided:

[0199]

[0200] In formula (I3-1) or (I3-2),

[0201] 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0202] Y1, Y2, and Y3 are independently selected from O and S, respectively;

[0203] R1 is selected from hydrogen, cyano, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups;

[0204] R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, and halogens;

[0205] R7 is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, deuterium, or C1-C6 alkoxy groups.

[0206] R8 and R9 are independently selected from hydrogen, It is stipulated that R8 and R9 cannot both be hydrogen; among them,

[0207] The n1 mentioned above is selected from 1, 2, and 3;

[0208] W1 is either O or S;

[0209] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, C1-C6 alkyl groups substituted or unsubstituted with one or more substituents, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium, halogens, hydroxyl groups and C1-C6 alkoxy groups;

[0210] R a3 and R a4 They are independently selected from C1-C6 alkyl groups substituted or unsubstituted with one or more halogen atoms, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more halogen atoms;

[0211] R b1 Selected from in,

[0212] The above R c1 and R c2Each group is independently selected from the following groups, each being hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or R c1 and R c2 The carbon atoms connected to it are linked together to form a ring, and the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

[0213] R d Selected from in,

[0214] The above W2 and W3 are independently selected from O and S, respectively;

[0215] R c3 R c4 R c5 and R c6 Each group is independently selected from the following groups, each being hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, 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 they are connected to form a ring, or, R c5 and R c6 The carbon atoms connected to it are linked together to form a ring, and the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

[0216] R e and R f The following groups are selected independently from hydrogen, substituted with one or more substituents, or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, and C3-C8 heterocycloalkyl, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0217] Rb2 Selected from the following groups, which may be 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;

[0218] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I3-3):

[0219]

[0220] The substituents in equation (I3-3) are defined as defined in equation (I3-1).

[0221] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I3-4):

[0222]

[0223] The substituents in equation (I3-4) are defined as defined in equation (I3-1).

[0224] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I3-5):

[0225]

[0226] The substituents in equation (I3-5) are defined as defined in equation (I3-2).

[0227] In some embodiments, in the above formulas (I3-1)-(I3-5), 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, L is O, S and Se.

[0228] In some implementations, in the above formulas (I3-1)-(I3-5), Y1 is selected from O and S; preferably, Y1 is O.

[0229] In some implementations, in the above formulas (I3-1)-(I3-5), Y2 is selected from O and S; preferably, Y2 is O.

[0230] In some implementations, in the above formulas (I3-1), (I3-3)-(I3-4), Y3 is selected from O and S; preferably, Y3 is O.

[0231] In some embodiments, in the above formulas (I3-1)-(I3-5), R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups; preferably, R1 is selected from hydrogen, cyano, C1-C6 alkyl and C3-C6 cycloalkyl groups; more preferably, R1 is selected from cyano and C1-C6 alkyl groups.

[0232] In some embodiments, in the above formulas (I3-1)-(I3-5), R2 is selected from hydrogen, deuterium, and halogen; preferably, R2 is selected from hydrogen and deuterium.

[0233] In some embodiments, in the above formulas (I3-1)-(I3-5), R3 is selected from hydrogen, deuterium, and halogens; preferably, R3 is selected from halogens; more preferably, R3 is selected from Cl and Br.

[0234] In some embodiments, in the above formulas (I3-1)-(I3-5), R4 is selected from hydrogen, deuterium, and halogens; preferably, R4 is selected from halogens; more preferably, R4 is selected from Cl and Br.

[0235] In some embodiments, in the above formulas (I3-1)-(I3-5), R5 is selected from hydrogen, deuterium, and halogen; preferably, R5 is selected from hydrogen and deuterium.

[0236] In some embodiments, in the above formulas (I3-1)-(I3-5), R6 is selected from hydrogen, deuterium, and halogen; preferably, R6 is selected from hydrogen and deuterium.

[0237] In some embodiments, in formulas (I3-1)-(I3-5) above, R7 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, C1-C6 alkoxy; preferably, R7 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium, C1-C6 alkoxy; more preferably, R7 is C1-C6 alkyl and deuterated C1-C6 alkyl; most preferably, R7 is isopropyl and isopropyl with any hydrogen atom deuterated;

[0238] In some implementations, R8 is hydrogen in the above formulas (I3-1) and / or (I3-3);

[0239] In some implementations, in the above formulas (I3-1)-(I3-2) and / or (I3-4)-(I3-5), R8 is selected from... in,

[0240] The n1 mentioned above is selected from 1, 2, and 3; preferably, n1 is selected from 1 and 2; more preferably, n1 is 1;

[0241] W1 is selected from O, and S;

[0242] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a1 and R a2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl; more preferably, R a1 and R a2 All are hydrogen, R a1 and R a2 All are deuterium;

[0243] R a3 and R a4 Each is independently selected from C1-C6 alkyl groups substituted or unsubstituted with one or more halogen atoms, and C3-C6 cycloalkyl groups substituted or unsubstituted with one or more halogen atoms; preferably, R a3 and R a4 One of them is hydrogen, and the other is trifluoromethyl;

[0244] R b1 not yet in,

[0245] The above R c1 and R c2 Each group is independently selected from the following groups, each being hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or R c1 and R c2 The carbon atoms connected to it are linked together to form a ring, wherein the substituents are deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably, R c1 and R c2Each is independently selected from C1-C6 alkyl groups substituted with hydrogen, deuterium, halogen, or one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, or trifluoromethyl; more preferably, R c1 and R c2 Each is independently selected from hydrogen, methyl, and isopropyl;

[0246] R d Selected from in,

[0247] The above W2 is selected from O or S;

[0248] W3 is selected from O or S;

[0249] R c3 and R c4 Each group is independently selected from the following groups, each being hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or R c3 and R c4 The carbon atoms connected to it form a ring, and the substituents are hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably, R c3 and R c4 Each is independently selected from C1-C6 alkyl groups substituted with hydrogen, deuterium, halogen, or one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, or phenyl; more preferably, R c3 and R c4 Each of the following is independently selected from hydrogen, benzyl, isopropyl, isobutyl, deuterated isopropyl, and deuterated isobutyl;

[0250] R c5 and R c6 Each group is independently selected from the following groups, each being hydrogen, deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted by one or more substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl, or R c5 and R c6The carbon atoms connected to it form a ring, and the substituents are hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably, R c5 and R c6 Each is independently selected from C1-C6 alkyl groups substituted with hydrogen, deuterium, halogen, or one or more deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, or phenyl; more preferably, R c5 and R c6 Each is independently selected from hydrogen, methyl, and deuterated methyl;

[0251] R e The group is selected from hydrogen, substituted with one or more substituents, or unsubstituted from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, and C3-C8 heterocycloalkyl, wherein the substituent is hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloyl, aryl, and heteroaryl; preferably, R e It is hydrogen;

[0252] R f The group is selected from hydrogen, substituted with one or more substituents, or unsubstituted from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl, and C3-C8 heterocycloalkyl, wherein the substituent is hydrogen, deuterium, halogen, cyano, carboxyl, amino, nitro, methyl, ethyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, trifluoromethyl, difluoromethyl, cycloalkyl, heterocycloyl, aryl, and heteroaryl; preferably, R f It is hydrogen;

[0253] R b2 Selected from the following groups, substituted or unsubstituted: 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; preferably, R b2 Selected from methyl, ethyl, deuterated methyl, and deuterated ethyl.

[0254] In some implementations, R9 is hydrogen in the above formulas (I3-1) and / or (I3-4)-(I3-5);

[0255] In some implementations, R9 in the above formulas (I3-1)-(I3-3) is selected from... in,

[0256] The above n1, n2, R a1 R a2 R a3 R a4 W1, R b1 and R b2 As defined above.

[0257] In some embodiments, a novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof, as shown in formula (I4-1) or (I4-2), is provided:

[0258]

[0259] In formula (I4-1) or (I4-2),

[0260] 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0261] Y1, Y2, and Y3 are independently selected from O and S, respectively;

[0262] R1 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0263] R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, and halogens;

[0264] R7 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 groups, deuterium and C1-C6 alkoxy groups;

[0265] R8 and R9 are independently selected from hydrogen, Specifically, R8 and R9 cannot both be hydrogen; among them,

[0266] The n1 mentioned above is selected from 1, 2, and 3;

[0267] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups and C1-C6 alkoxy groups;

[0268] Rb1 Selected from the following groups, whether substituted or unsubstituted: 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...

[0269] The above R c1 and R c2 They are independently selected from hydrogen and C1-C6 alkyl groups, respectively;

[0270] R b2 The substituent is selected from the following groups, whether substituted or unsubstituted: 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;

[0271] And stipulates that,

[0272] When L is 0, R b1 Selected from those substituted with or unsubstituted with one or more deuterium or fluorine atoms. The following groups, or those substituted with 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;

[0273] When L is 0, R b2 Selected from the following groups substituted with 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.

[0274] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I4-3):

[0275]

[0276] The substituents in equation (I4-3) are defined as defined in equation (I4-1).

[0277] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formula (I4-4):

[0278]

[0279] The substituents in equation (I4-4) are defined as defined in equation (I4-1).

[0280] In some embodiments, the present invention provides a novel pyridazine compound, tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof as shown in formulas (I4-5):

[0281]

[0282] The substituents in equation (I4-5) are defined as defined in equation (I4-2).

[0283] In some embodiments, in the above formulas (I4-1)-(I4-5), 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, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, L is O, S and Se.

[0284] In some implementations, in the above formulas (I4-1)-(I4-5), Y1 is selected from O and S; preferably, Y1 is O.

[0285] In some implementations, in the above formulas (I4-1)-(I4-5), Y2 is selected from O and S; preferably, Y2 is O.

[0286] In some implementations, in the above formulas (I4-1), (I4-3)-(I4-4), Y3 is selected from O and S; preferably, Y3 is O.

[0287] In some embodiments, in the above formulas (I4-1)-(I4-5), R1 is selected from hydrogen, cyano, 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, R1 is selected from hydrogen, cyano, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R1 is selected from cyano and C1-C6 alkyl.

[0288] In some embodiments, in the above formulas (I4-1)-(I4-5), R2 is selected from hydrogen, deuterium, and halogen; preferably, R2 is selected from hydrogen and deuterium.

[0289] In some embodiments, in the above formulas (I4-1)-(I4-5), R3 is selected from hydrogen, deuterium, and halogens; preferably, R3 is selected from halogens; more preferably, R3 is selected from Cl and Br.

[0290] In some embodiments, in the above formulas (I4-1)-(I4-5), R4 is selected from hydrogen, deuterium, and halogens; preferably, R4 is selected from halogens; more preferably, R4 is selected from Cl and Br.

[0291] In some embodiments, in the above formulas (I4-1)-(I4-5), R5 is selected from hydrogen, deuterium, and halogen; preferably, R5 is selected from hydrogen and deuterium.

[0292] In some embodiments, in the above formulas (I4-1)-(I4-5), R6 is selected from hydrogen, deuterium, and halogen; preferably, R6 is selected from hydrogen and deuterium.

[0293] In some embodiments, in formulas (I4-1)-(I4-5) above, R7 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; preferably, R7 is selected from substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl, deuterium, and C1-C6 alkoxy; more preferably, R7 is a C1-C6 alkyl or a deuterated C1-C6 alkyl; most preferably, R7 is isopropyl or an isopropyl with any hydrogen atom deuterated.

[0294] In some implementations, R8 is hydrogen in the above formulas (I4-1) and / or (I4-3);

[0295] In some implementations, in the above formulas (I4-1)-(I4-2) and / or (I4-4)-(I4-5), R8 is selected from... in,

[0296] The n1 mentioned above is selected from 1, 2, and 3; preferably, n1 is selected from 1 and 2; more preferably, n1 is 1;

[0297] R a1 and R a2 The substituents are independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C6 cycloalkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C1-C6 alkoxy groups; preferably, R a1 and R a2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl; more preferably, R a1 and R a2 All are hydrogen, or R a1 and R a2 All are deuterium;

[0298] R b1Selected from the following groups, whether substituted or unsubstituted: 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 Selected from C1-C6 alkyl groups substituted with or unsubstituted with deuterium, fluorine, and... Among them, the above R c1 and R c2 Each is independently selected from hydrogen and C1-C6 alkyl groups, preferably R. c1 and R c2 All are hydrogen;

[0299] R b2 Selected from the following groups, whether substituted or unsubstituted: 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; preferably, R b2 Selected from C1-C6 alkyl groups that are substituted with deuterium, fluorine, or unsubstituted.

[0300] Regulation,

[0301] When L is 0, R b1 Selected from those substituted with or unsubstituted with one or more deuterium or fluorine atoms. The following groups, or those substituted with 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;

[0302] When L is 0, R b2 Selected from the following groups substituted with one or more deuterium or fluorine groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl, C6-C20 arylalkyl, C6-C20 heteroaryl, C6-C20 heteroarylalkyl;

[0303] In some embodiments, the novel pyridazine compounds, tautomers, stereoisomers, isotope derivatives, or pharmaceutically acceptable salts thereof provided by the present invention are selected from the following compounds:

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned novel pyridazine compounds, tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts thereof.

[0316] In another aspect, the present invention provides the use of the above-mentioned novel pyridazine compounds, tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of thyroid hormone receptor-related diseases.

[0317] In another aspect, the present invention provides the above-mentioned novel pyridazine compounds, tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions, for use in the prevention or treatment of thyroid hormone receptor-related diseases.

[0318] In another aspect, the present invention provides a method for preventing or treating thyroid hormone receptor-related diseases, comprising administering to an individual in need a therapeutically effective amount of the aforementioned novel pyridazine compound, solvate, stereoisomer, tautomer, isotope derivative or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0319] This invention provides the use or method of the above-described pharmaceutical composition in the preparation of a drug for the prevention or treatment of thyroid hormone receptor-related diseases, wherein the prevention or treatment of thyroid hormone receptor-related diseases includes obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH), hypertriglyceridemia, and hepatic steatosis.

[0320] In some embodiments, the novel compounds of the present invention can be formulated as pharmaceutical compositions and administered to patients via a variety of suitable routes of administration, including systemic (e.g., oral or parenteral), intravenous, intramuscular, transdermal, or subcutaneous routes.

[0321] The compounds disclosed in this invention have superior selective THRβ agonist activity.

[0322] The compounds disclosed in this invention have superior pharmacokinetic properties. When administered by gavage, the half-life is prolonged by about 1.5 times, the time to peak concentration is shortened by about 1.5 times, the exposure is increased by more than 2 times, the residence time is prolonged by more than 1.6 times, the bioavailability is increased by more than 1.5 times, and there are obvious enterohepatic circulation characteristics.

[0323] The compounds disclosed in this invention exhibit superior efficacy in reducing liver index, liver TC and TG, liver fibrosis ratio, and NAS score in a NASH mouse model.

[0324] definition:

[0325] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0326] Some compounds of this invention can exist in either a solvated or a solvent-based form, such as hydrates or ethanolates. Generally, the solvent-based and the solvent-based forms are equivalent and are both included within the scope of this invention.

[0327] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0328] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound 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 amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0329] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one to three, and most preferably one or two.

[0330] 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 can be substituted or unsubstituted. There can be one or more carbon-carbon double bonds.

[0331] The term "cycloalkyl" refers to a monocyclic or fused-ring group consisting entirely of carbon atoms (a "fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system), wherein one or more rings do not have a fully connected π-electron system. Examples of cycloalkyl groups (but not limited to) include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cyclohepttriene. Cycloalkyl groups can be substituted or unsubstituted.

[0332] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group with 1 to 12 carbon atoms and a fully conjugated π-electron system. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene. Aryl groups can 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.

[0333] The term "heteroaryl" refers to a monocyclic or fused cyclic group of multiple atoms containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining cyclic atoms being C, and possessing a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazolium, triazine, and carbazole.

[0334] The term "alkoxy" refers to an alkyl group bonded to an oxygen atom, where the alkyl group can be straight-chain, branched, or cycloalkyl.

[0335] The term "hydroxyl group" refers to the -OH group.

[0336] The term "amino" refers to the -NH2 group.

[0337] The term "carboxyl group" refers to the -COOH group.

[0338] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0339] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc.

[0340] The term "stereoisomer" refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups.

[0341] The numerical range mentioned in this application, such as "C1-C6", means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms. Attached Figure Description

[0342] Figure 1 The curve is for administering the drug via gavage.

[0343] Figure 2 The result is for TC in the liver.

[0344] Figure 3 The result is for liver TG.

[0345] Figure 4 The NAS rating results.

[0346] Figure 5 This is the result of the fibrosis evaluation. Detailed Implementation

[0347] The following examples provide numerous exemplary methods for preparing the compounds of the present invention. The invention is described in detail below through examples, but this does not imply any adverse limitation thereof. The invention has been described in detail herein, and specific embodiments thereof are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope thereof. Some compounds of the present invention can be used as intermediates for preparing other compounds of the present invention; the structures of all compounds have been determined by liquid chromatography-mass spectrometry. Unless otherwise specified, the materials used in the examples of this application were commercially available.

[0348] Example 1: Synthesis of ZJT1 in the compound

[0349] Reaction formula:

[0350]

[0351] Preparation method:

[0352] Step 1: Preparation of compound ZJT1-03:

[0353] Under nitrogen protection and at room temperature, 3,6-dichloro-4-isopropylpyridazine (3.82 g, 0.02 mol) was dissolved in dimethyl sulfoxide (25 mL), followed by 2,6-dichloro-4-aminophenol (3.56 g, 0.02 mol), anhydrous potassium carbonate (13.8 g, 0.1 mol), and cuprous iodide (3.81 g, 0.02 mol) sequentially. The reaction mixture was reacted at 90 °C for 24 hours, then cooled to room temperature and poured into water (750 mL). The pH was adjusted to 7-8 with 1 N dilute hydrochloric acid, and then ethyl acetate was added and stirred thoroughly. The system was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was purified and separated, the organic phase was collected, and the aqueous phase was extracted twice more with ethyl acetate. 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 give compound ZJT1-03 (3.15 g), with a yield of 47.4%. ESI-MS(+): m / z = 332.03.

[0354] Step 2: Preparation of compound ZJT1-02:

[0355] 100 mL of glacial acetic acid was added to the reaction flask, followed by the sequential addition of compound ZJT1-03 (3.0 g, 9.0 mmol) and sodium acetate (2.21 g, 27.0 mmol) under stirring at room temperature. After the addition was complete, the system was heated to 100 °C and reacted for 24 h, then cooled to room temperature and reacted for 2 days. The system was concentrated, and the residue was diluted with water. The pH of the system was then adjusted to 9 with 1 N sodium hydroxide. The system was extracted twice with ethyl acetate, and the aqueous phase was adjusted to pH 5 with concentrated hydrochloric acid and extracted twice more with ethyl acetate. All layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol, and 1N sodium hydroxide (63 mL, 63 mmol) was added. The mixture was heated to 120 °C and reacted for 24 hours. Then, the mixture was cooled and concentrated. The residue was extracted twice with ethyl acetate with an appropriate amount of purified water. The combined organic phases were washed twice with dilute hydrochloric acid and saturated brine, respectively. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound ZJT1-02 (1.29 g), with a yield of 45.6%. ESI-MS(+): m / z = 314.08.

[0356] Step 3: Preparation of compound ZJT1-01:

[0357] Compound ZJT1-02 (1.2 g, 3.82 mmol) was added to water (65 mL), followed by concentrated hydrochloric acid (25 mL). 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. The mixture was then stirred at 0 °C for 30 minutes. The reaction solution was then rapidly filtered, and the filtrate was rapidly added to a mixture of N-cyanoaceturane (0.66 g, 4.23 mmol), water (100 mL), and pyridine (25 mL) pre-cooled to 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes, filtered, and the filter cake was washed successively with water and petroleum ether. The solution was purified by column chromatography to give compound ZJT1-01 (0.85 g), with a yield of 46.2%. ESI-MS(+): m / z = 481.10.

[0358] Step 4: Preparation of compound ZJT1:

[0359] Compound ZJT1-01 (0.70 g, 1.45 mmol) was added to glacial acetic acid (15 mL) at room temperature, followed by sodium acetate (0.6 g, 7.25 mmol). The reaction mixture was heated to 120 °C and maintained for 1.5 hours, then cooled to 0 °C. The system was diluted with water and stirred for 30 minutes. After filtration, the filter cake was dissolved in hot acetonitrile and decolorized with activated carbon. The mixture was filtered through diatomaceous earth, washed, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixture of water and acetonitrile, filtered, and dried to give compound ZJT1 (0.35 g), yield 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).

[0360] Example 2: Synthesis of compound ZJT2

[0361] Reaction formula:

[0362]

[0363] Preparation method:

[0364] 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. The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, water and dichloromethane were added, the mixture was shaken, and the layers were separated. The aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to obtain compound ZJT2 (0.33 g), with a yield of 35.4%. ESI-MS (+): m / z = 465.07.

[0365] Example 3: Synthesis of compound ZJT3

[0366] Reaction formula:

[0367]

[0368] Preparation method:

[0369] Step 1: Preparation of compound ZJT3-01

[0370] 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 sequentially to 1,4-dioxane (20 mL). After the addition was complete, the mixture was heated to 65 °C and reacted for 16 hours. The mixture was then concentrated under reduced pressure, and the residue was separated by pre-liquid chromatography to give compound ZJT3-01 (0.53 g), with a yield of 51.0%. ESI-MS (+): m / z = 519.14.

[0371] Step 2: Preparation of compound ZJT3

[0372] Following the procedure described in Example 2, compound ZJT3 (0.24 g) was obtained in a yield of 30.1%. ESI-MS(+): m / z = 549.15.

[0373] Example 4: Synthesis of compound NASH161-01

[0374] Reaction formula:

[0375]

[0376] Preparation method:

[0377] In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added sequentially to dichloromethane (10 mL). Then, a solution of dichloromethane (5 mL) containing NASH161-01-SM (0.16 g, 1 mmol) was added dropwise at 0 °C. The mixture was stirred and reacted for 5 hours. The system was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound NASH161-01 (0.18 g), with a yield of 30.7%. ESI-MS(+): m / z = 586.10.

[0378] Example 5: Synthesis of compound NASH161-02

[0379] Reaction formula:

[0380]

[0381] Preparation method:

[0382] Step 1: Preparation of compound NASH161-0201

[0383] In the reaction flask, toluene (10 mL), NASH161-02-SM (0.29 g, 1.2 mmol), and 2 drops of N,N-dimethylformamide were added sequentially. Then, thionyl chloride (0.22 g, 1.8 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was carried out at 70 °C for 1 hour. The system was then cooled and concentrated under reduced pressure. The residue was then concentrated under reduced pressure again after adding toluene to remove excess thionyl chloride. The residue was compound NASH161-0201, which was used directly in the next step without further processing.

[0384] Step 2: Preparation of compound NASH161-02

[0385] In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added sequentially to dichloromethane (10 mL). Then, a dichloromethane solution (5 mL) containing NASH161-0201 (1.2 mmol, based on a 100% yield from the previous step) was added dropwise at 0 °C. 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 chromatography to give compound NASH161-02 (0.19 g), with a yield of 27.7%. ESI-MS(+): m / z = 685.17.

[0386] Example 6: Synthesis of compound NASH161-03

[0387] Reaction formula:

[0388]

[0389] Preparation method:

[0390] Following the procedure in Example 4, compound NASH161-03 (0.21 g) was prepared by replacing NASH161-01-SM with NASH161-03-SM, with a yield of 32.8%. ESI-MS(+): m / z = 601.05.

[0391] Example 7: Synthesis of compound NASH161-04

[0392] Reaction formula:

[0393]

[0394] Preparation method:

[0395] Step 1: Preparation of compound NASH161-0401

[0396] In the reaction flask, toluene (10 mL), 3-sulfopropionic acid (0.19 g, 1.2 mmol), and 2 drops of N,N-dimethylformamide were added sequentially. Then, thionyl chloride (0.22 g, 1.8 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was carried out at 55 °C for 30 minutes. The system was then cooled and concentrated under reduced pressure. The residue was then concentrated again under reduced pressure after adding toluene to remove excess thionyl chloride. The residue was compound NASH161-0401, which was used directly in the next step without further processing.

[0397] Step 2: Preparation of compound NASH161-04

[0398] In a reaction flask, ZJT2 (0.47 g, 1 mmol) and triethylamine (0.15 g, 1.5 mmol) were added sequentially to dichloromethane (10 mL). Then, a dichloromethane solution (5 mL) containing NASH161-0401 (1.2 mmol, based on a 100% yield from the previous step) was added dropwise at 0 °C. The reaction was stirred for 6 hours while maintaining the temperature. The system was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound NASH161-04 (0.14 g), with a yield of 23.3%. ESI-MS(+): m / z = 601.07.

[0399] Example 8: Synthesis of compound NASH161-09

[0400] Reaction formula:

[0401]

[0402] Preparation method:

[0403] Step 1: Synthesis of compound NASH161-0906

[0404] 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 sequentially to a reaction flask. After the additions were complete, the temperature was raised to 55 °C, and a solution of concentrated sulfuric acid (4.8 mL) in water (15 mL) was added. Then, a solution of ammonium persulfate (10.2 g, 44.6 mmol) in water (15 mL) was added dropwise over 40 minutes. After the additions were complete, the temperature was raised to 70 °C and reacted for 20 minutes. The mixture was then cooled to room temperature and stirred at room temperature for 24 hours. The system was cooled to 0°C, and the pH was adjusted to 8 with ammonia. After dilution with water, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was allowed to stand to separate the organic phase, which was then extracted twice with ethyl acetate. The organic phases were combined, washed separately with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound NASH161-0906 (3.98 g), with a yield of 68.0%. ESI-MS(+): m / z = 197.08.

[0405] Steps 2-5 followed the procedures outlined in Example 1 to prepare compound NASH161-0902 (0.48 g), with an overall yield of 6.2%. ESI-MS (+): m / z = 441.11.

[0406] Example 9: Synthesis of compound NASH161-13

[0407] Reaction formula:

[0408]

[0409] Preparation method:

[0410] Step 1: Synthesis of compound NASH161-1301

[0411] Following the procedure in Example 4, compound NASH161-1301 (0.76 g) was prepared by replacing ZJT2 with ZJT3, with a yield of 31.7%. ESI-MS(+): m / z = 670.18.

[0412] Step 2: Synthesis of compound NASH161-13

[0413] Compound NASH161-1301 (0.67 g, 1.0 mmol) and dichloromethane (50 mL) were added sequentially to a reaction flask, followed by the dropwise addition of trifluoroacetic acid (7 mL). After the addition was complete, the reaction mixture was allowed to react at room temperature for 6 hours, then quenched and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain the target compound NASH161-13 (0.21 g), with a yield of 35.8%. ESI-MS(+): m / z = 586.11.

[0414] Example 10: Synthesis of compound NASH161-14

[0415] Reaction formula:

[0416]

[0417] Preparation method:

[0418] Step 1: Synthesis of compound NASH161-1401

[0419] Following the procedure in step 2 of Example 5, compound NASH161-1401 (0.54 g) was prepared by replacing ZJT2 with ZJT3, with a yield of 28.8%. ESI-MS(+): m / z = 769.24.

[0420] Step 2: Synthesis of compound NASH161-14

[0421] Following the procedure in step 2 of Example 9, NASH161-14 (0.16 g) was prepared by replacing NASH161-1301 with NASH161-1401, with a yield of 38.2%. ESI-MS(+): m / z = 685.19.

[0422] Example 11: Synthesis of compound NASH161-15

[0423] Reaction formula:

[0424]

[0425] Preparation method:

[0426] Step 1: Synthesis of compound NASH161-1501

[0427] Following the procedure described in Example 6, compound NASH161-1501 (0.43 g) was prepared by replacing ZJT2 with ZJT3, with a yield of 26.7%. ESI-MS(+): m / z = 685.11.

[0428] Step 2: Synthesis of compound NASH161-15

[0429] Following the procedure in step 2 of Example 9, NASH161-15 (0.22 g) was prepared by replacing NASH161-1301 with NASH161-1501, with a yield of 36.5%. ESI-MS(+): m / z = 601.08.

[0430] Example 12: Synthesis of compound NASH161-16

[0431] Reaction formula:

[0432]

[0433] Preparation method:

[0434] Step 1: Synthesis of compound NASH161-1601

[0435] Following the procedure in step 2 of Example 7, compound NASH161-1601 (0.43 g) was prepared by replacing ZJT2 with ZJT3, with a yield of 26.7%. ESI-MS(+): m / z = 685.11.

[0436] Step 2: Synthesis of compound NASH161-16

[0437] Following the procedure in step 2 of Example 9, NASH161-16 (0.36 g) was prepared by replacing NASH161-1301 with NASH161-1601, with a yield of 32.8%. ESI-MS(+): m / z = 601.05.

[0438] Example 13: Synthesis of compound NASH161-26

[0439] Reaction formula:

[0440]

[0441] Preparation method:

[0442] Under argon protection, Lawson's reagent (14.2 g, 35 mmol) was added to anhydrous toluene (200 mL) containing ZJT1 (4.35 g, 10 mmol) at room temperature. The mixture was heated to 110 °C and reacted for 5 hours. The reaction was monitored by TLC until completion, and then cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound NASH161-26 (2.7 g), with a yield of 55.9%. ESI-MS (+): m / z = 482.99.

[0443] Example 14: Synthesis of compound NASH161-29

[0444] Reaction formula:

[0445]

[0446] Preparation method:

[0447] Step 1: Synthesis of compound NASH161-2901

[0448] Following the procedure described in Example 2, compound NASH161-2901 (0.61 g) was prepared by replacing ZJT2 with NASH161-26, with a yield of 30.1%. ESI-MS(+): m / z = 512.91.

[0449] Step 2: Synthesis of compound NASH161-29

[0450] Following the procedure in step 2 of Example 5, compound NASH161-29 (0.21 g) was prepared by replacing ZJT2 with NASH161-2901, with a yield of 25.2%. ESI-MS(+): m / z = 733.11.

[0451] Example 15: Synthesis of compound NASH161-36

[0452] Reaction formula:

[0453]

[0454] Preparation method:

[0455] Step 1-Step 2: Preparation of compound NASH161-3602

[0456] Following the procedure in Example 3, compound NASH161-3602 (0.98 g) was prepared by replacing ZJT1 with NASH161-29, with an overall yield of 17.3%. ESI-MS(+): m / z = 597.09.

[0457] Step 3: Preparation of compound NASH161-3601

[0458] Following the procedure in step 2 of Example 5, compound NASH161-3601 (0.46 g) was prepared by replacing ZJT2 with ZNASH161-3602, with a yield of 25.7%. ESI-MS(+): m / z = 817.16.

[0459] Step 4: Preparation of compound NASH161-36

[0460] Following the procedure in step 2 of Example 9, NASH161-36 (0.37 g) was prepared by replacing NASH161-1301 with NASH161-3601, with a yield of 33.3%. ESI-MS(+): m / z = 733.11. Yield 40.8%.

[0461] ESI-MS(+): m / z = 287.15.

[0462] Example 16: Synthesis of ZJT1 in the compound

[0463] Reaction formula:

[0464]

[0465] Preparation method:

[0466] Step 1: Preparation of compound ZJT1-03:

[0467] Under nitrogen protection and at room temperature, 3,6-dichloro-4-isopropylpyridazine (3.82 g, 0.02 mol) was dissolved in dimethyl sulfoxide (25 mL), followed by 2,6-dichloro-4-aminophenol (3.56 g, 0.02 mol), anhydrous potassium carbonate (13.8 g, 0.1 mol), and cuprous iodide (3.81 g, 0.02 mol). The reaction mixture was reacted at 90 °C for 24 hours, then cooled to room temperature and poured into water (750 mL). The pH was adjusted to 7-8 with 1 N dilute hydrochloric acid, and then ethyl acetate was added and stirred thoroughly. The mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was purified and separated, the organic phase was collected, and the aqueous phase was extracted twice more with ethyl acetate. 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 give compound ZJT1-03 (3.37 g), with a yield of 50.7%. ESI-MS(+): m / z = 332.08.

[0468] Step 2: Preparation of compound ZJT1-02:

[0469] 100 mL of glacial acetic acid was added to the reaction flask, followed by the sequential addition of compound ZJT1-03 (3.3 g, 9.9 mmol) and sodium acetate (2.43 g, 29.7 mmol) under stirring at room temperature. After the addition was complete, the system was heated to 100 °C and reacted for 24 h, then cooled to room temperature and reacted for 2 days. The system was concentrated, and the residue was diluted with water. The pH of the system was then adjusted to 9 with 1 N sodium hydroxide. The system was extracted twice with ethyl acetate, and the aqueous phase was adjusted to pH 5 with concentrated hydrochloric acid and extracted twice more with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol, and 1N sodium hydroxide (63 mL, 65 mmol) was added. The mixture was heated to 120 °C and reacted for 24 hours. Then, the mixture was cooled and concentrated. The residue was extracted twice with ethyl acetate with an appropriate amount of purified water. The combined organic phases were washed twice with dilute hydrochloric acid and saturated brine, respectively. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound ZJT1-02 (1.62 g), with a yield of 52.0%. ESI-MS(+): m / z = 314.11.

[0470] Step 3: Preparation of compound ZJT1-01:

[0471] Compound ZJT1-02 (1.6 g, 5.08 mmol) was added to water (90 mL), followed by concentrated hydrochloric acid (35 mL). 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. The mixture was then stirred at 0 °C for 30 minutes. The reaction solution was then rapidly filtered, and the filtrate was rapidly added to a mixture of N-cyanoacetylurane (0.88 g, 5.63 mmol), water (130 mL), and pyridine (35 mL) pre-cooled to 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes, filtered, and the filter cake was washed successively with water and petroleum ether. The solution was purified by column chromatography to give compound ZJT1-01 (1.16 g), with a yield of 47.3%. ESI-MS (+): m / z = 481.12.

[0472] Step 4: Preparation of compound ZJT1:

[0473] Compound ZJT1-01 (1.10 g, 2.28 mmol) was added to glacial acetic acid (25 mL) at room temperature, followed by sodium acetate (0.94 g, 11.38 mmol). The reaction mixture was heated to 120 °C and maintained for 1.5 hours, then cooled to 0 °C. The system was diluted with water and stirred for 30 minutes. The mixture was filtered, the filter cake was dissolved in hot acetonitrile and decolorized with activated carbon, filtered through diatomaceous earth, washed, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixture of water and acetonitrile, filtered, and dried to give compound ZJT1 (0.58 g), yield 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).

[0474] Example 17: Synthesis of compound ZJT2A

[0475] Reaction formula:

[0476]

[0477] Preparation method:

[0478] 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. The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, water and dichloromethane were added, the mixture was shaken, and the layers were separated. The aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated by liquid chromatography to give compound ZJT2A (0.89 g), with a yield of 47.8%. ESI-MS (+): m / z = 465.11.

[0479] Example 18: Synthesis of compound NASH179-01

[0480] Reaction formula:

[0481]

[0482] Preparation method:

[0483] Step 1: Preparation of chloromethyl (methyl-d3) carbonate

[0484] 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. The reaction was carried out at room temperature for 3 h. After the reaction was complete, the mixture was quenched with water (12 mL), extracted with dichloromethane (25 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to give the target substance (4.6 g), with a yield of 72.1%.

[0485] Step 2: Preparation of compound NASH179-0102

[0486] Compound ZJT1 (0.60 g, 1.38 mmol), pyridinium 4-methylbenzenesulfonic acid (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 sequentially to a Schlenk tube. After the addition was complete, the reaction mixture was heated to 65 °C and reacted at this temperature for 18 hours. The mixture was then cooled, concentrated under reduced pressure, and the residue was purified by liquid chromatography to give compound NASH179-0102 (0.37 g), with a yield of 51.7%. ESI-MS (+): m / z = 519.16.

[0487] Step 3: Preparation of compound NASH179-0101

[0488] Compound NASH179-0102 (0.35 g, 0.67 mmol) and N,N-dimethylformamide (15 mL) were added to a reaction flask, followed by sodium hydride (0.04 g, 1.67 mmol). The mixture was stirred for 10 minutes, and then chloromethyl (methyl-d3) carbonate (0.13 g, 1.00 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 55 °C and maintained at this temperature for 18 hours. The system was quenched with water and then purified by preparative liquid chromatography to give compound NASH179-0101 (156 mg), in 38.0% yield. ESI-MS(+): m / z = 610.17.

[0489] Step 4: Preparation of compound NASH179-01

[0490] Compound NASH179-0101 (155 mg, 0.25 mmol) and dichloromethane (15 mL) were added to a reaction flask, followed by the dropwise addition of trifluoroacetic acid (TFA, 1.5 mL). After the addition was complete, the reaction was allowed to proceed for 5 hours. The system was then quenched, concentrated under reduced pressure, and the residue was purified by liquid chromatography to give compound NASH179-01 (37.9 mg), with a yield of 28.8%. ESI-MS (+): m / z = 526.22.

[0491] Example 19: Synthesis of compounds NASH179-03 and NASH179-05

[0492] Reaction formula:

[0493]

[0494] Preparation method:

[0495] In a reaction flask, 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 sequentially. The reaction mixture was reacted at room temperature for 23 hours. The crude product was purified by preparative liquid chromatography to give two compounds: compound NASH179-03 (23 mg, 31.7%), ESI-MS(+): m / z = 526.13; and compound NASH179-05 (21 mg, 28.9%), ESI-MS(+): m / z = 526.18.

[0496] Example 20: Synthesis of compound NASH179-13

[0497] Reaction formula:

[0498]

[0499] Preparation method:

[0500] Step 1: Preparation of isobutyryl chloride-D6 deuterated

[0501] 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 added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 hours, concentrated under reduced pressure, and the residue was used directly.

[0502] Step 2: Preparation of compound NASH179-13

[0503] In a reaction flask, dichloromethane (20 mL), compound ZJT2 (0.64 g, 1.38 mmol), and triethylamine (0.88 g, 2.70 mmol) were added sequentially. Then, a dichloromethane solution (5 mL) containing isobutyryl chloride-D6 deuterated (0.16 g, 1.38 mmol, yield from the previous step was 100%) was added dropwise at 0 °C. 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 chromatography to obtain compound NASH179-13 (0.20 g, 26.9%), ESI-MS(+): m / z = 541.19.

[0504] Example 21: Synthesis of compound NASH179-19

[0505] Reaction formula:

[0506]

[0507] Preparation method:

[0508] Step 1: Preparation of Trimethylacetyl chloride-D9

[0509] Trimethylacetic acid-D9 (0.15 g, 1.38 mmol) was added to dichloromethane (10 mL), and then thionyl chloride (0.33 g, 2.76 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 hours, concentrated under reduced pressure, and the residue was used directly.

[0510] Step 2: Preparation of compound NASH179-19

[0511] In a reaction flask, dichloromethane (20 mL), compound ZJT2 (0.64 g, 1.38 mmol), and triethylamine (0.88 g, 2.70 mmol) were added sequentially. Then, a dichloromethane solution (5 mL) containing trimethylacetyl chloride-D9 (1.38 mmol, based on a 100% yield from the previous step) was added dropwise at 0 °C. 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 chromatography to obtain compound NASH179-19 (0.23 g, 29.8%), ESI-MS (+): m / z = 558.25.

[0512] Example 22: Synthesis of compound NASH179-24

[0513] Reaction formula:

[0514]

[0515] Preparation method:

[0516] Step 1: Preparation of compound NASH179-2407

[0517] 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), followed by the addition of isobutyric acid (2.8 g, 0.03 mol) and silver nitrate (2.6 g, 0.03 mol).

[0518] 0.0153 mol). 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 the dropwise addition of ammonium persulfate (10.4 g, 0.044 mol) in water (15 mL) over 30 minutes. The system was heated to 70 °C and reacted for 15 minutes, then cooled to room temperature and allowed to react for another 24 hours. The system was then cooled to 0 °C and the pH was slowly adjusted to 8 with 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 successively with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the target compound (1.758 g), with a yield of 62%. ESI-MS(+): m / z = 191.21.

[0519] Step 2: Preparation of compound NASH179-2406

[0520] At 25 °C, 4-amino-2,6-dichloro-benzylthiol (1.5 g, 7.8 mmol) was added to N,N-dimethylformamide, followed by compound NASH179-2407 (1.485 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol). The system was heated to 90 °C and reacted for 18 h. Subsequently, the system was cooled to 25 °C and poured into a mixture of ice water and 1N hydrochloric acid aqueous solution (15 mL). The pH was adjusted to 7 with 1N hydrochloric acid aqueous solution, and the mixture was 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 subjected to silica gel column chromatography to give the target compound NASH179-2406 (1.74 g) in 65% yield. ESI-MS(+): m / z = 347.91.

[0521] Step 3: Preparation of compound NASH179-2405

[0522] 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. The mixture was then 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 give compound NASH179-2405 (1.51 g), 96% yield, as a grayish-white solid. This solid was used directly in the next step without further purification. ESI-MS(+): m / z = 372.15.

[0523] Step 4: Preparation of compound NASH179-2404

[0524] Compound NASH179-2405 (1.0 g, 2.675 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), followed by the addition of powdered sodium hydroxide (0.535 g, 13.375 mmol). 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 a saturated aqueous sodium chloride solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound NASH179-2404 (0.857 g), 97% yield, as a pale brown solid. This compound was used directly in the next step without further purification. ESI-MS(+): m / z = 330.23.

[0525] Step 5: Preparation of compound NASH179-2403

[0526] 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 min, filtered, and rapidly added to a pre-cooled solution of N-cyanoacetylurane (216 mg, 1.38 mmol), water (30 mL), and pyridine (10 mL). The resulting suspension was stirred at 0 °C for 30 min and then filtered. The filter cake was washed successively with water and petroleum ether. The product was dried under vacuum at 80 °C for 12 h to obtain the target product (311 mg), yield 51%. ESI-MS(+): m / z = 497.23.

[0527] Step 6: Preparation of compound NASH179-2402

[0528] At room temperature, compound NASH179-2403 (300 mg, 0.604 mmol) was added to a glacial acetic acid solution (5 mL), followed by the addition of sodium acetate (0.25 g, 3 mmol). The system was then heated to 120 °C and reacted for 1.5 hours. Afterward, the system was cooled to 0 °C, diluted with water (20 mL), and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed sequentially with water and petroleum ether. It was then dried in a forced-air drying oven for 60 minutes, and finally slurried with a mixture of acetonitrile and water to obtain the target product (0.138 g), with a yield of 51%. ESI-MS(+): m / z = 451.34.

[0529] Step 7: Preparation of compound NASH179-2401

[0530] Compound NASH179-2402 (1.0 g, 2.3 mmol) was added to methanol (20 mL), followed by 37% formaldehyde aqueous solution (3.75 mL, 50.36 mmol). The system was then heated to 100 °C and reacted for 18 h. The system was then cooled to 25 °C and poured into water (20 mL). A precipitate formed, which was collected by filtration. The filter cake was washed with water and dried in a vacuum drying oven to give compound NASH179-2401 (952 mg), 89% yield, as a pale yellow solid. ESI-MS(+): m / z = 481.25.

[0531] Step 8: Preparation of compound NASH179-24

[0532] 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). The system was then 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 h. The system was then heated to 40 °C and stirred overnight. The system was then cooled to 25°C and poured into water (100 mL). Extraction was performed with dichloromethane (100 mL), followed by washing three times with 1N hydrochloric acid solution (100 mL), then with water (100 mL), then with saturated sodium chloride (100 mL), drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The residue was then subjected to silica gel column chromatography 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.

[0533] Example 23: Synthesis of compounds NASH179-38 and NASH179-39

[0534] Reaction formula:

[0535]

[0536] Preparation method:

[0537] 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 reaction was carried out at room temperature for 20 hours. The crude product was separated by preparative liquid chromatography to give two compounds: compound NASH179-38 (32.5 mg), yield 23%, ESI-MS(+): m / z = 539.34; and NASH179-39 (17 mg), yield 12%, ESI-MS(+): m / z = 539.23.

[0538] Example 24: Synthesis of compound NASH179-47

[0539] Reaction formula:

[0540]

[0541] Preparation method:

[0542] 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). The system was then 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 h. The system was then heated to 40 °C and stirred overnight. The system was then cooled to 25°C and poured into water (30 mL). Extraction was performed with dichloromethane (30 mL), followed by washing three times with 1N hydrochloric acid solution (30 mL), water (30 mL), and saturated sodium chloride (30 mL). The mixture was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound NASH179-47 (48.3 mg), yield 27%. ESI-MS(+): m / z = 577.18.

[0543] Example 25: Synthesis of compounds NASH179-50 and NASH179-51

[0544] Reaction formula:

[0545]

[0546] Preparation method:

[0547] 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 isopropyl carbonate-1-chloroethyl (72 mg, 0.43 mmol). The reaction was carried out at room temperature for 20 hours. The crude product was separated by preparative liquid chromatography to give two compounds: compound NASH179-50 (48.6 mg), yield 19%, ESI-MS(+): m / z = 581.36; and NASH179-51 (31.8 mg), yield 12%, ESI-MS(+): m / z = 581.27.

[0548] Example 26: Synthesis of compound NASH179-52

[0549] Reaction formula:

[0550]

[0551] Preparation method:

[0552] Compound ZJT1 (0.44 g, 1.0 mmol) (0.35 g, 0.67 mmol) and N,N-dimethylformamide (15 mL) were added to a reaction flask and dissolved. Sodium hydride (0.06 g, 2.50 mmol) (0.04 g, 1.67 mmol) was then added. The mixture was stirred for 15 minutes, and then chloromethyl (methyl-d3) carbonate (0.26 g, 2.00 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 60 °C and maintained at this temperature for 24 hours. The system was quenched with water and then purified by preparative liquid chromatography to give compound NASH179-52 (157 mg), yield 25%. ESI-MS(+): m / z = 617.38.

[0553] Example 27: Synthesis of compound NASH179-55

[0554] Reaction formula:

[0555]

[0556] Preparation method:

[0557] Step 1: Preparation of compound NASH179-5504

[0558] 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, and the mixture was stirred and cooled to approximately 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 the mixture was stirred and reacted in an ice-water bath at 0°C for 3 hours. The ice bath was then removed, and the mixture was stirred overnight. The THF solvent was removed by rotary evaporation, and the turbid oily substance was dissolved in ethyl acetate (EA, 15 mL). The white insoluble substance was removed by filtration. The EA solution was washed successively with 10% citric acid solution, saturated saline solution, 4% NaHCO3 solution and saturated saline solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was compound NASH179-5504, which was used directly without further treatment.

[0559] Step 2: Preparation of compound NASH179-5503

[0560] The prepared compound NASH179-5504 was dissolved in dichloromethane (20 mL), followed by the addition of acetic acid (1.0 mL) and 10% palladium on carbon (1.0 g). Hydrogen gas was introduced, and the reduction reaction was carried out at room temperature for 1.5 hours. The system was filtered through diatomaceous earth, eluted with a large amount of dichloromethane, and the filtrate was evaporated to dryness under reduced pressure. 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.

[0561] Step 3: Preparation of compound NASH179-5502

[0562] Under nitrogen protection, compound NASH179-0102 (2.08 g, 4.0 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen hydride (0.48 g, 20 mmol) was added, followed by the slow addition of formaldehyde aqueous solution (35–40%, 2.0 g). The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, and water and dichloromethane were added. The mixture was shaken, separated, and the aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to give compound NASH179-5502 (1.0 g), with a yield of 45.5%. ESI-MS (+): m / z = 549.36.

[0563] Step 4: Preparation of compound NASH179-5501

[0564] In a reaction flask, compounds NASH179-5502 (1.0 g, 1.83 mmol) and NASH179-5503 (0.63 g, 1.83 mmol) were added to THF (20 mL), followed by NMM (0.22 g, 2.2 mmol). The mixture was stirred and cooled to approximately 0°C in an ice-water bath. HOSu (0.21 g, 1.83 mmol) and DCC (0.38 g, 1.83 mmol) were then added. The mixture was stirred and reacted in an ice-water bath at 0°C for 3 hours. The ice bath was then removed, and the mixture was stirred overnight. The THF solvent was removed by rotary evaporation. Ethyl acetate was added, and the mixture was washed successively with 10% citric acid solution, saturated brine, 4% NaHCO3 solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was the crude compound NASH179-5501, which was used directly without further processing.

[0565] Step 5: Preparation of compound NASH179-55

[0566] 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 chromatography to obtain compound NASH179-55 (0.46 g), with a yield of 36.3%. ESI-MS(+): m / z = 692.56.

[0567] Example 28: Synthesis of compound NASH179-56

[0568] Reaction formula:

[0569]

[0570] Preparation method:

[0571] Step 1: Preparation of compound NASH179-5601

[0572] 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), followed by NMM (0.43 g, 4.2 mmol). The mixture was stirred and cooled to approximately 0°C in an ice-water bath. HOSu (0.32 g, 2.8 mmol) and DCC (0.58 g, 1.83 mmol) were then added. The mixture was stirred and reacted in an ice-water bath at 0°C for 3 hours. The ice bath was then removed, and the mixture was stirred overnight. The THF solvent was removed by rotary evaporation. Ethyl acetate was added, and the mixture was washed successively with 10% citric acid solution, saturated brine, 4% NaHCO3 solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue, which was the crude compound NASH179-5601, was used directly without further processing.

[0573] Step 2:

[0574] 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 chromatography to obtain compound NASH179-56 (0.63 g), with a yield of 32.5%. ESI-MS(+): m / z = 692.44.

[0575] Example 29: Preparation of compound PY-50

[0576] Reaction formula:

[0577]

[0578] Preparation method:

[0579] Step 1: Preparation of compound NASH181-0101

[0580] Thiopronine (11.0 g, 67.5 mmol), water (300 mL), dichloromethane (300 mL), tetrabutylammonium bisulfate (2.3 g, 6.75 mmol), and sodium bicarbonate (22.7 g, 270 mmol) were placed in a three-necked flask. Chloromethylchlorosulfonate (13.5 g, 81.7 mmol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography (eluting with a 0-5% ethyl acetate / hexane gradient) to give compound NASH181-0101 (10.5 g), yield 73.5%. ESI-MS(+): m / z = 212.33.

[0581] Step 2: Preparation of compounds NASH181-01 and NASH181-02

[0582] In a reaction flask, 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 sequentially. The reaction solution was reacted at room temperature for 24 hours. The crude product was purified by preparative liquid chromatography to give two compounds: compound NASH181-01 (62 mg, 3.7%), ESI-MS(+): m / z = 610.29; and compound NASH181-02 (55 mg, 3.3%), ESI-MS(+): m / z = 610.36.

[0583] Example 30: Synthesis of compound NASH181-03

[0584] Reaction formula:

[0585]

[0586] Preparation method:

[0587] Step 1: Preparation of compound NASH181-0303

[0588] Compound ZJT1 (1.20 g, 2.76 mmol), pyridinium 4-methylbenzenesulfonic acid (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 sequentially to a Schlenk tube. After the addition was complete, the reaction mixture was heated to 65 °C and reacted at this temperature for 18 hours. The mixture was then cooled, concentrated under reduced pressure, and the residue was purified by liquid chromatography to give compound NASH181-0303 (0.76 g), with a yield of 53.1%. ESI-MS (+): m / z = 519.23.

[0589] Step 2: Preparation of compound NASH181-0302

[0590] Under nitrogen protection, compound NASH181-0303 (1.04 g, 2.0 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydrogen hydride (0.24 g, 10 mmol) was added, and then formaldehyde aqueous solution (35–40%, 1.0 g) was slowly added. The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, water and dichloromethane were added, the mixture was shaken, and the layers were separated. The aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to give compound NASH181-0302 (0.49 g), with a yield of 44.5%. ESI-MS (+): m / z = 549.43.

[0591] Step 3: Preparation of compound NASH181-0301

[0592] In a reaction flask, compound NASH181-0302 (1.0 g, 1.83 mmol) and thiopronine (0.30 g, 1.83 mmol) were added to THF (20 mL), followed by N-methylmorpholine (NMM, 0.22 g, 2.2 mmol). The mixture was stirred and cooled to approximately 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 then added. The mixture was stirred and reacted in an ice-water bath at 0°C for 3 hours. The ice bath was then removed, and the mixture was stirred overnight. The THF solvent was removed by rotary evaporation. Ethyl acetate was added, and the mixture was washed successively with 10% citric acid solution, saturated brine, 4% NaHCO3 solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was the crude compound NASH181-0301, which was used directly without further processing.

[0593] Step 3: Preparation of compound NASH181-03

[0594] 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 chromatography to obtain compound NASH181-03 (0.52 g), with a yield of 46.6%. ESI-MS(+): m / z = 610.46.

[0595] Example 31: Synthesis of compound NASH181-04

[0596] Reaction formula:

[0597]

[0598] Preparation method:

[0599] Step 1: Preparation of compound NASH181-0402

[0600] Thiopronine (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, concentrated under reduced pressure, and the residue was used directly.

[0601] Step 2: Preparation of compound NASH181-0401

[0602] Under nitrogen protection, compound ZJT1 (1.74 g, 4.0 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen hydride (0.72 g, 30 mmol) was added, and then formaldehyde aqueous solution (35–40%, 4.0 g) was slowly added. The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, water and dichloromethane were added, the mixture was shaken, and the layers were separated. The aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to give compound NASH181-0401 (0.76 g), with a yield of 38.3%. ESI-MS (+): m / z = 495.41.

[0603] Step 3: Preparation of compound NASH181-04

[0604] In a reaction flask, dichloromethane (20 mL), compound NASH181-0401 (0.68 g, 1.38 mmol), and triethylamine (0.88 g, 2.70 mmol) were added sequentially. Then, a dichloromethane solution (10 mL) containing NASH181-0402 (0.50 g, 2.76 mmol, yield from the previous step was 100%) was added dropwise at 0 °C. 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 chromatography to obtain compound NASH181-04 (0.35 g, 32.3%), ESI-MS(+): m / z = 785.46.

[0605] Example 32: Synthesis of compound NASH181-07

[0606] Reaction formula:

[0607]

[0608] Preparation method:

[0609] Step 1: Preparation of compound NASH181-0704

[0610] 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, and the mixture was stirred and cooled to approximately 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, and the mixture was stirred and reacted in an ice-water bath at 0°C for 3 hours. The ice bath was then removed, and the mixture was stirred overnight. The THF solvent was removed by rotary evaporation, and the turbid oily substance was dissolved in ethyl acetate (EA, 45 mL) and filtered. The EA solution was washed successively with 10% citric acid solution, saturated saline solution, 4% NaHCO3 solution, and saturated saline solution. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (60 mL). Acetic acid (3.0 mL) and 10% palladium on carbon (3.0 g) were added, and hydrogen gas was bubbled through the solution. The reduction reaction was carried out at room temperature for 1.5 hours. The system was filtered through diatomaceous earth, eluted with a large amount of dichloromethane, and the filtrate was evaporated to dryness under reduced pressure. The residue was passed through a column chromatography column to give compound NASH181-0704 (3.70 g), with a yield of 61.1%. ESI-MS (-): m / z = 335.21.

[0611] Step 2: Preparation of compound NASH181-0703

[0612] 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 conditions. The mixture was heated to reflux for 16 hours, cooled, and the solution was adjusted to alkalinity with triethylamine. The mixture was filtered, the filtrate was concentrated, 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.

[0613] Step 3: Preparation of compound NASH181-0702

[0614] 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. The mixture was heated to 55 °C and reacted for 8 h. The reaction was confirmed to be complete by TLC. The system was concentrated, water and dichloromethane were added, the mixture was shaken, and the layers were separated. The aqueous phase was extracted again with dichloromethane. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated by liquid chromatography to give compound NASH181-0702 (1.26 g), with a yield of 45.0%. ESI-MS (+): m / z = 465.22.

[0615] Step 3: Preparation of compound NASH181-0701

[0616] Under nitrogen protection, compound NASH181-0703 (0.80 g, 2.27 mmol) was added to acetonitrile (50 mL). 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 conditions. Triethylamine (0.46 g, 4.54 mmol) was then slowly added. After stirring at room temperature for 1 hour, compound NASH181-0702 (1.06 g, 2.27 mmol) was slowly added. Stirring continued at room temperature for 16 hours. The mixture was filtered, and the acetonitrile solvent was removed by rotary evaporation of the filtrate. Ethyl acetate was added, and the mixture was washed successively with 10% citric acid solution, saturated saline solution, 4% NaHCO3 solution, and saturated saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was the crude compound NASH181-0701, which was used directly without further processing.

[0617] Step 4: Preparation of compound NASH181-07

[0618] 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 chromatography to obtain compound NASH181-07 (0.43 g), with a yield of 27.1%. ESI-MS(+): m / z = 699.56.

[0619] Example 33: Synthesis of compound NASH181-08

[0620] Reaction formula:

[0621]

[0622] Preparation method:

[0623] Step 1: Preparation of compound NASH181-0801

[0624] 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 in an ice bath, followed by the slow addition of triethylamine (0.61 g, 6.0 mmol). After stirring at room temperature for 1 hour, compound NASH181-0302 (1.65 g, 3.0 mmol) was slowly added, and stirring continued at room temperature for 16 hours. The mixture was filtered, and the acetonitrile solvent was removed by rotary evaporation of the filtrate. Ethyl acetate was added, and the mixture was washed successively with 10% citric acid solution, saturated saline solution, 4% NaHCO3 solution, and saturated saline solution. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was the crude compound NASH181-0801, which was used directly without further processing.

[0625] Step 2: Preparation of compound NASH181-08

[0626] 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 chromatography to obtain compound NASH181-08 (0.53 g), with a yield of 25.2%. ESI-MS(+): m / z = 699.42.

[0627] Example 34: Synthesis of compound NASH181-11

[0628] Reaction formula:

[0629]

[0630] Preparation method:

[0631] Under argon protection, at room temperature, compound NASH181-07 (1.12 g, 1.6 mmol) was added to anhydrous toluene (100 mL). Lawson's reagent (0.81 g, 2.0 mmol) was added under ice-water bath conditions, and the reaction was heated to 110 °C for 5 hours. The reaction was monitored by TLC until completion, and then cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound NASH181-11 (0.60 g), with a yield of 52.4%. ESI-MS (+): m / z = 715.28.

[0632] Rate 52.4%. ESI-MS(+): m / z = 715.28.

[0633] Example 35: Synthesis of compounds NASH181-31 and NASH181-32

[0634] Reaction formula:

[0635]

[0636] Preparation method:

[0637] Step 1: Preparation of compound NASH181-3101

[0638] Trifluoroacetaldehyde (58.0 g, 0.5 mol) and anhydrous zinc chloride (13.6 g, 0.1 mol) were added to a reaction flask, and the mixture was cooled to 0–5 °C. Then, ethyl chloroformate (54.3 g, 0.5 mol) was added dropwise over 1 hour. After the addition was complete, the mixture was heated to room temperature, and then further heated to 50–55 °C. The reaction mixture was reacted for 8–10 hours. The reaction mixture was then vacuum distilled to obtain the target compound NASH181-3101 (44.0 g), with a yield of 42.6%.

[0639] Step 2: Preparation of compounds NASH181-31 and NASH181-32

[0640] 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 chromatography to give two compounds: compound NASH181-31 (67 mg), yield 20.8%, ESI-MS(+): m / z = 605.67; and NASH181-32 (57 mg), yield 17.7%, ESI-MS(+): m / z = 605.52.

[0641] Example 36: Synthesis of compound NASH181-33

[0642] Reaction formula:

[0643]

[0644] Preparation method:

[0645] Step 1: Preparation of compound NASH181-3301

[0646] Compound NASH181-0302 (0.56 g, 1.01 mmol) and N,N-dimethylformamide (30 mL) were added to a reaction flask, followed by sodium hydride (0.06 g, 2.51 mmol). The mixture was stirred for 10 minutes, and then NASH181-3101 (0.32 g, 1.50 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 55 °C and maintained at this temperature for 18 hours. The system was quenched with water and then purified by preparative liquid chromatography to obtain compound NASH181-3301 (293 mg), with a yield of 42.1%. ESI-MS (+): m / z = 689.57.

[0647] Step 2: Preparation of compound NASH181-33

[0648] Compound NASH181-3301 (290 mg, 0.42 mmol) and dichloromethane (30 mL) were added to a reaction flask, followed by the dropwise addition of trifluoroacetic acid (TFA, 3.0 mL). After the addition was complete, the reaction was allowed to proceed for 5 hours. The system was then quenched, concentrated under reduced pressure, and the residue was purified by liquid chromatography to give compound NASH181-33 (92 mg), with a yield of 36.2%. ESI-MS (+): m / z = 605.64.

[0649] Example 37: Synthesis of compound NASH181-34

[0650] Reaction formula:

[0651]

[0652] Preparation method:

[0653] Compound ZJT1 (0.44 g, 1.0 mmol) and N,N-dimethylformamide (20 mL) were added to a reaction flask and dissolved. Sodium hydride (0.06 g, 2.50 mmol) was then added. The mixture was stirred for 15 minutes, and then compound NASH181-3101 (0.41 g, 2.00 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 60 °C and maintained at this temperature for 24 hours. The system was quenched with water and then purified by preparative liquid chromatography to obtain compound NASH181-34 (239 mg), with a yield of 30.8%. ESI-MS (+): m / z = 775.48.

[0654] Example 38: Synthesis of NASH192-05 and NASH192-06 compounds

[0655] Reaction formula:

[0656]

[0657] Preparation method:

[0658] Step 1: Preparation of compound NASH192-L01-7:

[0659] 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), followed by the addition of isobutyric acid-D6 deuterated (2.82 g, 0.03 mol) and silver nitrate (2.6 g, 0.0153 mol). 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 the dropwise addition of ammonium persulfate (10.4 g, 0.044 mol) in water (15 mL) over 30 minutes. The system was heated to 70 °C and reacted for 15 minutes, then cooled to room temperature and allowed to react for another 24 hours. The system was then cooled to 0 °C, and the pH was slowly adjusted to 8 with 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 and washed successively with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the target compound (3.49 g, yield 59.1%). ESI-MS(+): m / z = 197.08.

[0660] Step 2: Preparation of compound NASH192-L01-6:

[0661] 2,6-Dichloro-4-aminophenol (1.38 g, 7.8 mmol) was added to N,N-dimethylformamide at 25 °C, followed by compound NASH192-L01-7 (1.54 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol). The system was heated to 90 °C and reacted for 18 h. Subsequently, the system was cooled to 25 °C and poured into a mixture of ice water and 1N hydrochloric acid aqueous solution (15 mL). The pH was adjusted to 7 with 1N hydrochloric acid aqueous solution, and the mixture was 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 purified by silica gel column chromatography to give the target compound NASH192-L01-6 (1.69 g, 64.2%). ESI-MS(+): m / z = 338.51.

[0662] Step 3: Preparation of compound NASH192-L01-5:

[0663] 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. The mixture was then extracted twice with ethyl acetate (150 mL). The combined organic compounds were washed with saturated sodium chloride aqueous solution (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound NASH192-L01-5 (1.36 g, 90.1%), a grayish-white solid, which was used directly in the next step without further purification. ESI-MS(+): m / z = 362.22.

[0664] Step 4: Preparation of compound NASH192-L01-4:

[0665] Compound NASH192-L01-5 (0.968 g, 2.675 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), followed by the addition of powdered sodium hydroxide (0.535 g, 13.375 mmol). 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 a saturated aqueous sodium chloride solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound NASH192-L01-4 (0.819 g, 95.7%) as a pale brown solid. This compound was used directly in the next step without further purification. ESI-MS(+): m / z = 320.21.

[0666] Step 5: Preparation of compound NASH192-L01-3

[0667] 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 min, filtered, and rapidly added to a pre-cooled solution of N-cyanoacetylurane (216 mg, 1.38 mmol), water (30 mL), and pyridine (10 mL). The resulting suspension was stirred at 0 °C for 30 min and then filtered. The filter cake was washed successively with water and petroleum ether. The product was dried under vacuum at 80 °C for 12 h to obtain the target product (370 mg, yield 60.2%). ESI-MS(+): m / z = 487.33.

[0668] Step 6: Preparation of compound NASH192-L01-2

[0669] At room temperature, compound NASH192-L01-3 (294 mg, 0.604 mmol) was added to a solution of glacial acetic acid (5 mL), followed by the addition of sodium acetate (0.25 g, 3 mmol). The system was then heated to 120 °C and reacted for 1.5 h. Afterward, the system was cooled to 0 °C, diluted with water (20 mL), and stirred for 30 min. The mixture was filtered, and the filter cake was washed sequentially with water and petroleum ether. It was then dried in a forced-air drying oven for 60 min, and finally slurried with a mixture of acetonitrile and water to obtain the target product (0.153 g, yield 57.4%). ESI-MS(+): m / z = 441.26.

[0670] Step 7: Preparation of compound NASH192-L01-1

[0671] NASH192-L01-SM2 (180 mg, 1.395 mmol) was added to dichloromethane (10 mL), and the system was then cooled to -15 °C. Triethylamine (155 mg, 1.534 mmol) was slowly added dropwise, keeping the internal temperature below -5 °C. After the addition was complete, the system was cooled to -15 °C again, and deuterated ethanol (79.93 mg, 1.534 mmol) was added dropwise, keeping the internal temperature below -5 °C. After the addition was complete, the system was slowly raised to room temperature, and the reaction was continued for 3 hours. The system was then quenched in water, and the aqueous phase was extracted with dichloromethane (100 mL). The organic phase was then washed with saturated sodium chloride (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil (178.0 mg, 88.9% yield). ESI-MS (+): m / z = 144.52.

[0672] Step 8: Preparation of compounds NASH192-05 and NASH192-06

[0673] 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). The system was then 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 h. The system was then heated to 40 °C and stirred overnight. The system was then cooled to 25°C and poured into water (100 mL). Extraction was performed with dichloromethane (100 mL), followed by washing three times with 1N hydrochloric acid solution (100 mL), then with water (100 mL), then with saturated sodium chloride (100 mL), drying with magnesium sulfate, filtering, and concentrating under reduced pressure. The crude product was then subjected to preparative liquid chromatography 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.

[0674] Example 39: Synthesis of compound NASH192-04

[0675] Reaction formula:

[0676]

[0677] Preparation method:

[0678] NASH192-L01-2 (117 mg, 0.266 mmol) was added to THF (8 mL), followed by 4M n-butyllithium (67 μL, 0.266 mmol). The system was then cooled to -25 °C, and NASH192-L01-1 (38.17 mg, 0.266 mmol) was added. The system was slowly heated to 25 °C and reacted for 3.5 h. The system was then heated to 40 °C and stirred overnight. Subsequently, the system was cooled to 25 °C and poured into water (100 mL). Extraction was performed with dichloromethane (100 mL), and the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 mL), then with water (100 mL), then with saturated sodium chloride (100 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative liquid chromatography to obtain the target compound: NASH192-04 (49.5 mg, 34.1%). ESI-MS(+): m / z = 548.43.

[0679] Example 40: Synthesis of compounds NASH192-07 and NASH192-08

[0680] Reaction formula:

[0681]

[0682] Preparation method:

[0683] Step 1: Preparation of compound NASH192-L02-7

[0684] 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), followed by the addition of 2-methylpropionic acid-D7 (2.85 g, 0.03 mol) and silver nitrate (2.6 g, 0.0153 mol). 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 the dropwise addition of ammonium persulfate (10.4 g, 0.044 mol) in water (15 mL) over 30 minutes. The system was heated to 70 °C and reacted for 15 minutes, then cooled to room temperature and allowed to react for another 24 hours. The system was then cooled to 0 °C, and the pH was slowly adjusted to 8 with 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 and washed successively with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the target compound (3.38 g, yield 57.3%). ESI-MS(+): m / z = 198.17.

[0685] Step 2: Preparation of compound NASH192-L02-6

[0686] At 25°C, 2,6-dichloro-4-aminophenol (1.5 g, 7.8 mmol) was added to N,N-dimethylformamide, followed by compound NASH192-L02-7 (1.544 g, 7.8 mmol) and potassium carbonate (3.24 g, 23.4 mmol). The system was heated to 90°C and reacted for 18 h. Subsequently, the system was cooled to 25°C and poured into a mixture of ice water and 1N hydrochloric acid aqueous solution (15 mL). The pH was adjusted to 7 with 1N hydrochloric acid aqueous solution, and the mixture was 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 subjected to silica gel column chromatography to obtain the target compound, NASH192-L02-6 (1.64 g, 62.3%), as a grayish-white bubbly substance. ESI-MS(+): m / z = 339.61.

[0687] Step 3: Preparation of compound NASH192-L02-5

[0688] 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. The mixture was then extracted twice with ethyl acetate (150 mL). The combined organic compounds were washed with saturated sodium chloride aqueous solution (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound NASH192-L02-5 (1.4 g, 92.7%), a grayish-white solid, which was used directly in the next step without further purification. ESI-MS(+): m / z = 363.22.

[0689] Step 4: Preparation of compound NASH192-L02-4

[0690] Compound NASH192-L02-5 (971 mg, 2.675 mmol) was added to a mixture of methanol (5 mL) and water (5 mL), followed by the addition of powdered sodium hydroxide (0.535 g, 13.375 mmol). 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 a saturated aqueous sodium chloride solution (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound NASH192-L02-4 (0.802 g, 93.8%) as a pale brown solid. This compound was used directly in the next step without further purification. ESI-MS(+): m / z = 321.21.

[0691] Step 5: Preparation of compound NASH192-L02-3

[0692] 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 min, filtered, and rapidly added to a pre-cooled solution of N-cyanoacetylurane (216 mg, 1.38 mmol), water (30 mL), and pyridine (10 mL). The resulting suspension was stirred at 0 °C for 30 min and then filtered. The filter cake was washed successively with water and petroleum ether. The product was dried under vacuum at 80 °C for 12 h to obtain the target product (386 mg, yield 62.9%). ESI-MS(+): m / z = 488.34.

[0693] Step 6: Preparation of compound NASH192-L02-2

[0694] At room temperature, compound NASH192-L02-3 (295 mg, 0.604 mmol) was added to a solution of glacial acetic acid (5 mL), followed by the addition of sodium acetate (0.25 g, 3 mmol). The system was then heated to 120 °C and reacted for 1.5 h. Afterward, the system was cooled to 0 °C, diluted with water (20 mL), and stirred for 30 min. The mixture was filtered, and the filter cake was washed sequentially with water and petroleum ether. It was then dried in a forced-air drying oven for 60 min, and finally slurried with a mixture of acetonitrile and water to obtain the target product (0.145 g, yield 54.7%). ESI-MS(+): m / z = 442.26.

[0695] Step 7: Preparation of compounds NASH192-07 and NASH192-08

[0696] 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). The system was then 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 h. The system was then heated to 40 °C and stirred overnight. The system was then cooled to 25°C and poured into water (100 mL). Extraction was performed with dichloromethane (100 mL), followed by washing three times with 1N hydrochloric acid solution (100 mL), then with water (100 mL), then with saturated sodium chloride (100 mL), drying with magnesium sulfate, filtering, and concentrating under reduced pressure. The crude product was then subjected to preparative liquid chromatography to obtain two compounds: 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.

[0697] Example 41: Synthesis of compound NASH192-09

[0698] Reaction formula:

[0699]

[0700] Preparation method:

[0701] NASH192-L02-2 (117 mg, 0.266 mmol) was added to THF (8 mL), followed by 4M n-butyllithium (67 μL, 0.266 mmol). The system was then cooled to -25 °C, and NASH192-L01-1 (38 μL, 17 mg, 0.266 mmol) was added. The system was slowly heated to 25 °C and reacted for 3.5 h. The system was then heated to 40 °C and stirred overnight. Subsequently, the system was cooled to 25 °C and poured into water (100 mL). Extraction was performed with dichloromethane (100 mL), and the organic matter was washed three times with 1N hydrochloric acid aqueous solution (100 mL), then with water (100 mL), then with saturated sodium chloride (100 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative liquid chromatography to obtain the target compound: NASH192-09 (47.6 mg, yield 32.6%). ESI-MS(+): m / z = 549.52.

[0702] Example 42: Synthesis of compound NASH179-43

[0703] Reaction formula:

[0704]

[0705] Preparation method:

[0706] Step 1: Synthesis of compound NASH179-4301

[0707] 9 g (69.8 mmol) of chloromethyl chloroformate was added to 90 mL of dichloromethane. The system was then cooled to -5 °C, and triethylamine (7.77 g, 76.76 mmol) was slowly added dropwise, keeping the internal temperature below 0 °C. After the addition was complete, the system was cooled to -5 °C again, and deuterated ethanol (4 g, 76.76 mmol) was added dropwise, keeping the internal temperature below 0 °C, with solid gradually precipitating out. After the addition was complete, the system was slowly raised to room temperature, and the reaction continued for 3 hours. TLC showed no starting material. The system was quenched in water, separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography. A yellow liquid, NASH179-4301 (2.5 g), was obtained, with a yield of 25%. ESI-MS (+): m / z = 144.12.

[0708] Step 2: Synthesis of compound NASH179-43

[0709] ZJT1 (3 g, 6.89 mmol) was added to DMF (30 mL), followed by cesium carbonate (4.49 g, 13.79 mmol). The system was then cooled to -5 °C, and NASH179-4301 (1.99 g, 13.79 mmol) was added. The system was slowly heated to 25 °C and reacted for 3 h. TLC showed no starting material. The system was then poured into water, separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 5:1) to give compound NASH179-43 (650 mg), yield: 17%. ESI-MS(+): m / z = 542.31. 1 HNMR (400MHz, DMSO-d6) δ7.81 (s, 2H), 7.56 (s, 1H), 5.74 (s, 2H), 3.10 (p, J = 6.9Hz, 1H), 1.23 (d, J = 6.9Hz, 6H).

[0710] Example 43: Synthesis of NASH192-05 in the compound

[0711] Reaction formula:

[0712]

[0713] Preparation method:

[0714] Step 1: Preparation of M01

[0715] 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 sequentially to a reaction flask. The mixture was heated to 70 °C, and an aqueous solution (50 nmL) of ammonium persulfate (16.7 g, 0.07 mol) was added dropwise. The temperature was maintained, and the reaction was continued for approximately 1 hour. The reaction was confirmed to be complete by TLC. The mixture was then cooled, extracted with ethyl acetate, separated, concentrated, and the residue was separated by column chromatography to obtain SM01 (2.4 g), with a yield of 24.4%. ESI-MS (+): m / z = 197.23.

[0716] Step 2: Preparation of MO2

[0717] M01 (3.5 g, 18 mmol) was added to dimethyl sulfoxide (DMSO, 50 mL), followed by SMO2 (3.17 g, 18 mmol), potassium carbonate (K2CO3, 9.8 g, 71 mmol), and ketone iodide (CuI, 3.0 g, 16 mmol). After the addition was complete, the mixture was heated to 100 °C and reacted for 8 hours. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (180 mL × 3), concentrated, and column chromatography was performed to obtain a brown solid (1.6 g). Yield: 26.6%. ESI-MS(+): m / z = 338.32.

[0718] Step 3: Preparation of M03

[0719] MO2 (1.6 g, 4.7 mmol) and sodium acetate (0.8 g, 9.8 mmol) were added sequentially to acetic acid (60 mL), and the mixture was heated to 110 °C and refluxed for approximately 10 hours. The reaction was confirmed to be complete by TLC. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The extract was concentrated to obtain an oily substance (1.4 g), which was used directly in the next step. ESI-MS(+): m / z = 362.16.

[0720] Step 4: Preparation of M04

[0721] 40 mL of 1 M sodium hydroxide aqueous solution was added to 40 mL of methanol and mixed thoroughly. Then, 1.4 g of the MO3 obtained in step 3 was added to the above system. The mixture was heated to 100 °C and reacted for 8 hours. The reaction was completed by TLC. The methanol was removed by concentration, and the pH was adjusted to 5-6 by adding 3 M hydrochloric acid. The mixture was extracted with ethyl acetate, concentrated, and the residue was separated by column chromatography to obtain a brownish-gray solid (700 mg), with a yield of 565%. ESI-MS(+): m / z = 320.24.

[0722] Step 5: Preparation of M05

[0723] A: Dissolve MO4 (700mg, 2.2mmol) in hydrochloric acid aqueous solution (10mL hydrochloric acid + 30mL water), add sodium nitrite (0.43g, 6.2mmol) in portions under ice bath conditions, and stir for 1 hour under ice bath conditions after the addition is complete.

[0724] B: Dissolve SM03 (0.3g, 1.9mmol) in a mixed solution of pyridine (10mL) and water (10mL), stir in an ice-water bath for 30 minutes, and then react in an ice-water bath for 30 minutes.

[0725] A was quickly poured into the reaction flask of B, and the mixture was reacted in an ice-water bath for 1 hour. The reaction was monitored by TLC until completion. The mixture was extracted with 25 mL of ethyl acetate (25 mL × 3). The organic phase was then washed with water and salt, dried, filtered, and concentrated to obtain a brownish-red solid (2.3 g), which was used directly in the next step. ESI-MS(+): m / z = 487.36.

[0726] Step 6: Preparation of M06

[0727] The above-mentioned M05 (2.3 g, 4.72 mmol) and sodium acetate (2.3 g, 28 mmol) were added sequentially to acetic acid (40 mL), and the mixture was refluxed for 5 hours. The reaction was confirmed to be complete by TLC. The reaction solution was directly evaporated to dryness, and then water (80 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was dried and evaporated to dryness to obtain 1.4 g of crude product. This crude product was added to acetonitrile (50 mL), followed by activated carbon (1.4 g). The mixture was refluxed for 2 hours, and the mother liquor was collected by filtration. The mother liquor was evaporated to dryness to obtain 540 mg of crude product. M06 (210 mg) was then separated using a preparative dichloromethane / methanol (10:1) solution, with a yield of 10.1%. ESI-MS (+): m / z = 441.31.

[0728] Step 7: Preparation of NASH192-05

[0729] M06 (200 mg, 0.45 mmol), N,N-diisopropylethylamine (DIEA, 175.3 mg, 1.36 mmol), and 4-dimethylaminopyridine (DMAP, 30 mg, 0.25 mmol) were added to dichloromethane (50 mL), then the mixture was cooled to 0 °C under nitrogen protection. A dichloromethane solution (10 mL) of isobutyric acid-D6 deuterated (94.2 mg, 0.66 mmol) was added dropwise. The mixture was reacted in an ice-water bath for 2 hours, then stirred at room temperature for 24 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was directly evaporated to dryness, and the residue was separated by column chromatography (D / M ratio 10:1) to give NASH192-05 (17 mg), yield 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).

[0730] The compounds of the following examples were synthesized using the same method as in the above embodiments, either commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739] Example 44: In vitro TRα or TRβ agonism test

[0740] The agonistic effects of TRα or TRβ were investigated using a time-resolved fluorescence resonance energy transfer (FRET) coactivator peptide recruitment assay. This assay employed a Europium-anti-GST antibody (Cisbio, 6IGSTKLB), a 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). The Europium-anti-GST antibody indirectly labeled RXRα-LBD or TRβ-LBD by binding to a GST tag. Streptavidin-d2 (Cisbio, 610SADAB) indirectly labeled the SRC2-2 coactivator peptide by binding to a biotin tag. In the presence of RXRα, TRα-LBD or TRβ-LBD can form heterodimers TRα-LBD / RXRα or TRβ-LBD / RXRα, respectively. The agonist binds to TRα-LBD / RXRα or TRβ-LBD / RXRα, leading to a conformational change in TRα-LBD or TRβ-LBD, thereby increasing the recruitment capacity of the heterodimer to the SRC2-2 coactivator peptide. Simultaneously, the resulting decrease in the distance between the d2-labeled SRC2-2 coactivator peptide and the Europium-anti-GST antibody increases the TR-FRET signal. The agonistic activity of compounds can be evaluated based on the effect of different concentrations on TRα or TRβ activity.

[0741] The structures of the positive compound (ZJT1), control compound 1 (NASH192-L01-2), control compound 2, control compound 3, and control compound 4 are as follows:

[0742]

[0743] Comparative compound 2 was synthesized according to the relevant synthesis method in CN101801960B; comparative compound 3 was synthesized according to the relevant synthesis method in CN112707892A; and comparative compound 4 was synthesized according to the synthesis method in NASH192-05 in Example 38 of this invention.

[0744] Specific methods:

[0745] A 6 mM positive compound (ZJT1) and a test compound solution (100×, control compound 1, control compound 2, control compound 3, control compound 4, and the compound disclosed in this invention) were prepared using dimethyl sulfoxide (DMSO). The negative control was 100% DMSO. The positive compound or test compound was serially diluted 1:3 from 6 mM (100×) with 100% DMSO to obtain 10 concentrations, and then transferred to a 96-well plate. The solution was prepared using 1× reaction buffer (50 mM HEPES (pH 7.0), 50 mM KF, 1 mM... Prepare 4X serially diluted compounds using DTT (0.05% NP-40, 0.2% BSA); add 5 μL of the serially diluted 4X compounds to a 384-well plate; prepare 4× TRβ-LBD and 4× RXRβ using 1× reaction buffer; add 5 μL of 4× TRβ-LBD and 4× RXRβ to a 384-well plate; prepare a mixture of 2× biotin-SRC2-2, 2× Europium-anti-GST, and 2× streptavidin-d2 using 1× reaction buffer, and add 10 μL of the 2× mixture to a 384-well plate; centrifuge at 1000 rpm for 1 min and incubate at room temperature and in the dark for 4 hours. Read the fluorescence signal values ​​at 665 nm and 615 nm using an EnVision 2104 (PerkinElmer) microplate reader.

[0746] Data calculation:

[0747] The relative ratio per well is calculated as follows: Ratio = 665nm fluorescence signal value / 615nm fluorescence signal value;

[0748] The agonist activity (%) was calculated as follows: (Ratio of test compound - Ratio of negative control) / (Ratio of positive compound - Ratio of negative control) × 100%. Then, using Graphpad 8.0, the relationship between the agonist activity (%) and the logarithmic concentration of the compound was fitted by nonlinear regression to obtain the THR-βEC50 (nM) of each test compound.

[0749] The THR-αEC50 (nM) of the test compound was measured and calculated using a method similar to that described above.

[0750] The agonist selectivity (SI) for THR-β is THR-β / THR-α = THR-αEC50 / THR-βEC50.

[0751] The experimental results are shown in Table 1.

[0752] Table 1. Agonistaltic activity and selectivity of the compounds of the present invention for THR-β and THR-α.

[0753]

[0754]

[0755]

[0756] Comparative analysis of compounds 1-4 with positive control compounds showed that simply deuterating the parent nucleus, esterifying the parent nucleus with carboxylic acid derivatives via hydroxymethyl groups, or esterifying the carboxylic acid derivatives via hydroxymethyl groups after deuteration of the parent nucleus without deuteration of the side chains did not significantly improve the agonistic activity and selectivity for THR-β. However, the dipeptide derivatives, tripeptide derivatives, thiol-containing glycine derivatives, sulfonic acid derivatives, and deuterated carboxylic acid derivatives of this invention, after esterification with the parent nucleus via hydroxymethyl groups, all exhibited higher agonistic activity and selectivity for THR-β than the positive control compounds and comparative compounds 1-4, regardless of whether the parent nucleus was deuterated. Unexpectedly, when the parent nucleus structure contained deuteration and the carboxylic acid derivatives esterified with the parent nucleus via hydroxymethyl groups were also deuterated, this series of compounds all exhibited extremely superior agonistic activity and selectivity for THR-β.

[0757] Example 45: Pharmacokinetic Study

[0758] Experimental animals: 54 male SD rats, weighing 200±20g, were allowed free access to food and water. They were acclimatized for 3 days under conditions of room temperature 20–26℃, humidity 40–70%, and a light:dark ratio of 12h:12h. The animals were fasted from 8 PM the day before drug administration, for 12–13 hours before administration, followed by another 4 hours of fasting, for a total fasting period of 16–17 hours. Water was not restricted throughout the experiment.

[0759] Preparation of samples for gavage administration: Weigh appropriate amounts of the test sample and place them in separate reagent bottles. Add appropriate amounts of a mixed solution of 2% Klucel LF and 0.1% Tween 80 to prepare the administration solution. Prepare and use immediately.

[0760] Preparation of intravenous injection sample: Weigh appropriate amounts of the test sample and place them in separate reagent bottles. Add an appropriate amount of mixed solvent (10% DMSO: 30% PEG400: 60% physiological saline for injection). Prepare the drug solution of the appropriate concentration. Before use, filter the solution through a microporous membrane in a sterile environment (if a transfer bottle is used, ensure sterility). Prepare and use immediately.

[0761] Experimental grouping and administration: The experimental rats were divided into 18 groups of 3 rats each, with a total of 9 test products. Each test product was administered by gavage and intravenous injection, respectively, as shown in Table 2.

[0762] Table 2 Dosing regimens for pharmacokinetic studies

[0763]

[0764] Blood collection during gavage administration: Blood was collected within 0.5 hours before gavage administration (0h), and at 0.5h, 1.5h, 3.0h, 4.5h, 6.0h, 8.0h, 10.0h, and 24.0h after administration. Animals were fed 4 hours after administration, and water was allowed throughout the entire process.

[0765] Blood collection for intravenous administration: Blood was collected within 0.5 hours before a single intravenous injection (0h), and at 0.15h, 0.5h, 1.0h, 3.0h, 5.0h, 8.0h, 10.0h, and 24.0h after administration. Animals were fed 4 hours after administration, and water was allowed throughout the entire process.

[0766] Plasma Sample Processing and Detection: Blood Sample Collection and Processing: At each blood collection time point, approximately 300 μL of blood was collected from the rat orbital vein and added to a pre-chilled centrifuge tube containing heparin sodium. The tube was then placed in an ice bath and centrifuged (4000 rpm, 10 min). Plasma was collected and aliquoted into 50 μL units, placed in sterile EP tubes, and stored at -80℃ for later use. The concentration of the target analyte in the plasma was determined as soon as possible. Analyte Information: NASH192-05 and control compound 4 were used to detect NASH192-L01-2; control compounds 3, NASH161-24, NASH179-43, NASH179-56, NASH181-01, and NASH181-07 were used to detect ZJT1.

[0767]

[0768] Pharmacokinetic parameters for injection administration are shown in Table 3, and pharmacokinetic parameters for gavage administration are shown in Table 4. The pharmacokinetic time-pharmaceutical curves for gavage administration are shown in Table 4. Figure 1 .

[0769] Table 3 Pharmacokinetic parameters after injection

[0770]

[0771]

[0772] Table 4. Pharmacokinetic parameters after gavage administration

[0773]

[0774] Comparative data for compounds 3 and 4 with the positive control compound indicate that carboxylic acid derivatives linked to the positive control compound (i.e., the parent nucleus) via a hydroxymethyl group, regardless of the presence of deuteration in the parent nucleus, show that in the absence of deuteration, the exposure levels (AUC) of carboxylic acid derivatives are significantly lower. Inf Peak plasma concentration (C) max ), half-life (T) 1 / 2 No significant differences were observed in terms of residence time (MRT) and bioavailability. However, when the parent nucleus was esterified with the side chains of the dipeptide derivatives, tripeptide derivatives, mercapto-containing glycine derivatives, sulfonic acid derivatives, and deuterated carboxylic acid derivatives of the present invention via hydroxymethylation, superior effects were observed in terms of exposure, half-life, peak plasma concentration, and bioavailability, regardless of the presence of deuteration in the parent nucleus. Specifically, compared with the positive control compound, comparative compound 3, and comparative compound 4, compound NASH192-05, when administered orally, showed a half-life extended by approximately 1.5 times, a peak plasma concentration shortened by approximately 1.5 times, an exposure increased by more than 2 times, a residence time extended by more than 1.6 times, and a bioavailability increased by more than 1.5 times. Furthermore, the pharmacokinetic curves of oral administration indicated that compound NASH192-05 exhibited more pronounced enterohepatic circulation characteristics compared to the positive control compound, comparative compound 3, comparative compound 4, and NASH179-43.

[0775] Example 46: Pharmacological effect experiment on HFD-induced NASH mouse model

[0776] Test compounds: Comparative compound 3, Comparative compound 4, NASH179-43, NASH192-05.

[0777] Preparation of test compounds: Weigh appropriate amounts of the test compounds and place them in reagent bottles. Add a mixed solution of 2% Klucel LF and 0.1% Tween 80, stir well, and set aside. Prepare and vortex thoroughly before administering the drug daily.

[0778] Experimental Methods: Eighty male, SPF-grade, 6-week-old C57BL / 6J mice (Liaoning Changsheng Biotechnology Co., Ltd.), weighing 18g-20g, were randomly divided into a normal control group (n=10) and a NASH model group (n=70) after 7 days of acclimatization. The normal control group was fed a normal diet (Beijing Huafukang Biotechnology Co., Ltd., with crude protein ≥20.0% and crude fat ≥4.0% as the main nutrients), while the NASH model group was fed a high-fat diet (Beijing Huafukang Biotechnology Co., Ltd., with crude fat ≥60%, crude protein ≥10%, and calories (carbohydrates or sugars) ≥25% as the main nutrients). Eight weeks after the end of acclimatization, blood biochemical indicators and body weight were measured. Mice with significantly abnormal indicators were excluded, and mice with uniform indicators were selected for the experiment. Eight mice were randomly selected from the normal control group and fed a normal diet. Fifty-six mice were randomly selected from the NASH model group and fed a high-fat diet. These mice were randomly divided into seven groups of eight each: model group, control compound group 3, control compound group 4, NASH179-43 group, low-dose NASH192-05 group, medium-dose NASH192-05 group, and high-dose NASH192-05 group. Administered the medication once daily by gavage for six weeks. The administration regimen is shown in Table 5.

[0779] Table 5 Dosage regimens for efficacy tests

[0780]

[0781] After the last administration, the mice were fasted for 12 hours but allowed free access to water. They were then anesthetized and sacrificed, and the intact liver tissue was separated.

[0782] Observation, sample processing, and detection indicators:

[0783] 1) General clinical symptom observation and weight measurement

[0784] Before administering the medication each day (at 10 a.m.), observe the general clinical symptoms of the experimental animals. Measure their weight once each Monday and Thursday at 8 a.m.

[0785] Weigh the liver wet weight and calculate the liver index: Liver index = Liver weight (g) / Body weight (g) × 100.

[0786] 2) Determination of triglyceride (TG) and total cholesterol (TC) levels in the liver:

[0787] TG content determination: Follow the instructions of the triglyceride test kit (enzymatic method) (Zhejiang Dongou Diagnostic Products Co., Ltd.) and use an ELISA reader for detection;

[0788] TC content determination: Follow the instructions of the total cholesterol content test kit (cholesterol oxidase method) (Nanjing Jiancheng Bioengineering Institute) and use an enzyme-linked immunosorbent assay (ELISA) reader for detection.

[0789] 3) Histopathological analysis

[0790] All liver samples were dehydrated using a dehydrator (Leica ASP300, Germany), then embedded in paraffin using a paraffin embedding machine (Leica EG1160, Germany), and finally sectioned using a scanning microtome (Leica SCN400, Germany). The liver tissues were observed and analyzed under a microscope, and the severity of liver inflammation, necrosis, and fibrosis in each group of mice was assessed using the NAS scoring method (see Table 6).

[0791] Table 6 NAS Scoring Evaluation Method

[0792]

[0793]

[0794] Lesion assessment criteria:

[0795] (1) Hepatocyte ballooning: Pathological changes resembling vacuoles are observed in hepatocytes. Due to the vacuolar changes, the size of hepatocytes increases, and the hepatocyte nuclei are concentrated or deviated.

[0796] (2) Inflammatory cell infiltration: A large number of inflammatory cells, mainly neutrophils and macrophages, are found in the portal vein area, ventral vein area or around the liver lobules.

[0797] (3) Changes in hepatocyte fat: Regular round vacuoles were observed in hepatocytes of different sizes, with the hepatocyte nucleus located at the edge.

[0798] Percentage of fibrosis: All Sirius red-stained sections were scanned using a Leica Aperio AT2 Brightfield scanner, and the percentage of Sirius red-positive stained area was calculated using the HALO AI system to assess the percentage area of ​​Sirius red on the total scanned liver area.

[0799] Statistical analysis:

[0800] Experimental data were processed using SPSS 23.0 software. Mean and standard deviation were calculated using... The independent samples t-test was used for comparisons between groups, and P<0.05 or P<0.01 indicated that the difference was statistically significant.

[0801] Experimental results:

[0802] The changes in animal body weight, liver wet weight, and liver index after drug administration are shown in Table 7.

[0803] Table 7 Animal body weight, liver wet weight, and liver index after drug administration.

[0804]

[0805] Note: Compared with the normal group, *P<0.05, **P<0.01; compared with the model group # P<0.05, ## P<0.01;

[0806] Compared with the normal group, the model group mice showed significant increases in body weight, liver wet weight, and liver index 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, control compound 4 group, NASH179-43 group, low-dose NASH192-05 group, medium-dose NASH192-05 group, and high-dose NASH192-05 group were all decreased. Compared with control compound 3 and control compound 4, the body weight, liver wet weight, and liver index of the NASH179-43 group, low-dose NASH192-05 group, medium-dose NASH192-05 group, and high-dose NASH192-05 group were all decreased, with the most significant decreases in the medium-dose NASH192-05 group and the high-dose NASH192-05 group. The low-dose NASH192-05 group (5 mg / kg) was comparable to that of the NASH179-43 group (10 mg / kg).

[0807] Figure 2 and Figure 3 The results showed elevated TC and TG levels in the liver of mice after drug administration. Compared with the normal control group, the TC and TG levels in the liver tissue of the model group mice were increased. Compared with the model group, the TC and TG levels in the control compound 3 group, control compound 4 group, NASH179-43 group, low-dose NASH192-05 group, medium-dose NASH192-05 group, and high-dose NASH192-05 group all showed a decreasing trend. Compared with control compound 3 and control compound 4, the TC and TG levels in the NASH179-43 group, low-dose NASH192-05 group, medium-dose NASH192-05 group, and high-dose NASH192-05 group decreased significantly, with the most significant decreases in the medium-dose NASH192-05 group and the high-dose NASH192-05 group. The levels in the low-dose NASH192-05 group (5 mg / kg) were comparable to those in the NASH179-43 group (10 mg / kg).

[0808] Figure 4The NAS score is shown on the vertical axis, representing the sum of scores for hepatocellular ballooning degeneration, intralobular inflammation, and steatosis. Compared to the model group, control compound 3 group, and control compound 4 group, the NASH179-43 group, the low-dose NASH192-05 group, the medium-dose NASH192-05 group, and the high-dose NASH192-05 group all achieved significant score reductions. Among them, the medium-dose and high-dose NASH192-05 groups showed extremely significant score reductions, and the reduction was dose-dependent. Furthermore, the low-dose NASH192-05 group (5 mg / kg) was comparable in efficacy to the NASH179-43 group (10 mg / kg).

[0809] Figure 5 The results are for fibrosis evaluation. Compared with the model group, control compound 3 group, and control compound 4 group, the NASH179-43 group, the low-dose NASH192-05 group, the medium-dose NASH192-05 group, and the high-dose NASH192-05 group all achieved a significant reduction in the proportion of fibrosis. Among them, the medium-dose NASH192-05 group and the high-dose NASH192-05 group showed extremely significant reductions in scores, and the NASH192-05 showed a dose-dependent effect. At the same time, the low-dose NASH192-05 group (5 mg / kg) was comparable to and slightly better than the NASH179-43 group (10 mg / kg).

[0810] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can 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 defined by the claims.

Claims

1. A pyridazine compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

2. A pharmaceutical composition comprising a pyridazine compound as described in claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the pyridazine compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a thyroid hormone receptor β agonist medicament.

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