Pyridazinone or pyridazine compound and derivative and pharmaceutical composition thereof

Abstract

The invention relates to pyridazinone or pyridazine compounds as well as derivatives and pharmaceutical compositions thereof. Specifically, the invention provides a pyridazinone or pyridazine compound as shown in a formula (I) or (Ia) or a stereoisomer, a tautomer, an enantiomer, a diastereoisomer, a resonator, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal form of the pyridazinone or pyridazine compound. The compound shown in the formula (I) or (Ia) has excellent agonistic effect and pharmacodynamic performance on a thyroid hormone beta receptor.

Description

[0001] This application is a divisional application of Chinese application No. 201911019555.X, entitled "Pyridazinone or pyridazine compounds and their derivatives and pharmaceutical compositions", filed on October 24, 2019. Technical Field

[0002] This invention relates to the pharmaceutical field, and more specifically to pyridazinones or pyridazine compounds and their derivatives and pharmaceutical compositions. Background Technology

[0003] Thyroid hormones are primarily responsible for maintaining homeostasis in the human body, making them crucial for growth and development. Hypothyroidism can lead to abnormalities in heart function, weight, metabolism, cholesterol, muscle mass, and behavior. While thyroid hormones can regulate weight and cholesterol levels, they can also cause various side effects, particularly on the heart and skeletal muscles. Thyroid hormones exert their biological activity primarily through thyroid hormone receptors. There are two subtypes of thyroid hormone receptors: α and β. α receptors are mainly associated with heart rate control, while β receptors are primarily associated with lowering cholesterol and promoting metabolism.

[0004] Synthetic thyroid hormone beta receptor agonists can selectively act on thyroid hormone beta receptors. Preclinical animal studies have shown that they can significantly reduce weight, regulate lipids, and enhance insulin sensitivity, while exhibiting fewer side effects such as tachycardia and skeletal muscle loss compared to natural thyroid hormones. Therefore, they hold promise as a next-generation treatment for inflammatory and metabolic diseases (such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, and cirrhosis). Currently, companies such as Madrigal and Viking are developing specific agonists targeting thyroid hormone beta receptors, such as MGL-3196 (Martha J. Kelly, Sherrie Pietranico-Cole, J. Douglas Larigan et al., J. Med. Chem. 2014, 57: 3912-3923), which is in early clinical stages. The structural formula of MGL-3196 is shown below:

[0005]

[0006] However, existing thyroid hormone beta receptor agonists also have many drawbacks, such as short duration of action in the body, low bioavailability, and the need for multiple administrations, which limit the efficacy of thyroid hormone beta receptor agonists.

[0007] Therefore, there is still a need in this field to develop thyroid hormone β-receptor agonists with better pharmacodynamic properties, thereby improving the treatment effect of the disease. Summary of the Invention

[0008] The purpose of this invention is to improve a pyridazinone or pyridazine compound of formula (I) or (Ia), or its stereoisomers, tautomers, enantiomers, diastereomers, resonance bodies, or pharmaceutically acceptable salts thereof. The compound of formula (I) or (Ia) exhibits excellent agonistic activity and pharmacodynamic properties against thyroid hormone β-receptors.

[0009] In a first aspect, the present invention provides a pyridazinone or pyridazine compound of formula (I) or (Ia) or a stereoisomer, tautomer, enantiomer, diastereomer, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof.

[0010]

[0011] In the formula,

[0012] X is selected from H or -C(R) 17 R 18 )OZ, Y is selected from H or -C(R) 19 R 20 )OW, with the condition that X and Y are not both hydrogen;

[0013] Z and W are each independently selected from -C(O)OR5, -C(O)NHR5, and -C(O)NR5R. 10 -C(O)R5, -P(=O)(X1R 11 (X2R) 12 -P(=O)(X1R) 11 (X3R) 14 R 15 -P(=O)(X3R) 14 R 15 (X3R) 14 R 15 -CH2P(=O)(X1R) 11 (X2R) 12 -CH2P(=O)(X1R) 11 (X3R) 14 R 15 -CH2P(=O)(X3R) 14 R 15 (X3R) 14 R 15 -P(=S)(X1R) 11 (X2R) 12 -P(=S)(X1R) 11 (X3R) 14 R 15 -P(=S)(X3R)14 R 15 )(X3R 14 R 15 )、-CH2P(=S)(X1R 11 )(X2R 12 )、-CH2P(=S)(X1R 11 )(X3R 14 R 15 )、-CH2P(=S)(X3R 14 R 15 )(X3R 14 R 15 )、-P(=NR 13 )(X1R 11 )(X2R 12 )、-P(=NR 13 )(X1R 11 )(X3R 14 R 15 )、-P(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 )、-CH2P(=NR 13 )(X1R 11 )(X2R 12 )、-CH2P(=NR 13 )(X1R 11 )(X3R 14 R 15 )、-CH2P(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 )、-OP(=O)(X1R 11 )(X2R 12 )、-OP(=O)(X1R 11 )(X3R 14 R 15 )、-OP(=O)(X3R 14 R 15 )(X3R 14 R 15 )、-OCH2P([O)(X1R 11 )(X2R 12 )、-OCH2P([O)(X1R 11 )(X3R 14 R 15 )、-OCH2P([O)(X3R 14 R 15)(X3R 14 R 15 )、-OP(=S)(X1R 11 )(X2R 12 )、-OP(=S)(X1R 11 )(X3R 14 R 15 )、-OP(=S)(X3R 14 R 15 )(X3R 14 R 15 )、-OCH2P(=S)(X1R 11 )(X2R 12 )、-OCH2P(=S)(X1R 11 )(X3R 14 R 15 )、-OCH2P(=S)(X3R 14 R 15 )(X3R 14 R 15 ) 、 -OP(=NR 13 )(X1R 11 )(X2R 12 ) 、-OP(=NR 13 )(X1R 11 )(X3R 14 R 15 ) 、 -OP(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 ) 、-OCH2P(=NR 13 )(X1R 11 )(X2R 12 ) 、 -OCH2P(=NR 13 )(X1R 11 )(X3R 14 R 15 ) 、-OCH2P(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 ):

[0014] R1, R2, and R3 are each independently selected from the group consisting of hydrogen, deuterium, undeuterated or one or more (preferably 1-4) deuterated or fully deuterated C1-C4 alkyl groups, hydroxyl groups, or R1, R2, and R3 combined with adjacent C groups to form substituted or unsubstituted C3-C8 cycloalkyl groups, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of C1-C4 alkyl, C3-C8 cycloalkyl, hydroxyl, amino, carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide.

[0015] R4, R6, R7, R8, and R9 are each independently selected from the following group: hydrogen, deuterium, and halogens;

[0016] R5 can be a substituted or unsubstituted C1-C20 alkyl, a substituted or unsubstituted C3-C20 cycloalkyl, a substituted or unsubstituted 4-20 heterocyclic alkyl, a substituted or unsubstituted C6-C20 aryl, a substituted or unsubstituted C6-C20 aryl-C1-C8 alkyl-, or a substituted or unsubstituted 5-12 heteroaryl, a substituted or unsubstituted 5-12 heteroaryl-C1-C8 alkyl-, or a substituted or unsubstituted C1-C4 alkyl- (substituted or unsubstituted C1-C4 alkyl-O). m -Substituted or unsubstituted C1-C4 alkyl-, wherein m is a positive integer from 1 to 8, and the substitution refers to being substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, amino, C2-C8 carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide;

[0017] R 10 The group is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 4-10 heterocyclic alkyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, amino, C2-C8 carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide.

[0018] X1 and X2 are each independently selected from the following group: oxygen or sulfur;

[0019] X3 is nitrogen;

[0020] R 11 R 12 R 13 R 14 R 15Each group is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 heteroaryl, or R 11 and R 12 It combines with adjacent X1, X2, and P to form substituted or unsubstituted 5-7 membered heterocyclic alkyl groups, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, C1-C20 alkyl, halo-C1-C20 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, 4-10 membered heterocyclic alkyl, C6-C10 aryl, halo-C6-C10 aryl, C5-C10 heteroaryl, halogen, amino, nitro, -COR 16 -COOR 16 -OCOOR 16 , cyano, hydroxyl, amide, sulfonamide;

[0021] R 16 The group is selected from the following group: hydrogen, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C6-C10 aryl, amino, substituted or unsubstituted 4-10 heterocyclic alkyl, wherein the substitution refers to being substituted by one or more C6-C10 aryl groups;

[0022] R 17 R 18 R 19 R 20 Each group is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C3 alkyl groups, provided that X is attached to N and Y is hydrogen. 17 R 18 They are not both hydrogen.

[0023] In another preferred embodiment, the compound is a compound of formula Ib:

[0024]

[0025] In another preferred embodiment, X is selected from H, and Y is selected from -C(R) 19 R 20 )OW.

[0026] In another preferred embodiment, X is selected from -C(R) 17 R 18 )OZ, Y is selected from H or -C(R) 19 R 20 )OW.

[0027] In another preferred embodiment, in equation (I), X is selected from -C(R) 17 R 18 OZ, Y is selected from H.

[0028] In another preferred embodiment, in equation (I), X is selected from -C(R) 17 R 18 OZ, Y is selected from H.

[0029] In another preferred embodiment, in equation (Ia), X is selected from -C(R) 17 R 18 OZ, Y is selected from H.

[0030] In another preferred embodiment, the heterocyclic alkyl and heteroaryl groups each have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S on their respective heterocycles.

[0031] In another preferred embodiment, at least one of R1, R2, R3, and R4 is deuterated or deuterated.

[0032] In another preferred embodiment, at least two of R1, R2, R3, and R4 are deuterated or deuterated.

[0033] In another preferred embodiment, at least three of R1, R2, R3, and R4 are deuterated or deuterated.

[0034] In another preferred embodiment, all four of R1, R2, R3, and R4 are either deuterated or deuterated.

[0035] In another preferred embodiment, all four of R1, R2, R3, and R4 are either fully deuterated or deuterated.

[0036] In another preferred embodiment, at least one of R1, R2, R3, and R4 is selected from the group consisting of deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0037] In another preferred embodiment, at least two of R1, R2, R3, and R4 are selected from the group consisting of deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0038] In another preferred embodiment, at least three of R1, R2, R3, and R4 are selected from the group consisting of deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0039] In another preferred embodiment, R1, R2, R3, and R4 are independently selected from the group consisting of: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0040] In another preferred embodiment, R1 and R3 are independently selected from the group consisting of one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0041] In another preferred embodiment, R2 and R4 are independently selected from the group consisting of hydrogen and deuterium.

[0042] In another preferred embodiment, R1 and R3 are CD3.

[0043] In another preferred embodiment, R2 is deuterium.

[0044] In another preferred embodiment, R4 is deuterium.

[0045] In another preferred embodiment, R7 and R9 are deuterium.

[0046] In another preferred embodiment, at least one of R1, R2, and R3 is selected from the group consisting of deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0047] In another preferred embodiment, at least two of R1, R2, and R3 are selected from the group consisting of deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0048] In another preferred embodiment, R1, R2, and R3 are independently selected from the group consisting of: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.

[0049] In another preferred embodiment, the compound contains a higher content of deuterium isotopes at the deuterated position than the natural deuterium isotopes.

[0050] In another preferred embodiment, the deuterium isotope content at the deuterated position in the compound is at least 30% greater than the natural deuterium isotope content (0.015%), more preferably 50%, more preferably 75%, more preferably 95%, most preferably 99%, such as 100%.

[0051] In another preferred embodiment, only one of X and Y is hydrogen.

[0052] In another preferred embodiment, X is hydrogen and Y is not hydrogen.

[0053] In another preferred embodiment, Y is hydrogen and X is not hydrogen.

[0054] In another preferred embodiment, neither X nor Y is hydrogen.

[0055] In another preferred embodiment, R1, R2, and R3 are each independently selected from the group consisting of hydrogen, deuterium, undeuterated or one or more (preferably 1-4) deuterated or fully deuterated C1-C4 alkyl groups.

[0056] In another preferred embodiment, R1, R2, and R3 are each independently hydrogen or undeuterated C1-C4 alkyl groups.

[0057] In another preferred embodiment, R1, R2, and R3 are each independently hydrogen or methyl.

[0058] In another preferred embodiment, R4 is hydrogen or deuterium.

[0059] In another preferred embodiment, R5 is a substituted or unsubstituted C1-C20 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted 4-10 membered heterocyclic alkyl, a substituted or unsubstituted C6-C12 aryl, a substituted or unsubstituted C6-C12 aryl-C1-C4 alkyl-, a substituted or unsubstituted C6-C12 heteroaryl, a substituted or unsubstituted C6-C12 heteroaryl-C1-C4 alkyl-, or a substituted or unsubstituted C1-C4 alkyl- (substituted or unsubstituted C1-C4 alkyl-O). m -Substituted or unsubstituted C1-C4 alkyl-.

[0060] In another preferred example, Z and W are each independently -C(O)OR5.

[0061] In another preferred embodiment, R5 is a substituted or unsubstituted C1-C8 alkyl group.

[0062] In another preferred embodiment, R7 is hydrogen or deuterium.

[0063] In another preferred embodiment, R9 is hydrogen or deuterium.

[0064] In another preferred embodiment, R6 is a halogen.

[0065] In another preferred embodiment, R8 is a halogen.

[0066] In another preferred embodiment, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, deuterium, and halogens.

[0067] In another preferred embodiment, R 17 R 18 R 19 R 20 Each is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C3 alkyl groups, provided that X is attached to N and Y is hydrogen, R 17 R 18 They are not both hydrogen.

[0068] In another preferred embodiment, R 17 R 18 R 19 R 20 Each is independently selected from the following group: hydrogen, methyl, with the condition that X is attached to N and Y is hydrogen, R 17 R 18 They are not both hydrogen.

[0069] In another preferred embodiment, R 17 For hydrogen, R 18It is hydrogen, substituted or unsubstituted C1-C3 alkyl.

[0070] In another preferred embodiment, when X is attached to N and Y is hydrogen, R 17 R 18 They are not both hydrogen.

[0071] In another preferred embodiment, R 19 For hydrogen, R 20 It is hydrogen, substituted or unsubstituted C1-C3 alkyl.

[0072] In another preferred embodiment, R 17 For hydrogen, R 18 It can be hydrogen or methyl.

[0073] In another preferred embodiment, R 19 For hydrogen, R 20 It can be hydrogen or methyl.

[0074] In another preferred embodiment, the compound is a compound of formula (II-A) or formula (II-B):

[0075]

[0076] X, Y, R1, R2, R3, R4, R6, and R8 are defined as above.

[0077] In another preferred embodiment, the compound is a compound of formula (III-A) or formula (III-B):

[0078]

[0079] X, Y, R1, R2, R3, and R4 are defined as above.

[0080] In another preferred embodiment, the compound has pyridazinones or pyridazine compounds of formulas (IV-A), (IV-B), (IV-C), and (IV-D), or their stereoisomers, tautomers, enantiomers, diastereomers, resonance bodies, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms.

[0081]

[0082]

[0083] Among them, R1, R2, R3, R4, R 17 R 18 R 19 R 20 Z and W are defined as above.

[0084] In another preferred embodiment, the compound has pyridazinones or pyridazine compounds of formulas (VA), (VB), (VC), and (VD), or stereoisomers, tautomers, enantiomers, diastereomers, resonance bodies, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof.

[0085]

[0086] Among them, R4, R 17 R 18 R 19 R 20 Z and W are as defined above.

[0087] In another preferred embodiment, the compound is selected from the group consisting of:

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] A second aspect of the present invention provides a method for preparing pyridazinones or pyridazine compounds of formula (I) or (Ia) as described in the first aspect of the present invention, or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, the method comprising the steps of:

[0100]

[0101] (1) Compound of formula (VI) reacts with XR or YR' under alkaline conditions to generate intermediates of formula (VI-A), formula (VI-B) or formula (Ib);

[0102] (2) The intermediate of formula (VI-A) or formula (VI-B) or formula (Ib) reacts with YR' or XR under alkaline conditions to give the compound shown in formula (I) or formula (Ia);

[0103] Where R and R' are leaving groups.

[0104] In another preferred embodiment, the alkaline condition is an alkaline reagent selected from the group consisting of NaH, cesium carbonate, triethylamine, DIPEA, or a combination thereof.

[0105] In another preferred embodiment, the leaving group is a halogen, preferably Cl, Br or I.

[0106] Or it may include steps:

[0107]

[0108] (1) The compound of formula (VI) is protected with a protecting group (PG is the protecting group, such as SEM or THP) to generate an intermediate (VI-C), and then reacts with YR' under basic conditions to generate the compound of formula (I) (X is hydrogen);

[0109] In a third aspect, the present invention provides a pharmaceutical composition comprising:

[0110] 1) A therapeutically effective amount of a pyridazinone or pyridazine compound of formula (I) or (Ia) as described in the first aspect of this invention, or a stereoisomer, tautomer, enantiomer, diastereomer, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof; and

[0111] 2) Pharmaceutically acceptable carrier.

[0112] In another preferred embodiment, the content of the pyridazinone or pyridazine compound of formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof is 0.01-99.99 wt.%, preferably 0.1-99.9 wt.%, more preferably 1-99 wt.%, more preferably 5-95 wt.%, more preferably 10-90 wt.%, more preferably 20-80 wt.%, and most preferably 30-70 wt.%, based on the weight of the composition.

[0113] In another preferred embodiment, the pharmaceutical composition further comprises other active ingredients.

[0114] In another preferred embodiment, the other active ingredient is an active ingredient for the prevention and / or treatment of diseases selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.

[0115] In another preferred embodiment, the pharmaceutical composition further comprises other drugs for the prevention and / or treatment of diseases selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or combinations thereof.

[0116] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: interferon α (standard INFα and polyethanolated INFα), nucleoside analogues (such as Telbivudine, Lamivudine, Clevudine, Adefovir, Tenofovir, Besifovir, Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide Fumarate (TAF), and HDP-PMPA (CMX157), etc.), capsid protein allosteric modulators (such as BAY41-4109, RG-7907, NVR3-778, ABI-H0731, ABI-H2158, JNJ-56136379, GLS 4JHS, etc.), cccDNA inhibitors, TLR3 / 7 / 8 / 9 agonists (such as RG-7854, GS9620, etc.), and hepatitis B virus entry inhibitors (such as Myrcludex). HBV surface antigen inhibitors (such as RG7834, REP2139, REP2165), CRISPER / Cas9, or combinations thereof, bile acid receptor (FXR) agonists (such as Obeticholic acid, Tropifexor, GS-9674, ZG5266), and peroxisome proliferator-activated receptor (PPAR) agonists (such as Elafibranor, Saroglitazar, Remogliflozin). Etabonate, thyroid hormone receptor β (THRβ) agonists (such as MGL-3196), diacylglycerol-O-acyltransferase (DGAT) inhibitors (such as Pradigastat, PF-06865571), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (such as Vismodegib), galactocele inhibitors (such as... Dual antagonists of GR-MD-02), CCR2 and CCR5 chemokine receptors (such as Centicriviroc), ketoxokinase (KHK) inhibitors (PF-06835919), glucagon-like peptide-1 (GLP-1) receptor agonists (such as liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibodies (such as simtuzumab), a complex of bile acids and arachidonic acid Aramchol, or combinations thereof.

[0117] In another preferred embodiment, the other active ingredient is an active ingredient for the prevention and / or treatment of diseases selected from the group consisting of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, cirrhosis (such as primary biliary cirrhosis), gallstones, atherosclerosis, obesity, diabetes, or a combination thereof.

[0118] In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral formulation or a parenteral formulation (such as an injection or infusion).

[0119] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: injections, capsules, tablets, pills, powders, granules, aerosols, suppositories, films, drop pills, and topical liniments.

[0120] In another preferred embodiment, the pharmaceutical composition is a controlled-release, sustained-release, or nano-formulation.

[0121] In a fourth aspect, the present invention provides the use of pyridazinones or pyridazine compounds of formula (I) or (Ia) as described in the first aspect of the present invention, or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms, or pharmaceutical compositions as described in the third aspect of the present invention, characterized in that it is used for (i) the preparation of pharmaceutical formulations or drugs of thyroid hormone receptor agonists; (ii) the preparation of pharmaceutical formulations or drugs of diseases associated with decreased thyroid hormone receptor activity; and / or (ii) the preparation of pharmaceutical formulations or drugs for the prevention and / or treatment of diseases selected from the group consisting of: inflammation, cancer, cardiovascular diseases, infections, immune disorders, metabolic diseases, or combinations thereof.

[0122] In another preferred embodiment, the diseases associated with decreased thyroid hormone receptor activity are selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.

[0123] In another preferred embodiment, the thyroid hormone receptor is a thyroid hormone α receptor and / or a thyroid hormone β receptor.

[0124] In another preferred embodiment, the thyroid hormone receptor is a thyroid hormone β receptor.

[0125] In another preferred embodiment, the disease is selected from the group consisting of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, cirrhosis (such as primary biliary cirrhosis), gallstones, atherosclerosis, obesity, hyperlipidemia, and diabetes.

[0126] In another preferred embodiment, the hyperlipidemia is hypertriglyceridemia and / or hypercholesterolemia.

[0127] In another preferred embodiment, the obesity is obesity caused by a high-fat diet.

[0128] In another preferred embodiment, the disease is selected from the group consisting of: primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, type I diabetes, type II diabetes, and obesity.

[0129] In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, leukemia, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, or combinations thereof.

[0130] In a fifth aspect, the present invention provides a thyroid hormone receptor agonist, said agonist comprising an effective amount of pyridazinone or pyridazine compound of formula (I) or (Ia) as described in the first aspect of the present invention, or a stereoisomer, tautomer, enantiomer, diastereomer, resonator, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof.

[0131] In a sixth aspect, the present invention provides a method for enhancing or increasing the activity of thyroid hormone receptors in vitro in a non-therapeutic and non-diagnostic manner, characterized in that the method comprises the step of: in an in vitro culture system, contacting thyroid hormone receptors or cells expressing thyroid hormone receptors with pyridazinones or pyridazine compounds or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms as shown in formula (I) or (Ia) of the first aspect of the present invention, thereby enhancing or increasing the activity of thyroid hormone receptors.

[0132] In a seventh aspect, the present invention provides a method for preventing and / or treating diseases selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, and diabetes, by administering a therapeutically effective amount of a pyridazinone or pyridazine compound of formula (I) or (Ia) as described in the first aspect of the present invention, or a stereoisomer, tautomer, enantiomer, diastereomer, resonator, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof, to the desired patient.

[0133] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0134] Figure 1 The blood concentration-time curves are for MGL-3196 (curve number 1) in Test Example 1 and compound (curve number 2) in WO2009037172A1 Example 5, where the blood concentration is the concentration of MGL-3196.

[0135] Figure 2 The blood concentration-time curves for MGL-3196 (curve number 1) and compound 6A (curve number 2) in test example 2 are shown, where the blood concentration is the concentration of MGL-3196.

[0136] Figure 3 The blood concentration-time curves for MGL-3196 (curve number 1) and compound 6B (curve number 2) in test example 3 are shown, where the blood concentration is the concentration of MGL-3196.

[0137] Figure 4 The blood concentration-time curves for MGL-3196 (curve number 1), compound 2A (curve number 3), and compound 2B (curve number 2) in test example 4 are shown, where the blood concentration is the concentration of MGL-3196. Detailed Implementation

[0138] Through long-term and in-depth research, the inventors unexpectedly developed a pyridazinone or pyridazine compound of formula (I) or (Ia), or its stereoisomers, tautomers, enantiomers, diastereomers, resonance bodies, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms. The pyridazinone or pyridazine compound of formula (I) or its isomer of formula (Ia) of this invention exhibits excellent selective agonist activity against thyroid hormone β-receptors and better pharmacodynamic properties. Based on this, the inventors completed this invention.

[0139] the term

[0140] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0141] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds, which can be synthesized using techniques known in the art and the methods described below. If substituted by more than one substituent, it should be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0142] As used in this article, "R1", "R1", and "R" are... 1 The meanings of "" are the same and they can be used interchangeably. Other similar definitions have the same meaning.

[0143] In this invention, unless otherwise specified, the terms used have their general meanings known to those skilled in the art. As used herein, substitution refers to the independent substitution of one or more (preferably 1, 2, 3 or 4) hydrogens and / or deuterium groups by substituents.

[0144] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number qualifier (e.g., C1-C20 alkyl), it means that the alkyl group contains 1-20 carbon atoms. For example, C1-C4 alkyl means an alkyl group containing 1-4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0145] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C20), it means that the cycloalkyl group has 3-20 carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Representative examples of cycloalkyl groups are as follows, including but not limited to:

[0146]

[0147] As used herein, the term "cycloalkenyl" refers to a single ring, bicyclic or polycyclic (fused, bridged or spirocyclic) having at least one carbon-carbon double bond in the cycloalkenyl chain, but not an aromatic structure. When the cycloalkenyl is preceded by a carbon atom number limit (e.g., C3-C8), it means that the cycloalkenyl contains 3-8 cycloalkenyl carbon atoms.

[0148] As used herein, the term "carbonyl" refers to the =O group, where the double bond (=) is connected to carbon to form an organic functional group (C=O).

[0149] As used in this article, the term "cyano" means -CN.

[0150] The term "heterocyclic alkyl," also known as "heterocyclic group," refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic systems), wherein at least one heteroatom is present in a ring with at least one carbon atom. When a member is specified before "heterocyclic alkyl," it refers to the number of ring atoms in the heterocyclic alkyl group. For example, a 4-20 membered heterocyclic alkyl group refers to a heterocyclic alkyl group having 4-20 ring atoms. Each heterocycle containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom residue in a ring or cyclic molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0151] The term "aryl" refers to an aromatic cyclic hydrocarbon compound group, such as having 1, 2, 3, 4, or 5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have its aromatic rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). When an aryl group is preceded by a carbon number qualifier, it refers to the number of ring carbon atoms in the aryl group; for example, C6-C20 aryl refers to an aryl group having 6-20 ring carbon atoms. "Substituted aryl" means that one or more (preferably 1-3) positions in the aryl group are substituted, and substitution can occur at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR bP(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic rings, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0152] The term "heteroaryl" refers to an aromatic heterocyclic system having one to several (preferably 1, 2, 3, or 4) heteroatoms. These heterocycles can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle containing a heteroatom may carry one or more (e.g., 1, 2, 3, or 4) heterocyclic atoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When a member is specified before "heteroaryl," it refers to the number of ring atoms in the heteroaryl group; for example, a 4-20 member heteroaryl refers to a heteroaryl group having 4-20 ring atoms.

[0153] The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. The "heteroaryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0154] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0155] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0156] The term "amine" refers to a -NRR' group with the structure R and R', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0157] The term "ether group" refers to a -OR group with a structure, wherein R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl. Preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, or substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are as defined above.

[0158] The term "thioether group" refers to a -SR group with the structure R, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl. Preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, or substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are as defined above.

[0159] The term "acyl" refers to a -COR group with a structure where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above.

[0160] The term "ester group" refers to a -COOR group with a structure where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above.

[0161] The term "amide group" refers to an R-CO-NR- or -CO-NRR' group, where R is hydrogen or alkyl. When the amide group is preceded by a carbon number limit (e.g., C2-C8 amide group), it means that the amide group contains 2-8 carbon atoms. R and R' are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkeny or substituted cycloalkeny, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl. Preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkeny, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, or substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl, cycloalkeny, aryl, heteroaryl, and heterocycloalkyl are as defined above.

[0162] The term "sulfonamide group" refers to a -SO2NRR' group with the structure R and R', where R and R' are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl. Preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, or substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are as defined above.

[0163] The term "alkoxy" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above herein. When the alkoxy group is preceded by a carbon number qualifier, such as C1-C6 alkoxy, it means that the alkyl group in the alkoxy group has 1-6 carbon atoms. Representative examples of alkoxy groups include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0164] In this invention, the term "deuteration" refers to being replaced by deuterium (D).

[0165] As used herein, the term "amino" means -NH2, either alone or as part of other substituents.

[0166] As used herein, the term "nitro" means -NO2, either alone or as part of other substituents.

[0167] As used herein, the term "cyano" means -CN, either alone or as part of other substituents.

[0168] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include, but are not limited to: deuterium, halogens (e.g., monohalogen or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears herea R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e The group can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The aforementioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings, can be optionally substituted. Typical substitutions also include spirocyclic, bridged-cyclic, or fused-cyclic substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaromatic rings), bridged-cycloalkyl, bridged-cycloalkenyl, bridged-cyclic heterocyclic (excluding heteroaromatic rings), fused-cycloalkyl, fused-cycloalkenyl, fused-cycloheterocyclic, or fused-cycloaryl groups, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0169] Active ingredients

[0170] As used herein, “compound of the present invention”, “pyridazinone or pyridazine compound of the present invention”, or “compound of formula (I) or (Ia) of the present invention”, or “compound of formula (I) or (Ia) of the present invention”, or “compound of formula (I) or (Ia)” are used interchangeably to refer to a pyridazinone or pyridazine compound of formula (I) or (Ia) or a stereoisomer, tautomer, enantiomer, diastereomer, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof.

[0171]

[0172] The definitions of each group are as described in the first aspect of this invention above. It should be understood that this term also includes mixtures of the above-described components.

[0173] In this invention, “Formula I” and “Formula (I)” can be used interchangeably, “Formula Ia” and “Formula (Ia)” can be used interchangeably, and so on, such as “Formula Ib” and “Formula (Ib)” can be used interchangeably.

[0174] In this invention, all or substantially (>99 wt%) of the elements other than H in the compounds of formula (I) or (Ia) are the most abundant naturally occurring elements, for example... 14 N、 12 C 16 O and 19 F.

[0175] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0176] In another preferred embodiment, in the compound of formula (I) or (Ia) of the present invention, the said groups (such as X, Y, Z, W, R1, R2, R3, R4, R5, R6, R7, R8, R9, R...) 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Any one of the groups on the compound in equation (I) or (Ia) corresponds to the group in the specific compound described in Table 1.

[0177] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0178] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. Furthermore, when a compound of the present invention contains a basic fragment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic fragment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may be formed are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for use in separation or purification steps during preparation. The compounds of the present invention may form salts, for example, by reacting the compound with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0179] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acid salts that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates (e.g., p-toluenesulfonate), dodecanoates, etc.

[0180] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0181] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0182] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0183] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0184] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0185] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0186] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0187] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0188] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0189] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0190] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotope-labeled compounds can be prepared using general methods by replacing the non-isotope reagent with an readily available isotope-labeling reagent, according to the schemes disclosed in the schematic diagram and / or examples.

[0191] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0192] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0193] The compounds involved in this invention and their pharmaceutically acceptable salt metabolites, as well as compounds that can be converted into the compounds involved in this invention in vivo, are also included within the scope of this invention.

[0194] Preparation method

[0195] The preparation methods of compounds of formula (I) or (Ia) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0196] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0197] For example, the compound shown in formula (I) is prepared as follows:

[0198]

[0199] The compound of formula (VI) is reacted with XR or YR' (R, R' being a leaving group, such as Cl, Br, or I) under alkaline conditions (such as NaH, cesium carbonate, triethylamine, or DIPEA) to generate an intermediate of formula (VI-A) or (VI-B); the intermediate is then further reacted with YR' or XR (R', R being a leaving group, such as Cl, Br, or I) under alkaline conditions (such as NaH, cesium carbonate, triethylamine, or DIPEA) to obtain the target compound (I).

[0200] Alternatively, synthesize it by following these steps:

[0201]

[0202] Compound (VI) is protected with a protecting group (PG is the protecting group, such as SEM or THP) to generate an intermediate (VI-C), which is then reacted with YR' under basic conditions to generate an intermediate of formula (I) (X is hydrogen).

[0203] Pharmaceutical Compositions and Administration

[0204] The present invention also provides a pharmaceutical composition comprising:

[0205] 1) A therapeutically effective amount of the pyridazinone or pyridazine compound of formula (I) or (Ia) of the present invention, or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof; and

[0206] 2) Pharmaceutically acceptable carrier.

[0207] In a preferred embodiment, the content of the pyridazinone or pyridazine compound of formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof is 0.01-99.99 wt.%, more preferably 0.1-99.9 wt.%, more preferably 1-99 wt.%, more preferably 5-95 wt.%, more preferably 10-90 wt.%, more preferably 20-80 wt.%, and most preferably 30-70 wt.%, based on the weight of the composition.

[0208] The present invention provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a pyridazinone or pyridazine compound of formula (I) or (Ia) of the present invention, or a stereoisomer, tautomer, enantiomer, diastereomer, resonator, pharmaceutically acceptable salt, hydrate, solvate, crystal form or prodrug thereof, thereby forming a pharmaceutical composition.

[0209] It should be understood that compounds of formula (I) or (Ia) can be used in combination with other known drugs for treating or improving similar symptoms. When used in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula (I) or (Ia) is taken simultaneously or subsequently. When a compound of formula (I) or (Ia) is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and a compound of formula (I) or (Ia) is preferred. Drug combination also includes taking a compound of formula (I) or (Ia) with one or more other known drugs during overlapping time periods. When a compound of formula (I) or (Ia) is used in combination with one or more other drugs, the dosage of the compound of formula (I) or (Ia) or the known drug may be lower than the dosage of either drug when used alone.

[0210] Other active ingredients described in this invention include, but are not limited to: bile acid receptor (FXR) agonists (such as Obeticholic acid, Tropifexor, GS-9674, ZG5266), peroxisome proliferator-activated receptor (PPAR) agonists (such as Elafibranor, Saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor β (THRβ) agonists (such as MGL-3196), diacylglycerol-O-acyltransferase (DGAT) inhibitors (such as Pradigastat, PF-06865571), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (such as Vismodegib), and galactocele inhibitors. (e.g., GR-MD-02), dual antagonists of CCR2 and CCR5 chemokine receptors (e.g., Centicriviroc), hexokinase (KHK) inhibitors (PF-06835919), glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), and the bile acid and arachidonic acid complex Aramchol, etc.

[0211] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.1-2000 mg of the compound of the present invention per dose, more preferably, 1-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0212] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and be mixed with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0213] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0214] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0215] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0216] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0217] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0218] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0219] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0220] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0221] The compounds of formula (I) or (Ia) described in this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0222] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0223] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0224] The inflammation, cardiovascular disease, infection, immune disease, metabolic disease, or cancer involved in this invention include (but are not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or liver fibrosis; arteriosclerosis, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia; type I diabetes, type II diabetes, or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, leukemia, bone cancer, kidney cancer, stomach cancer, liver cancer, or colorectal cancer.

[0225] use

[0226] The present invention also provides the use of pyridazinones or pyridazine compounds of formula (I) or (Ia) or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, or pharmaceutical compositions as described in the present invention, for (i) the preparation of pharmaceutical formulations or medicaments of thyroid hormone receptor agonists; (ii) the preparation of pharmaceutical formulations or medicaments of diseases associated with decreased thyroid hormone receptor activity; and / or (ii) the preparation of pharmaceutical formulations or medicaments for the prevention and / or treatment of diseases including (but not limited to) the following group: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or combinations thereof.

[0227] In this invention, the term "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the subject's risk of contracting the disease.

[0228] In this invention, the term "treatment" refers to any treatment of a disease in mammals, including (but not limited to): (a) suppressing the disease, i.e., slowing or preventing the development of clinical symptoms; and / or (b) alleviating the disease, i.e. causing the remission of clinical symptoms; and / or (c) reducing or eliminating the disease and / or its accompanying symptoms.

[0229] In a preferred embodiment, the thyroid hormone receptor is a thyroid hormone α receptor and / or a thyroid hormone β receptor. Preferably, the thyroid hormone receptor is a thyroid hormone β receptor.

[0230] In the invention, diseases associated with decreased thyroid hormone receptor activity include (but are not limited to): inflammation, cancer, cardiovascular disease, infection, immune disorders, metabolic disorders, or combinations thereof.

[0231] In another preferred embodiment, the disease includes (but is not limited to): non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, cirrhosis (such as primary biliary cirrhosis), gallstones, atherosclerosis, obesity, hyperlipidemia, and diabetes.

[0232] In another preferred embodiment, the hyperlipidemia is hypertriglyceridemia and / or hypercholesterolemia.

[0233] In another preferred embodiment, the obesity is obesity caused by a high-fat diet.

[0234] In another preferred embodiment, the disease includes (but is not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, type I diabetes, type II diabetes, and obesity.

[0235] In another preferred embodiment, the cancer includes (but is not limited to): lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, leukemia, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, or combinations thereof.

[0236] Typically, the compounds of formula (I) or (Ia) described in this invention are used to prepare medicaments for the prevention and / or treatment of obesity.

[0237] The present invention also provides an in vitro non-therapeutic and non-diagnostic method for enhancing or increasing the activity of thyroid hormone receptors, the method comprising the steps of: in an in vitro culture system, contacting thyroid hormone receptors or cells expressing thyroid hormone receptors with pyridazinones or pyridazine compounds of formula (I) or (Ia) as described in the present invention, or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, thereby enhancing or increasing the activity of thyroid hormone receptors.

[0238] The present invention also provides a method for preventing and / or treating diseases including (but not limited to) the following group: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, diabetes, the method comprising the step of: administering a therapeutically effective amount of a pyridazinone or pyridazine compound of formula (I) or (Ia) as described in the present invention, or a stereoisomer, tautomer, enantiomer, diastereomer, resonator, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof to the desired patient.

[0239] It should be understood in this invention that the term "symptom" includes disease and its symptoms.

[0240] thyroid hormone receptor agonists

[0241] The present invention also provides a thyroid hormone receptor agonist, said agonist comprising an effective amount of pyridazinone or pyridazine compound of formula (I) or (Ia) of the present invention, or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof.

[0242] The main advantages of this invention include:

[0243] (1) The compounds represented by formula (I) or (Ia) of the present invention have superior metabolic properties and pharmacological efficacy in vivo (e.g., in rats);

[0244] (2) The compounds represented by formula (I) or (Ia) of the present invention have higher drug concentrations in liver tissue in vivo (e.g., in rats), thereby having better pharmacological efficacy.

[0245] (3) The compound or its metabolite represented by formula (I) or (Ia) of the present invention has excellent selective agonistic effect on thyroid hormone β receptor.

[0246] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0247] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0248] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0249] NMR was performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

[0250] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC determinations were performed using an Agilent 100 high-performance chromatograph (Microsorb 5micron C18 100x 3.0 mm column).

[0251] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Yantai Huanghai 200-300 mesh silica gel as the support.

[0252] The starting materials used in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature reported in the art.

[0253] Unless otherwise specified, all reactions in this invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.

[0254] Example 1

[0255] Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile)

[0256]

[0257] Step 1: Preparation of 3,6-dichloro-4-isopropylpyridazine

[0258] At room temperature, isobutyric acid (1.4 g, 0.0151 mol) was added to a mixture of acetonitrile (3.5 mL), sulfolane (10.7 mL), and water (24.5 mL) containing 2.25 g, 0.015 mol of 3,6-dichloropyridazine, followed by silver nitrate (1.3 g, 0.015 mol). The reaction mixture was heated to 55 °C, and a solution of concentrated sulfuric acid (2.4 mL) in water (7.5 mL) was added in one step, followed by dropwise addition of ammonium persulfate (5.2 g, 0.022 mol) in water (7.5 mL) over 35 minutes. The reaction mixture was reacted at 70 °C for 20 minutes, then cooled to room temperature and stirred at room temperature for 24 hours. The resulting reaction mixture was cooled to 0 °C and the pH was slowly adjusted to 8 with ammonia (10 mL). The resulting mixture was diluted with water (50 mL) and filtered. The filter cake was washed with ethyl acetate (50 mL). The organic phase was collected from the filtrate, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed sequentially with water (40 mL) and saturated brine (40 mL), dried, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was then subjected to silica gel column chromatography to obtain the target compound (1.9 g, 67% yield).

[0259] LC-MS: m / z 191 (M+H) + .

[0260] Step 2: Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline

[0261] Under argon protection, 4-amino-2,6-dichlorophenol (0.5 g, 2.8 mmol), anhydrous potassium carbonate (1.6 g, 11.2 mmol), and cuprous iodide (0.32 g, 1.7 mmol) were added to a solution of 3,6-dichloro-4-isopropylpyridazine (0.54 g, 2.8 mmol) in anhydrous DMSO (2 mL) at room temperature. The reaction mixture was reacted at 90 °C for 24 h, then cooled to room temperature and poured into water (100 mL). The resulting mixture was adjusted to pH 8 with dilute hydrochloric acid (1 N), and then ethyl acetate (50 mL) was added. The mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was collected separately, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the target product (0.5 g, 53% yield).

[0262] LC-MS: m / z 338(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.629 (s, 1H), 6.674 (s, 2H), 5.649 (brs, 2H), 3.114 (m, 1H), 1.237 (d, J = 6.8Hz, 6H).

[0263] Step 3: Preparation of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one

[0264] A mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1.0 g, 3.0 mmol), glacial acetic acid (30 mL), and sodium acetate (860 mg, 10.5 mmol) was reacted at 100 °C for 24 h, then cooled to room temperature and stirred at room temperature for 2 days. The resulting mixture was diluted with water and then the pH was adjusted to 9 with an aqueous sodium hydroxide solution (1 N). The resulting suspension was extracted with ethyl acetate. After separation of the aqueous phase, the pH was adjusted to 5 with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phases were combined, dried, and filtered. The filtrate was concentrated by vacuum drying. The resulting residue was diluted with methanol (20 mL) and then an aqueous sodium hydroxide solution (1 N, 20 mL, 20 mmol) was added. The resulting reaction mixture was reacted at 120 °C for 24 h, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (100 mL) and then extracted with ethyl acetate. The organic phases were combined, washed with a dilute aqueous hydrochloric acid solution (pH 5) and saturated brine, dried, and filtered. The filtrate was concentrated under vacuum, and the residue was subjected to preparative chromatography to obtain the target compound (0.48 g, 50% yield).

[0265] LC-MS: m / z 314 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.125(s,1H),7.270(s,1H),6.671(s,2H),5.624(brs,2H),3.013(m,1H),1.177(d,J=6.8Hz,6H).

[0266] Step 4: Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)hydrazone)acetyl)carbamate

[0267] Concentrated hydrochloric acid (2.8 mL) was added to a suspension of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (134 mg, 0.42 mmol) in water (5.6 mL). The reactants were cooled to 0 °C and then a solution of sodium nitrite (36.5 mg, 0.529 mmol) in water (0.2 mL) was added. The resulting mixture was stirred at 0 °C for 30 min, then rapidly filtered and quickly added to a mixture of N-cyanoacetylurane (72 mg, 0.46 mmol), water (9.4 mL), and pyridine (2.8 mL) pre-cooled to 0 °C. The resulting suspension was stirred at 0 °C for 30 min and then filtered. The solid was washed successively with water and petroleum ether and then dried under vacuum at 80 °C overnight to give the target product (114 mg, yield 56%).

[0268] LC-MS: m / z 481 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),12.22(s,1H),10.89(s,1H),7.99(s,2H),7. 36(s,1H),4.21(q,J=7.1Hz,2H),3.06(m,1H),1.27(t,J=7.1Hz,3H),1.20(m,6H).

[0269] Step 5: Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile)

[0270] Sodium acetate (0.3 g, 3.6 mmol) was added to a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)hydrazone)acetyl)carbamate (0.35 g, 0.72 mmol) in glacial acetic acid (7.2 mL) at room temperature. The reactants were reacted at 120 °C for 1.5 hours, then cooled to 0 °C, diluted with water (20 mL), and stirred for 30 minutes. After filtration, the mixture was washed successively with water and petroleum ether, then air-dried for 30 minutes, and finally slurried with acetonitrile and water to obtain the target product (0.16 g, 50% yield).

[0271] LC-MS: m / z 435 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ13.200(brs,1H),12.257(s,1H),7.795(s,2H),7.458(s,1H),3.059(m,1H),1.177(d,J=6.9Hz,6H).

[0272] Example 2

[0273] Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxadiazine)ethyl isopropyl carbonate)

[0274]

[0275] Step 1: Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxadiazine)ethyl isopropyl carbonate)

[0276] In a round-bottom flask, compound 2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-cyano (500 mg, 1.15 mmol), cesium carbonate (747 mg, 2.30 mmol), isopropyl 1-chloroethyl carbonate (287 mg, 1.72 mmol), and N,N-dimethylformamide (20 mL) were added sequentially. The reaction mixture was allowed to react at room temperature for 20 hours. The crude product was purified by preparative liquid chromatography to give two compounds: compound 2A (34 mg) and compound 2B (77 mg).

[0277] Compound 2A: 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)ethyl isopropyl carbonate

[0278]

[0279] LC-MS: m / z 587 (M+Na) + . 1H NMR (400MHz, DMSO-d6) δ7.82 (s, 2H), 7.53 (s, 1H), 6.89 (q, J = 6.0Hz, 1H), 4.67-4.73 (m, 1H ), 3.06-3.13(m,1H),1.29(d,J=6.0Hz,3H),1.21(d,J=7.2Hz,6H),1.18(d,J=6.4Hz,6H).

[0280] Compound 2B: 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxy)ethylisopropyl carbonate

[0281]

[0282] LC-MS: m / z 565 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.80(s,2H),7.66(s,1H),6.96(q,J=5.2Hz,1H),4.73-4.79(m,1H),3.01- 3.08 (m, 1H), 1.61 (d, J = 5.2Hz, 3H), 1.24 (dd, J = 6.8Hz, 12.4Hz, 6H), 1.18 (dd, J = 6.4Hz, 9.6Hz, 6H).

[0283] Example 3

[0284] Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-1,1,1,3,3,3-d6)pyridazin-1(6H)-yl)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-4-(propane-2-yl-1,1,1,3,3,3-d6)pyridazin-3-yl)oxo)ethyl isopropyl carbonate)

[0285] Following the preparation methods of Examples 1 and 2, compounds 3A and 3B were synthesized by using 2-(trideuterated methyl)-3,3,3-trideuterated propionic acid instead of isobutyric acid as the starting material.

[0286] Compound 3A: 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-1,1,1,3,3,3-d6)pyridazine-1(6H)-yl)ethyl isopropyl carbonate

[0287]

[0288] LC-MS: m / z 571 (M+H) + .

[0289] Compound 3B: 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-(propane-2-yl-1,1,1,3,3,3-d6)pyridazine-3-yl)oxy)ethyl isopropyl carbonate

[0290]

[0291] LC-MS: m / z 571 (M+H) + .

[0292] Example 4

[0293] Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-d7)pyridazin-1(6H)-yl)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-4-(propane-2-yl-d7)pyridazin-3-yl)oxo)ethyl isopropyl carbonate)

[0294] Following the preparation methods of Examples 1 and 2, compounds 4A and 4B were synthesized by using 2-(methyl-d3)propyl-2,3,3,3-d4 acid instead of isobutyric acid as the starting material.

[0295] Compound 4A: 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-d7)pyridazine-1(6H)-yl)ethyl isopropyl carbonate

[0296]

[0297] LC-MS: m / z 572 (M+H) + .

[0298] Compound 4B: 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-(propane-2-yl-d7)pyridazine-3-yl)oxy)ethyl isopropyl carbonate

[0299]

[0300] LC-MS: m / z 572 (M+H) + .

[0301] Example 5

[0302] Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-d7)pyridazin-1(6H)-yl-4-d)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-4-(propane-2-yl-d7)pyridazin-3-yl-5-d)oxo)ethyl isopropyl carbonate)

[0303] Following the preparation methods of Examples 1 and 2, compounds 5A and 5B were synthesized by replacing isobutyric acid with 2-(methyl-d3)propyl-2,3,3,3-d4 acid and replacing 3,6-dichloropyridazine-4,5-d2 as starting materials.

[0304] Compound 5A: 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-6-oxo-5-(propane-2-yl-d7)pyridazine-1(6H)-yl-4-d)ethyl isopropyl carbonate

[0305]

[0306] LC-MS: m / z 573 (M+H) + .

[0307] Compound 5B: 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-(propane-2-yl-d7)pyridazine-3-yl-5-d)oxy)ethyl isopropyl carbonate

[0308]

[0309] LC-MS: m / z 573 (M+H)+ .

[0310] Example 6

[0311] Preparation of Compound 6: (3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)methylisopropyl carbonate and (6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methylisopropyl carbonate)

[0312] Following the preparation method of Example 2, compound 6 was synthesized by using chloromethyl isopropyl carbonate instead of isopropyl carbonate-1-chloroethyl ester as the starting material.

[0313] Compound 6A: (3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)methylisopropyl carbonate

[0314]

[0315] LC-MS: m / z 551 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.79(s,2H),7.54(s,1H),5.72(s,2H),4.69-4.75(m,1H),3.05-3.12(m,1H),1.19-1.22(m,12H).

[0316] Compound 6B: ((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxy)methylisopropyl carbonate)

[0317]

[0318] LC-MS: m / z 551 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.80(s,2H),7.68(s,1H),6.08(s,2H),4.77-4.86(m,1H),3.01-3.11(m,1H),1.21-1.25(m,12H).

[0319] Example 7 Preparation of 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)ethyl ethyl carbonate and 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxadiazine)ethyl ethyl carbonate)

[0320] Following the preparation method of Example 2, compound 7 was synthesized by using ethyl 1-chloroethyl carbonate instead of isopropyl 1-chloroethyl carbonate as the starting material.

[0321] Compound 7A: 1-(3-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-5-isopropyl-6-oxadiazine-1(6H)-yl)ethyl ethyl carbonate

[0322]

[0323] LC-MS: m / z 551 (M+H) + .

[0324] Compound 7B: 1-((6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3-yl)oxy)ethyl ethyl carbonate

[0325]

[0326] LC-MS: m / z 551 (M+H) + .

[0327] Example 8

[0328] Preparation of isobutyric acid-(6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl ester

[0329]

[0330] Step 1: Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile)

[0331] In a Schlenk tube, 2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-cyano (500 mg, 1.15 mmol), p-toluenesulfonic acid pyridinium salt (29 mg, 0.16 mmol), 3,4-dihydropyran (386 mg, 4.6 mmol), and 1,4-dioxane (5 mL) were added sequentially. After the addition was complete, the reaction mixture was heated to 65 °C and reacted at this temperature for 16 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by liquid chromatography to give the target compound (350 mg, yield 59%).

[0332] LC-MS: m / z 519 (M+H) + .

[0333] Step 2: Preparation of (6-cyano-2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl isobutyrate

[0334] In a round-bottom flask, add compound 2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-2-)

[0335] (214 mg, 0.41 mmol)-1,6-dihydropyridazine-3-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile (10 mL) and N,N-dimethylformamide (10 mL) were added, followed by sodium hydride (41 mg, 1.03 mmol). The resulting mixture was stirred for 10 min, and then methyl chloride isobutyrate (113 mg, 0.82 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 55 °C and reacted at this temperature for 17 h. The resulting mixture was quenched with water and then purified to give the target compound (110 mg, 43% yield).

[0336] LC-MS: m / z 663(M+HCOO) - ) - .

[0337] Step 3: Preparation of isobutyric acid-(6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl ester

[0338] In a round-bottom flask, 110 mg (0.18 mmol) of compound (6-cyano-2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl isobutyrate and 10 mL of dichloromethane were added, followed by dropwise addition of trifluoroacetic acid (1 mL). After the addition was complete, the reaction mixture was reacted at room temperature for 6 hours, then quenched and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain the target compound (31 mg, yield 33%).

[0339] LC-MS: m / z 535 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),7.80(s,2H),7.45(s,1H),5.85(s,2H),3. 11-3.00(m,1H),2.62-2.54(m,1H),1.20(d,J=7.2Hz,6H),1.10(d,J=6.8Hz,6H).

[0340] The compounds of Examples 9 and 10 were synthesized using different raw materials and the same method according to Example 8:

[0341] Example 9: Preparation of methyl tervastatin-(6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl) ester

[0342]

[0343] LC-MS: m / z 549 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),7.80(s,2H),7.45(s,1H),5.83(s,2H),3.09-3.02(m,1H),2.62-2.54(m,1H),1.24-1.16(m,15H).

[0344] Example 10: Preparation of L-alanine-(6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl ester trifluoroacetate

[0345]

[0346] LC-MS: m / z 536 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.38(s,3H),7.75(s,2H),7.36(s,1H),5.91(dd,J=10.4Hz ,19.2Hz,2H),4.07-4.08(m,1H),2.94-3.01(m,1H),1.32(d,J=7.2Hz,3H),1.12(d,J=6.8Hz,6H).

[0347] Example 11 Preparation of ((6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)dihydrophosphate

[0348]

[0349] Step 1: Preparation of di-tert-butyl((6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)phosphate

[0350] In a round-bottom flask, add compound 2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-2-)

[0351] The reaction mixture was prepared by reacting (300 mg, 0.58 mmol) with (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-cyano) (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-cyano) and N,N-dimethylformamide (10 mL), followed by sodium hydride (58 mg, 1.44 mmol). The reaction mixture was stirred at room temperature for 10 min, and then di-tert-butylchloromethyl phosphate (299 mg, 1.16 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to 65 °C and reacted for 46 hours. The resulting mixture was quenched with water and then purified to give the target compound (15 mg, 4% yield).

[0352] LC-MS: m / z 785(M+HCOO) - ) - .

[0353] Step 2: Preparation of ((6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)dihydrophosphate

[0354] In a round-bottom flask, 15 mg (0.02 mmol) of di-tert-butyl(6-cyano-2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl phosphate and 3 mL of dichloromethane were added, followed by the dropwise addition of trifluoroacetic acid (0.2 mL). The mixture was then reacted at room temperature for 5 hours. The resulting mixture was purified to obtain the target compound (6 mg, yield 54%).

[0355] LC-MS: m / z 545 (M+H) + . 1 H NMR (400MHz, DMSO-d6): δ 12.25 (s, 1H), 7.81 (s, 2H), 7.45 (s, 1H), 5.51 (d, J = 7.2Hz, 2H), 3.05 (m, 1H), 1.20 (d, J = 6.8Hz, 6H). 31 PNMR (162MHz, DMSO-d6): δ-3.2(s).

[0356] Example 12 Preparation of (6-cyano-2-(3,5-dichloro-4-((1-((isobutyryloxy)methyl)-5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxo)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl isobutyrate

[0357]

[0358] Compound 2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-cyano (50 mg, 0.12 mmol) and N,N-dimethylformamide (3 mL) were added to a Schlenk tube and stirred to dissolve. Sodium hydride (14 mg, 0.35 mmol) was then added. The resulting mixture was stirred at room temperature for 10 minutes, followed by dropwise addition of methyl isobutyrate (63 mg, 0.46 mmol). After the addition was complete, the reaction mixture was reacted at 60 °C for 23 hours. The resulting mixture was purified by preparative liquid chromatography to give the target compound (15 mg, 21% yield).

[0359] LC-MS: m / z 657 (M+Na) + . 1 H NMR (400MHz, CDCl3): δ7.65(s,2H),7.09(s,1H),6.02(s,2H),5.79(s,2H),3.29-3.20(m,1H),2.64- 2.57(m,1H),2.55-2.48(m,1H),1.28(d,J=6.8Hz,6H),1.20(d,J=6.8Hz,6H),1.11(d,J=6.8Hz,6H).

[0360] Test Example 1

[0361] Pharmacokinetic testing and evaluation

[0362] Male SD rats, weighing approximately 220g, were fasted overnight and then randomly divided into two groups of four rats each. The first group was administered 10 mg / kg of the MGL-3196 compound solution prepared in Example 1 via gavage, while the second group was administered 10 mg / kg of the compound solution from WO2009037172A1 Example 5 via gavage (dosage was calculated based on the relative content of the MGL-3196 compound prepared in Example 1). Both the MGL-3196 and WO2009037172A1 Example 5 compound solutions were carried out on DMSO / PEG400. Blood samples were collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC / MS / MS.

[0363] The structure of compound MGL-3196 is as follows:

[0364]

[0365] The compound structure of Example 5 in patent WO2009037172A1 is as follows:

[0366]

[0367] Pharmacokinetic test results

[0368] The plasma concentration-time curves of MGL-3196 and WO2009037172A1 prepared in Example 1 and the compounds in Example 5 are shown below. Figure 1 As shown in Table 2, the pharmacokinetic parameters are as follows:

[0369] Table 2 Summary of pharmacokinetic parameters (n=4, mean)

[0370]

[0371] Note: The blood drug concentration is the concentration of MGL-3196.

[0372] Test Example 2

[0373] Pharmacokinetic testing and evaluation

[0374] Male SD rats, weighing approximately 220g, were fasted overnight and then randomly divided into two groups of four rats each. The first group was administered 10 mg / kg of the MGL-3196 compound solution prepared in Example 1 via gavage, while the second group was administered 10 mg / kg of compound 6A solution prepared in Example 6 via gavage (dosage was calculated based on the relative content of the MGL-3196 compound prepared in Example 1). Both the MGL-3196 compound solution and the compound 6A solution prepared in Example 6 were transported using DMSO / PEG400. Blood samples were collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC / MS / MS.

[0375] Pharmacokinetic test results

[0376] The plasma concentration-time curves of MGL-3196 prepared in Example 1 and compound 6A prepared in Example 6 are shown below. Figure 2 As shown in Table 3, the pharmacokinetic parameters are as follows:

[0377] Table 3 Summary of pharmacokinetic parameters (n=4, mean)

[0378]

[0379] Test Example 3

[0380] Pharmacokinetic testing and evaluation

[0381] Male SD rats, weighing approximately 220g, were fasted overnight and then randomly divided into three groups of four rats each. Group 1 was administered 10mg / kg of the MGL-3196 compound solution prepared in Example 1 via gavage. Group 2 was administered 10mg / kg of compound 6B solution prepared in Example 6 via gavage (dosage was calculated based on the relative content of the MGL-3196 compound prepared in Example 1). The carriers for both the MGL-3196 compound solution and the compound 6B solution prepared in Example 6 were DMSO / PEG400. Blood samples were collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC / MS / MS.

[0382] Pharmacokinetic test results

[0383] The plasma concentration-time curves of MGL-3196 prepared in Example 1 and compound 6B prepared in Example 6 are shown below. Figure 3 As shown in Table 4, the pharmacokinetic parameters are as follows:

[0384] Table 4 Summary of pharmacokinetic parameters (n=4, mean)

[0385]

[0386] Test Example 4

[0387] Pharmacokinetic testing and evaluation

[0388] Male SD rats, weighing approximately 220g, were fasted overnight and then randomly divided into three groups of four rats each. Group 1 was administered 10 mg / kg of the MGL-3196 compound solution prepared in Example 1 via gavage. Group 2 was administered 10 mg / kg of compound 2A solution prepared in Example 2 via gavage (dosage calculated based on the relative content of the MGL-3196 compound prepared in Example 1). Group 3 was administered 10 mg / kg of compound 2B solution prepared in Example 2 via gavage (dosage calculated based on the relative content of the MGL-3196 compound prepared in Example 1). The carriers for the MGL-3196 compound solution, compound 2A solution, and compound 2B solution were DMSO / PEG400. Blood samples were collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC / MS / MS.

[0389] Pharmacokinetic test results

[0390] The plasma concentration-time curves of MGL-3196 prepared in Example 1, and compounds 2A and 2B prepared in Example 2 are shown below. Figure 4As shown in Table 5, the pharmacokinetic parameters are as follows:

[0391] Table 5 Summary of pharmacokinetic parameters: (n=4, mean)

[0392]

[0393] In summary, from Table 2-5 and Figure 1-4 As can be seen, compared with the control compounds MGL-3196 prepared in Example 1 and the compounds of WO2009037172A1 Example 5, compounds 2A, 2B, and 6B of the present invention exhibit better metabolic properties in rats, with longer half-lives, higher maximum plasma concentrations (Cmax), and higher plasma exposure AUC (compound 2A is 2.4 times that of compound MGL-3196, compound 2B is 1.87 times that of compound MGL-3196, and compound 6B is 2.0 times that of compound MGL-3196). The results indicate that compounds 2A, 2B, and 6B possess excellent bioavailability and efficacy.

[0394] Test Example 5

[0395] Study on diet-induced obesity (DIO) C57Bl / 6J mouse model

[0396] Six-week-old C57Bl / 6J mice were fed a high-fat diet for 34 weeks. Starting on day 0 (day 1 of week 35), mice were administered either by oral gavage with a solvent (2% Klucel LF, 0.1% Tween 80 aqueous solution), or by oral gavage with 1, 3, or 10 mg / kg of compound 2A, compound 2B prepared in Example 2, or compound MGL-3196 prepared in Example 1, with nine mice per group, for 23 consecutive days. In parallel studies, starting on day 0 (day 1 of week 35), mice were administered either by oral gavage with a solvent (Dulbecco phosphate-buffered saline, pH adjusted to 9.0 with 1N NaOH) or by oral gavage with 10, 30, or 100 μg / kg of triiodothyronine (T3), with nine mice per group, for 23 consecutive days. Body weight and food intake were monitored during the study. BMD and body composition analysis were performed on day 22. At necropsy on day 23, organs were weighed, and cholesterol and other blood biochemical parameters in blood samples were assessed.

[0397] Compounds 2A and 2B prepared in Example 2 of this invention have excellent cholesterol-lowering and liver fat-reducing effects.

[0398] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A pyridazinone or pyridazine compound of formula (I) or (Ia) or a stereoisomer, tautomer, enantiomer, diastereomer, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof. In the formula, X is selected from H or -C(R) 17 R 18 )OZ, Y is selected from H or -C(R) 19 R 20 )OW, with the condition that X and Y are not both hydrogen; Z and W are each independently selected from -C(O)OR5, -C(O)NHR5, and -C(O)NR5R. 10 -C(O)R5, -P(=O)(X1R 11 (X2R) 12 -P(=O)(X1R) 11 (X3R) 14 R 15 -P(=O)(X3R) 14 R 15 (X3R) 14 R 15 -CH2P(=O)(X1R) 11 (X2R) 12 -CH2P(=O)(X1R) 11 (X3R) 14 R 15 -CH2P(=O)(X3R) 14 R 15 (X3R) 14 R 15 -P(=S)(X1R) 11 (X2R) 12 -P(=S)(X1R) 11 (X3R) 14 R 15 -P(=S)(X3R) 14 R 15 (X3R) 14 R 15 -CH2P(=S)(X1R) 11 (X2R) 12 -CH2P(=S)(X1R) 11 (X3R) 14 R 15 -CH2P(=S)(X3R) 14 R 15 (X3R) 14 R 15 -P (=NR) 13 (X1R) 11 (X2R) 12 -P (=NR) 13 (X1R) 11 (X3R) 14 R 15 -P (=NR) 13 (X3R) 14 R 15 (X3R) 14 R 15 -CH2P(=NR) 13 )(X1R 11 )(X2R 12 )、-CH2P(=NR 13 )(X1R 11 )(X3R 14 R 15 )、-CH2P(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 )、-OP(=O)(X1R 11 )(X2R 12 )、-OP(=O)(X1R 11 )(X3R 14 R 15 )、-OP(=O)(X3R 14 R 15 )(X3R 14 R 15 )、-OCH2P([O)(X1R 11 )(X2R 12 )、-OCH2P([O)(X1R 11 )(X3R 14 R 15 )、-OCH2P([O)(X3R 14 R 15 )(X3R 14 R 15 )、-OP(=S)(X1R 11 )(X2R 12 )、-OP(=S)(X1R 11 )(X3R 14 R 15 )、-OP(=S)(X3R 14 R 15 )(X3R 14 R 15 )、-OCH2P(=S)(X1R 11 )(X2R 12 )、-OCH2P(=S)(X1R 11 )(X3R 14 R 15 )、-OCH2P(=S)(X3R 14 R 15 )(X3R 14 R 15 )、-OP(=NR 13 )(X1R 11 )(X2R 12 )、-OP(=NR 13 )(X1R 11 )(X3R 14 R 15 )、-OP(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 )、-OCH2P(=NR 13 )(X1R 11 )(X2R 12 )、-OCH2P(=NR 13 )(X1R 11 )(X3R 14 R 15 )、-OCH2P(=NR 13 )(X3R 14 R 15 )(X3R 14 R 15 ): R1, R2, and R3 are each independently selected from the group consisting of hydrogen, deuterium, undeuterated or one or more (preferably 1-4) deuterated or fully deuterated C1-C4 alkyl groups, hydroxyl groups, or R1, R2, and R3 combined with adjacent C groups to form substituted or unsubstituted C3-C8 cycloalkyl groups, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of C1-C4 alkyl, C3-C8 cycloalkyl, hydroxyl, amino, carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide. R4, R6, R7, R8, and R9 are each independently selected from the following group: hydrogen, deuterium, and halogens; R5 can be a substituted or unsubstituted C1-C20 alkyl, a substituted or unsubstituted C3-C20 cycloalkyl, a substituted or unsubstituted 4-20 heterocyclic alkyl, a substituted or unsubstituted C6-C20 aryl, a substituted or unsubstituted C6-C20 aryl-C1-C8 alkyl-, or a substituted or unsubstituted 5-12 heteroaryl, a substituted or unsubstituted 5-12 heteroaryl-C1-C8 alkyl-, or a substituted or unsubstituted C1-C4 alkyl- (substituted or unsubstituted C1-C4 alkyl-O). m -substituted or unsubstituted C1-C4 alkyl-, wherein, m is a positive integer from 1 to 8, and the substitution refers to being substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, amino, C2-C8 carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide. R 10 The group is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 4-10 heterocyclic alkyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, amino, C2-C8 carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide. X1 and X2 are each independently selected from the following group: oxygen or sulfur; X3 is nitrogen; R 11 R 12 R 13 R 14 R 15 Each group is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 heteroaryl, or R 11 and R 12 It combines with adjacent X1, X2, and P to form substituted or unsubstituted 5-7 membered heterocyclic alkyl groups, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, C1-C20 alkyl, halo-C1-C20 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, 4-10 membered heterocyclic alkyl, C6-C10 aryl, halo-C6-C10 aryl, C5-C10 heteroaryl, halogen, amino, nitro, -COR 16 -COOR 16 -OCOOR 16 , cyano, hydroxyl, amide, sulfonamide; R 16 The group is selected from the following group: hydrogen, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C6-C10 aryl, amino, substituted or unsubstituted 4-10 heterocyclic alkyl, wherein the substitution refers to being substituted by one or more C6-C10 aryl groups; R 17 R 18 R 19 R 20 Each group is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C3 alkyl groups, provided that X is attached to N and Y is hydrogen. 17 R 18 They are not both hydrogen.

2. The compound of claim 1, wherein the compound has the pyridazinone or pyridazine compound of formula (IV-A), (IV-B), (IV-C), and (IV-D), or a stereoisomer, tautomer, enantiomer, diastereomer, resonance form, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof. in, R1, R2, R3, R4, R 17 R 18 R 19 R 20 Z and W are as described in claim 1.

3. The compound of claim 1, wherein the compound has the form of a pyridazinone or pyridazine compound of formula (VA), (VB), (VC), and (VD), or a stereoisomer, tautomer, enantiomer, diastereomer, resonance form, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof. in, R4, R 17 R 18 R 19 R 20 Z and W are as described in claim 1.

4. The pyridazinone or pyridazine compound of formula (I) or (Ia) as described in claim 1, or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, characterized in that, The compounds are selected from the group consisting of:

5. A method for preparing pyridazinones or pyridazine compounds of formula (I) or (Ia) as described in claim 1, or their stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, characterized in that, The method includes the following steps: (1) Compound of formula (VI) reacts with XR or YR' under alkaline conditions to produce formula (VI-A), formula (VI-B) or formula (Ib); (2) The compound of formula (VI-A), (VI-B), or (Ib) is reacted with YR' or XR under alkaline conditions to give the compound of formula (I) or (Ia); Where R and R' are leaving groups.

6. A pharmaceutical composition, characterized in that, The composition comprises: 1) A therapeutically effective amount of the pyridazinone or pyridazine compound of formula (I) or (Ia) of claim 1, or a stereoisomer, tautomer, enantiomer, diastereomer, resonator, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof; and 2) a pharmaceutically acceptable carrier.

7. The use of a pyridazinone or pyridazine compound of formula (I) or (Ia) as claimed in claim 1, or a stereoisomer, tautomer, enantiomer, diastereomer, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof, or the use of a pharmaceutical composition as claimed in claim 6, characterized in that, Used for (i) the preparation of pharmaceutical formulations or drugs for thyroid hormone receptor agonists; (ii) the preparation of pharmaceutical formulations or drugs for diseases associated with decreased thyroid hormone receptor activity; and / or (ii) the preparation of pharmaceutical formulations or drugs for the prevention and / or treatment of diseases selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or combinations thereof.

8. A pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition further comprises other drugs for the prevention and / or treatment of diseases selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or combinations thereof.

9. The use as described in claim 7, characterized in that, The thyroid hormone receptors mentioned are thyroid hormone α receptors and / or thyroid hormone β receptors.

10. The use as described in claim 7, characterized in that, The diseases mentioned are selected from the following group: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, cirrhosis (such as primary biliary cirrhosis), gallstones, arteriosclerosis, obesity, hyperlipidemia, and diabetes.

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