Thyroid hormone receptor beta agonist compounds

Abstract

The present invention provides a compound, preferably a thyroid hormone receptor beta, THRbeta, agonist compound, compositions thereof, methods of making and methods of agonizing THRbeta, and methods for treating conditions mediated by THRbeta.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 745,195, filed October 12, 2018, the disclosure of which is hereby incorporated, in its entirety, for all purposes. Technical Field

[0003] This invention relates to compounds, preferably thyroid hormone receptor β (THRβ) agonist compounds, compositions thereof, methods of preparation thereof, methods of agonizing THRβ, and methods for treating conditions that benefit from the agonizing effect of THRβ. Background Technology

[0004] The beneficial effects of treating patients with hyperthyroidism or hypothyroidism with endogenous T3 / T4 ligands or early analogues of these ligands have been described in the literature (Richardson Hill Jr. et al., Journal of Clinical Research, 1960, 39, 523-533). These early studies, and similar follow-up studies, identified the heart as the primary organ through which the side effects of both hyperthyroidism and hypothyroidism manifest (Klein I. et al., Circulation, 2007, 1725-1735). Specifically, tachycardia, hypertrophy, atrial arrhythmias, and atrial fibrillation are serious problems. Additionally, increased bone turnover leading to decreased bone mineral density has been noted. The negative effects in the heart and bones are associated with the activating effects of THRα isoforms, while the beneficial effects of THR activation in the liver are mostly associated with THRβ isoforms (Sinha, RA et al., Nat. Rev. Endocrinology 2018, 14, 259-269).

[0005] Diseases or conditions associated with THRβ include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. There is a need to develop new thyroid hormone analogs that are selective agonists for THRβ, preferably those that avoid unwanted effects associated with the agonist effect of THRα and maintain the positive effects of thyroid hormones, for example, for the treatment of patients with nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia. Summary of the Invention

[0006] In one aspect, this document provides a compound of formula (I):

[0007]

[0008] in:

[0009] R1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, -C(O)N(R7)(R8), or -N(R9)C(O)(R 10 ) or halogen;

[0010] R2 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0011] R3 is an H group or a halogen group;

[0012] R4 is H or a substituted or unsubstituted straight-chain C1-C3 alkyl group;

[0013] L can be -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-;

[0014] R5 and R6 are independently H, halogen, -CN or substituted or unsubstituted C1-C6 alkyl groups, or R5 and R6 are bonded to the carbon atom to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups.

[0015] R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups, or R7 and R8 are bonded to the nitrogen atom to which they are attached to form substituted or unsubstituted 3- to 7-membered heterocyclic alkyl groups.

[0016] R9 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0017] R 10 It can be a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 );

[0018] R 11 It is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl;

[0019] M1 and M2 are independently halogroups, or substituted or unsubstituted C1-C6 alkyl groups; and

[0020] M3 is H, a halogen, or a substituted or unsubstituted C1-C6 alkyl group, or M3 combined with M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0021] Or its pharmaceutically acceptable salt.

[0022] In some embodiments, this document provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0023] R1 is a C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)N(R7)(R8), or -N(R9)C(O)(R 10 ) or halogen, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN and halogen;

[0024] R2 is H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0025] R3 is an H group or a halogen group;

[0026] R4 is a straight-chain C1-C3 alkyl group substituted with H or optionally with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, halogen and -O (C1-C2 alkyl);

[0027] L can be -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-;

[0028] R5 and R6 are independently H, a halogroup, -CN, or a C1-C6 alkyl group, or R5 and R6 are bonded together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl group, wherein each C1-C6 alkyl group or C3-C6 cycloalkyl group is optionally independently substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogroups;

[0029] R7 and R8 are independently H or C1-C6 alkyl, or R7 and R8 are bonded together with the nitrogen atom to which they are attached to form a 3- to 7-membered heterocyclic alkyl group, wherein each C1-C6 alkyl or 3- to 7-membered heterocyclic alkyl group is optionally independently substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0030] R9 is H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0031] R 10 It is a C1-C6 alkyl, C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 ), wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0032] R 11 It is a C1-C6 alkyl or C3-C6 cycloalkyl, each of which may optionally be substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0033] M1 and M2 are independently a halogenated or optionally substituted C1-C6 alkyl groups with 1 to 5 substituents selected from the group consisting of -OH, -CN and halogenated groups; and

[0034] M3 is a C1-C6 alkyl group substituted with H, a halogen, or optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen, or M3 is combined with M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0035] In some embodiments, R1 is a C1-C6 alkyl or C3-C6 cycloalkyl, each optionally substituted by one to five substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is cyclopropyl, isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0036] In some embodiments, R2 is H or a C1-C6 alkyl group optionally substituted with one to five substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, R2 is H or methyl.

[0037] In some embodiments, R3 is H.

[0038] In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group optionally substituted with one to three substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is H, methyl, ethyl, -CH2C(O)O(CH2CH3), -CH2CF3, -CH2CN, or -CH2CHF2.

[0039] In some embodiments, L is -O-, -C(O)-, or -CH2-.

[0040] In some embodiments, M1 and M2 are independently a halogen or optionally a C1-C3 alkyl group substituted with one to three substituents selected from the group consisting of -OH, -CN, and halogen. In some embodiments, M1 and M2 are independently a halogen or methyl. In some embodiments, M1 and M2 are each chlorine. In some embodiments, M1 and M2 are each methyl.

[0041] In some embodiments, M3 is H, a halogen, or a C1-C3 alkyl group optionally substituted with one to three substituents selected from the group consisting of -OH, -CN, and halogens. In some embodiments, M3 is H, F, or methyl.

[0042] In some embodiments, this document provides compounds selected from compounds 1-3 and 5-35, or pharmaceutically acceptable salts thereof.

[0043] A pharmaceutical composition is further provided, comprising the compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0044] In another aspect, this article provides a method for contacting thyrotropin receptor β (THRβ), which includes contacting an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising the compound described herein, with THRβ.

[0045] In another aspect, this document provides a method for treating a patient in need of a THRβ-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein. In some embodiments, the condition is nonalcoholic steatohepatitis (NASH). Detailed Implementation

[0046] definition

[0047] As used herein, unless otherwise indicated, the following definitions shall apply. Furthermore, if any term or symbol used herein is not defined as set forth below, it shall have its general meaning in the field of its application.

[0048] "Comprising" inherently means that a composition or method includes the stated elements, but does not exclude other elements. When used to define a composition or method, "consistently of..." should mean that it does not include other elements that are of any fundamental significance to the composition. For example, a composition consisting essentially of elements as defined herein will not exclude other elements that do not substantially affect the essential and novel features of the claimed invention. "Constitutes of..." should mean excluding, for example, other stated ingredients and substantial method steps in trace amounts. Embodiments defined by each of these transitional terms are within the scope of the invention. Therefore, it should be understood that aspects and embodiments described herein as "comprising" include embodiments "consisting of..." and / or "consistently of...".

[0049] The “effective amount” or dosage of a compound or composition refers to the amount of the compound or its pharmaceutically acceptable salt or composition that produces the desired results as required based on the disclosures herein. The effective amount can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, for example and (but not limited to) by determining the LD50. 50 (Lethal dose for 50% of the population) and ED 50 The effective dose for 50% of the population was determined.

[0050] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the production of pharmaceuticals or medicines (such as tablets containing compounds of the present invention as active ingredients). The term excipient can cover a wide range of substances, including (but not limited to) any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for non-enteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, etc. Gum), maltodextrin, enteric coating, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose DC (DC = "directly compressible"), honey DC, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include, for example, sodium croscarmellose, gellan gum, sodium glycolate starch, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricant Lubricants include, for example, magnesium stearate, stearic acid, sodium stearoyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose DC, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium glycolate starch, saccharin, etc.; sweeteners include, for example, aspartame, dextrose, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0051] "Patient" means mammal and includes both humans and non-human mammals. Examples of patients include (but are not limited to) mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, a patient refers to a human.

[0052] "Pharmaceutical acceptable" means safe and non-toxic, preferably for in vivo administration, and more preferably for human administration.

[0053] "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. The compounds described in this article can be administered as pharmaceutically acceptable salts.

[0054] A "prodrug" is a compound that, upon administration, is metabolized or otherwise transformed into a compound (or drug) with biological activity or greater activity regarding at least one property. A prodrug is chemically modified in a manner that renders it less or inactive relative to the drug, but such modification allows the drug to be produced via metabolism or other biological methods upon administration of the prodrug. Compared to the active drug, a prodrug may have altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (e.g., see Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pp. 388-392, incorporated herein by reference). Prodrugs can be synthesized using reactants other than those used in the formulation of the corresponding drug. For illustrative purposes and not for limitation, the prodrug comprises carboxylic esters, linear and cyclic phosphates and phosphoramides, as well as aminophosphates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, wherein the aryl and heteroaryl groups may optionally be substituted) and the like.

[0055] “Salt” refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain an acidic functional group, such salts include (but are not limited to) alkali metal salts, alkaline earth metal salts, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen groups and alkylated nitrogen groups. Exemplary and non-limiting cations suitable for pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds used herein contain a basic functional group, such salts include (but are not limited to) salts of organic acids (such as carboxylic acids and sulfonic acids) and inorganic acids (such as hydrogen halides, sulfuric acid, phosphoric acid, and the like). Exemplary and non-limiting anions suitable for pharmaceutically acceptable salts include oxalates, maleates, acetates, propions, succinates, tartrates, chlorides, sulfates, hydrogen sulfates, monophosphates, diphosphates and triphosphates, methanesulfonates, toluenesulfonates, and the like.

[0056] The "therapeutic effective amount" or dose of a compound or composition refers to the amount of a compound or composition that reduces or suppresses symptoms or prolongs survival in a patient. Multiple doses of the compound or composition may be required to achieve the desired effect.

[0057] As used herein, “treatment / treating” refers to a method for achieving a beneficial or desired outcome (including clinical outcomes). For the purposes of this invention, a beneficial or desired outcome includes (but is not limited to) one or more of the following: alleviating one or more symptoms caused by a disease or condition; reducing the severity of a disease or condition; stabilizing a disease or condition (e.g., preventing or delaying the worsening of a disease or condition); delaying the onset or recurrence of a disease or condition; delaying or slowing the progression of a disease or condition; improving the condition of a disease or condition; providing relief (partial or complete) from a disease or condition; reducing the dosage of one or more other agents required to treat a disease or condition; enhancing the effect of another agent used to treat a disease or condition; delaying the progression of a disease or condition; improving the patient's quality of life and / or prolonging the patient's survival. “Treatment” also covers the reduction of the pathological consequences of a disease or condition. The methods of this invention cover any one or more of these aspects of treatment.

[0058] An "isotope" of a compound is a compound in which one or more atoms have been replaced by isotopes of those same atoms. For example, where H has been replaced by D or T, or... 12 C has 11 C-displacement, or 14 N has 15 N substitution. For example, and without limitation, D substitution can reduce metabolic rate and thus prolong half-life in some cases. T substitution for H can provide potentially suitable radioligands for binding studies. Short-lived isotopes... 11 C replacement 12 C can provide ligands suitable for positron emission tomography (PET) scans. 15 N displacement 14 N provides access via 15 Compounds detected / monitored by NNMR spectroscopy. For example, the isotopic isotope of a compound containing -CH2CH3 is a compound containing -CD2CD3 instead of -CH2CH3.

[0059] "Stereoisomers" refer to compounds whose constituent atoms have different stereoisomeric origins, such as (but not limited to) chiral aspects of one or more stereocenters or cis or trans configurations of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0060] "Tautomers" refer to alternative compound forms with different proton positions, such as enol-ketone and imine-enamine tautomers; or tautomers containing heteroaryl groups attached to both the ring-NH- and ring=N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0061] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. By way of example, this term includes straight-chain and branched hydrocarbon groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x carbon atoms.

[0062] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1 to 2 vinyl (>C=C<) unsaturated sites. Examples of such groups include vinyl, allyl, and but-3-en-1-yl. This term includes cis and trans isomers or mixtures of these isomers. x An alkenyl group refers to an alkenyl group having x carbon atoms.

[0063] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2, alkynyl (-C≡C-) unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH). x The alkynyl group refers to an alkynyl group that has x carbon atoms.

[0064] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclic amino The following groups are included: carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxo, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, thiohydrothio, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0065] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclic amino, carboxyl, carboxyl ester, (carboxyl ester)amino, (Carboxylate)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, thiohydrothio, alkylthio, and substituted alkylthio, wherein the substituents are defined herein and are limited by the condition that any hydroxyl or thiohydrothio substituent is not attached to a vinyl (unsaturated) carbon atom.

[0066] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloamino, carboxyl, carboxyl ester, (carboxyl ester) Amino, (carboxylate)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, thiohydrothio, alkylthio, and substituted alkylthio, wherein the substituents are defined herein and are limited by the condition that any hydroxyl or thiohydrothio substituent is not attached to an acetylene carbon atom.

[0067] "Alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined herein. By way of example, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0068] "Substituted alkoxy" refers to the group -O- (substituted alkyl), wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups in -O- (substituted alkyl) include haloalkyl, and especially halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl and similar groups.

[0069] “Acyl” means the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. The acyl group contains the "acetyl" CH3C(O)-.

[0070] "Acylamino" refers to the -NR group. 30 C(O)alkyl, -NR 30 C(O) substituted alkyl groups, -NR 30 C(O)cycloalkyl, -NR 30 C(O) substituted cycloalkyl groups, -NR 30 C(O) alkenyl, -NR 30 C(O) substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O) ynyl group, -NR 30 C(O) substituted alkynyl groups, -NR 30 C(O)aryl, -NR 30 C(O)-substituted aryl, -NR 30 C(O) heteroaryl, -NR 30 C(O)-substituted heteroaryl, -NR 30 C(O) heterocycles and -NR 30 C(O)-substituted heterocycles, where R 30 The alkyl group is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0071] "Acyloxy group" refers to alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0072] "Amino" refers to the group -NH2.

[0073] "Substituted amino" refers to the -NR group. 31 R 32 , where R 31 and R 32 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, aromatic amino, substituted aromatic amino, heteroaryl amino, substituted heteroaryl amino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclic amino, sulfonylamino and substituted sulfonyl, wherein R 31 and R 32 Optionally, it may be bonded together with nitrogen to form a heterocyclic group or a substituted heterocyclic group, subject to the condition R. 31 and R 32 None of them are hydrogen, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. When R 31 It is hydrogen and R 32 When R is an alkyl group, the substituted amino group is sometimes referred to as an alkylamino group in this text. 31 and R 32 When the amino group is alkyl, the substituted amino group is sometimes referred to as dialkylamino in this text. When referring to a monosubstituted amino group, it indicates R. 31 or R 32 It is hydrogen, but not both are hydrogen. When referring to a disubstituted amino group, it indicates R. 31 and R 32 Neither of them is hydrogen.

[0074] "Amino carbonyl" refers to the group -C(O)NR 33 R 34 , where R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0075] "Aminothiocarbonyl" refers to the group -C(S)NR 33 R 34 , where R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0076] "Aminocarbonylamino" refers to the group -NR 30 C(O)NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0077] "Aminothiocarbonylamino" refers to the group -NR 30 C(S)NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0078] "Aminocarbonyloxy group" refers to the group -OC(O)NR 33 R 34 , where R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0079] "Aminosulfonyl" refers to the group -SO2NR 33 R 34 , where R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0080] "Aminosulfonyloxy" refers to the group -O-SO2NR. 33 R 34 , where R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0081] "Aminosulfonylamino" refers to the group -NR 30 -SO2NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0082] "Formamidinyl" refers to the group -C (=NR) 35 )NR 33 R 34 , where R 33 R 34 and R 35 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 Optionally, it is joined with nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0083] "Aryl" or "aryl (Ar)" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, comprising a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthracene), which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl and the like), with the limiting condition that the linkage is located at an aromatic carbon atom. Preferably, the aryl group comprises phenyl and naphthyl groups.

[0084] "Substituted aryl" refers to an aryl group having 1 to 5 substituents, preferably 1 to 3 or more preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkaneamino, substituted The following groups are included: cycloalkylamino, heterocycloalkylamino, substituted heterocyclic amino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, thiohydrothio, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0085] "Aryloxy group" refers to the group -O-aryl, where aryl is as defined herein, and includes, for example, phenoxy and naphthoxy groups.

[0086] "Substituted aryl group" refers to the group -O- (substituted aryl), wherein the substituted aryl group is as defined herein.

[0087] "Arylthio" refers to the group -S-aryl, where aryl is as defined in this article.

[0088] "Substituted arylthio" refers to the group -S- (substituted aryl), wherein the substituted aryl group is as defined herein.

[0089] "Aromatic amino" refers to the -NR group. 37 (aryl), where aryl is as defined herein, and R 37 It is hydrogen, alkyl, or substituted alkyl.

[0090] "Substituted aromatic amino" refers to the -NR group. 37 (Substituted aryl), where R 37 It is hydrogen, alkyl or substituted alkyl, wherein the substituted aryl group is as defined herein.

[0091] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0092] "Carboxy" refers to -COOH or its salt.

[0093] “Carboxyl ester” refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-ynyl, -C(O)O-substituted ynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic and -C(O)O-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0094] "(Carboxylate)amino" refers to the -NR group. 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl groups, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O- substituted alkenyl groups, -NR 30 -C(O)O-alkynyl group, -NR 30 -C(O)O- substituted alkynyl groups, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O- substituted aryl, -NR 30 -C(O)O-cycloalkyl, -NR 30 -C(O)O-substituted cycloalkyl groups, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O- substituted heteroaryl groups, -NR 30 -C(O)O- heterocycles and -NR 30 -C(O)O- substituted heterocycles, where R 30 It is an alkyl or hydrogen, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0095] "(Carboxyl ester)oxy" refers to the group -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0096] "Cyano" refers to the group -C≡N.

[0097] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having a single or multiple cyclic rings, including fused, bridged, and spirocyclic systems. x A cycloalkyl group is a cycloalkyl group having x number of ring carbon atoms. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings may be aryl, heteroaryl, or heterocyclic, subject to the constraint that the linkage passes through a non-aromatic, non-heterocyclic saturated carbon ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of: oxo, thion, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, amide, acoxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl Ester, (carboxyester)amino, (carboxyester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioyl, thiohydrothio, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0098] “Cycloalkyloxy” refers to -O-cycloalkyl.

[0099] "Substituted cycloalkyloxy group" refers to -O- (substituted cycloalkyl group).

[0100] "Cycloalkylamino" refers to the -NR group. 37 (cycloalkyl), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0101] "Substituted cycloalkylamino" refers to the -NR group. 37 (substituted cycloalkyl), wherein R 37 It is hydrogen, alkyl, or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0102] "Cycloalkylthio" refers to -S-cycloalkyl.

[0103] "Substituted cycloalkyl thio" refers to -S- (substituted cycloalkyl).

[0104] "Guidinyl" refers to the group -NHC(=NH)NH2.

[0105] "Substituted guanidine group" refers to -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and two R atoms attached to the same guanidine nitrogen atom. 36 The group may optionally be bonded together with a nitrogen atom to form a heterocyclic group or a substituted heterocyclic group, wherein at least one R 36 It is not hydrogen, and the substituents therein are as defined herein.

[0106] "Halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine or chlorine being preferred.

[0107] "Hydroxy" refers to the -OH group.

[0108] "Heteroalkylene" refers to an alkylene group in which one or more carbon atoms are substituted with the following: -O-, -S-, -SO2-, -NR. Q -、

[0109]

[0110] Part, of which R QIt is an H or C1-C6 alkyl group. "Substituted heteroalkyl" refers to a heteroynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, which are selected from the substituents disclosed for substituted heteroalkyl groups.

[0111] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups may have a single ring (e.g., pyridyl or furanyl) or multiple condensed rings (e.g., indoleazinyl or benzothiopheneyl), wherein the condensed rings may or may not be aromatic and / or contain heteroatoms, the limiting condition being that the bonding point passes through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryl groups comprise 5- or 6-membered heteroaryl groups, such as pyridyl, pyrroleyl, thiopheneyl, and furanyl. Other preferred heteroaryl groups comprise 9- or 10-membered heteroaryl groups, such as indolyl, quinolinyl, quinoloneyl, isoquinolinyl, and isoquinoloneyl.

[0112] "Substituted heteroaryl" means a heteroaryl group substituted with 1 to 5, preferably 1 to 3 or more preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of the same substituents as defined for substituted aryl groups.

[0113] "Heteroaryloxy" refers to the group -O-heteroaryl.

[0114] "Substituted heteroaryl group" refers to the group -O- (substituted heteroaryl group).

[0115] "Heteroarylethio" refers to the group -S-heteroaryle.

[0116] "Substituted heteroarylthio" refers to the group -S- (substituted heteroaryl).

[0117] "Heteroaromatic amino" refers to the group -NR 37 (Heteroarylene), of which R 37 It is hydrogen, alkyl, or substituted alkyl.

[0118] "Substituted heteroarylamine" refers to the group -NR 37 (Substituted heteroaryl), where R 37 It is hydrogen, alkyl, or substituted alkyl, and the substituted heteroaryl is as defined herein.

[0119] "Heterocycle" or "heterocyclic" or "heterocyclic alkyl" or "heterocyclic group" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 cyclic carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, and 1 to 4 cyclic heteroatoms, preferably 1 to 3 heteroatoms, and more preferably 1 to 2 heteroatoms, said heteroatoms being selected from the group consisting of nitrogen, sulfur, or oxygen. x Heterocyclic alkyl groups are those having x number of ring atoms (including cyclic heteroatoms). Heterocycles encompass single or multiple condensed rings, including fused, bridged, and spirocyclic systems. In fused ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, provided that the linker passes through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom of the heterocyclic group is optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0120] "Hypocyclic group" refers to a divalent saturated or partially saturated but non-aromatic group having 1 to 10 cyclic carbon atoms and 1 to 4 cyclic heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. "Substituted heterocyclic group" refers to a heterocyclic group substituted with 1 to 5, or preferably 1 to 3, substituents that are the same as those defined for substituted cycloalkyl groups.

[0121] "Substituted heterocycle" or "substituted heterocyclic alkyl" or "substituted heterocyclic group" refers to a heterocyclic group substituted with 1 to 5, or preferably 1 to 3, substituents that are the same as those defined for substituted cycloalkyl.

[0122] "Heterocyclic group" refers to the -O-heterocyclic group.

[0123] "Substituted heterocyclic group" refers to the group -O- (substituted heterocyclic group).

[0124] "Heterocyclic thio group" refers to the -S-heterocyclic group.

[0125] "Substituted heterocyclic thio group" refers to the group -S- (substituted heterocyclic group).

[0126] "Heterocyclic amino" refers to the -NR group. 37 (heterocyclic group), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0127] "Substituted heterocyclic amino" refers to the -NR group. 37 (Substituted heterocyclic group), where R 37 It is hydrogen, alkyl, or substituted alkyl, and the substituted heterocyclic group is as defined herein.

[0128] Examples of heterocyclic and heteroaryl groups include (but are not limited to) aza-butyl, pyrroloyl, imidazolyl, pyrazolyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinolinyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, carbazolyl, phenidyl, acridineyl, phenidyl The following groups are listed: , isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl, phenthiazinyl, imidazoalkyl, imidazolinyl, piperidinyl, piperazinyl, indololinyl, phthalimino, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazoyl, thiazoalkyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also known as thiomorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0129] "Nitro" refers to the group -NO2.

[0130] "O-group" refers to an atom (=O) or (O).

[0131] A "spirocyclic system" refers to a bicyclic system that has a single ring carbon atom shared by both rings.

[0132] "Sulinate" refers to a divalent group -S(O)- or -S(=O)-.

[0133] "Sulfoyl group" refers to the divalent group -S(O)2- or -S(=O)2-.

[0134] "Substituted sulfonyl" refers to groups such as -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl groups include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. The substituted alkyl group on SO2- preferably includes a haloalkyl group, and especially a halomethyl group, such as trifluoromethyl, difluoromethyl, fluoromethyl and similar groups.

[0135] "Substituted sulfinyl" refers to the groups -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfinyl groups include groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferably, the substituted alkyl group on the substituted alkyl-SO- contains a haloalkyl group, and especially a halomethyl group, such as trifluoromethyl, difluoromethyl, fluoromethyl, and similar groups.

[0136] "Sulfoyloxy" or "substituted sulfonyloxy" means the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-OH, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0137] "Sulfonylamino" refers to the -NR group. 37 (Substituted sulfonyl group), where R 37 It is hydrogen, alkyl, or substituted alkyl, and the substituted sulfonyl group is as defined herein.

[0138] "Thioyl" refers to the group HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0139] "Mercapto" or "thiohydrogen" refers to the group -SH.

[0140] "Formyl group" refers to the group -C(O)H.

[0141] "Thiocarbonyl" refers to the divalent group -C(S)-, which is equivalent to -C(=S)-.

[0142] "Thione" refers to the atom (=S).

[0143] "Alkylthio" refers to the -S-alkyl group, where the alkyl group is as defined herein.

[0144] "Substituted alkylthio" refers to the group -S- (substituted alkyl), wherein the substituted alkyl is as defined herein. Preferably, the substituted alkyl on -S- (substituted alkyl) comprises a haloalkyl, and in particular a halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl and similar groups.

[0145] "Vinyl" refers to the unsaturated hydrocarbon group -CH=CH2 derived from ethylene.

[0146] As used throughout this specification, the terms "optional" or "optionally" indicate that the events or conditions described below may occur but are not necessarily to occur, and the description includes instances of the events or conditions occurring and instances of them not occurring. For example, "nitrogen atoms are optionally oxidized to obtain an N-oxide (N→O) portion" means that nitrogen atoms may be oxidized but are not necessarily oxidized, and the description includes cases where nitrogen atoms are not oxidized and cases where nitrogen atoms are oxidized.

[0147] The term "optionally substituted" refers to a substituted or unsubstituted group. A substituted group (e.g., an alkyl group in "substituted alkyl") may be substituted with one or more substituents, which may be the same or different (such as 1, 2, 3, 4, or 5 substituents). Preferably, the substituents are selected from the functional groups provided herein. In some more preferred embodiments, the substituents are selected from: oxo groups, halogen groups, -CN, NO2, -CO2R. 100 -OR 100 -SR 100 -SOR 100 -SO2R 100 -NR 101 R 102 -CONR 101 R 102 -SO2NR 101 R 102 C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R) 100 )2、-CCR 100 C3-C 10 cycloalkyl, C4-C10 Heterocyclic group, C6-C 14 Aryl and C5-C 12 heteroaryl, wherein each R 100 Independently hydrogen or C1-C8 alkyl, C3-C 12 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 The heteroaryl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1 to 3 halogroups, 1 to 3 C1-C6 alkyl groups, 1 to 3 C1-C6 haloalkyl groups, or 1 to 3 C1-C6 alkoxy groups. More preferably, the substituents are selected from the group consisting of: chlorine, fluorine, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0148] R 101 and R 102 Independently hydrogen, optionally C1-C8 alkyl, C1-C6 alkoxy, oxo group, or -CR group substituted with -CO2H or its esters 103 =C(R) 103 )2、-CCR、C3-C 10 cycloalkyl, C3-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 heteroaryl, wherein each R 103 Independently hydrogen or C1-C8 alkyl, C3-C 12 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 Heteroaryl groups, wherein each cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally associated with one to three alkyl groups or one to three halogen groups or R groups. 101 and R 102 The nitrogen atom to which it is attached is replaced to form a 5- to 7-membered ring.

[0149] Unless otherwise indicated, the naming of substituents not explicitly defined herein is accomplished by naming the terminal portion of the functional group, followed by naming the adjacent functional group toward the junction. For example, the substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.

[0150] It should be understood that polymers defined above that are achieved by defining themselves as having other substituents (e.g., substituted aryl groups having substituted aryl groups as substituents, said substituents being substituted themselves by substituted aryl groups, etc.) are not necessarily included herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is subject to the following limitations: for example, substituted aryl groups are limited to -substituted aryl groups - (substituted aryl groups) - substituted aryl groups.

[0151] In some embodiments of the substituted portion, the portion is substituted with one group, which may also be substituted with another group, but the other group may not be further substituted. For example, in some embodiments of the "substituted alkyl", the alkyl portion is substituted with one group, which may be further substituted (e.g., substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclic amino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidine, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclicoxy, substituted heterocyclic thio, substituted... (sulfonyl, substituted alkylthio), but the substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclic amino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidine, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclicoxy, substituted heterocyclic thio, substituted sulfonyl or substituted alkylthio is not further substituted by itself. Although “substituted alkyl” is provided as an example, such examples are intended for each substituted portion described herein.

[0152] In some embodiments of the substituted portion, the portion is substituted with groups that are not further substituted. Therefore, in some embodiments, "substituted alkyl" is an alkyl moiety partially substituted by one or more, and in some aspects by 1 or 2 or 3 or 4 or 5 independently selected from the group consisting of: alkoxy, acyl, amide, acyloxy, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, aryloxy, arylthio, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidinyl, halogen, hydroxyl, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclicoxy, heterocyclic thio, nitro, SO3H, sulfonyloxy, sulfonylamino, thioyl, thiohydrothio, and alkylthio. Although “substituted alkyl” is provided as an example, such embodiments are intended for each substituted portion described herein.

[0153] It should be understood that the above definition does not inherently include prohibited substitution patterns (e.g., methyl groups substituted with four fluorine groups). Such prohibited substitution patterns are well known to those skilled in the art.

[0154] It should be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables are particularly encompassed by and disclosed herein as compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), as each combination and each combination is individually and explicitly disclosed herein. In addition, all sub-combinations of chemical groups listed in embodiments describing such variables are also particularly encompassed by and disclosed herein as each such sub-combination of chemical groups and each such sub-combination is individually and explicitly disclosed herein.

[0155] compound

[0156] In one aspect, this document provides a compound of formula (I):

[0157]

[0158] in:

[0159] R1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, -C(O)N(R7)(R8), or -N(R9)C(O)(R 10) or halogen;

[0160] R2 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0161] R3 is an H group or a halogen group;

[0162] R4 is H or a substituted or unsubstituted straight-chain C1-C3 alkyl group;

[0163] L can be -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-;

[0164] R5 and R6 are independently H, halogen, -CN or substituted or unsubstituted C1-C6 alkyl groups, or R5 and R6 are bonded to the carbon atom to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups.

[0165] R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups, or R7 and R8 are bonded to the nitrogen atom to which they are attached to form substituted or unsubstituted 3- to 7-membered heterocyclic alkyl groups.

[0166] R9 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0167] R 10 It can be a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 );

[0168] R 11 It is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl;

[0169] M1 and M2 are independently halogroups, or substituted or unsubstituted C1-C6 alkyl groups; and

[0170] M3 is H, a halogen, or a substituted or unsubstituted C1-C6 alkyl group, or M3 combined with M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0171] Or its pharmaceutically acceptable salt.

[0172] In some embodiments, this document provides a compound or a pharmaceutically acceptable salt thereof, wherein:

[0173] R1 is a C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)N(R7)(R8), or -N(R9)C(O)(R10 ) or halogen, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN and halogen;

[0174] R2 is H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0175] R3 is an H group or a halogen group;

[0176] R4 is a straight-chain C1-C3 alkyl group substituted with H or optionally with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, halogen and -O (C1-C2 alkyl);

[0177] L can be -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-;

[0178] R5 and R6 are independently H, a halogroup, -CN, or a C1-C6 alkyl group, or R5 and R6 are bonded together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl group, wherein each C1-C6 alkyl group or C3-C6 cycloalkyl group is optionally independently substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogroups;

[0179] R7 and R8 are independently H or C1-C6 alkyl, or R7 and R8 are bonded together with the nitrogen atom to which they are attached to form a 3- to 7-membered heterocyclic alkyl group, wherein each C1-C6 alkyl or 3- to 7-membered heterocyclic alkyl group is optionally independently substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0180] R9 is H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0181] R 10 It is a C1-C6 alkyl, C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 ), wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups are optionally substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0182] R 11 It is a C1-C6 alkyl or C3-C6 cycloalkyl, each of which may optionally be substituted by 1 to 5 substituents selected from the group consisting of -OH, -CN and halogen groups;

[0183] M1 and M2 are independently a halogenated or optionally substituted C1-C6 alkyl groups with 1 to 5 substituents selected from the group consisting of -OH, -CN and halogenated groups; and

[0184] M3 is a C1-C6 alkyl group substituted with H, a halogen, or optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen, or M3 is combined with M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0185] In some embodiments, R1 is a C1-C6 alkyl or C3-C6 cycloalkyl, each optionally substituted by one to five substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is cyclopropyl, isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0186] In some embodiments, R1 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1 to 4 halogen atoms. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1 to 4 chlorine or fluorine atoms. In some embodiments, R1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. In some embodiments, R1 is a substituted or unsubstituted C3-C6 alkyl group, such as an unsubstituted C3-C6 alkyl group, which in one aspect is a branched C3-C6 alkyl group. In some embodiments, R 1R1 is isopropyl. In some embodiments, R1 is a substituted or unsubstituted C1-C3 alkyl group, such as an unsubstituted C1-C3 alkyl group, which in one aspect is a straight-chain C1-C3 alkyl group. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1-2 -OH groups. In some embodiments, R1 is a C1-C6 alkyl group substituted with one -OH group, such as -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), or -CH(OH)(CH3). In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with one oxo group. In some embodiments, R1 is a C1-C6 alkyl group substituted with an oxo group, such as -C(O)(CH3). In some embodiments, R1 is an unsubstituted C1-C6 alkyl group, such as methyl, ethyl, isopropyl, -CH(CH2CH3)2, or -CH(CH3)(CH2CH3). In some embodiments, R1 is isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0187] In some embodiments, R1 is a substituted or unsubstituted C3-C6 cycloalkyl group. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with 1 to 4 chlorine or fluorine atoms. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with 1 to 4 C1-C6 alkyl groups. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 methyl, ethyl, or propyl groups. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is a C3-C6 cycloalkyl group optionally substituted with one to three substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R 1 It is an unsubstituted C3-C6 cycloalkyl group.

[0188] In some embodiments, R1 is a halogen group. In some embodiments, R1 is fluorine, chlorine, bromine, or iodine. In some embodiments, R1 is fluorine or chlorine. In some embodiments, R1 is chlorine.

[0189] In some embodiments, R1 is -C(O)N(R7)(R8). In some embodiments, R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R7 and R8 are each H. In some embodiments, R7 is H, and R8 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R7 is H, and R8 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 and R8 are independently substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R7 and R8 are independently methyl, ethyl, propyl, isopropyl, or butyl. In any of these variations of R7 and / or R8 being C1-C6 alkyl groups, the C1-C6 alkyl group is optionally substituted with 1 to 4 halogen atoms. In some embodiments, R 7 and R 8 It combines with the nitrogen atom to which it is attached to to form a 3- to 7-membered heterocyclic alkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups. In some embodiments, R 7 and R 8 It combines with the nitrogen atom to which it is attached to form a 3- to 5-membered heterocyclic alkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0190] In some embodiments, R1 is -N(R9)C(O)(R 10 In some embodiments, R9 is H. In some embodiments, R9 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R9 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R9 is a substituted or unsubstituted C3-C6 cycloalkyl group. In some embodiments, R9 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 10 It is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R 10 It is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 10 It is a substituted or unsubstituted C3-C6 cycloalkyl group. In some embodiments, R 10 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In R9 and / or R... 10 In any of these variations of C1-C6 alkyl groups, the C1-C6 alkyl group is optionally substituted with 1 to 4 halogen atoms. In R9 and / or R... 10In any of these variations of the C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups. In some embodiments, R9 is H and R 10 It is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R9 is H and R 10 R is methyl. In some embodiments, R9 is a substituted or unsubstituted C1-C6 alkyl group and R 10 It is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R9 and R 10 Each is a methyl group.

[0191] When R1 is -N(R9)C(O)(R 10 In some embodiments of R, 10 The form is -N(R7)(R8). In some embodiments, R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R7 and R8 are each H. In some embodiments, R7 is H, and R8 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R7 is H, and R8 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 and R8 are independently substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R7 and R8 are independently methyl, ethyl, propyl, isopropyl, or butyl. In any of these variations in which R7 and / or R8 are C1-C6 alkyl groups, the C1-C6 alkyl group is optionally substituted with 1 to 4 halogen atoms. In some embodiments, R 7 and R 8 It combines with the nitrogen atom to which it is attached to to form a 3- to 7-membered heterocyclic alkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups. In some embodiments, R 7 and R 8 It combines with the nitrogen atom to which it is attached to form a 3- to 5-membered heterocyclic alkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0192] When R1 is -N(R9)C(O)(R 10 In some embodiments of R, 10 -O(R) 11 In some embodiments, R 11 It is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R 11 It is a C1-C6 alkyl group optionally substituted with 1 to 4 halogen atoms. In some embodiments, R 11 It is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 11It is a substituted or unsubstituted C3-C6 cycloalkyl group. In some embodiments, R 11 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 11 It is a C3-C6 cycloalkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0193] In some embodiments, R2 is H, a C1-C6 alkyl, or a C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, R2 is H or a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, R2 is H or methyl.

[0194] In some embodiments, R2 is H. In some embodiments, R2 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R2 is a C1-C6 alkyl group optionally substituted with 1 to 4 halogen atoms. In some embodiments, R2 is a C1-C6 alkyl group optionally substituted with 1 or 2 chlorine or fluorine atoms. In some embodiments, R2 is methyl, ethyl, propyl, isopropyl, butyl, or pentyl. In some embodiments, R2 is methyl. In some embodiments, R2 is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, R2 is a C1-C6 alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, R2 is an unsubstituted C1-C6 alkyl group.

[0195] In some embodiments, R3 is H. In some embodiments, R3 is a halogen group. In some embodiments, R3 is fluorine, chlorine, bromine, or iodine. In some embodiments, R3 is fluorine or chlorine.

[0196] In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group optionally substituted with one to five substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group optionally substituted with one to three substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is H, methyl, ethyl, -CH2C(O)OCH2CH3, -CH2CF3, -CH2CN, or -CH2CHF2.

[0197] In some embodiments, R4 is H.

[0198] In some embodiments, R4 is a substituted or unsubstituted linear C1-C3 alkyl group. In some embodiments, R4 is a linear C1-C3 alkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 hydroxyl groups. In some embodiments, R4 is a linear C1-C3 alkyl group optionally substituted with 1 to 2 halogen atoms and / or 1 to 2 hydroxyl groups. In some embodiments, R4 is a linear C1-C3 alkyl group optionally substituted with 1 or 2 chlorine or fluorine atoms. In some embodiments, R4 is a linear C1-C3 alkyl group optionally substituted with 1 to 2 hydroxyl groups. In some embodiments, R4 is a substituted or unsubstituted linear C1-C2 alkyl group. In some embodiments, R4 is a linear C1-C2 alkyl group optionally substituted with 1 to 2 halogen atoms and / or 1 to 2 hydroxyl groups. In some embodiments, R4 is an unsubstituted linear C1-C3 alkyl group.

[0199] In some embodiments, R4 is an unsubstituted straight-chain C1-C2 alkyl group. In some embodiments, R4 is methyl, ethyl, or propyl. In some embodiments, R4 is methyl. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is a C1-C3 alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with 1 to 3 halogen groups (such as chlorine or fluorine). In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with 1 to 3 fluorine groups. In some embodiments, R4 is -CF3, -CH2CF3, or -CH2CHF2. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one oxo group. In some embodiments, R4 is -CH2C(O)CH3, -C(O)CH2CH3, or -C(O)CH3. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one -O (C1-C2 alkyl group). In some embodiments, R4 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one oxo group and one -O (C1-C2 alkyl group). In some embodiments, R4 is -CH2C(O)OCH3, -C(O)OCH3, or -C(O)OCH2CH3. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one or two cyano groups. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one cyano group. In some embodiments, R4 is -CH2CN or -CH2CH2CN. It should be understood that when R4 is a straight-chain C1-C3 alkyl group optionally substituted with carbon-containing moieties such as -CN and -O (C1-C2 alkyl), the total number of carbon atoms in R4 may exceed three. In some embodiments, R4 is -CH2CH2CH2CN. In some embodiments, R4 is -CH2C(O)OCH2CH3, -CH2CH2C(O)OCH2CH3, or -CH2CH2C(O)OCH3. In some embodiments, R4 is methyl, ethyl, -CH2C(O)OCH2CH3, -CH2CF3, -CH2CN, or -CH2CHF2.

[0200] In some embodiments, L is -O- or -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -C(O)-. In some embodiments, L is -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -C(R5)(R6)-. In some embodiments, R5 and R6 are independently H, a halogen group, -CN, or a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R5 and R6 are each H. In some embodiments, R5 and R6 are independently C1-C6 alkyl groups optionally substituted with 1 to 4 halogen atoms. In some embodiments, R5 is H, and R6 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, R5 and R6 are bonded to the carbon atom to form a substituted or unsubstituted C3-C6 cycloalkyl group. In some embodiments, R5 and R6 are bonded to the carbon atom to form a C3-C6 cycloalkyl group optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups. In some embodiments, L is -O-, -C(O)-, or -CH2-.

[0201] In some embodiments, M1 and M2 are independently a halogen or optionally a C1-C6 alkyl group substituted with one to five substituents selected from the group consisting of -OH, -CN, and halogen. In some embodiments, M1 and M2 are independently a halogen or methyl. In some embodiments, M1 and M2 are each chlorine. In some embodiments, M1 and M2 are each methyl.

[0202] In some embodiments, M1 and M2 are independently a halogroup or a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, M1 and M2 are independently a halogroup. In some embodiments, M1 and M2 are independently fluorine, chlorine, bromine, or iodine. In some embodiments, M1 and M2 are independently fluorine or chlorine. In some embodiments, M1 and M2 are each chlorine. In some variations, at least one of M1 and M2 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, at least one of M1 and M2 is a C1-C6 alkyl group optionally substituted with 1 to 4 halogen atoms. In some embodiments, at least one of M1 and M2 is a C1-C6 alkyl group optionally substituted with 1 or 2 halogen atoms. In some embodiments, at least one of M1 and M2 is a C1-C4 alkyl group optionally substituted with 1 or 5 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, M1 and M2 are independently C1-C6 alkyl groups optionally substituted with one to three substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, M1 and M2 are independently unsubstituted C1-C6 alkyl groups. In some embodiments, M1 and M2 are independently unsubstituted C1-C3 alkyl groups. In some embodiments, M1 and M2 are each methyl. In some embodiments, M1 and M2 are the same. In other embodiments, M1 and M2 are different. In some embodiments, M1 is methyl and M2 is ethyl. In some embodiments, M1 is ethyl and M2 is methyl. In some embodiments, M1 is methyl and M2 is chlorine. In some embodiments, M1 is chlorine and M2 is methyl.

[0203] In some embodiments, M3 is an H, a halogroup, or a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogen groups, or M3 is bonded to M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3 is an H, a halogroup, or a C1-C3 alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, -CN, and halogen groups. In some embodiments, M3 is H, F, or methyl.

[0204] In some embodiments, M3 is H, a halogroup, or a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, M3 is H. In some embodiments, M3 is a halogroup. In some embodiments, M3 is fluorine, chlorine, bromine, or iodine. In some embodiments, M3 is fluorine. In some embodiments, M3 is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, M3 is a C1-C6 alkyl group optionally substituted with 1 to 4 halogen atoms. In some embodiments, M3 is a C1-C6 alkyl group optionally substituted with 1 or 2 chlorine or fluorine atoms. In some embodiments, M3 is methyl, ethyl, propyl, isopropyl, butyl, or pentyl. In some embodiments, M3 is methyl. In some embodiments, M3 is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halogroups. In some embodiments, M3 is a C1-C6 alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, -CN, and halogroups. In some embodiments, M3 is -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CF3, -CHF2, -CH2F, -CCl3, or -CHCl2. In some embodiments, M3 is an unsubstituted C1-C6 alkyl group.

[0205] In some embodiments, M3 and M2, along with their attached carbon atoms, combine to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the groups consisting of N, O, and S. In some embodiments, M3 and M2, along with their attached carbon atoms, combine to form a 5- to 7-membered ring containing 0 heteroatoms. In some embodiments, M3 and M2, along with their attached carbon atoms, combine to form a 5- to 7-membered ring containing 1 or 2 heteroatoms selected from the groups consisting of N, O, and S. In some embodiments, M3 and M2, along with their attached carbon atoms, are linked together to form a 5- to 7-membered ring containing 1 or 2 heteroatoms selected from the groups consisting of N and O. In some embodiments, M3 and M2, along with their attached carbon atoms, combine to form a 5- to 7-membered ring containing 1 heteroatomide selected from the groups consisting of N, O, and S. In some embodiments, M3 and M2, along with their attached carbon atoms, are linked together to form a saturated 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the groups consisting of N, O, and S. In some embodiments, M3 and M2, along with their attached carbon atoms, are linked together to form a partially unsaturated 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3 and M2, along with their attached carbon atoms, are linked together to form an aromatic 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0206] It is hoped and understood that, when present, each variation of L described by equation (I) and each variation thereof can be related to R1, R2, R3, R4, R5, R6, R7, R8, R9, R... described by equation (I). 10 R 11 The variations and combinations of each variation of M1, M2, and M3 are described as if each combination were specifically and individually described. Similarly, it is desired and understood that the variables described in equation (I) can be combined with the variables and combinations described below with respect to equations (Ia), (Ib), (Ic), and (Id), as if each combination were specifically and individually described. Furthermore, all sub-combinations of chemical groups listed in the embodiments describing such variables are also particularly encompassed by the present invention and disclosed herein, as if each such sub-combination of chemical groups were individually and explicitly disclosed herein.

[0207] In some embodiments, the compound of formula (I) has formula (Ia):

[0208]

[0209] Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined with respect to compounds of formula (I). In some embodiments, R1 is a C1-C3 alkyl or a C3-C5 cycloalkyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halogen groups. In some embodiments, R1 is ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3). In some embodiments, R2 is H or a C1-C3 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or a straight-chain C1-C3 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, R4 is a straight-chain C1-C3 alkyl group optionally substituted with one to five substituents selected from the group consisting of -OH, oxo, -CN, halogen, and -O (C1-C2 alkyl). In some embodiments, R4 is ethyl, -CH2C(O)O(CH2CH3), -CH2CF3, -CH2CN, or -CH2CHF2. In some embodiments, M3 is H or a C1-C3 alkyl group. In some embodiments, M3 is H. In some embodiments, M3 is methyl. In some embodiments, M3 is a halogen. In some embodiments, M3 is F.

[0210] In some embodiments, the compound of formula (I) has formula (Ib):

[0211]

[0212] Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined with respect to compounds of formula (I). In some embodiments, R1 is a C1-C3 alkyl group. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or a C1-C3 alkyl group. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or a C1-C3 alkyl group. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0213] In some embodiments, the compound of formula (I) has formula (Ic):

[0214]

[0215] Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined with respect to compounds of formula (I). In some embodiments, R1 is a C1-C3 alkyl group. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or a C1-C3 alkyl group. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or a C1-C3 alkyl group. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0216] In some embodiments, the compound of formula (I) has formula (Id):

[0217]

[0218] Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined with respect to compounds of formula (I). In some embodiments, R1 is a C1-C3 alkyl group. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or a C1-C3 alkyl group. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or a straight-chain C1-C3 alkyl group. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or a C1-C3 alkyl group. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0219] In some embodiments, the compound of formula (I) is a synergist of THRβ. In some embodiments, the compound of formula (I) is a synergist of THRβ and has better selectivity than THRα. In some embodiments, the compound of formula (I) has at least 2-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 5-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 10-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 20-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 50-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 75-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has at least 100-fold selectivity relative to THRα for THRβ. In some embodiments, the compound of formula (I) has a selectivity of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times that of THRβ relative to THRα. In any such embodiment, in one aspect, the selectivity is assessed via biochemical analysis, such as the TR-FRET analysis described in Example B1.

[0220] In one embodiment, this document provides compounds of formula (I) selected from those listed in Table 1 below, or pharmaceutically acceptable salts thereof:

[0221] Table 1

[0222]

[0223]

[0224]

[0225]

[0226] *Compound 4 is not within the scope of Formula (I) and is provided for comparative purposes only. **The stereochemistry of the compounds reported in Table 2 is arbitrarily assigned to the biological data in Table 1. For details of the corresponding synthetic examples, refer to the appropriate compounds in Table 1. Therefore, compounds that may be associated with a given chiral chromatographic elution pattern and biological dataset may have the same or different absolute stereochemistry as compounds arbitrarily specified in Table 1.

[0227] In some embodiments, the compound of formula (I) is selected from compounds 1-3 and 5-35 or pharmaceutically acceptable salts thereof.

[0228] In some embodiments, this document provides compounds selected from the group consisting of:

[0229]

[0230]

[0231] Or its pharmaceutically acceptable salt.

[0232] This invention also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. This invention also includes any or all stereochemical forms of the described compounds, including any enantiomers or diastereomers, and any tautomers or other forms, such as N-oxides, solvates, prodrugs, or isotopic isomers. Unless the stereochemistry is explicitly specified by a chemical structure or name, the structure or name is intended to cover all possible stereoisomers of the depicted compound. Furthermore, when a particular stereochemical form is described, it should be understood that this invention also covers other stereochemical forms. This invention also covers all forms of compounds, such as crystalline or amorphous forms of compounds. Compositions including compounds of this invention are also contemplated, such as compositions of substantially pure compounds (containing their specific stereochemical forms). This invention also covers compositions comprising mixtures of compounds of this invention in any ratio, mixtures comprising two or more stereochemical forms of compounds of this invention in any ratio, and therefore covering racemic, non-racemic, enantiomerically enriched, and achiral mixtures of compounds.

[0233] Synthesis Methods - General Process

[0234] The following procedures S1 to S8 illustrate the synthetic route for preparing the compounds of the present invention. In each of procedures S1 to S8, unless otherwise specified, the variables R1, R2, R3, R4, M1, M2 and M3 are as defined with respect to the compound of formula (I); other variables V, T and W (where EWG is a suitable electron-withdrawing group) are as defined in the particular procedure; and the variable R is H or a suitable borate ester protecting group, such as an alkyl group.

[0235] Process S1 illustrates the general synthesis of compound (I), where L is O or S.

[0236] Process S1:

[0237]

[0238]

[0239] Process S2 Overview: General synthesis of compounds of formula (I), where L is -C(O)-.

[0240] Process S2:

[0241]

[0242]

[0243] Process S3 illustrates the general synthesis of compound (I), where L is -CH2-.

[0244] Process S3:

[0245]

[0246] Process S4 illustrates the general synthesis of compound (I), where L is -S(O)- or -S(O)2-.

[0247] Process S4:

[0248]

[0249] Process S5 illustrates a general synthetic method for compound (I), where L is -CHF-.

[0250] Process S5:

[0251]

[0252] Process S6 illustrates a general synthetic method for compound (I), where L is -CF2-.

[0253] Process S6:

[0254]

[0255] Process S7 outlines a general synthetic method for compounds of formula (I), where L is -CH(CH3)-.

[0256] Process S7:

[0257]

[0258] Process S8 illustrates the general synthesis of compound (I), where L is...

[0259] Process S8:

[0260]

[0261] The synthesis of some of the compounds described herein is illustrated above and provided in the Examples section below. Based on the guidance provided herein and the synthetic methods well known to those skilled in the art, the synthesis of other compounds described herein will be readily apparent to them.

[0262] In cases where a specific enantiomer of a compound is required, this can be accomplished using any suitable known procedure for separating or resolving enantiomers, performed from a corresponding mixture of enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers (e.g., a racemic mixture) with a suitable chiral compound. The diastereomeric derivative can then be separated by any convenient means, such as by crystallization, and the desired enantiomer can be recovered. In another analytical method, a chiral high-performance liquid chromatography (HPLC) method can be used to separate the racemic mixture. Alternatively, if necessary, a suitable chiral intermediate can be used in one of the described processes to obtain the specific enantiomer.

[0263] If a specific isomer is required or the product of the reaction needs to be further purified, chromatography, recrystallization and other known separation procedures can also be used for intermediates or final products.

[0264] This also covers solvates and / or polymorphs of the compounds described herein or their pharmaceutically acceptable salts. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during crystallization. When the solvent is water, a hydrate is formed; when the solvent is alcohol, an alcoholic compound is formed. Polymorphs consist of different crystal stacks of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and / or solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, can contribute to the dominance of a single crystalline form.

[0265] It should be understood that the synthetic methods disclosed herein can be modified to obtain various compounds of the present invention by selecting appropriate reagents and starting materials. It should also be understood that, in cases where protection of certain active or incompatible groups (e.g., amines or carboxylic acids) is required, compounds with a given chemical formula, such as those in the processes provided herein, containing such active or incompatible groups in a suitably protected form, are used. For a general description of protecting groups and their uses, see PGM Woods and TW Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006.

[0266] Pharmaceutical compositions and formulations

[0267] This invention covers pharmaceutical compositions of any of the compounds detailed herein. Therefore, this invention comprises pharmaceutical compositions comprising the compounds of this invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may be in forms suitable for oral, buccal, non-enteric, nasal, topical, or rectal administration, or in forms suitable for inhalation administration.

[0268] In one aspect, the compounds detailed herein are in purified form, and compositions comprising compounds in purified form are provided. Compositions comprising compounds as detailed herein or salts thereof are provided, such as compositions comprising substantially pure compounds. In some embodiments, compositions containing compounds as detailed herein or salts thereof are in substantially pure form. In one variation, “substantially pure” means that the composition contains no more than 10% impurities, wherein said impurities represent compounds different from the majority of the composition. For example, a composition of substantially pure compounds selected from Table 1 means a composition containing no more than 10% impurities, wherein said impurities represent compounds different from said compounds or salts thereof. In one variation, a composition of substantially pure compounds or salts thereof is provided, wherein said composition contains no more than 5% impurities. In another variation, a composition of substantially pure compounds or salts thereof is provided, wherein said composition contains 2% or no more than 2% impurities. In yet another variation, a composition of substantially pure compounds or salts thereof is provided, wherein said composition contains 1% or no more than 1% impurities. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains 0.5% or no more than 0.5% impurities. In other variations, a composition of a substantially pure compound means that the composition contains no more than 10%, preferably no more than 5%, more preferably no more than 1%, or even more preferably no more than 0.5%, and most preferably no more than 0.1% impurities, which may be compounds in different stereochemical forms. For example (but not limited to), a composition of a substantially pure (S) compound means that the composition contains no more than 10%, no more than 5%, no more than 3%, no more than 1%, or no more than 0.5% of a compound in the (R) form.

[0269] In one variation, the compounds described herein are synthetic compounds prepared for administration to a patient (such as a human). In another variation, a pharmaceutical composition comprising a compound in a substantially pure form is provided. In yet another variation, the invention covers pharmaceutical compositions comprising the compounds detailed herein and pharmaceutically acceptable carriers or excipients. In yet another variation, a method of administering the compound is provided. The purified forms, pharmaceutical compositions, and methods of administering the compound are applicable to any of the compounds or their forms detailed herein.

[0270] The compound can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), non-intestinal (e.g., intramuscular, subcutaneous, or intravenous), topical, or percutaneous delivery forms. The compound can be formulated with suitable carriers to provide delivery forms, including (but not limited to) lozenges, tablets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), flat capsules, sugar-coated lozenges, lozenges, gels, dispersions, suppositories, ointments, catalysts / poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs.

[0271] Formulations, such as pharmaceutical formulations, can be prepared using one or more of the compounds described herein, by combining one or more compounds as active ingredients with pharmaceutically acceptable carriers (such as those described above). The carrier can take various forms depending on the therapeutic form of the system (e.g., a transdermal patch versus an oral tablet). Additionally, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and osmolarity-regulating salts, buffers, coating agents, or antioxidants. Formulations containing compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared using known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0272] The compounds described herein can be administered to patients (e.g., humans) in generally acceptable oral compositional forms (such as lozenges, coated lozenges, and gel capsules, emulsions, or suspensions in hard or soft shells). Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearates or salts thereof. Acceptable carriers for gel capsules with soft shells include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Additionally, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and osmotic pressure regulating salts, buffers, coating agents, or antioxidants.

[0273] Any of the compounds described herein can be formulated in tablet form in any of the dosage forms described.

[0274] Pharmaceutical compositions, such as those comprising the compounds provided herein or pharmaceutically acceptable salts thereof, are also described. In one variation, the composition comprises a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compounds or pharmaceutically acceptable salts thereof is provided.

[0275] Use / Treatment

[0276] The compounds and compositions detailed herein (such as pharmaceutical compositions containing compounds of any of the forms provided herein) or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients may be used in the administration and treatment methods provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering the compounds or their salts or compositions to cells for screening purposes and / or for quality control analysis.

[0277] In another aspect, this document provides a method for stimulating thyroid hormone receptor β (THRβ), comprising contacting an effective amount of a compound provided herein or a salt thereof (such as a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition provided herein with THRβ. In one aspect, this document provides a method for selectively stimulating THRβ relative to THRα, comprising contacting an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof or an effective amount of a pharmaceutical composition provided herein with THRβ. In one such aspect, the method selectively stimulates THRβ at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times relative to THRα. In any such embodiment, in one aspect, the selectivity is assessed via biochemical analysis, such as the TR-FRET analysis described in Example B1.

[0278] In one aspect, this article provides a method for treating a THRβ-mediated disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, the disease or condition is a liver disease or condition. In one aspect, this article provides a method for treating a liver disease or condition associated with suboptimal THRβ agonist effects in a patient in need, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound selectively agonizes THRβ relative to THRα.

[0279] In one aspect, this invention provides a method for treating non-alcoholic fatty liver disease in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for treating non-alcoholic steatohepatitis (NASH) in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for treating metabolic syndrome in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for treating dyslipidemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for treating hypertriglyceridemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for treating hypercholesterolemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein.

[0280] In any of the embodiments described herein, a patient with a disease or condition associated with the activating effect of THRβ may include (but is not limited to) a patient with underlying hypothyroidism.

[0281] In another aspect, a method is provided to delay the onset and / or development of a THRβ-mediated disease or condition in a patient (such as a human) who is at risk of developing the disease or condition. It should be understood that delaying development may encompass prevention in the absence of the disease or condition in the individual. In one aspect, an individual at risk of developing a THRβ-mediated disease or condition has one or more risk factors for developing the disease or condition, such as aging, increased waist circumference, higher body mass index, or the presence of related comorbidities.

[0282] In one aspect, this invention provides a method for delaying the onset and / or development of non-alcoholic fatty liver disease in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of non-alcoholic steatohepatitis (NASH) in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of metabolic syndrome in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of dyslipidemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of hypertriglyceridemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this article provides a method for delaying the onset and / or development of hypercholesterolemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein.

[0283] In one aspect, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof suitable for therapeutic purposes. In some embodiments, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, suitable for treating non-alcoholic fatty liver disease. In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, for treating non-alcoholic steatohepatitis (NASH). In some embodiments, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, suitable for treating metabolic syndrome. In some embodiments, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, for treating dyslipidemia. In some embodiments, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, for treating hypertriglyceridemia. In some embodiments, a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, is provided for the treatment of hypercholesterolemia.

[0284] In another embodiment, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating non-alcoholic fatty liver disease. In another embodiment, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating non-alcoholic steatohepatitis (NASH). In another embodiment, this document provides a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating metabolic syndrome. In some embodiments, the agent is used to treat dyslipidemia. In some embodiments, the agent is used to treat hypertriglyceridemia. In some embodiments, the agent is used to treat dyslipidemia. In some embodiments, the agent is used to treat hypercholesterolemia.

[0285] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least approximately or approximately 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than or approximately 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old.

[0286] Dosage and method of administration

[0287] The dosage of the compound or its stereoisomers, tautomers, solvates or salts described herein administered to an individual (such as a human) may vary depending on the specific compound or its salt, the method of administration, and the specific disease or condition being treated (such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia). In some embodiments, the amount of the compound or its stereoisomers, tautomers, solvates or salts is a therapeutically effective amount.

[0288] The compounds or their salts described herein can be administered to individuals via various routes, including intravenous, intramuscular, subcutaneous, oral, and transdermal routes.

[0289] In one aspect, the effective amount of the compound is a dose between about 0.01 mg / kg and about 100 mg / kg. The effective amount or dose of the compound of the present invention can be determined by conventional methods such as modeling, dose escalation, or clinical trials, taking into account conventional factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the individual's health status, symptoms, and weight. Exemplary doses are in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 g to 7 g per day.

[0290] In one aspect, any of the methods provided herein may include administering to an individual a pharmaceutical composition containing an effective amount of the compound provided herein or its stereoisomers, tautomers, solvates or salts and pharmaceutically acceptable excipients.

[0291] The compounds or compositions described herein may be administered to an individual for the desired period of time or duration, depending on an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer, which in some variations may extend the individual's lifespan. In one variation, the compound is administered daily or intermittently. The compound may be administered to an individual continuously (e.g., at least once daily) for a period of time. The dosing frequency may also be less than once daily, such as about once a week. The dosing frequency may be greater than once daily, such as twice or three times daily. The dosing frequency may also be intermittent, including 'drug holidays' (e.g., seven days of once-daily dosing followed by seven days without dosing, repeated over any 14-day period, such as about two months, about four months, about six months, or longer). Any of the dosing frequencies may be achieved using any of the compounds described herein and any of the dosages described herein.

[0292] Products and reagent kits

[0293] The present invention further provides articles comprising, in suitable packaging, the compounds described herein or salts thereof, the compositions described herein, or one or more unit doses described herein. In some embodiments, the articles are suitable for any of the methods described herein. Suitable packaging is known in the art and comprises, for example, vials, containers, ampoules, bottles, cans, flexible packaging, and the like. The articles may be further sterilized and / or sealed.

[0294] The present invention further provides a kit for performing the methods of the invention, comprising one or more compounds described herein or pharmaceutically acceptable salts thereof, or a composition comprising compounds described herein or pharmaceutically acceptable salts thereof. The kit may use any of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In one variation, the kit uses compounds described herein or pharmaceutically acceptable salts thereof. The kit may be used for any one or more of the uses described herein and may therefore contain instructions for treating any disease or disease described herein, such as for treating non-alcoholic steatohepatitis (NASH).

[0295] Kits typically include suitable packaging. Kits may include one or more containers containing any of the compounds described herein or their pharmaceutically acceptable salts. Various components (if more than one component is present) may be packaged in individual containers, or, where cross-reactivity and shelf life permit, some components may be combined in one container.

[0296] The kit may be available in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit dose. For example, a kit may be provided containing sufficient doses of a compound as disclosed herein or a pharmaceutically acceptable salt thereof and / or additional pharmaceutically active compounds suitable for the diseases detailed herein, for providing an individual with an extended period of effective treatment, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more months. The kit may also contain multiple unit doses of the compound and instructions for use, packaged in quantities sufficient for storage and use by a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0297] Regarding the use of the components in the method of this invention, the kit may optionally include a set of instructions, typically in written form, but electronic storage media (e.g., disks or optical discs) containing the instructions are also acceptable. The instructions included in the kit typically contain information about the components and their administration to individuals.

[0298] Exemplary Examples

[0299] The invention is further described through the following embodiments. Where appropriate and feasible, the features of each embodiment may be combined with any other embodiment.

[0300] Example 1. A compound of formula (I),

[0301]

[0302] in:

[0303] R1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, -C(O)N(R7)(R8), or -N(R9)C(O)(R 10 ) or halogen;

[0304] R2 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0305] R3 is an H group or a halogen group;

[0306] R4 is H or a substituted or unsubstituted straight-chain C1-C3 alkyl group;

[0307] L can be -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-;

[0308] R5 and R6 are independently H, halogen, -CN or substituted or unsubstituted C1-C6 alkyl groups, or R5 and R6 are bonded to the carbon atom to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups.

[0309] R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups, or R7 and R8 are bonded to the nitrogen atom to which they are attached to form substituted or unsubstituted 3- to 7-membered heterocyclic alkyl groups.

[0310] R9 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group;

[0311] R 10 It can be a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 );

[0312] R 11 It is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl;

[0313] M1 and M2 are independently halogroups, or substituted or unsubstituted C1-C6 alkyl groups; and

[0314] M3 is H, a halogen, or a substituted or unsubstituted C1-C6 alkyl group, or M3 combined with M2 and the carbon atom to which it is attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0315] Or its pharmaceutically acceptable salt.

[0316] Example 2. A compound as in Example 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl.

[0317] Example 3. A compound as in Example 2 or a pharmaceutically acceptable salt thereof, wherein R1 is isopropyl.

[0318] Example 4. A compound as in Example 2 or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl.

[0319] Example 5. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 4, wherein R2 is a substituted or unsubstituted C1-C6 alkyl group.

[0320] Example 6. A compound as described in Example 5 or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.

[0321] Example 7. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 4, wherein R2 is H.

[0322] Example 8. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 7, wherein R3 is H.

[0323] Example 9. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 8, wherein R4 is H.

[0324] Example 10. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 8, wherein R4 is a substituted or unsubstituted straight-chain C1-C3 alkyl group.

[0325] Example 11. A compound as described in Example 10 or a pharmaceutically acceptable salt thereof, wherein R4 is methyl.

[0326] Example 12. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 11, wherein L is -O-.

[0327] Example 13. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 11, wherein L is -C-(O)-.

[0328] Example 14. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 11, wherein L is -CH2-.

[0329] Example 15. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 14, wherein M1 and M2 are independently halogen groups.

[0330] Example 16. A compound as in Example 15 or a pharmaceutically acceptable salt thereof, wherein M1 and M2 are each chlorine.

[0331] Example 17. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 16, wherein M3 is H.

[0332] Example 18. A compound or a pharmaceutically acceptable salt thereof as in any of Examples 1 to 16, wherein M3 is a substituted or unsubstituted C1-C6 alkyl group.

[0333] Example 19. A compound as in Example 18 or a pharmaceutically acceptable salt thereof, wherein M3 is methyl.

[0334] Example 20. A compound selected from the group consisting of:

[0335]

[0336]

[0337] Or its pharmaceutically acceptable salt.

[0338] Example 21. A pharmaceutical composition comprising a compound as described in any of Examples 1 to 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0339] Example 22. A method of stimulating thyroid hormone receptor β (THRβ) comprising contacting an effective amount of a compound as in any of Examples 1 to 20 or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition as in Example 21, with THRβ.

[0340] Example 23. A method of treating a patient with a THRβ-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as in any of Examples 1 to 20, or a therapeutically effective amount of a pharmaceutical composition, as in Example 21.

[0341] Example

[0342] The following abbreviations may be used in connection with this application.

[0343] abbreviation

[0344] Ac: Acetyl group

[0345] ACN: Acetonitrile

[0346] Boc: tert-butoxycarbonyl

[0347] BSA: Bis(trimethylsilyl)acetamide

[0348] Bu: Butyl

[0349] CAN: Cerium ammonium nitrate

[0350] DBA: Diphenylmethyleneacetone

[0351] DCM: Dichloromethane

[0352] DMAP: Dimethylaminopyridine

[0353] DMF: Dimethylformamide

[0354] DMF-DMA: Dimethylformamide dimethyl acetal

[0355] DMSO: Dimethyl sulfoxide

[0356] DSC: Disuccinimino carbonate

[0357] Et: Ethyl

[0358] HPLC: High Performance Liquid Chromatography

[0359] MeOH: Methanol

[0360] OAc: Acetate

[0361] Pr: Propyl

[0362] Py or Pyr: Pyridine

[0363] rt: room temperature

[0364] SEMCl: 2-(trimethylsilyl)chloroethoxymethyl

[0365] SFC: Supercritical Fluid Chromatography

[0366] TEA: Triethylamine

[0367] THF: Tetrahydrofuran

[0368] TFA: Trifluoroacetic acid

[0369] Si-TMT: 2,4,6-trithiotriazine bonded to silica

[0370] Toluene

[0371] Ts: Toluenesulfonyl group

[0372] t-Bu Xphos: 2-Di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl

[0373] Synthesis Example

[0374] Example S1: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 1)

[0375] Process 1

[0376]

[0377]

[0378] 3,6-Dichloro-4-isopropylpyridazine (1a). Sulfuric acid (19.75 g, 201.37 mmol, 10.73 mL) was added to a mixture of 3,6-dichloropyridazine (10 g, 67.12 mmol), 2-methylpropionic acid (6.21 g, 70.48 mmol, 6.54 mL), and AgNO3 (5.70 g, 33.56 mmol, 5.64 mL) in 200 mL of H2O at 60 °C. Subsequently, a solution of ammonium persulfate (45.95 g, 201.37 mmol) in 100 mL of H2O was added dropwise to the mixture at 75 °C, and the mixture was stirred at 75 °C for 30 minutes. TLC showed the reaction was complete. After cooling, the pH was adjusted to 9–10 using NH3 / H2O. The mixture was extracted with ethyl acetate (200 mL × 2), the organic phase was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to give 1a (11 g, 57.57 mmol, yield 85.77%), a pale yellow oil. The product was used directly in the next step. [M+1] + The calculated MS quality requirement value for (C7H8Cl2N2) is 191.1 m / z, and the experimental LCMS value is also 191.1 m / z. 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 3.24-3.31 (m, 1H), 1.31 (d, J = 6.8Hz, 6H).

[0379] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline (1b). K₂CO₃ (9.32 g, 67.41 mmol) and CuI (1.93 g, 10.11 mmol) were added to a solution of 4-amino-2,6-dichlorophenol (3 g, 16.85 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (3.22 g, 16.85 mmol) in DMSO (30 mL). The mixture was then degassed and purged three times with N₂, and stirred at 90 °C under N₂ atmosphere for 16 h. TLC and LCMS showed complete depletion of the starting material and detection of the desired MS. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (1000 mL × 2) and H₂O (500 mL). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 3:1, according to TLC) to give 1b (3.5 g, 10.52 mmol, 62.44% yield) as a pale brown oil. [M+1] + (C 13 H 12 The MS quality requirement value (m / z) calculated by Cl3N3O is 332.0, and the experimental value (m / z) of LCMS is also 332.0. 1 H NMR (400MHz, DMSO-d6) δ7.66 (s, 1H), 6.67-6.76 (m, 2H), 5.67 (s, 2H), 3.11-3.21 (m, 1H), 1.28 (d, J = 6.85Hz, 6H).

[0380] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1c). NaOAC (3.21 g, 39.08 mmol) was added to a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (2.6 g, 7.82 mmol) and isobenzofuran-1,3-dione (1.16 g, 7.82 mmol) in HOAC (5 mL). The mixture was stirred at 120 °C for 6 hours. LC-MS showed complete depletion of the starting material and detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to approximately 9 with a saturated solution of NaHCO3 (10 mL). The mixture was then partitioned with ethyl acetate (30 mL × 2) and H2O (30 mL). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The solid was diluted with ethyl acetate (10 mL), and then petroleum ether (50 mL) was added to the mixture. The mixture was filtered to collect the solid. The solid was dried to give 1c (2.48 g, 3.65 mmol, 46.71% yield) as a brown solid. [M+1] + (C 21 H 15 The calculated MS quality requirement value (m / z) for Cl2N3O4 is 444.0, and the experimental LCMS value (m / z) is 444.1. 1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),7.98-8.06(m,2H),7.90-7.97(m,2H) ,7.78-7.83(m,2H),7.46(s,1H),3.03-3.10(m,1H),1.20(d,J=6.85Hz,6H).

[0381] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1d). A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1c) (500 mg, 1.13 mmol) in DMF-DMA (4 mL) was stirred at 110 °C for 2.5 h. TLC showed complete depletion of the starting material and the formation of two new spots. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL × 2) and H₂O (3 mL). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 1d as a yellow solid. The product was used directly in the next step without further purification.

[0382] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H),-one (1e). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoindoline-1,3-dione (1d) (700 mg, 1.53 mmol) and butyl-1-amine (335.13 mg, 4.58 mmol) in MeOH (10 mL) was stirred at 70 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1, P1:R) f =0.6) and LCMS showed complete depletion of the starting material and detection of the desired MS. The mixture was concentrated under vacuum to obtain the residue. Preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R) was performed. f =0.6) Purify the residue to give 1e as a white solid (285 mg, 868.39 μmol, 56.85% yield). For [M+1] + (C 14 H 15 The calculated MS quality requirement value (m / z) for Cl2N3O2 is 328.1, and the experimental LCMS value (m / z) is 328.2. 1 HNMR (400MHz, MeOH-d4) δ7.22 (s, 1H) 6.70 (s, 1H) 3.52 (s, 3H) 3.17 (dt, J = 13.81, 7.13Hz, 1H) 1.43 (s, 2H) 1.25 (d, J = 6.58Hz, 6H).

[0383] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3-(2H)-one (1f). The reaction was carried out at 20 °C with 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methylpyridazin-3-one (1e) (50 mg, 152.35 μmol). 4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (116.06 mg, 457.05 μmol) was added dropwise to a solution of CH3CN (3 mL) with tert-butyl nitrite (23.57 mg, 228.52 μmol, 27.18 μL). The mixture was stirred at 20 °C for 2 hours. LCMS and TLC (petroleum ether:ethyl acetate = 5:1, R f=0.6) indicates the reaction is complete and the desired MS is detected. The mixture was extracted with EtOAC (10 mL) and the organic layer was washed with H2O (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The result was obtained by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f =0.6) Purify the residue to obtain 1f (40 mg, crude substance) as a pale yellow solid. For [M+1] + (C 20 H 25 The MS quality requirement value (m / z) calculated for BCl2N2O4 is 439.1, and the experimental values ​​(m / z) for LCMS are 439.0 and 356.9 (MS for boric acid). 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.01-7.09(m,1H),3.46-3.55(m,2H),3.18-3.32(m,1H,)1.36(s,5H),1.21-1.29(m,12H).

[0384] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (1). K2CO3 (25.18 mg, 182.17 μmol) was added to a mixture of 6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy]-4-isopropyl-2-methyl-pyridazin-3-one (1f) (40 mg, 91.09 μmol) and 6-bromo-2H-1,2,4-triazin-3,5-dione (26.23 mg, 136.63 μmol) in dioxane (3 mL) and H2O (1.5 mL). Next, Pd(dppf)Cl2 (6.66 mg, 9.11 μmol) was added to the mixture under N2. The mixture was then stirred at 80 °C under N2 for 2 hours. LCMS and TLC (petroleum ether:ethyl acetate = 0:1, R0) were used to analyze the mixture. f =0.6) indicates the reaction is complete, and the desired MS is detected. The mixture is concentrated under vacuum, and the residue is extracted with EtOAC (10 mL) and H2O (5 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under vacuum. The residue is purified by preparative HPLC (column: Luna C18 100*30 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 36-66%, 10 min) to give 1 (4.5 mg, 10.52 μmol, 11.55% yield). For [M+1] + (C 20 H 25The MS quality requirement value (m / z) calculated for BCl2N2O4 is 424.1, and the experimental value (m / z) for LCMS is 424.0. 1 H NMR (400MHz, MeOH-d4) δ8.18 (s, 2H), 7.34 (d, J = 0.74Hz, 1H), 3.50 (s, 3H), 3.10-3.25 (m, 1H), 1.28 (d, J = 6.8Hz, 6H).

[0385] Example S2: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 2)

[0386] Process 2

[0387]

[0388] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazine (2a). NaNO₂ (124.47 mg, 1.80 mmol) was added to a solution of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazine-3-yl)oxy-aniline (1b) (500 mg, 1.50 mmol) in HCl (15.03 mmol, 5 M, 1.79 mL) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. A solution of KI (499.08 mg, 3.01 mmol) in H₂O (5 mL) was then added, and the mixture was stirred again at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.6) indicates that 1b is completely exhausted. The reaction mixture was extracted with EtOAC (10 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 1:1) to give 2A as a pale yellow solid (340 mg, 613.31 μmol, 40.80% yield).

[0389] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropylpyridazine (2b). Pd(dppf)Cl2 (28.05 mg, 38.33 μmol) and KOAc (376.19 mg, 3.83 mmol) were added to a solution of 3-chloro-6-(2,6-dichloro-4-iodo-phenoxy)-4-isopropylpyridazine (2a) (340 mg, 766.64 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (584.04 mg, 2.30 mmol) in dioxane (10 mL). The mixture was degassed and purged three times with N2, and stirred at 90°C for 16 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) indicates complete depletion of 2a. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with EtOAC (10 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1) to give 2b as a white gel (380 mg, 685.37 μmol, 89.40% yield). For [M+1] + (C 19 H 22 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 443.1, and the experimental value (m / z) of LCMS is also 443.1. 1 HNMR (400MHz, CDCl3) δ7.82-7.80(m,2H),7.22-7.20(m,1H),3.31-3.23(m,1H),1.36-1.36(m,3H),1.36-1.35(m,12H),1.35-1.34(m,3H).

[0390] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (2c). Pd(dppf)Cl2 (11.55 mg, 15.78 μmol) and K2CO3 (65.43 mg, 473.44 μmol) were added to a solution of 3-chloro-6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy]-4-isopropylpyridazine (2b) (70 mg, 157.81 μmol) and 6-bromo-2H-1,2,4-triazin-3,5-dione (45.44 mg, 236.72 μmol) in dioxane (4 mL) and H2O (1 mL). The mixture was degassed and purged three times with N2, and then stirred at 80°C for 16 hours under an N2 atmosphere. TLC (petroleum ether:ethyl acetate = 1:1, R...) f =0.30) indicates the reaction is complete. The suspension was filtered through a diatomaceous earth pad and the filter cake was washed with EtOAC (5 mL × 4). The combined filtrates were concentrated under vacuum, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give 2c (10.5 mg, 22.05 μmol, 13.97% yield) as a pale yellow solid. For [M+1] + (C 16 H 12 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 428.0, and the experimental LCMS value (m / z) is 428.1 / 430.1.

[0391] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (2). NaOAC (6.89 mg, 83.98 μmol) was added to a solution of 6-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-phenyl]-2H-1,2,4-triazin-3,5-dione (2c) (10 mg, 21.00 μmol) in AcOH (2 mL). The mixture was stirred at 120 °C for 2 hours. LC-MS showed a retention of approximately 10% of 2c and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100*30 5μm; mobile phase: [water (0.2% FA)-ACN]; B%: 25-50%, 12 min) to give 2 (2.56 mg, 6.24 μmol, 29.72% yield). [M+1] + (C 16 H 13The MS quality requirement value (m / z) calculated for Cl2N5O4 is 410.0, and the experimental values ​​for LCMS are 410.1 / 412.1. 1 H NMR (400MHz, CDCl3) δ8.15 (s, 2H), 7.34 (s, 1H), 3.12-3.18 (m, 1H), 1.27-1.29 (d, J = 8.0Hz, 6H).

[0392] Example S3: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 3)

[0393] Process 3a

[0394]

[0395] 6-Bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a). BSA (529.85 mg, 2.60 mmol) was added to a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (200 mg, 1.04 mmol) in MeCN (5 mL). The mixture was heated at 82 °C for 3 hours. Subsequently, MeI (221.81 mg, 1.56 mmol) was added to the mixture, and the resulting mixture was stirred at 90 °C for another 16 hours. TLC (petroleum ether:ethyl acetate = 1:1, product R) f =0.5) indicates complete depletion of the starting material. Extract the reaction mixture with EtOAC (10 mL × 3). Filter the combined organic layers and concentrate under reduced pressure. Purify the residue by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC) to give 3a as a white solid (170 mg, 660.20 μmol, 63.37% yield). 1 H NMR (400MHz, DMSO-d6) δ12.53-12.45(m,1H),3.43(s,3H).

[0396] Process 3b

[0397]

[0398] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (3b). To 6-bromo-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (3a) (50 mg, 112.72 μmol) and 3-chloro-6-(2,6-dichloro-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxane-2-yl)phenoxy)-4-isopropylpyridazine (2b) (69.66 mg, 338.17 μmol) was added to a solution of dioxane (4 mL) with Pd(dppf)Cl2 (8.25 mg, 11.27 μmol) and K2CO3 (46.74 mg, 338.17 μmol) in H2O (1 mL). The mixture was stirred at 80 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.4) indicates complete depletion of 2b. The suspension was filtered through a diatomaceous earth pad and the filter cake was washed with EtOAC (10 mL × 3). The combined filtrates were concentrated to dryness to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, according to TLC) to give 3b as a white solid (21 mg, 37.95 μmol, 33.67% yield). For [M+1] + (C 17 H 14 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 442.0, and the experimental value (m / z) for LCMS is 444.0.

[0399] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (3). NaOAC (15.75 mg, 192.01 μmol) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (3b) (17 mg, 38.40 μmol) in HOAC (5 mL). The mixture was stirred at 120 °C for 16 hours. LC-MS showed complete depletion of 3b and a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by preparative HPLC (column: Luna C18 100×30 5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30-70%, 15 min) to give 3 (2.57 mg, 5.82 μmol, 15.14% yield). [M+1] + (C 17 H15 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 424.1, and the experimental value (m / z) for LCMS is 424.0. 1 HNMR (400MHz, CDCl3) δ8.21-8.16(m,2H),7.37-7.34(m,1H),3.69-3.66(m,3H),3.21-3.13(m,1H),1.31-1.27(m,6H).

[0400] Example S4: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 4)

[0401] Process 4a

[0402]

[0403] 6-Bromo-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4a). BSA (397.38 mg, 1.95 mmol) was added to a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (150 mg, 781.37 μmol) in ACN (6 mL). The mixture was heated at 82 °C for 3 hours, followed by the addition of 2-iodopropane (199.24 mg, 1.17 mmol). The mixture was then stirred at 82 °C for 16 hours. TLC (ethyl acetate: petroleum ether = 2:1, R f =0.6) indicates that the starting material was completely exhausted. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate, petroleum ether = 1:1, according to TLC) to give 4a as a white solid (155 mg, 629.14 μmol, 80.52% yield). 1 H NMR (400MHz, DMSO-d6) δ12.50-12.28(m,1H),4.76-4.67(m,1H),1.23-1.20(m,6H).

[0404] Process 4b

[0405]

[0406] 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazin-3,5(2H,4H)-dione (4b). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropylpyridazine (2b) (100 mg, 225.45) A solution of 6-bromo-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4a) (105.53 mg, 450.90 μmol) in dioxane (4 mL) was mixed with Pd(dppf)Cl2 (16.50 mg, 22.54 μmol) and K2CO3 (93.48 mg, 676.35 μmol) in H2O (1 mL). The mixture was stirred at 80 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.3) and LCMS showed that 2b was completely depleted and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad and the filter cake was washed with EtOAC (10 mL × 3). The combined filtrates were concentrated to dryness to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC) to give 4b as a white solid (50 mg, 84.97 μmol, 37.69% yield). For [M+1] + (C 19 H 18 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 470.0, and the experimental value (m / z) for LCMS is 470.1.

[0407] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazin-3,5(2H,4H)-dione (4). NaOAC (43.56 mg, 531.08 μmol) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazin-3,5(2H,4H)-dione (4b) (50 mg, 106.22 μmol) in HOAC (5 mL). The mixture was stirred at 120 °C for 16 h. LC-MS showed complete depletion of 4b and a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Luna C18 100×30 5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20-60%, 15 min) to give 4 (9.21 mg, 20.16 μmol, 18.98% yield). [M+1]+ (C 19 H 19 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 452.1, and the experimental value (m / z) for LCMS is 452.0. 1 HNMR(400MHz,MeOH-d4)δ8.19-8.16(m,2H),7.37-7.34(m,1H),5.01-4.95(m,1H),3.21-3.13(m,1H),1.43-1.40(m,6H),1.30-1.28(m,6H).

[0408] Example S5: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compound 5)

[0409] Process 5

[0410]

[0411] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-2-methylaniline (15a). K₂CO₃ (287.87 mg, 2.08 mmol) and CuI (59.50 mg, 312.43 μmol) were added to a mixture of 4-amino-2,6-dichloro-3-methylphenol (1a) (0.1 g, 520.72 μmol), 3,6-dichloro-4-isopropylpyridazine (99.49 mg, 520.72 μmol) in DMSO (1 mL) at 25 °C. The mixture was stirred at 90 °C for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.43) indicates the reaction is complete. Add H₂O (5 mL) to the mixture and extract with ethyl acetate (20 mL × 2). Wash the combined organic layers with brine (20 mL × 2), dry over anhydrous Na₂SO₄, filter, and concentrate under vacuum to give 5a (0.1 g, 288.48 μmol, 55.40% yield) as a yellow solid. For [M+1] + (C 14 H 14 The MS quality requirement value (m / z) calculated by Cl3N3O is 346.0, and the experimental value (m / z) of LCMS is also 346.0. 1 H NMR (400MHz, DMSO-d6) δ7.68 (s, 1H), 6.78-6.80 (m, 1H), 5.50 (s, 2H,) 3.13-3.19 (m, 1H), 2.13 (s, 3H), 1.28 (d, J = 6.8Hz, 6H).

[0412] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)isoindoline-1,3-dione (5b). NaOAC (94.66 mg, 1.15 mmol) was added to a mixture of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-2-methylaniline (5a) (0.1 g, 288.48 μmol) and isobenzofuran-1,3-dione (42.73 mg, 288.48 μmol) in AcOH (3 mL) at 25 °C, and the mixture was stirred at 120 °C for 6 hours. LC-MS showed the reaction was complete. The mixture was concentrated to give a residue. H₂O (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was diluted with MTBE (5 mL) and filtered. The filter cake was dried under vacuum to give 5b as a yellow solid (0.05 g, 109.10 μmol, 37.82% yield). [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated for Cl2N3O4 is 458.1, and the experimental value (m / z) for LCMS is 458.0. 1 H NMR (400MHz, CDCl3) δ9.91 (br s,1H),8.00(dd,J=5.5,3.0Hz,2H),7.85(dd,J=5.5,3.0Hz,2H),7.30(s,1H),7. 16(s,1H),3.23-3.29(m,1H),3.22(s,1H),2.25(s,3H),1.30(d,J=6.85Hz,6H).

[0413] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)-1,3-dione (5c). A mixture of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]isoindoline-1,3-dione (5b) (0.37 g, 807.34 μmol) in DMF-DMA (5 mL) was stirred at 105 °C for 4 hours. LCMS showed the reaction was complete. H₂O (20 mL) was added to the mixture and it was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 5c as a yellow solid. The crude product was used directly in the next step. For [M+1]+ (C 23 H 19 The MS quality requirement value (m / z) calculated for Cl2N3O4 is 472.1, and the experimental value (m / z) for LCMS is also 472.1.

[0414] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one-(5d). Butyl-1-amine (2M, 1.40 mL) was added to a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]isoindoline-1,3-dione (5c) (440 mg, 931.57 μmol) in MeOH (1 mL) at 70 °C. The mixture was stirred at 70 °C for 1 hour. TLC (petroleum ether: ethyl acetate = 1:1, R f =0.6) and LCMS showed complete depletion of the starting material and detection of the desired MS. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give a 5d white solid. For [M+1] + (C 15 H 17 The calculated MS quality requirement value (m / z) for Cl2N3O2 is 341.1, and the experimental LCMS value (m / z) is 342.1. 1 H NMR (400MHz, MeOH-d4) δ7.22 (s, 1H), 6.77 (s, 1H), 3.50 (s, 3H), 3.17 (td, J = 6.8, 13.8Hz, 1H), 2.20 (s, 3H), 1.26 (d, J = 6.6Hz, 6H).

[0415] 6-(2,6-dichloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (5e). The reaction proceeded at 20 °C to 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (5d) (20 mg, 58.44 μm). A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (742.03 mg, 2.92 mmol) in CH3CN (8 mL) was mixed with tert-butyl nitrite (t-BuONO) (12.05 mg, 116.88 μmol, 13.90 μL). The mixture was then stirred at 20 °C for 16 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f=0.4) and LCMS showed complete depletion of the starting material and the desired MS was found. Vacuum concentration of the mixture. Preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, P1:R) was performed. f =0.4) Purify the residue to obtain 5e (25 mg, crude substance) as a white solid. [M+1] + (C 21 H 27 The MS quality requirement value (m / z) calculated for BCl2N2O4 is 453.2, and the experimental value (m / z) for LCMS is 453.0. 1 H NMR (400MHz, CDCl3) δ7.76(s,1H),7.04(s,1H),3.58-3.63(m,3H),3.49-3.51(m,5H),3.24(s,1H),2.62(s,3H),1.21-1.30(m,6H).

[0416] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (5). To 6-(2,6-dichloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane)-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3 (2H)-keto(5e) (25 mg, 55.17 μmol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (10.59 mg, 55.17 μmol) were added to a mixture of dioxane (2 mL) and H₂O (0.5 mL), followed by K₂CO₃ (22.87 mg, 165.50 μmol) and Pd(dppf)Cl₂ (4.04 mg, 5.52 μmol). The mixture was degassed and purged three times with N₂, and then stirred at 90 °C under an N₂ atmosphere for 16 hours. HPLC and LCMS showed complete depletion of the starting material and detection of the desired MS. The reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 25-60%, 12 min) to give the desired compound (20 mg, 40.77 μmol, 73.89% yield, 89.33% purity). The product was then further purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150*30 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to give 5 (0.26 mg, 2.60% yield). [M+1] + (C18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 438.3, and the experimental LCMS value (m / z) is 438.0. 1 H NMR (400MHz, DMSO-d6) δ7.57 (s, 1H), 7.46 (s, 1H), 3.39 (br s, 3H), 3.08 (s, 1H), 2.25 (s, 3H), 1.19 (d, J = 7.0Hz, 6H).

[0417] Example S6: 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compound 6)

[0418] Process 6

[0419]

[0420] 3,6-Dichloro-4-cyclopropylpyridazine (6a). H₂SO₄ (1.98 g, 20.14 mmol, 1.07 mL) was added to a solution of 3,6-dichloropyridazine (1 g, 6.71 mmol), cyclopropanecarboxylic acid (577.86 mg, 6.71 mmol, 530.15 μL), and AgNO₃ (1.14 g, 6.71 mmol) in H₂O (20 mL) at 60 °C. Then, ammonium persulfate (4.60 g, 20.14 mmol, 4.38 mL) in H₂O (10 mL) was added to the mixture at 70 °C. The mixture was stirred at 70 °C for 30 minutes. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) indicates the reaction is complete. The mixture was extracted with ethyl acetate (20 mL × 2), the combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by MPLC (SiO₂, petroleum ether:ethyl acetate = 5:1) to give 6a (0.64 g, 3.39 mmol, 50.44% yield) as a colorless oil. [M+1] + The calculated MS quality requirement value for (C7H6Cl2N2) is m / z 189.0, and the experimental LCMS value is m / z 189.1. 1 H NMR (400MHz, CDCl3) δ6.94 (s, 1H), 2.22 (tt, J = 5.0, 8.4Hz, 1H), 1.37-1.28 (m, 2H), 0.93-0.83 (m, 2H).

[0421] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline (6b). 3,6-Dichloro-4-cyclopropylpyridazine (6a) (0.3 g, 1.59 mmol), 4-amino-2,6-dichlorophenol (282.50 mg, 1.59 mmol), K₂CO₃ (328.99 mg, 2.38 mmol), and CuI (60.45 mg, 317.39 μmol) in DMA (5 mL) were degassed and subsequently heated to 100 °C under N₂ for 16 hours. LCMS and TLC (petroleum ether:ethyl acetate = 3:1, R₂) were used to determine the desired MS and TLC results. f =0.33) showed a new spot. The mixture was filtered, and the filtrate was extracted with water (20 mL) and ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated, and the residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 6b as a yellow solid (0.3 g, 907.45 μmol, 57.18% yield). For [M+1] + (C 13 H 10 The MS quality requirement value calculated by Cl3N3O is 330.0 m / z, and the experimental value of LCMS is 330.1 m / z. 1 HNMR (400MHz, DMSO-d6) δ7.34(s,1H),6.70(s,2H),5.67(s,2H),2.17-2.11(m,1H),1.23-1.19(m,2H),1.07-1.01(m,2H).

[0422] 3-Chloro-4-cyclopropyl-6-(2,6-dichloro-4-iodophenoxy)pyridazine (6c). NaNO₂ (31.30 mg, 453.72 μmol) was added fractionally to a solution of 3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazine-3-yl)oxy)aniline (6b) (0.1 g, 302.48 μmol) in concentrated HCl (2 mL) and H₂O (2 mL) at 0 °C, and the mixture was stirred for 30 minutes. Then, KI (100.43 mg, 604.97 μmol) in H₂O (1 mL) was added dropwise to the mixture. The mixture was stirred at 25 °C for 1.5 hours to obtain a brown suspension. LCMS showed the desired MS, and TLC (petroleum ether:ethyl acetate = 5:1, R f =0.59) indicates the reaction is complete. The mixture is filtered, the filter cake is washed with water (2 mL × 2) and dried. The solid is purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 6c (0.11 g, 249.16 μmol, 82.37% yield) as a yellow solid. For [M+1]+ (C 13 The MS quality requirement value (m / z) calculated by H8Cl3IN2O is 440.9, and the experimental value (m / z) of LCMS is also 440.9. 1 HNMR (400MHz, CDCl3) δ7.77-7.69(m,2H),6.78(s,1H),2.25-2.18(m,1H),1.31-1.26(m,2H),0.94-0.89(m,2H).

[0423] (3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)boronic acid (6d). 3-chloro-4-cyclopropyl-6-(2,6-dichloro-4-iodophenoxy)pyridazine (6c) (0.11 g, 249.16 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane-pentaborane) (189.82 mg, 747.49 μmol, 3 equivalents), KOAc (146.72 mg, 1.49 mmol), and Pd(dppf)Cl2 (18.23 mg, 24.92 μmol) in dioxane (5 ml) were degassed and then heated to 90 °C under N2 for 16 h. The desired MS was detected by LC-MS, and TLC (petroleum ether:ethyl acetate = 3:1, R f =0.35) showed new spots. The mixture was filtered, the filter cake was washed with ethyl acetate (10 mL × 2), and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to give 6d (85 mg, 236.51 μmol, 94.92% yield) as a white solid. For [M+1] + (C 13 H 10 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 359.0, and the experimental value (m / z) of LCMS is also 359.0.

[0424] 6-(3,5-dichloro-4-(6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (6e). The (3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)boronic acid (6d) (85 mg, 236.51 μmol), 6-bromo-2H-1,2,4-triazin-3,5-dione (59.02 mg, 307.46 μmol), Pd(dppf)Cl2 (17.31 mg, 23.65 μmol), and K2CO3 (65.37 mg, 473.01 μmol) in dioxane (5 mL) and H2O (0.5 mL) were degassed and then heated to 90 °C under N2 for 16 hours. LCMS shows the required MS, TLC (DCM:MeOH = 10:1, R f =0.42) showed the formation of new spots. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give 6e as a yellow solid (30 mg, 70.32 μmol, 29.73% yield). For [M+1] + (C 16 H 10 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 426.0, and the experimental value (m / z) for LCMS is also 426.0. 1 H NMR (400MHz, MeOH-d4) δ8.23(s,2H),7.26(s,1H),2.33-2.26(m,1H),1.33-1.30(m,2H),1.08-1.02(m,2H).

[0425] 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (6). A mixture of 6-(3,5-dichloro-4-(6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (6e) (30 mg, 70.32 μmol) and NaOAC (28.84 mg, 351.58 μmol) in HOAC (3 mL) was heated to 110 °C for 16 hours. The reaction was completed by LC-MS, and the desired MS was found. The mixture was concentrated. The residue was purified by preparative HPLC (FA) to give 6 (10.19 mg, 24.96 μmol, 35.50% yield). For [M+1] + (C 16 H 10The MS quality requirement value (m / z) calculated for Cl3N5O3 is 408.0, and the experimental value (m / z) for LCMS is also 408.0. 1 H NMR (400MHz, DMSO-d6) δ12.60(s,1H),12.18(br s,1H),8.01(s,2H),7.15(s,1H),2.12(br s,1H),1.06(br d,J=6.8Hz,2H),0.99(br s,2H).

[0426] Example S7: 6-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (Compound 7)

[0427] Process 7

[0428]

[0429] Ethyl 2-cyano-2-(2,6-dichloro-4-nitro-phenyl)acetate (7a). Ethyl 2-cyanoacetate (9.99 g, 88.32 mmol, 9.42 mL) was added dropwise to a suspension of NaH (3.53 g, 88.32 mmol, 60% purity) in DMSO (100 mL) at 0 °C, and the mixture was stirred at 25 °C for 30 min. Subsequently, 1,2,3-trichloro-5-nitro-benzene (10 g, 44.16 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.49) indicates the reaction is complete. The reaction mixture was quenched at 25°C by adding water (100 mL). The pH was then adjusted to 1 with HCl (4 M), and the yellow precipitate was collected by vacuum filtration and dried under vacuum to give 7a as a yellow solid (12.5 g, 41.24 mmol, 93.39% yield). The product was used directly in the next step without further purification.

[0430] 2-(2,6-dichloro-4-nitro-phenyl)acetonitrile (7b). A mixture of ethyl 2-cyano-2-(2,6-dichloro-4-nitro-phenyl)acetonitrile (7a) (12.5 g, 41.24 mmol) and LiCl (2.62 g, 61.86 mmol) in DMSO (16 mL) and H₂O (6 mL) was heated to 165 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, R f=0.8) indicates the reaction was complete, and a new spot was formed. According to TLC, the reaction was clean. After cooling, the mixture was quenched with water (100 mL × 4) and extracted with ethyl acetate (50 mL × 4). The combined organic phases were washed with brine (20 mL × 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to give 7b as a brown solid (9.2 g, 39.82 mmol, 96.56% yield). The product was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ8.33-8.21(m,2H), 4.11-4.07(m,3H).

[0431] 2-(4-amino-2,6-dichloro-phenyl)acetonitrile (7c). Iron powder (6.04 g, 108.21 mmol) was added to a solution of 2-(2,6-dichloro-4-nitro-phenyl)acetonitrile (7b) (5 g, 21.64 mmol) in HOAC (30 mL). The mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.4) indicates the reaction is complete and a new spot has formed. Filter the mixture; extract the filtrate with water (100 mL × 4) and ethyl acetate (50 mL × 4). Neutralize the combined organic layers with saturated NaHCO3 (30 mL × 5), wash with brine (30 mL × 2), dry to Na2SO4, filter and concentrate to give 7c (4.2 g, 20.89 mmol, 96.53% yield) as a brown solid. The product was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ6.67 (s, 2H), 3.88 (s, 2H).

[0432] 2-(4-amino-2,6-dichloro-phenyl)-2-(6-chloro-5-isopropyl-pyridazin-3-yl)acetonitrile (7d). t-BuOK (1M in THF, 41.78 mL) was added dropwise to a solution of 2-(4-amino-2,6-dichloro-phenyl)acetonitrile (7c) (4.2 g, 20.89 mmol) and 3,6-dichloro-4-isopropyl-pyridazine (3.99 g, 20.89 mmol) in THF (20 mL) at 60 °C. The mixture was stirred at this temperature for 2 hours. TLC (petroleum ether:ethyl acetate = 2:1, R f=0.49) indicated the detection of a major new spot with lower polarity. After cooling the mixture, the organic layer was extracted with ethyl acetate (100 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 1:1) to give 7d (4 g, 11.25 mmol, 53.84% yield) as an orange solid. 1 H NMR (400MHz, CDCl3) δ7.62-7.56(m,1H),6.68(s,2H),6.32(s,1H),3.35-3.27(m,1H),1.33-1.28(m,6H).

[0433] (4-Amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)methyl ketone (7e). t-BuOK (1M in THF, 6.19 mL) was added to a solution of 2-(4-amino-2,6-dichloro-phenyl)-2-(6-chloro-5-isopropyl-pyridazin-3-yl)acetonitrile (7d) (2.2 g, 6.19 mmol) in MeCN (15 mL) at 25 °C. The mixture was stirred at this temperature for 0.5 h and then cooled to 0 °C. H₂O₂ (1.40 g, 12.37 mmol, 1.19 mL, 30% purity) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 2:1, R f =0.69) showed the formation of a new spot. LCMS showed the desired mass. The reaction mixture was quenched by adding Na2SO3 (5 mL) and then stirred at 20 °C for 1 hour. The mixture was then concentrated under vacuum. The residue was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to give 7e as a pale yellow solid (885 mg, 2.57 mmol, 41.51% yield). For [M+1] + (C 14 H 12 The MS quality requirement value (m / z) calculated by Cl3N3O is 344.0, and the experimental value (m / z) of LCMS is 344.1. 1 H NMR (400MHz, MeOH-d4) δ8.23-8.21(m,1H),6.69-6.66(m,2H),3.44-3.36(m,1H),1.40-1.36(m,6H).

[0434] 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1H-pyridazin-3-carbonyl)phenyl]isoindoline-1,3-dione (7f). NaOAC (297.55 mg, 3.63 mmol) and isobenzofuranyl-1,3-dione (107.45 mg, 725.43 μmol) were added to a solution of (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl) methyl ketone (7e) in HOAC (10 mL). The mixture was stirred at 120 °C for 16 hours. TLC (petroleum ether:ethyl acetate = 2:1, R f =0.31) showed the formation of a new spot. LCMS showed the desired mass was detected. The mixture was concentrated under vacuum, and the residue was diluted with H2O (50 mL) and NaHCO3 aqueous solution (50 mL). The mixture was then extracted with ethyl acetate (30 mL × 2). The combined organic layers were concentrated under vacuum to give 7f (200 mg, 438.33 μmol, 60.42% yield) as a white solid. The crude product was used in the next step without further purification. For [M+1] + (C 22 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O4 is 456.0, and the experimental value (m / z) for LCMS is 456.1.

[0435] 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazine-3-carbonyl)phenyl]isoindoline-1,3-dione (7 g). A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1H-3-carbonyl)phenyl]isoindoline-1,3-dione (7 f) (350 mg, 767.08 μmol) in DMF-DMA (10 mL) was stirred at 110 °C for 3 h. LC-MS showed that the reaction was complete and the desired mass was found. The reaction mixture was partitioned between H₂O (50 mL × 2) and ethyl acetate (50 mL × 2). The organic phase was concentrated under vacuum to give 7 g (300 mg, 637.89 μmol, 83.16% yield) as a white solid. The product was used in the next step without further purification. For [M+1] + (C 23 H 17 The MS quality requirement value (m / z) calculated for Cl2N3O4 is 470.1, and the experimental value (m / z) for LCMS is also 470.1.

[0436] 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazin-3-one (7 h). To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-carbonyl)phenyl]isoindoline-1,3-dione (7 g) (300 mg, 637.89 μmol) in MeOH (2 mL), n-butylamine (285.58 mg, 1.91 mmol, 307.08 μL) was added. The mixture was stirred at 70 °C for 0.5 h. TLC (petroleum ether:ethyl acetate = 2:1) showed the formation of two new spots (R). f =0.41, 0.31). Vacuum concentration of the mixture. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1) to give a pale yellow solid at 7h (122 mg, 358.61 μmol, 56.22% yield). 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 1.0 Hz, 1H), 6.65-6.61 (m, 2H), 3.77-3.74 (m, 3H), 3.27-3.18 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H).

[0437] 6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzoyl]-4-isopropyl-2-methyl-pyridazin-3-one (7i). Tert-butyl nitrite (24.25 mg, 235.15 μmol, 27.97 μL) was added to a solution of 6-(4-amino-2,6-dichloro-benzoyl)-4-isopropyl-2-methyl-pyridazin-3-one (7h) (40 mg, 117.58 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (89.57 mg, 352.73 μmol) in MeCN (2 mL). The mixture was stirred at 25°C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 4:1) to give 7i as a pale yellow solid (31 mg, 68.71 μmol, 58.44% yield). [M+1] + (C 21 H 24 The MS quality requirement value (m / z) calculated by BCl2N2O4 is 451.1, and the experimental value (m / z) of LCMS is 451.2. 1H NMR (400MHz, CDCl3) δ7.86 (d, J = 0.6Hz, 1H), 7.75 (s, 2H), 3.71 (s, 3H), 3.27-3.19 (m, 1H), 1.37 (s, 12H), 1.29-1.27 (m, 6H).

[0438] 6-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazine-3-carbonyl)phenyl]-2H-1,2,4-triazine-3,5-dione (7). A mixture of 7i (30 mg, 66.50 μmol, 6-bromo-2H-1,2,4-triazine-3,5-dione (12.77 mg, 66.50 μmol) in dioxane (4 mL) and H2O (1 mL) was degassed and purged three times with N2, and then added... Add Pd(dppf)Cl2 (4.87 mg, 6.65 μmol) and K2CO3 (27.57 mg, 199.49 μmol). The mixture was then stirred at 90 °C under a nitrogen atmosphere for 1 hour. LCMS showed the desired mass. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (NH4CO3) to give 7 (7.65 mg, 17.44 μmol, yield 26.23%). [M+1] + (C 18 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 436.2, and the experimental value (m / z) for LCMS is 436.0. 1 H NMR (400MHz, MeOH-d4) δ8.16 (s, 2H), 7.93-7.91 (m, 1H), 3.72-3.68 (m, 3H), 3.24-3.16 (m, 1H), 1.29 (d, J = 6.8Hz, 6H).

[0439] Example S8: 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (Compound 8)

[0440] Process 8

[0441]

[0442] (6-Chloro-5-isopropylpyridazin-3-yl)(2,6-dichloro-4-iodophenyl) methyl ketone (8a). NaNO₂ (28.83 mg, 417.85 μmol) was added to a solution of (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyridazin-3-yl) methyl ketone (7e) (120 mg, 348.21 μmol) in HCl (5 M, 2 mL) at 0 °C, and the mixture was stirred for 0.5 h. Subsequently, a solution of KI (115.60 mg, 696.41 μmol) in H₂O (5 mL) was added to the mixture, and the mixture was stirred again at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.6) indicates complete depletion of 7e. The reaction mixture was extracted with EtOAC (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 5:1, according to TLC) to give 8a as a white solid (75 mg, 131.72 μmol, 37.83% yield). For [M+1] + (C 14 H 10 The MS quality requirement value (m / z) calculated by Cl3IN2O is 454.9, and the experimental value (m / z) of LCMS is also 454.9.

[0443] (6-Chloro-5-isopropylpyridazin-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl) methyl ketone (8b). Pd(dppf)Cl2 (8.03 mg, 10.98 μmol) and KOAc (107.73 mg, 1.10 mmol) were added to a solution of (6-chloro-5-isopropylpyridazin-3-yl)(2,6-dichloro-4-iodophenyl) methyl ketone (8a) (100 mg, 219.54 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (167.25 mg, 658.61 μmol) in dioxane (3 mL). The mixture was degassed and purged three times with N2, and stirred at 90°C for 16 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) and LCMS showed that 8a was completely depleted and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with EtOAC (10 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, according to TLC) to give 8b (150 mg, crude substance) as a white solid. For [M+1] + (C20 H 22 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 455.1, and the experimental value (m / z) of LCMS is 455.0. 1 HNMR (400MHz, CDCl3) δ8.20-8.18(m,1H),7.79-7.74(m,2H),3.40-3.32(m,1H),1.38-1.34(m,18H).

[0444] 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8c). To (6-chloro-5-isopropylpyridazine-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl) methyl ketone (8b) (50 mg, 109 A solution of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (63.21 mg, 329.26 μmol) in dioxane (4 mL) was mixed with Pd(dppf)Cl2 (8.03 mg, 10.98 μmol) and K2CO3 (45.51 mg, 329.26 μmol) in H2O (1 mL). The mixture was stirred at 80 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) and LCMS showed complete depletion of 18b and detection of the desired mass. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with EtOAC (10 mL × 3). The combined filtrates were concentrated to dryness to give the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 20:1, according to TLC) to give 8c (25 mg, 28.37 μmol, 25.85% yield) as a white solid. [M+1] + (C 17 H 12 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 440.0, and the experimental value (m / z) for LCMS is 442.0.

[0445] 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8). NaOAC (23.27 mg, 283.66 μmol) was added to a solution of 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8c) (25 mg, 56.73 μmol) in HOAC (3 mL). The mixture was stirred at 120 °C for 16 h. LC-MS showed complete depletion of 8c and a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Nano-Micro UniSil5-100C18 ULTRA 100×250mm 5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 25-65%, 10 min) to give 8 (1.86 mg, 4.19 μmol, 7.38% yield). [M+1] + (C 17 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 422.0, and the experimental value (m / z) for LCMS is 422.1. 1 H NMR (400MHz, MeOH-d4) δ 8.16-8.12 (m, 2H), 7.92-7.90 (m, 1H), 3.21-3.12 (m, 1H), 1.29 (d, J = 7.0Hz, 6H).

[0446] Example S9: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 9)

[0447] Process 9

[0448]

[0449] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (9). To 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1f)(3 A solution of 0 mg (68.32 μmol) of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (42.22 mg, 204.95 μmol) in dioxane (2 mL) was added to a solution of Pd(dppf)Cl2 (5.00 mg, 6.83 μmol) and K2CO3 (28.33 mg, 204.95 μmol) in H2O (0.5 mL). The mixture was stirred at 80 °C for 3 hours. LCMS showed complete depletion of 1f and detection of the desired mass. Palladium scavenger Si-TMT (1 g) was added to the mixture and the mixture was stirred at 20 °C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 9. Regarding [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 438.1, and the experimental value (m / z) for LCMS is 438.0. 1 H NMR (400MHz, MeOH-d4) δ 8.14-8.24 (m, 2H), 7.32-7.35 (m, 1H), 3.64-3.72 (m, 3H), 3.49 (s, 3H), 3.20 (td, J = 7.0, 13.6Hz, 1H), 1.28 (d, J = 6.8Hz, 6H).

[0450] Example S10: 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 10)

[0451] Process 10

[0452]

[0453] 6-(3,5-dichloro-4-(6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (10a). 3-chloro-4-cyclopropyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)pyridazine (6d) (75 mg, 169.86 μmol) was prepared under N2. A mixture of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (45.49 mg, 220.82 μmol), Pd(dppf)Cl2 (12.43 mg, 16.99 μmol), and K2CO3 (46.95 mg, 339.72 μmol, 2 equivalents) in dioxane (5 mL) and H2O (0.5 mL) was heated to 90 °C for 16 hours. LC-MS showed complete depletion and detection of the desired MS on day 6. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (ethyl acetate: MeOH) to give 10a. [M+1] + (C 17 H 12 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 440.0, and the LCMS experimental value (m / z) is 440.1. 1 H NMR(400MHz,DMSO-d6)δ8.16-8.10(m,2H),7.51(s,1H),3.58(s,4H),1.22-1.20(m,1H),1.2 3-1.20(m,1H),1.19-1.14(m,1H),1.19-1.14(m,1H),1.11-1.05(m,1H),1.10-1.05(m,1H).

[0454] 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (10). A mixture of 6-(3,5-dichloro-4-(6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (10a) (28 mg, 63.54 μmol) and NaOAC (26.06 mg, 317.70 μmol) in HOAC (1 mL) was heated to 110 °C for 16 hours. LCMS showed complete depletion of 10a and detection of the desired MS. The mixture was concentrated. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30mm×5μm; mobile phase: [water (0.1% TFA)-ACN]) to obtain 10. For [M+1]+ (C 17 H 13 C l2 The MS quality requirement value (m / z) calculated for N5O4 is 422.0, and the experimental value (m / z) for LCMS is also 422.0. 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),12.17(s,1H),8.07(s,2H),7.16(s,1H), 3.57(s,3H),2.19-2.10(m,1H),1.11-1.05(m,2H),1.01(td,J=2.8,5.2Hz,2H).

[0455] Example S11: 6-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 11)

[0456] Process 11

[0457]

[0458] Compound 11 can be prepared using intermediate 6b by replacing 5a with 6b and following the remaining synthetic sequence, according to the procedure described for example S5.

[0459] Example S12: 6-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 12)

[0460] Process 12

[0461]

[0462] Compound 12 can be prepared by reacting borate ester derivative d (whose synthesis is summarized in Example S11) with 3A, according to the reaction conditions used to prepare compound 7.

[0463] Example S13: 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 13)

[0464] Process 13

[0465]

[0466] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzoyl)-4-isopropylpyridazin-3(2H)-one (13a). NaOAC (180.07 mg, 2.20 mmol) was added to a solution of (6-chloro-5-isopropylpyridazin-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl) ketone (8b) (200 mg, 439.01 μmol) in HOAC (10 mL). The mixture was stirred at 120 °C for 16 h. LCMS showed the formation of a main peak of the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3) and H₂O (10 mL). The combined organic layers were washed with NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 13a. [M+1] + (C 20 H 23 The MS quality requirement value (m / z) calculated by BCl2N2O4 is 437.1, and the experimental value (m / z) of LCMS is also 437.1. 1 H NMR (400MHz, CD3OD) δ7.90(s,1H),7.68-7.70(m,1H),7.43-7.46(m,1H),3.13-3.20(m,1H),1.29-1.30(m,6H),1.20(s,12H).

[0467] 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 13). p-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzoyl)-4-isopropylpyridazine-3(2H)-one (13a) (60 mg, 137.26 μmol), 6-bromopyridazine-3(2H)-di ... -2-Methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (28.28 mg, 137.26 μmol), Pd(dppf)Cl2 (10.04 mg, 13.73 μmol), and K2CO3 (56.91 mg, 411.78 μmol) were degassed in a mixture of dioxane (4 mL) and H2O (1 mL) and purged three times with N2. The mixture was then stirred at 90 °C for 16 hours under N2 atmosphere. LCMS showed the formation of a main peak with the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150 × 30 mm × 5 μm; mobile phase: [water (0.225% FA)-ACN]) to give 13. [M+1] + (C 18 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 436.1, and the experimental value (m / z) for LCMS is 436.0. 1 HNMR (400MHz, CD3OD) δ8.14-8.17(m,2H),7.90-7.93(m,1H),3.67-3.70(m,3H),3.35(s,3H),3.13-3.21(m,1H),1.30(d,J=6.8Hz,6H).

[0468] Example 14: 6-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 14)

[0469] Process 14

[0470]

[0471] Compound 14 can be prepared by reacting 7i with 3A according to the reaction conditions used to prepare compound 7.

[0472] Example S15: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 15)

[0473] Process 15

[0474]

[0475] 6-(4-Amino-2,6-dichlorophenylmethyl)-4-isopropylpyridazin-3(2H)-one (15a). A solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (7d) (0.15 g, 421.76 μmol) in HOAC (0.6 mL), H₂O (0.6 mL), and concentrated HCl (2.4 mL) was heated to 120 °C and maintained for 32 h. LC-MS showed that the reaction was complete and the desired MS was detected. After cooling, the mixture was adjusted to pH 7 with 4 M NaOH at 0 °C, the solid was filtered and dried to give 15a (0.12 g, crude substance). [M+1] + (C 14 H 15 The MS quality requirement value (m / z) calculated by Cl2N3O is 312.1, and the LCMS experimental value (m / z) is 312.1.

[0476] 6-(4-Amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15b). PMB-Cl (120.39 mg, 768.75 μmol, 104.69 μL) and K₂CO₃ (106.25 mg, 768.75 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (15a) (200 mg, 640.63 μmol) in DMF (5 mL). The mixture was stirred at 20 °C for 16 hours. TLC showed approximately 10% retention of 15a and the formation of a new spot. The suspension was filtered through a diatomaceous earth mat and the mat cake was washed with EtOH (5 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain 15b. 1H NMR (400MHz, DMSO-d6) δ7.17(d,J=8.6Hz,2H),7.04(s,1H),6.85-6.80(m,2H),6.65(s,2H),5.63( s,2H),5.02(s,2H),4.01(s,2H),3.71(s,3H),2.97(td,J=6.8,13.5Hz,1H),1.07(d,J=7.0Hz,6H).

[0477] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15c). 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15b) (70 mg, 161.91 mg) at 0 °C. 3,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (822.29 mg, 3.24 mmol) in CH3CN (2 mL) was mixed with tert-butyl nitrite (33.39 mg, 323.82 μmol, 38.51 μL) and stirred at 0 °C for 4 h. The mixture was then stirred at 25 °C for another 12 h. TLC indicated complete depletion of reactant 15b and the formation of numerous new spots. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic phase was separated, washed with brine (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 15c (100 mg, crude product). [M+1] + (C 28 H 33 The MS quality requirement value (m / z) calculated by BCl2N2O4 is 543.2, and the experimental value (m / z) of LCMS is 543.1.

[0478] 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (15d). To 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3-yl)phenyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3-yl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (15d). A solution of 15c (20 mg, 36.81 μmol) of azinon-3(2H)-one and 6-bromo-2H-1,2,4-triazin-3,5-dione (10.60 mg, 55.22 μmol) in dioxane (2 mL) and H₂O (0.5 mL) was mixed with Pd(dppf)Cl₂ (2.69 mg, 3.68 μmol) and K₂CO₃ (15.26 mg, 110.44 μmol). The mixture was stirred at 90 °C for 12 h. LC-MS showed 15c depletion and detection of the desired MS. The reaction mixture was partitioned between 5 mL of ethyl acetate and 5 mL of H₂O. The organic phase was separated, washed with brine (3 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂) to give 15d. [M+1] + (C 25 H 23 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 528.1, and the LCMS experimental value (m / z) is 528.0.

[0479] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (15). CAN (77.82 mg, 141.94 μmol, 70.74 μL) was added to a solution of 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (15d) (15 mg, 28.39 μmol) in CH3CN (2 mL) and H2O (0.5 mL). The mixture was stirred at 25 °C for 16 h. LC-MS showed complete depletion at 15d and a main peak with the desired m / z. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 15. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O3 is 408.1, and the LCMS experimental value (m / z) is 408.0. 1H NMR (400MHz, MeOH-d4) δ8.10-8.13(m,2H),7.24-7.27(m,1H),4.36(s,2H),3.07-3.15(m,1H),1.19-1.23(m,6H).

[0480] Example S16: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 16)

[0481] Process 16

[0482]

[0483] 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (16a). p-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3(2H)-one (15c) (130 mg, 23 9.28 μmol), 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (73.94 mg, 358.93 μmol), Pd(dppf)Cl2 (17.51 ​​mg, 23.93 μmol), and K2CO3 (99.21 mg, 717.85 μmol) were degassed in a mixture of dioxane (4 mL) and H2O (1 mL) and purged three times with N2. The mixture was then stirred at 90 °C for 16 hours under N2 atmosphere. LCMS showed the formation of a peak with the desired mass. The reaction mixture was extracted with ethyl acetate (10 mL × 3) and H2O (10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol) to give 16a. [M+1] + (C 26 H 25 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 542.1, and the LCMS experimental value (m / z) is also 542.1.

[0484] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (16). CAN (80.86 mg, 147.49 μmol, 73.51 μL) was added to a solution of 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (16a) (20 mg, 36.87 μmol) in CH3CN (2 mL) and H2O (0.5 mL). The mixture was stirred at 20 °C for 16 hours. TLC and LCMS showed a main peak of the desired quality. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN)) to give 16. [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O3 is 422.1, and the LCMS experimental value (m / z) is 422.0. 1 H NMR (400MHz, CD3OD) δ8.12-8.14(m,2H),7.24-7.26(m,1H),4.35-4.37(m,2H),3.66-3.68(m,3H),3.12-3.15(m,1H),1.21(d,J=6.8Hz,6H).

[0485] Example S17: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (Compound 17)

[0486] Process 17

[0487]

[0488] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17a). Isobenzofuranyl-1,3-dione (213.50 mg, 1.44 mmol) was added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (15a) (450 mg, 1.44 mmol) in HOAC (5 mL). The mixture was stirred at 130 °C for 4 hours. LC-MS showed a peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove HOAc. This mixture was extracted with water (50 mL) and ethyl acetate (50 mL), washed with NaHCO3 (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 17a. [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 442.1, and the experimental value (m / z) for LCMS is also 442.1.

[0489] 2-(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17b). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17a) (600 mg, 1.36 mmol) and DMF-DMA (5 mL) was heated to 105 °C for 3 hours. LC-MS showed the formation of a peak with the desired mass. The reaction mixture was concentrated under reduced pressure to give 17b. [M+1] + (C 23 H 19 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 456.1, and the experimental value (m / z) for LCMS is also 456.1.

[0490] 6-(4-Amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17c). A solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17b) (600 mg, 1.31 mmol) in n-butylaniline (981.11 mg, 6.57 mmol, 1.05 mL) and MeOH (3 mL) was heated to 70 °C for 3 hours. LC-MS showed the formation of a peak with the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 17c. [M+1]+ (C 15 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O is 326.1, and the experimental value (m / z) of LCMS is also 326.1. 1 H NMR (400MHz, CD3OD) δ7.04-7.08(m,1H),6.69-6.72(m,2H),4.13(s,2H),3.70(s,3H),3.06-3.14(m,1H),1.15(d,J=6.8Hz,6H).

[0491] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17d). Tert-butyl nitrite (20.86 mg, 202.32 μmol, 24.06 μL) was added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17c) (33 mg, 101.16 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (77.06 mg, 303.48 μmol) in MeCN (1 mL). The mixture was stirred at 20 °C for 16 hours. LCMS showed the formation of a peak with the desired mass. The reaction mixture was extracted with ethyl acetate (20 mL × 3) and H₂O (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 17d. [M+1] + (C 21 H 27 The MS quality requirement value (m / z) calculated by BCl2N2O3 is 437.1, and the experimental value (m / z) of LCMS is also 437.1. 1 H NMR (400MHz, CDCl3) δ7.75 (s, 2H), 6.88 (s, 1H), 4.27 (s, 2H), 3.71 (s, 3H), 3.16 (td, J = 7.0, 13.8Hz, 1H), 1.36 (s, 12H), 1.15 (d, J = 6.8Hz, 6H).

[0492] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (17). p-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17d) (24.7 mg, 56.50 μmol) The mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (10.85 mg, 56.50 μmol), Pd(dppf)Cl2 (4.13 mg, 5.65 μmol), and K2CO3 (23.43 mg, 169.50 μmol, 3 equivalents) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged three times with N2, followed by stirring at 90 °C for 16 h under N2 atmosphere. LCMS showed the formation of a peak with the desired mass. The mixture was then added to the palladium scavenger SiT-TMT (3 g) and stirred at 20 °C for 1 h, followed by filtration and concentration under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5 u; mobile phase: [water (0.225% FA)-ACN)) to give 17. [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O3 is 422.1, and the experimental value (m / z) for LCMS is also 422.1. 1 H NMR (400MHz, MeOH-d4) δ8.10-8.14(m,2H),7.21-7.23(m,1H),4.35-4.37(m,2H),3.64(s,3H),3.13(quin,J=6.9Hz,1H),1.19(d,J=6.8Hz,6H).

[0493] Example S18: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 18)

[0494] Process 18

[0495]

[0496] Compound 18 can be prepared by reacting 17d with 3A according to the procedure described for example S17.

[0497] Example S19: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 19)

[0498] Process 19

[0499]

[0500] 6-Bromo-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19a). BSA (132.46 mg, 651.15 μmol, 160.95 μL) was added to a solution of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (50 mg, 260.46 μmol) in CH3CN (2 mL). The mixture was then stirred at 82 °C for 3 h. Iodoethane (60.93 mg, 390.69 μmol, 31.25 μL) was then added to the mixture. The mixture was further stirred at 82 °C for 16 h. LC-MS and T-LC showed depletion of the starting material and detection of the desired MS. The mixture was concentrated under vacuum. The residue was purified by preparative T-LC (dichloromethane:methanol) to give 19a. [M+1] + The calculated MS quality requirement value for (C5H6BrN3O2) is 220.0 m / z, and the experimental LCMS value is 219.9 m / z. 1 H NMR (400MHz, DMSO-d6) δ12.45 (br s, 1H), 3.79-3.89 (m, 2H), 1.19 (t, J = 7.2Hz, 3H).

[0501] 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-yl)phenyl)-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19b). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropylpyridazine (2b) (40 mg, 9 0.18 μmol) of 6-bromo-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19a) (19.84 mg, 90.18 μmol) was added to a solution of dioxane (4 mL) and H₂O (1 mL) along with K₂CO₃ (37.39 mg, 270.54 μmol) and Pd(dppf)Cl₂ (659.85 μg). The mixture was then stirred at 80 °C under N₂ for 2 hours. LCMS showed that 19a was complete. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL × 2) and H₂O (5 mL). The combined organic layers were concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane:methanol) to give 19b (20 mg, crude product). The product was used directly in the next step. For [M+1] + (C 18 H 16 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 456.0, and the experimental value (m / z) for LCMS is 456.1.

[0502] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-oxo)oxy)phenyl)-2-ethyl-1,2,4-triazin-3,5(2H,4H)-dione (19). NaOAC (17.96 mg, 218.96 μmol) was added to a solution of 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazin-3,5(2H,4H)-dione (19b) (20 mg, 43.79 μmol) in AcOH (3 mL). The mixture was then stirred at 120 °C for 16 hours. LCMS and HPLC showed that 19b was complete and the desired peak was found in the main peak. The mixture was then concentrated under vacuum. The residue was purified by preparative HPLC (column: Nano-Micro UniSil 5-100C18 ULTRA 100×250mm 5μm; mobile phase: [water (0.1% TFA)-ACN]) to obtain 19. [M+1] + The MS quality requirement value for (C18H17Cl2N5O4) is 438.1, and the LCMS experimental value is 438.0. 1H NMR (400MHz, MeOH-d4) δ 8.18 (s, 2H), 7.36 (s, 1H), 4.10 (q, J = 7.2Hz, 2H), 3.15 (d, J = 13.2Hz, 1H), 1.39 (t, J = 7.0Hz, 3H), 1.29 (d, J = 7.0Hz, 6H).

[0503] Example S20: 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (compound 20)

[0504] Process 20

[0505]

[0506] Ethyl 2-(6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)acetate (20a). BSA (1.32 g, 6.51 mmol, 1.61 mL) was added to a mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (500 mg, 2.60 mmol) in CH3CN (5 mL) at 82 °C for 3 h, followed by the addition of ethyl 2-bromoacetate (652.45 mg, 3.91 mmol, 432.08 μL). The mixture was stirred at 82 °C for 16 h. LC-MS showed complete depletion of the starting material and detection of the desired MS. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phases were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, DCM:MeOH) to obtain 20a. [M+1] + The calculated MS quality requirement value for (C7H8BrN3O4) is 278.0 m / z, and the experimental LCMS value is also 278.0 m / z. 1 H NMR (400MHz, MeOH-d4) δ4.70 (s, 2H), 4.25 (q, J = 7.2Hz, 2H), 1.29 (t, J = 7.2Hz, 3H).

[0507] 2-(6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20b). To 2-(6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20a) (80 mg, 287.71 μmol) and 3-chloro-6-(2,6 A solution of 2b (128.20 mg, 287.71 μmol) in THF (2 mL) was added to H₂O (0.5 mL) with Pd(dppf)Cl₂ (18.75 mg, 28.77 μmol) and K₃PO₄ (122.14 mg, 575.42 μmol). The mixture was stirred at 80 °C under N₂ for 16 h. LCMS showed complete depletion of 20b and detection of the desired MS. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL × 2) and H₂O (3 mL). The combined organic phases were washed with brine (5 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 20b. Regarding [M+1] + (C 20 H 18 The MS quality requirement value (m / z) calculated for Cl3N5O5 is 514.0, and the experimental value (m / z) for LCMS is also 514.0.

[0508] Ethyl 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20b). A mixture of ethyl 2-(6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20b) (48 mg, 93.25 μmol) and NaOAC (38.25 mg, 466.25 μmol) in HOAC (3 mL) was heated to 110 °C and stirred for 16 hours. LCMS showed complete depletion of 20b and detection of the desired MS. The mixture was concentrated. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to obtain 20. For [M+1] + (C 20 H 19The MS quality requirement value (m / z) calculated for Cl2N5O6 is 496.1, and the experimental value (m / z) for LCMS is also 496.1. 1 HNMR(400MHz,DMSO-d6)δ12.67(s,1H),12.21(s,1H),8.09(s,2H),7.43(s,1H),4. 83(s,2H),4.19(q,J=7.2Hz,2H),3.05(td,J=6.8,13.5Hz,1H),1.25-1.18(m,9H).

[0509] Example S21: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 21)

[0510] Process 21

[0511]

[0512] 4-Allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a). NaH (41.67 mg, 1.04 mmol, 60% purity) was added fractionally to a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (1) (200 mg, 1.04 mmol) and 3-bromoprop-1-ene (126.04 mg, 1.04 mmol) in DMSO (2.5 mL) at 25 °C. The reaction mixture was stirred for 1 hour. LC-MS showed complete depletion of the starting material and detection of the desired MS. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 21a. 1 H NMR (400MHz, MeOH-d4) δ5.85-5.90(m,1H),5.19-5.28(m,2H),4.49-4.50(d,2H).

[0513] 4-Allyl-6-bromo-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21b). Cs₂CO₃ (154.46 mg, 474.07 μmol) was added to a solution of 4-allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a) (55 mg, 237.03 μmol) in DMF (2 mL). Subsequently, 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (66.02 mg, 284.44 μmol, 25.00 μL) was added to the mixture. The mixture was stirred at 20 °C for 1 hour. TLC showed the reaction was complete, with the formation of a new spot. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, petroleum ether: ethyl acetate) to give 21b. 1 H NMR (400MHz, CDCl3) δ7.28-7.98 (m, 1H), 5.86 (ddt, J = 17.0, 10.4, 6.2, 6.2Hz, 1H), 5.24-5.47 (m, 2H), 4.53-4.66 (m, 4H).

[0514] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (21c). Under N2, 4-allyl-6-bromo-2-(2,2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (21b) (20 mg, 63.68 μmol) and 3-chloro- 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenoxy)-4-isopropylpyridazine (2b) (33.90 mg, 76.42 μmol) was added to a solution of dioxane (3 mL) and H₂O (1 mL) with K₂CO₃ (17.60 mg, 127.36 μmol) and Pd(dppf)Cl₂ (4.66 mg, 6.37 μmol). The mixture was then stirred at 90 °C under N₂ for 16 hours. LC-MS and T-LC showed that the reaction was complete and the desired MS was detected. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, dichloromethane:methanol) to give 21c (20 mg, crude product). [M+1] + (C 18 H 13 The MS quality requirement value (m / z) calculated for Cl3F3N5O3 is 510.0, and the experimental value (m / z) for LCMS is 510.1.

[0515] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (21). NaOAC (16.06 mg, 195.82 μmol) was added to a solution of 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (21c) (20 mg, 39.16 μmol) in HOAC (3 mL). The mixture was then stirred at 120 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL × 2) and H₂O (5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Kromasil 150 × 25 mm × 10 μm; mobile phase: [water (0.04% NH₃H₂O + 10 mM NH₄HCO₃)-ACN]) to give 21. [M+1] + (C 18 H 14 The MS quality requirement value (m / z) calculated by Cl2F3N5O4 is 492.0, and the experimental value (m / z) of LCMS is also 492.0. 1 H NMR (400MHz, MeOH-d4) δ8.17 (s, 2H), 7.38 (d, J = 1Hz, 1H), 4.80 (q, J = 8.6Hz, 2H), 3.10-3.25 (m, 1H), 1.31 (d, J = 7.0Hz, 6H).

[0516] Example S22: 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazinyl-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazinyl-2(3H)-yl)acetonitrile (compound 22)

[0517] Process 22

[0518]

[0519] 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetamide (22a). A mixture of 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (27 mg, 54.40 μmol) in NH3·H2O (3 mL) was stirred at 20 °C under N2 for 1 h. LC-MS showed complete depletion and detection of the desired MS. The mixture was concentrated to give 22a. The product was used directly in the next step. [M+1] + (C 18 H 16 The MS quality requirement value (m / z) calculated for Cl2N6O5 is 467.1, and the experimental value (m / z) for LCMS is also 467.1.

[0520] 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetonitrile (22). SOCl2 (31.83 mg, 267.52 μmol, 19.41 μL) was added to anhydrous D at 25 °C with stirring. The solution in MF (2 mL) was added dropwise to a solution of 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetamide (22a) (25 mg, 53.50 μmol) in anhydrous DMF (1 mL). The mixture was heated to 120 °C for 3 hours. LC-MS showed complete depletion of 22a and detection of the desired MS. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL × 2) and H₂O (3 mL). The combined organic phases were washed with brine (5 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (conditions; column: Ultimate C18 150×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]) to obtain 22. [M+1] + (C 18 H 14 The MS quality requirement value (m / z) calculated for Cl2N6O4 is 449.0, and the experimental value (m / z) for LCMS is also 449.0. 1H NMR (400MHz, CDCl3) δ9.93 (br s, 1H), 8.08 (s, 2H), 7.18 (br s, 1H), 5.00 (s, 2H), 3.27 (br s, 1H), 1.33 (br d, J = 6.4Hz, 6H).

[0521] Example S23: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 23)

[0522] Process 23

[0523]

[0524] 4-Allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23a). Cs₂CO₃ (28.08 mg, 86.19 μmol) was added to a solution of 4-allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a) (10 mg, 43.10 μmol) in DMF (1 mL). Subsequently, 2,2-difluoroethyl trifluoromethanesulfonic acid (11.07 mg, 51.72 μmol, 25.00 μL) was added to the mixture. The mixture was stirred at 20 °C for 1 hour. TLC showed the reaction was complete and a new spot formed. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 23a. 1 H NMR (400MHz, DMSO-d6) δ12.45 (br s, 1H), 3.79-3.89 (m, 2H), 1.19 (t, J = 7.2Hz, 3H).

[0525] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23b). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-isopropylpyridazine (2b) (50 mg, 112.72 μg) Pd(dppf)Cl2 (8.25 mg, 11.27 μmol) and K2CO3 (31.16 mg, 225.45 μmol) were added to a solution of 4-allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23a) (36.71 mg, 124.00 μmol) in dioxane (3 mL) and H2O (1 mL). The mixture was then stirred at 90 °C under N2 for 16 hours. LCMS and TLC showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane:methanol) to give 23b (20 mg, crude product). [M+1] + (C 18 H 14 C l3 The MS quality requirement value (m / z) calculated for F2N5O3 is 492.0, and the experimental value (m / z) for LCMS is 492.1.

[0526] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (23). NaOAC (16.65 mg, 202.97 μmol) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-(2,2-trifluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (23b) (20 mg, 40.59 μmol) in HOAC (2 mL). The mixture was then stirred at 120 °C for 16 hours. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (5 mL × 2) and H₂O (5 mL). The organic layer was dried under vacuum. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.1% TFA)-ACN]) to obtain 23. [M+1] + (C 18 H 15The MS quality requirement value (m / z) calculated by Cl2F2N5O4 is 474.0, and the experimental value (m / z) of LCMS is also 474.0. 1 H NMR(400MHz,MeOH-d4)δ8.17(s,2H),7.36(s,1H),6.05-6.46(m,1H),4.87(s,13H) ,4.43(td,J=13.6,4.0Hz,2H), 3.17(dt,J=13.6,7.0Hz,1H), 1.29(d,J=6.8Hz,6H).

[0527] Example S24: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 24)

[0528] Process 24

[0529]

[0530] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (24). Under N2, 4-allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazin-3,5(2H,4H)-dione (23a) (40 mg, 135.10 μmol) and 6-(2, 6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1f) (59.33 mg, 135.10 μmol) was added to a solution of dioxane (3 mL) and H₂O (1 mL) with K₂CO₃ (37.34 mg, 270.21 μmol) and Pd(dppf)Cl₂ (9.89 mg, 13.51 μmol). The mixture was then stirred at 90 °C under N₂ for 16 hours. LCMS and TLC showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, dichloromethane:methanol) to give 24. [M+1] + (C 19 H 17 The MS quality requirement value (m / z) calculated by Cl2F2N5O4 is 488.0, and the LCMS experimental value (m / z) is also 488.0. 1HNMR(400MHz,DMSO-d6)δ12.62(br s,1H),8.13(s,2H),7.46(s,1H),6.24-6.60(m,1H),4.34-4.49(m,2H),3.39(s,3H),3.08-3.12(m,1H),1.21(d,J=7.0Hz,6H).

[0531] Example S25: 6-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (Compound 25)

[0532] Process 25

[0533]

[0534] 6-(4-Amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (25a). Select F (593.68 mg, 1.68 mmol) was added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (500 mg, 1.52 mmol) in MeCN (10 mL). The mixture was stirred at 15 °C for 3 h. TLC and LCMS showed complete depletion of 1e and detection of the desired MS. The reaction mixture was quenched by adding 10 mL of H₂O. The reaction mixture was partitioned between ethyl acetate (20 mL) and H₂O (30 mL). The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 25a. [M+1] + (C 14 H 14 C l2 The MS quality requirement value (m / z) calculated for FN3O2 is 346.0, and the experimental value (m / z) for LCMS is 346.2. 1 H NMR (400MHz, CDCl3) δ7.02 (d, J = 0.6 Hz, 1H), 6.78-6.85 (m, 1H), 3.88 (s, 1H), 3.52-3.57 (m, 3H), 3.24 (dt, J = 14.2, 7.0Hz, 1H), 1.26 (d, J = 6.8Hz, 6H).

[0535] (3,5-Dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl-1-boronic acid (25b). Tert-butyl nitrite (89.36 mg, 866.59 μmol, 103.07 μL) was added to a mixture of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (25a) (150 mg, 433.30 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxacyclopentaborane) (2.20 g, 8.67 mmol) in CH3CN (8 mL) at 15 °C. The mixture was then stirred at 15 °C for 16 hours. TLC, LCMS, and HPLC showed complete depletion of 25a and detection of the desired MS. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]) to give 25b. [M+1] + (C 14 H 14 The MS quality requirement value (m / z) calculated by BCl2FN2O4 is 375.0, and the experimental value (m / z) of LCMS is 375.1. 1 H NMR (400MHz, CDCl3) δ7.87(s,1H),7.07(s,1H),3.51(s,3H),3.23-3.29(m,1H),1.38(s,3H),1.27-1.29(m,6H).

[0536] 6-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (25). To (3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)boronic acid (25b)(10m) The mixture of 25b (26.67 μmol g) and 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (7.68 mg, 40.00 μmol) in THF (2 mL) and H2O (0.5 mL) was supplemented with di-tert-butyl(cyclopentyl)phosphine, palladium dichlorophosphate, iron (1.74 mg, 2.67 μmol), and K3PO4 (11.32 mg, 53.34 μmol). The mixture was then degassed and purged three times with N2, and stirred at 90 °C under an N2 atmosphere for 16 hours. LC-MS and HPLC showed complete depletion of 25b and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5 u; mobile phase: [water (0.1% TFA)-ACN]) to give 25b. [M+1] + (C 17 H 14 The MS quality requirement value (m / z) calculated by Cl2FN5O4 is 442.0, and the LCMS experimental value (m / z) is also 442.0. 1 H NMR (400MHz, MeOH-d4) δ7.72 (d, J = 6.8 Hz, 1H), 7.38 (s, 1H), 3.51 (s, 3H), 3.20 (dt, J = 13.6, 6.8 Hz, 1H), 1.28 (d, J = 6.8 Hz, 6H).

[0537] Example S26: 6-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 26)

[0538] Process 26

[0539]

[0540] 5-Bromo-2-(bromomethyl)-1,3-xylene (26a). PPh3 (1.83 g, 6.97 mmol) was added to a solution of (4-bromo-2,6-dimethylphenyl)methanol (1 g, 4.65 mmol) in DCM (30 mL) under N2. The mixture was then cooled to 0–5 °C and CBr4 (2.31 g, 6.97 mmol) was added fractionally to the mixture. The mixture was then stirred at 15 °C under N2 for 0.5 h. TLC showed complete depletion of the starting material and the formation of a new spot. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 26a. 1 H NMR (400MHz, CDCl3) δ7.21 (s, 2H), 4.50 (s, 2H), 2.39 (s, 6H).

[0541] 2-(4-Bromo-2,6-dimethylphenyl)acetonitrile (26b). NaCN (244.35 mg, 4.99 mmol) was added to a solution of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene (26a) (1.26 g, 4.53 mmol) in DMF (30 mL) at 15 °C. The mixture was then stirred at 15 °C for 16 h. TLC showed complete depletion of 26a and the formation of a new spot. The mixture was poured into an aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 26b. 1 H NMR (400MHz, MeOH-d4) δ7.28(s,2H),3.79(s,2H),2.38(s,6H).

[0542] 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (26c). t-BuOK (1M, 7.14 mL) was added dropwise to a solution of 2-(4-bromophenyl-2,6-dimethylphenyl)acetonitrile (26b) (800 mg, 3.57 mmol) and 3,6-dichloro-4-isopropylpyridazine (682.05 mg, 3.57 mmol) in THF (10 mL). The resulting mixture was heated to 60 °C for 1 hour. TLC and LCMS showed complete depletion of 26b and detection of the desired MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 26c. Regarding [M+1]+ (C 17 H 17 The MS quality requirement value (m / z) calculated by BrClN3 is 378.0, and the experimental value (m / z) of LCMS is 378.2. 1 H NMR(400MHz,MeOH-d4)δ7.34(s,3H),7.21(s,1H),6.28(s,1H),3.01(dt,J=13 .4, 6.8Hz, 1H), 2.89 (dt, J = 13.8, 6.8Hz, 1H), 2.27 (s, 6H), 1.30-1.27 (m, 6H).

[0543] 6-(4-Bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (26d). A solution of 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (26c) (1 g, 2.78 mmol) in AcOH (10 mL), H₂O (10 mL), and HCl (40 mL) was heated to 120 °C for 48 hours. LC-MS showed complete consumption of 26c and detection of the desired MS. The mixture was adjusted to pH 7 with 3M NaOH at 15 °C, and the batch solids were collected by filtration and dried to give 26d. [M+1] + (C 16 H 19 The MS quality requirement value (m / z) calculated by BrN2O is 335.1, and the experimental value (m / z) of LCMS is 335.2. 1 HNMR (400MHz, DMSO-d6) δ12.56(s,1H),7.24(s,2H),7.11(s,1H),3.90(s,2H),2.97(quin,J=6.8Hz,1H),2.21(s,6H),1.11(d,J=6.8Hz,6H).

[0544] 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropylpyridazin-3(2H)-one (26e). To 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (26d) (50 mg, 149.15 μmol) and 4,4,5,5-tetramethyl- A solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,3,2-dioxane (113.62 mg, 447.44 μmol) in dioxane (3 mL) was supplemented with KOAc (73.19 mg, 745.74 μmol) and Pd(dppf)Cl2 (10.91 mg, 14.91 μmol). The mixture was degassed and purged three times with N2, and stirred at 90 °C for 16 h. TLC and LCMS showed complete depletion and detection of the desired MS at 26 d. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate) to give 26e. [M+1] + (C 22 H 31 The MS quality requirement value (m / z) calculated for BN2O3 is 383.2, and the experimental value (m / z) for LCMS is 383.4. 1 H NMR (400MHz, MeOH-d4) δ7.42 (s, 2H), 6.98 (s, 1H), 4.05 (s, 2H), 3.06 (dt, J = 13.6, 6.8Hz, 1H), 2.29 (s, 6H), 1.34 (s, 12H), 1.14 (d, J = 6.8Hz, 6H).

[0545] 6-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (26). To 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)-4-isopropylpyridazin-3(2H)-one (26e)(32) Pd(dppf)Cl2 (5.46 mg, 8.37 μmol) and K3PO4 (35.53 mg, 167.41 μmol) were added to a mixture of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (25.86 mg, 125.55 μmol) in THF (4 mL) and H2O (1 mL). The mixture was then degassed and purged three times with N2. The mixture was then stirred at 90 °C for 16 hours under N2 atmosphere. HPLC and LCMS showed complete depletion of 26e and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 26. For [M+1] + (C 20 H 23 The MS quality requirement value (m / z) calculated for N5O3 is 382.2, and the experimental value (m / z) for LCMS is also 382.2. 1 HNMR (400MHz, MeOH-d4) δ7.68 (s, 2H), 7.04 (s, 1H), 4.07 (s, 2H), 3.65 (s, 3H), 3.07 (dt, J = 13.8, 6.6Hz, 1H), 2.33 (s, 6H), 1.15 (d, J = 6.8Hz, 6H).

[0546] Example S27: 6-(3,5-dichloro-4-((6-oxo-5-(pent-3-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 27)

[0547] Process 27

[0548]

[0549] 3,6-Dichloro-4-(pentan-3-yl)pyridazine (27a). AgNO3 (1.14 g, 6.71 mmol) and TFA (2.30 g, 20.14 mmol, 1.49 mL) were added in a single addition to a mixture of 3,6-dichloropyridazine (1 g, 6.71 mmol) and 2-ethylbutyric acid (779.70 mg, 6.71 mmol, 845.66 μL) in H2O (20 mL) at 50 °C. Subsequently, a solution of (NH4)2S2O8 (4.60 g, 20.14 mmol, 4.38 mL) in H2O (10 mL) was added to the mixture, and the mixture was stirred at 70 °C for 30 min. LC-MS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (2 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 27a. 1 H NMR (400MHz, CDCl3) δ7.23 (s, 1H), 2.89-2.98 (m, 1H), 1.67-1.80 (m, 2H), 1.55-1.64 (m, 2H), 0.82 (t, J = 7.4Hz, 6H).

[0550] 3,5-Dichloro-4-((6-chloro-5-(pent-3-yl)pyridazin-3-yl)oxy)aniline (27b). K₂CO₃ (1.34 g, 9.68 mmol) and CuI (276.40 mg, 1.45 mmol) were added to a solution of 3,6-dichloro-4-(pent-3-yl)pyridazine (27a) (530 mg, 2.42 mmol) and 4-amino-2,6-dichlorophenol (516.72 mg, 2.90 mmol) in DMSO (20 mL). The reaction mixture was degassed and purged three times with N₂, and then stirred at 90 °C under a N₂ atmosphere for 16 h. TLC and LCMS showed complete depletion of 27a and detection of the desired MS. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (50 mL × 2) and H₂O (20 mL). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 27b. [M+1] + (C 15 H 16 The MS quality requirement value calculated by Cl3N3O is 360.0 m / z, and the LCMS experimental value is 360.1 m / z. 1H NMR (400MHz, MeOH-d4) δ7.40 (s, 1H), 6.74 (s, 2H), 4.86 (s, 4H), 2.96-3.05 (m, 1H), 1.65-1.88 (m, 4H), 0.87 (t, J = 7.4Hz, 6H).

[0551] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(pent-3-yl)pyridazine (27c). NaNO₂ (132.00 mg, 1.91 mmol) was added to a solution of 3,5-dichloro-4-((6-chloro-5-(pent-3-yl)pyridazine-3-yl)oxy)aniline (27b) (575 mg, 1.59 mmol) in HCl (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Subsequently, a solution of KI (529.31 mg, 3.19 mmol) in H₂O (5 mL) was added to the reaction mixture, and the mixture was stirred again at 15 °C for 1.5 h. TLC and LCMS showed complete depletion of 27b and detection of the desired mass. The mixture was extracted with ethyl acetate (100 mL × 2) and H₂O (50 mL). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 27c. [M+1] + (C 15 H 14 The MS quality requirement value calculated by Cl3IN2O is 470.9 m / z, and the LCMS experimental value is 470.8 m / z. 1 H NMR (400MHz, CDCl3) δ7.73 (s, 2H), 7.13 (s, 1H), 2.96-3.05 (m, 1H), 1.61-1.87 (m, 4H), 0.89 (t, J = 7.46Hz, 6H).

[0552] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-(pent-3-yl)pyridazine (27d). KOAC (520.32 mg, 5.30 mmol) and Pd(dppf)Cl2 (77.59 mg, 106.03 μmol) were added to a solution of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(pent-3-yl)pyridazine (27c) (500 mg, 1.06 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (807.78 mg, 3.18 mmol) in dioxane (15 ml). The mixture was degassed and purged three times with N2, and stirred at 90°C for 16 hours. TLC and LCMS showed complete depletion of 27d and the desired mass was detected. The mixture was extracted with ethyl acetate (50 mL × 2) and H2O (20 mL). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 27d. [M+1] + (C 21 H 26 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 471.1, and the experimental value (m / z) of LCMS is also 471.1. 1 H NMR (400MHz, CDCl3) δ7.81 (s, 2H), 7.13 (s, 1H), 2.94-3.04 (m, 1H), 1.62-1.86 (m, 4H), 1.35 (s, 11H), 0.89 (t, J = 7.4Hz, 6H).

[0553] 6-(3,5-dichloro-4-((6-chloro-5-(pent-3-yl)pyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (27e). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-(pent-3-yl)pyridazine (27d) (150 mg, 318.06 μmol) and 6-bromo A mixture of 2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (98.28 mg, 477.09 μmol) in THF (4 mL) and H₂O (1 mL) was added to Pd(dppf)Cl₂ (20.73 mg, 31.81 μmol), and K₃PO₄ (135.03 mg, 636.12 μmol) was degassed and purged three times with N₂. The mixture was then stirred at 90 °C for 2 h under N₂ atmosphere. TLC and LCMS showed complete depletion of 27d and detection of the desired MS. The reaction mixture was dissolved in water and the pH was adjusted to 4 with HCl (1 M, 1 mL). The mixture was then partitioned with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 27e. Regarding [M+1] + (C 19 H 18 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 470.0, and the experimental value (m / z) for LCMS is 470.1. 1 H NMR (400MHz, MeOH-d4) δ8.25 (s, 2H), 7.61 (s, 1H), 4.10 (q, J = 7.2Hz, 1H), 3.69 (s, 3H), 1.71-1.90 (m, 5H), 0.90 (t, J = 7.4Hz, 7H).

[0554] 6-(3,5-dichloro-4-((6-oxo-5-(pent-3-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (27e) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-(pent-3-yl)pyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (27e) (80 mg, 169.95 μmol) in AcOH (5 mL) at 15 °C. The mixture was then stirred at 120 °C for 16 h. LC-MS and HPLC showed complete depletion of 27e and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to obtain 27. [M+1] + (C 19 H 19 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 452.1, and the LCMS experimental value (m / z) is also 452.1. 1 HNMR(400MHz,DMSO-d6)δ12.44(br s,1H),12.19(s,1H),8.09(s,2H),7.43(s,1H),3.57(s,3H),2.78(quin,J=7.0Hz,1H),1.59-1.68(m,4H),0.79(t,J=7.4Hz,6H).

[0555] Example S28: 6-(3,5-dichloro-4-((5-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 28)

[0556] Process 28

[0557]

[0558] 3,6-Dichloro-4-ethylpyridazine (28a). TFA (2.30 g, 20.14 mmol, 1.49 mL), AgNO3 (1.14 g, 6.71 mmol), and (NH4)2S2O8 (4.60 g, 20.14 mmol, 4.38 mL) were added in a single batch to a mixture of 3,6-dichloropyridazine (1 g, 6.71 mmol) and propionic acid (497.24 mg, 6.71 mmol, 500.75 μL) in H2O (30 mL) at 50 °C. The mixture was stirred at 70 °C for 30 min. LCMS showed that the 3,6-dichloropyridazine was complete. The residue was poured into NaHCO3 (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (15 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to obtain 28a. [M+1] + The MS quality requirement value (C6H6Cl2N2) is 177.0 m / z, and the LCMS experimental value is also 177.0 m / z. 1 H NMR (400MHz, CDCl3) δ 8.12-8.16 (m, 2H), 7.90-7.92 (m, 1H), 3.12-3.21 (m, 1H), 1.29 (d, J = 7.0Hz, 6H).

[0559] 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-ethylpyridazine (28b). A solution of 3,6-dichloro-4-ethylpyridazine (28a) (340 mg, 1.92 mmol) and 4-bromo-2,6-dichlorophenol (511.04 mg, 2.11 mmol) in Py (5 mL) was stirred in a microwave tube at 130 °C for 16 hours. LCMS and TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) showed complete depletion of 28a and detection of the desired MS. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 28b (200 mg, crude product). For [M+1] + (C 12 The MS quality requirement value (m / z) calculated by H8BrCl3N2O is 380.9, and the LCMS experimental value (m / z) is also 380.9. 1H NMR (400MHz, CDCl3) δ7.44(s,4H),7.15(s,1H),7.10(s,1H),2.72-2.80(m,3H),2.66-2.71(m,2H),1.22-1.31(m,7H),1.17(brt,J=7.58Hz,3H).

[0560] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-ethylpyridazine (28c). Pd(dppf)Cl2 (28.70 mg, 39.22 μmol) and KOAc (192.45 mg, 1.96 mmol) were added to a solution of 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-ethylpyridazine (28b) (150 mg, 392.19 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (298.78 mg, 1.18 mmol) in dioxane (6 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. TLC (petroleum ether:ethyl acetate) indicated complete depletion of 28b. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with ethyl acetate (15 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 28c. [M+1] + (C 18 H 20 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 429.1, and the experimental value (m / z) of LCMS is also 429.1.

[0561] 6-(3,5-dichloro-4-((6-chloro-5-ethylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (28d). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-ethylpyridazine (28c) (160 mg, 372.50) A solution of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (115.10 mg, 558.75 μmol) in THF (4 mL) was added to H2O (1 mL) along with Pd(dppf)Cl2 (24.28 mg, 37.25 μmol) and K3PO4 (158.14 mg, 745.00 μmol). The mixture was stirred at 80 °C for 16 h. LC-MS showed complete consumption of 28d and detection of the desired MS. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.2% FA)-ACN]) to give 28d. For [M+1] + (C 16 H 12 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 428.0, and the experimental value (m / z) for LCMS is also 428.0. 1 H NMR (400MHz, MeOH-d4) δ8.25 (s, 2H), 7.59 (s, 1H), 3.69 (s, 3H), 2.83-2.90 (m, 2H), 1.36 (t, J = 7.6Hz, 3H).

[0562] 6-(3,5-dichloro-4-((5-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (28). NaOAC (74.64 mg, 909.82 μmol) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (28d) (78 mg, 181.96 μmol) in HOAC (3 mL). The mixture was stirred at 120 °C for 16 h. LCMS showed complete depletion and detection of the desired mass after 28d. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Luna C18100 × 30 5u; mobile phase: [water (0.225% FA)-ACN]) to obtain 28. [M+1] + (C 16 H 13The MS quality requirement value (m / z) calculated for Cl2N5O4 is 410.0, and the experimental value (m / z) for LCMS is also 410.0. 1 HNMR (400MHz, DMSO-d6) δ8.32 (br s, 1H), 8.14 (s, 2H), 7.46 (s, 1H), 3.54 (s, 3H), 1.17 (t, J = 7.4Hz, 3H).

[0563] Example S29: 6-(3,5-dichloro-4-((5-(1-hydroxypropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (29)

[0564] Process 29a

[0565]

[0566] 2-Methyl-6-(trimethylstanyl)-1,2,4-triazine-3,5(2H,4H)-dione (29a). Trimethyl(trimethylstanyl)stanane (1.72 g, 5.24 mmol, 1.09 mL) and Pd(PPh3)4 (504.86 mg, 436.90 μmol) were added to a solution of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (900 mg, 4.37 mmol) in toluene (15 mL). The mixture was stirred at 110 °C for 16 hours under a N2 atmosphere. TLC indicated that the trace of the starting material was maintained and a new spot was formed. The reaction mixture was concentrated under vacuum and subsequently diluted with ethyl acetate (15 mL) and washed with KF aqueous solution (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to obtain 29a. [M+1] + (C7H 13 The MS quality requirement value (m / z) calculated for N3O2Sn is 292.0, and the experimental value (m / z) for LCMS is 292.2.

[0567] Process 29b

[0568]

[0569] 2-(3,6-Dichloropyridazine-4-yl)prop-1-ol (29b). TFA (1.88 g, 16.48 mmol, 1.22 mL) and AgNO3 (3.07 g, 18.07 mmol) were added to a mixture of 3,6-dichloropyridazine (2 g, 13.42 mmol) and 2-methylpropane-1,3-diol (2.65 g, 29.40 mmol, 2.62 mL) in H2O (10 mL) at 80 °C. Subsequently, (NH4)2S2O8 (6.72 g, 10.93 mmol) was added to the mixture in a single addition at 80 °C. The mixture was stirred at 80 °C for 30 min. TLC showed complete depletion of the starting material. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to obtain 29b. 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 3.84-3.91 (m, 2H), 3.33-3.42 (m, 1H), 1.35 (d, J = 7.0Hz, 3H).

[0570] 4-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3,6-dichloropyridazine (29c). Imidazole (276.18 mg, 4.06 mmol) was added to a solution of 2-(3,6-dichloropyridazine-4-yl)prop-1-ol (29b) (700 mg, 3.38 mmol) and tert-butylchloro-dimethylsilane (509.55 mg, 3.38 mmol, 414.26 μL) in DMF (15 mL). The mixture was stirred at 25 °C under a nitrogen atmosphere for 1 hour. TLC indicated complete depletion of 29b. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 29c. The product was used directly in the next step without further purification. For [M+1] + (C 13 H 22 The MS quality requirement value calculated by Cl2N2OSi is 321.1 m / z, and the experimental value of LCMS is 321.2 m / z. 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 3.73-3.81 (m, 2H), 3.29-3.39 (m, 1H), 1.32 (d, J = 7.2Hz, 3H), 0.84 (s, 9H), 0.01 (s, 3H), -0.04 (s, 3H).

[0571] 4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (29d). 4-amine-2,6-dichlorophenol (225.85 mg, 933.66 μmol), K₂CO₃ (387.12 mg, 2.80 mmol), and CuI (106.69 mg, 560.19 μmol) were added to a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3,6-dichloropyridazine (29c) (300 mg, 933.66 μmol) in DMSO (10 mL). The mixture was stirred at 90 °C under a N₂ atmosphere for 6 hours. LCMS indicated complete depletion of 29c and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad, and the pad cake was washed with ethyl acetate (50 mL). The reaction mixture was quenched at 20°C by adding H₂O (30 mL), followed by dilution with ethyl acetate (50 mL) and extraction with ethyl acetate (50 mL × 5). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]) to give 29 d. [M+1] + (C 19 H 26 The MS quality requirement value (m / z) calculated for Cl3N3O2Si is 462.1, and the experimental value (m / z) for LCMS is also 462.1. 1 H NMR (400MHz, MeOH-d4) δ7.44 (s, 1H), 6.73 (s, 2H), 3.83-3.92 (m, 2H), 3.37-3.45 (m, 1H), 1.34 (d, J = 7.0Hz, 3H), 0.83 (s, 9H), -0.01 (d, J = 7.2Hz, 6H).

[0572] 4-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (29e). Tert-butyl nitrite (22.28 mg, 216.04 μmol) and KI (35.86 mg, 216.04 μmol) were added to a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)prop-2-phenyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (29d) (50 mg, 108.02 μmol) in ACN (1 mL). The reaction mixture was then degassed and purged three times with N2. The mixture was stirred at 20 °C for 2 hours. TLC indicated complete depletion of 29d. The reaction mixture was concentrated under reduced pressure. The residue was diluted in H2O (5 mL) and ethyl acetate (10 mL). The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate) to give 29e. [M+1] + (C 19 H 24 The MS quality requirement value (m / z) calculated by Cl3IN2O2Si is 573.0, and the experimental value (m / z) of LCMS is also 573.0.

[0573] 6-(4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (29f). 2-methyl-6-(tributyltinyl)oxy)propyl-2-yl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (29e) (27 mg, 47.06 μmol) and Pd(dppf)Cl2.CH2Cl2 (3.84 mg, 4.71 μmol) were added to a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (29e) (27 mg, 47.06 μmol) in dioxane (1 mL). The mixture was then degassed and purged three times with N2, followed by stirring at 110°C under N2 atmosphere for 16 hours. LCMS indicated 40% retention of 29e and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with ethyl acetate (5 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 29f. [M+1] + (C 23 H 28The MS quality requirement value (m / z) calculated for Cl3N5O4Si is 572.1, and the experimental value (m / z) for LCMS is also 572.1.

[0574] 2-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (29 g). NaOAc (13.60 mg, 165.81 μmol) was added to a solution of 6-(4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (29 f) (19 mg, 33.16 μmol) in HOAc (1 mL). The mixture was stirred at 120 °C for 16 h. LC-MS showed complete depletion of 29 f and a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH, yielding 29 g (30 mg, crude product). The product was used in the next step without further purification. [M+1] + (C 19 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 482.1, and the experimental value (m / z) for LCMS is also 482.1.

[0575] 6-(3,5-dichloro-4-((5-(1-hydroxypropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (29 g). LiOH·H₂O (1 M, 3 mL) was added to a solution of 2-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)acetate (29 g) (30 mg, 62.21 μmol) in THF (1 mL). The mixture was stirred at 20 °C for 16 hours. LC-MS showed complete depletion of 29 g and detection of the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100×30mm 5μm; mobile phase: [water (0.225% FA)-ACN]) to obtain 29. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 440.0, and the experimental value (m / z) for LCMS is also 440.0. 1H NMR (400MHz, MeOH-d4) δ 8.18 (s, 2H), 7.39 (s, 1H), 3.78-3.86 (m, 1H), 3.64-3.74 (m, 4H), 3.21-3.27 (m, 1H), 1.30 (d, J = 7.0Hz, 3H).

[0576] Example S30: 6-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridyl-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 30)

[0577] Process 30

[0578]

[0579] 1-(3,6-Dichloropyridazin-4-yl)prop-1-ol (30a). Pentyl-1-yn-3-ol (334.34 mg, 3.97 mmol, 342.91 μL) was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (300 mg, 1.99 mmol) in toluene (5 mL). The mixture was stirred in a sealed tube at 110 °C for 16 h. TLC showed complete depletion of the starting material and the formation of numerous new spots. LCMS showed detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to give 30a. [M+1] + The MS quality requirement value for (C7H8Cl2N2O) is 207.0 m / z, and the LCMS experimental value is 207.1 m / z. 1 H NMR (400MHz, CDCl3) δppm 7.77(s,1H),4.91-4.96(m,1H),2.31(d,J=4.0Hz,1H),1.95(dqd,J=14.4,7.4,7.4,7 .4, 3.4Hz, 1H), 1.67 (dquin, J = 14.6, 7.4, 7.4, 7.4, 7.4Hz, 1H), 1.06 (t, J = 7.4Hz, 3H).

[0580] 3,6-Dichloro-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine (30b). TsOH (15.39 mg, 89.35 μmol) was added to a solution of 1-(3,6-dichloropyridazine-4-yl)prop-1-ol (30a) (370 mg, 1.79 mmol) and DHP (751.56 mg, 8.93 mmol, 816.91 μL) in DCM (8 mL). The mixture was stirred at 20 °C for 1 h. LC-MS and TLC showed complete depletion of 30a and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to give 30b. [M+1] + (C 12 H 16 The MS quality requirement value (m / z) calculated by Cl2N2O2 is 291.1, and the experimental value (m / z) of LCMS is also 291.1. 1 H NMR (400MHz, CDCl3) δppm 7.71(s,1H),7.56(s,1H),4.97(dt,J=7.8,4.0Hz,3H),4.78(dd,J=7.0,4.0Hz,1H),4.68-4.71(m,1H),4.58(br s, 6H), 4.40 (t, J = 3.4Hz, 1H), 1.02-1.09 (m, 4H), 0.95 (t, J = 7.4Hz, 3H).

[0581] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazin-3-yl)oxy)aniline (30c). A solution of 3,6-dichloro-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine (30b) (500 mg, 1.72 mmol) and 4-amino-2,6-dichlorophenol (305.69 mg, 1.72 mmol) in DMSO (15 mL) was degassed with K₂CO₃ (949.33 mg, 6.87 mmol) and CuI (196.22 mg, 1.03 mmol), purged three times with N₂, and then stirred at 90 °C under an N₂ atmosphere for 16 h. TLC showed complete depletion of 30b and the formation of a new spot. LCMS showed detection of the desired mass. The mixture was diluted in ethyl acetate (5 mL) and the filtrate was extracted with ethyl acetate (10 mL × 3) and H₂O (5 mL). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate) to give 30c. [M+1] + (C 18 H 20The MS quality requirement value (m / z) calculated for Cl3N3O3 is 432.1, and the experimental value (m / z) for LCMS is 432.0. 1 H NMR (400MHz, CDCl3) δppm 7.48 (s, 1H), 7.29 (s, 1H), 6.69 (s, 2H), 4.97 (dd, J = 7.2, 3.8Hz, 1H), 4.76-4.83 (m, 1H), 4.58 (br s,1H),4.46(brs,1H),3.98(br d,J=7.6Hz,1H),3.79(br d,J=3.6Hz,2H),3.33-3.63(m,3H),1.06(brt,J=7.2Hz,2H),0.96(br t,J=7.2Hz,2H).

[0582] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-(((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine (30d). KI (1) was added to a solution of 3,5-dichloro-4-((6-chloro-5-(1-(((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine-3-yl)oxy)aniline (30c) (170 mg, 392.86 μmol) in ACN (3 mL). 30.43 mg (785.71 μmol) and tert-butyl nitrite (202.56 mg (1.96 mmol, 233.63 μL) were added. The mixture was stirred at 20 °C for 2 hours. TLC showed complete depletion of 30d and the formation of a new spot. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to give 30d. [M+1] + (C 18 H 18 The MS quality requirement value (m / z) calculated by Cl3IN2O3 is 542.9, and the experimental value (m / z) of LCMS is also 542.9. 1 H NMR (400MHz, CDCl3) δ7.73(s,2H),7.57(s,1H),4.94(dt,J=7.6,3.8Hz,1H),2.19(d,J=4.0Hz,1H),2.03-1.94(m,1H),1 .85(dt,J=14.6,7.2Hz,1H),1.70(dquin,J=14.6,7.34,7.4,7.4,7.4Hz,1H),1.27(t,J=7.2Hz,1H),1.12-1.05(m,3H).

[0583] 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (30e). To 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazine-3-yl)phenyl ... A solution of 30d (70 mg, 128.77 μmol) and 2-methyl-6-(trimethyltinyl)-1,2,4-triazine-3,5(2H,4H)-dione (29a) (41.06 mg, 141.65 μmol) in dioxane (4 mL) was supplemented with Pd(dppf)Cl2.CH2Cl2 (10.52 mg, 12.88 μmol). The mixture was degassed and purged three times with N2, and stirred at 110 °C for 16 h. TLC and LCMS showed a retention of approximately 2 / 3 of 30d, and the desired MS was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 30e. Regarding [M+1] + (C 22 H 22 The MS quality requirement value (m / z) calculated for Cl3N5O5 is 542.1, and the experimental value (m / z) for LCMS is 452.1. 1 HNMR(400MHz, CDCl3)δ8.20(s,1H),7.58(s,1H),7.40(s,1H),7.40-7.41(m,1H) ,5.00(dd,J=7.4,3.6Hz,1H),4.77-4.85(m,1H),4.48-4.52(m,1H),3.94-4.02( m,1H),3.76(s,2H),3.56-3.67(m,1H),3.36-3.43(m,1H),1.51-2.01(m,6H),1. 19-1.32(m,1H),1.19-1.32(m,1H),1.08(t,J=7.4Hz,1H),0.98(t,J=7.4Hz,1H).

[0584] 1-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (30f). NaOAc (11.33 mg, 138.17 μmol) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (30e) (15 mg, 27.63 μmol) in HOAc (2 mL). The mixture was stirred at 120 °C for 16 h. LC-MS showed complete depletion of 30e and detection of the desired MS. The reaction mixture was concentrated under reduced pressure to give 30f (20mg, crude substance). For [M+1] + (C 19 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 482.1, and the LCMS experimental value (m / z) is 482.0.

[0585] 6-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (30). LiOH·H2O (1M, 82.94 μL) was added to a solution of 1-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)acetate (30f) (20 mg, 41.47 μmol) in MeOH (3 mL) and H2O (0.5 mL). The mixture was stirred at 25 °C for 1 hour. HPLC and LCMS showed complete depletion of 30f and detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-ACN]) to give 30. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 440.0, and the experimental value (m / z) for LCMS is 440.1. 1H NMR(400MHz,MeOH-d4)δ8.19(s,2H),7.50(d,J=1.0Hz,1H),4.74(dd,J=7.6,2.8Hz,1H),3.68(s ,3H),1.89-2.00(m,1H),1.59(dquin,J=14.2,7.2,7.2,7.2,7.2Hz,1H),1.03(t,J=7.4Hz,3H).

[0586] Example S31: 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 31)

[0587] Process 31

[0588]

[0589] 3,6-Dichloro-4-(2-methyl-1,3-dioxolane-2-yl)pyridazine (31a). 2-ethynyl-2-methyl-1,3-dioxolane (1.49 g, 13.25 mmol, 311.62 μL) was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (1000 mg, 6.62 mmol) in toluene (15 mL). The mixture was stirred in a sealed tube at 110 °C for 16 h. TLC indicated complete depletion of the starting material. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 31a. 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),4.19-4.08(m,2H),3.89-3.77(m,2H),1.80(s,3H).

[0590] 3,5-Dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxolane-2-yl)pyridazin-3-yl)oxy)aniline (31b). A solution of 4-amino-2,6-dichlorophenol (591.45 mg, 3.32 mmol) and 3,6-dichloro-4-(2-methyl-1,3-dioxolane-2-yl)pyridazine (31a) (710 mg, 3.02 mmol) in DMSO (25 mL) was degassed and purged three times with N2, followed by stirring at 90 °C under a N2 atmosphere for 16 h. TLC showed complete exhaustion of the reactants. The reaction mixture was diluted with H2O (50 mL) and the pH was subsequently adjusted to 4–6 with HCl (1 M). The mixture was extracted with 150 mL of ethyl acetate (50 mL × 3). The combined organic layers were washed with 50 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to give 31b. 1 H NMR (400MHz, CDCl3) δ7.50(s,1H),6.69(s,2H),4.20-4.11(m,2H),3.93-3.85(m,2H),3.79(br s,2H),1.83(s,3H).

[0591] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazine (31c). A solution of 3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazine-3-yl)oxy)aniline (31b) (600 mg, 1.59 mmol) in 30 mL of ACN was added to tert-butyl nitrite (821.41 mg, 7.97 mmol, 947.41 μL) and KI (528.91 mg, 3.19 mmol). The mixture was then stirred at 20 °C for 1 hour. TLC showed complete depletion of 31b and the formation of a major new spot. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to give 31c. 1 H NMR (400MHz, CDCl3) δ7.74(s,2H),7.57(s,1H),4.21-4.11(m,2H),3.95-3.84(m,2H),1.84(s,3H).

[0592] 6-(3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31d). p-3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazine (31c) (200 mg, 410.25 μmol) A mixture of 2-methyl-6-(trimethyltinyl)-1,2,4-triazine-3,5(2H,4H)-dione (30a) (237.87 mg, 820.51 μmol) and Pd(dppf)Cl2.CH2Cl2 (33.50 mg, 41.03 μmol) in dioxane (10 mL) was degassed and purged three times with N2, and then stirred at 110 °C under N2 atmosphere for 16 h. TLC and LCMS indicated complete depletion of 31c. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and then filtered to give 31d (162 mg, crude product). [M+1] + (C 18 H 14 The MS quality requirement value (m / z) calculated for Cl3N5O5 is 486.0, and the experimental value (m / z) for LCMS is also 486.0. 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.19-8.13(m,2H),7.83-7.80(m,1H),4.08(br t,J=7.0Hz,2H),3.87-3.82(m,2H),3.61-3.55(m,3H),1.77-1.74(m,3H).

[0593] 6-(4-((5-acetyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31e). HCl (4M, 4.11 mL) was added to a solution of 6-(3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31d) (160 mg, 328.75 μmol) in dioxane (4 mL). The mixture was stirred at 80 °C for 1 hour. LC-MS showed the formation of a main peak with the desired MS. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with ethyl acetate (5 mL × 3). The combined filtrates were extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 31e (80 mg, crude product). [M+1] + (C 16 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 424.0, and the experimental value (m / z) for LCMS is also 424.0.

[0594] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31e). NaBH4 (26.75 mg, 707.22 μmol) was added to a solution of 6-(4-((5-acetyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31e) (80 mg, 141.44 μmol) in MeOH (5 mL) at 0 °C. The mixture was stirred at 0–20 °C for 0.5 h. LC-MS showed complete depletion of 31e and detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (15 mL) and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 15 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]) to give 31. [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 426.0, and the LCMS experimental value (m / z) is also 426.0.1 HNMR (400MHz, DMSO-d6) δ12.44(br s,1H),12.29(br s,1H),8.10(s,2H),7.43(d,J=1.0Hz,1H),4.75-4.68(m,1H),3.58(s,3H),3.57(br s, 1H), 1.34 (d, J = 6.8Hz, 3H).

[0595] Examples S31 P1 and P2: (S)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione and (R)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (compounds 31P1 and 31P2)

[0596] Process 31a

[0597]

[0598] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31). Dichloro(p-isopropyltoluene)ruthenium(II) dimer (1.08 mg, 1.77 μmol) was suspended in degassed H2O (2 mL) and the mixture was degassed with nitrogen for 10 min. Add 6-(4-((5-acetyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31f) (20 mg, 35.36 μmol) to a solution of degassed THF (1 mL) and sodium formate (4.81 mg, 70.72 μmol, 3.82 μL). Degassed the reaction mixture with nitrogen for 5 min and stirred at 20 °C for 30 min. TLC and LCMS showed complete depletion of 31f. Dilute the mixture with water (5 mL) and extract with 30 mL of ethyl acetate (10 mL × 3). Wash the combined organic layers with brine (5 mL), dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30mm×5μm; mobile phase: [water (0.1% TFA)-ACN]) to obtain 31. [M+1] + (C 16 H 13The MS quality requirement value (m / z) calculated for Cl2N5O5 is 426.0, and the LCMS experimental value (m / z) is also 426.0. 1 H NMR (400MHz, MeOH-d4) δ8.21 (s, 2H), 7.54 (d, J = 1.0 Hz, 1H), 4.96-4.92 (m, 1H), 3.70 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H).

[0599] (S)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31P1) and (R)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31P2). Passed via SFC (column: DAICEL CHIRALPAK) AS (250 mm × 30 mm, 10 μm); mobile phase: [Neu-EtOH]; B%: 30%–30%, 8 min) separation of 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (31) (4.8 mg, 9.20 μmol) to 31P1 (1.05 mg, 2.43 μmol): against [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 426.0, and the experimental value (m / z) for LCMS is also 426.0. 1 ¹H NMR (400 MHz, MeOH-d⁴) δ 8.20 (s, 2H), 7.53 (d, J = 1.1 Hz, 1H), 4.94–4.92 (m, 1H), 3.69 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H); and 31P₂ (1.57 mg, 3.68 μmol): targeting [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 426.0, and the experimental value (m / z) for LCMS is also 426.0. 1¹H NMR (400MHz, MeOH-d⁴) δ 8.19 (s, 2H), 7.52 (s, 1H), 4.94–4.90 (m, 1H), 3.68 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H). In this example, isomers 31P1 and 31P2 were separated by chiral chromatography, but the absolute chirality of each isomer was not determined. The elution order was used to track individual isomers.

[0600] Example S32: 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (Compound 32)

[0601] Process 32

[0602]

[0603] 4-(sec-butyl)-3,6-dichloropyridazine (32a). AgNO3 (228.05 mg, 1.34 mmol) and TFA (459.22 mg, 4.03 mmol, 298.20 μL) were added in a single step to a mixture of 3,6-dichloropyridazine (200 mg, 1.34 mmol) and (2S)-2-methylbutyric acid (137.11 mg, 1.34 mmol, 146.17 μL) in H2O (2 mL) at 50 °C. Subsequently, (NH4)2S2O8 (919.07 mg, 4.03 mmol, 875.30 μL) was added to H2O (2 mL) at 70 °C. The mixture was stirred at 70 °C for 1 hour. TLC showed complete depletion of the starting material and the formation of a new spot. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate) to give 32a. 1 H NMR (400MHz, CDCl3) δ7.34 (s, 1H), 3.08 (sxt, J = 7.0Hz, 1H), 1.59-1.76 (m, 1H), 1. 58-1.61(m,1H),1.28(d,J=6.8Hz,2H),1.26-1.31(m,1H),0.95(t,J=7.4Hz,3H).

[0604] 4-((5-(sec-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (32b). K₂CO₃ (269.57 mg, 1.95 mmol) and CuI (55.72 mg, 292.56 μmol) were added to a solution of 4-(sec-butyl)-3,6-dichloropyridazine (32a) (100 mg, 487.61 μmol) and 4-amino-2,6-dichlorophenol (104.16 mg, 585.13 μmol) in DMSO (5 mL). The reaction mixture was degassed and purged three times with N₂, and then stirred at 90 °C under N₂ atmosphere for 16 h. TLC and LCMS showed complete depletion of 32a and detection of the desired MS. The mixture was concentrated under vacuum. The mixture was extracted with ethyl acetate (30 mL × 2) and H₂O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate) to give 32b. [M+1] + (C 14 H 14 The MS quality requirement value (m / z) calculated by Cl3N3O is 346.0, and the LCMS experimental value (m / z) is 346.1. 1 HNMR (400MHz, MeOH-d4) δ7.42 (s, 1H), 6.72-6.76 (m, 2H), 3.06-3.15 (m, 1H), 1.62-1.84 (m, 2H), 1.32 (d, J = 7.0Hz, 3H), 0.93-0.98 (m, 3H).

[0605] 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (32c). NaNO₂ (19.11 mg, 276.95 μmol) was added to a solution of 4-((5-(sec-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (32b) (80 mg, 230.79 μmol) in HCl (3 mL) at 0 °C, and the mixture was stirred for 0.5 h. Subsequently, a solution of KI (76.62 mg, 461.58 μmol) in H₂O (3 mL) was added to the mixture, and the mixture was stirred for another 1.5 h at 15 °C. TLC and LCMS indicated complete depletion of 32b and detection of the desired mass. The mixture was extracted with ethyl acetate (20 mL × 2) and 10 mL of H₂O. The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to obtain 32c. [M+1] + (C 14 H 12The MS quality requirement value calculated by Cl3IN2O is 456.9 m / z, and the LCMS experimental value is 457.0 m / z. 1 H NMR (400MHz, CDCl3) δ7.73 (s, 2H), 7.18 (s, 1H), 3.05-3.12 (m, 1H), 1.59-1.83 (m, 2H), 1.32 (d, J = 6.6Hz, 3H), 0.97 (t, J = 7.4Hz, 3H).

[0606] 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)pyridazine (32d). KOAc (64.35 mg, 655.71 μmol) and Pd(dppf)Cl2 (9.60 mg, 13.11 μmol) were added to a solution of 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (32c) (60 mg, 131.14 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (99.91 mg, 393.43 μmol) in dioxane (4 mL). The mixture was degassed and purged three times with N2, and stirred at 90°C for 16 hours. TLC and LCMS showed complete depletion of 32d and the desired mass was detected. The mixture was extracted with ethyl acetate (20 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 32d. [M+1] + (C 20 H 24 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 457.1, and the experimental value (m / z) of LCMS is 457.2. 1 HNMR (400MHz, CDCl3) δ7.81 (s, 2H), 7.17 (s, 1H), 3.04-3.12 (m, 1H), 1.59-1.81 (m, 3H), 1.27 (s, 102H), 0.94-1.00 (m, 1H), 0.97 (t, J = 7.4Hz, 3H).

[0607] 6-(4-((5-(sec-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (32e). To 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-(4-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)pyridazine (32d) (60 mg, 131.12 μmol) and 6-bromo-2-methyl- Di-tert-butylphosphine (3a) (40.52 mg, 196.68 μmol) was added to a mixture of 1,2,4-triazine-3,5(2H,4H)-dione (3a) in THF (4 mL) and H₂O (1 mL); the mixture was degassed with iron (8.55 mg, 13.11 μmol) and K₃PO₄ (55.67 mg, 262.25 μmol) and purged three times with N₂, followed by stirring at 90 °C under an N₂ atmosphere for 16 h. TLC and LCMS showed complete depletion at 32d and detection of the desired MS. The reaction mixture was dissolved in water and the pH was adjusted to 4 with HCl (1 M, 1 mL). The mixture was then extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate) to give 32e. Regarding [M+1] + (C 18 H 16 The MS quality requirement value (m / z) calculated for Cl3N5O3 is 456.0, and the experimental value (m / z) for LCMS is 455.8. 1 H NMR(400MHz,MeOH-d4)δ8.23-8.27(m,2H),7.60(s,1H),3.68(s,3H),3.09-3 .18(m,1H),1.65-1.88(m,2H),1.35(d,J=6.8Hz,3H),0.97(t,J=7.4Hz,3H).

[0608] 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (32e) was added to a solution of 6-(4-((5-(sec-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazin-3,5(2H,4H)-dione (32e) (40 mg, 87.58 μmol) in AcOH (3 mL) at 15 °C. The mixture was then stirred at 120 °C for 16 hours. LC-MS and HPLC showed complete depletion of 32e and detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to obtain 32. [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 438.1, and the experimental value (m / z) for LCMS is 438.0. 1 HNMR(400MHz,DMSO-d6)δ12.45(br s,1H),12.20(s,1H),8.10(s,2H),7.43(s,1H),3.58(s,3H),2.85-2.94 (m,1H),1.46-1.76(m,2H),1.18(d,J=7.0Hz,3H),0.86(t,J=7.4Hz,3H).

[0609] Examples S33 P1 and P2: (R)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione and (S)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compounds 33P1 and 33P2)

[0610] Process 33

[0611]

[0612] 6-(4-((5-(sec-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (33a). To 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)pyridazine (32d) (280mg, 61) A mixture of 1.91 μmol) of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (3a) (176.20 mg, 917.86 μmol) in THF (4 mL) and H₂O (1 mL) was supplemented with Pd(dppf)Cl₂ (39.88 mg, 61.19 μmol) and K₃PO₄ (259.78 mg, 1.22 mmol). The mixture was degassed and purged three times with N₂, and then stirred at 90 °C under N₂ atmosphere for 2 h. TLC and LCMS showed complete depletion and detection of the desired MS at 32 d. The mixture was extracted with ethyl acetate (50 mL × 2) and H₂O (15 mL). The combined organic phases were washed with brine (15 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 33a. [M+1] + (C 20 H 24 The MS quality requirement value (m / z) calculated by BCl3N2O3 is 457.1, and the experimental value (m / z) of LCMS is 457.2. 1 HNMR (400MHz, MeOH-d4) δ 8.21-8.24 (m, 1H), 7.60 (s, 1H), 3.10-3.16 (m, 1H), 1.66-1.86 (m, 2H), 1.35 (d, J = 6.84Hz, 3H), 0.97 (t, J = 7.39Hz, 3H).

[0613] 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (33b). NaOAc (162.14 mg, 1.98 mmol) was added to a solution of 6-(4-((5-(sec-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (33a) (175 mg, 395.32 μmol) in AcOH (8 mL) at 15 °C. The mixture was then stirred at 120 °C for 16 h. HPLC and LCMS showed complete depletion of 33a and detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (5 mL). The suspension was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5 u; mobile phase: [water (0.2% FA)-ACN]) to give 33b. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 424.1, and the experimental value (m / z) for LCMS is 424.2. 1 H NMR (400MHz, DMSO-d6) δ 8.16 (s, 1H), 7.34 (s, 1H), 2.97-3.04 (m, 1H), 1.55-1.82 (m, 2H), 1.26 (d, J = 7.0Hz, 3H), 0.96 (t, J = 7.4Hz, 3H).

[0614] (R)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione and (S)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compounds 33P1 and 33P2). Separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O] [IPA]; B%: 45%-45%) Separation of 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (33b) (28 mg, 66.00 μmol) to 33P1 (11.36 mg, 26.78 μmol, 40.57% yield): against [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 424.1, and the experimental value (m / z) for LCMS is 424.0. 1 ¹H NMR (400 MHz, MeOH-d⁴) δ 8.15 (s, 2H), 7.33 (s, 1H), 3.35 (s, 1H), 2.97–3.04 (m, 1H), 1.54–1.82 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); and 33P₂ (11.17 mg, 26.33 μmol, 39.89% yield): targeting [M+1] + (C 17 H 15 The calculated MS quality requirement value (m / z) for Cl2N5O4 is 424.1, and the experimental LCMS value (m / z) is 424.0. 1 ¹H NMR (400MHz, MeOH-d⁴) δ 8.16 (s, 2H), 7.33 (s, 1H), 2.97–3.04 (m, 1H), 1.54–1.83 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). In this example, isomers 33P1 and 33P2 were separated by chiral chromatography, but the absolute chirality of each isomer was not determined. The elution order was used to track individual isomers.

[0615] Example S34: (6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compound 34)

[0616] Process 34

[0617]

[0618] 1-(3,6-Dichloropyridazine-4-yl)ethanol (34a). But-3-yn-2-ol (278.59 mg, 3.97 mmol, 311.62 μL) was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (500 mg, 3.31 mmol) in toluene (3 mL). The reaction mixture was sealed in a tube and stirred at 110 °C for 16 h. TLC indicated complete depletion of the starting material. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to give 34a. 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 1.0 Hz, 1H), 5.14 (dq, J = 4.2, 6.3 Hz, 1H), 2.38 (d, J = 3.4 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H).

[0619] 3,6-Dichloro-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine (34b). TsOH (13.38 mg, 77.71 μmol) was added to a solution of 1-(3,6-dichloropyridazine-4-yl)ethanol (34a) (300 mg, 1.55 mmol) and DHP (653.68 mg, 7.77 mmol, 710.52 μL) in DCM (10 mL). The mixture was stirred at 20 °C for 1 h. TLC showed complete depletion of the reactants and the formation of numerous new spots. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to give 34b. 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),7.63(s,1H),5.10(q,J=6.4Hz,1H),4.98(q,J=6.6Hz,1H),4.81(br d,J=4.6Hz,1H),4.47(br s,1H),3.99-3.90(m,1H),3.67-3.53(m,2H),3.47-3.40(m,1H),1.95-1.55(m,12H),1.53(d,J=6.4Hz,3H),1.46(d,J=6.4Hz,3H).

[0620] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine-3-yl)oxy)aniline (34c). K₂CO₃ (299.21 mg, 2.16 mmol) and CuI (82.46 mg, 432.98 μmol) were added to a solution of 3,6-dichloro-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine (34b) (167.00 mg, 938.13 μmol) and 4-amino-2,6-dichlorophenol (200 mg, 721.64 μmol) in DMSO (5 mL). The reaction mixture was then degassed and purged three times with N₂. The mixture was stirred at 90 °C under a N₂ atmosphere for 2 hours. TLC and LCMS showed complete depletion of 34b. The reaction mixture was diluted with H₂O (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether: ethyl acetate) to give 34c. 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.37(s,1H),6.68(s,4H),5.10(q,J=6.6Hz,1H),5.00(q,J=6 .4Hz,1H),4.90-4.85(m,1H),4.52(t,J=3.6Hz,1H),3.96(ddd,J=3.8,7.5,11.2Hz,1H),3.81(br d,J=2.4Hz,4H),3.65(ddd,J=3.2,8.0,11.3Hz,1H),3.61-3.54(m,1H),3.47- 3.40(m,1H),1.96-1.60(m,12H),1.55(d,J=6.4Hz,3H),1.49(d,J=6.4Hz,3H).

[0621] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine (34d). Tert-butyl nitrite (609.56 mg, 5.91 mmol, 703.06 μL) and KI (130.83 mg, 788.15 μmol) were added to a solution of 3,5-dichloro-4-(6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine-3-yl)oxy)aniline (34c) (165 mg, 394.08 μmol) in ACN (5 mL) at 0 °C. The mixture was then stirred at 20 °C for 1 h. TLC and LCMS showed complete depletion of 34d and the formation of numerous new spots. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether: ethyl acetate) to obtain 34d. [M+1] + (C 17 H 16 The MS quality requirement value (m / z) calculated by Cl3IN2O3 is 528.9, and the experimental value (m / z) of LCMS is also 528.9.

[0622] A mixture of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine (34e). 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine (34d) (53 mg, 100.08 μmol), BPD (76.24 mg, 300.24 μmol), AcOK (49.11 mg, 500.39 μmol) and Pd(dppf)Cl2 (7.32 mg, 10.01 μmol) in dioxane (3 mL). The mixture was degassed and purged three times with N2, and then stirred at 90°C under a N2 atmosphere for 16 hours. TLC and LCMS showed complete depletion at 34d. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 34e (75 mg, crude product). The crude product was used directly in the next step. [M+1] + (C 23 H 28The MS quality requirement value (m / z) calculated by BCl3N2O5 is 529.1, and the LCMS experimental value (m / z) is 447.0.

[0623] 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazine-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (34f). To 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-4-(1-((tetrahydro-2H-piperan-2-yl)oxy) (34e)pyridazine (75 mg, 141.60 μmol), 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (32.62 mg, 169.92 μmol) were added to a solution of THF (2.4 mL) and H₂O (0.6 mL) with K₃PO₄ (60.12 mg, 283.21 μmol) and Pd(dppf)Cl₂ (9.23 mg, 14.16 μmol). The mixture was degassed and purged three times with N₂, and then stirred at 80 °C under a N₂ atmosphere for 16 hours. TLC and LCMS showed complete depletion of 34e in the reactants. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:MeOH) to obtain 34f. [M+1] + (C 20 H 18 The MS quality requirement value (m / z) calculated for Cl3N5O5 is 514.0, and the experimental value (m / z) for LCMS is also 514.0.

[0624] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (34). HCl (4M, 835.36 μL) was added to a solution of 6-(3,5-dichloro-4-(6-chloro-5-(1-((tetrahydro-2H-piperan-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (34f) (43 mg, 66.83 μmol) in dioxane (1 mL). The mixture was stirred at 80 °C for 16 h. LC-MS showed the reaction was complete and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]) to give 34. [M+1] + (C 15 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 412.0, and the experimental value (m / z) for LCMS is also 412.0. 1 H NMR (400MHz, MeOH-d4) δ 8.19-8.13 (m, 2H), 7.52 (d, J = 1.2 Hz, 1H), 4.93-4.88 (m, 1H), 1.46 (d, J = 6.6 Hz, 3H).

[0625] Example S35: 6-(4-((5-acetyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 35)

[0626] Process 35

[0627]

[0628] 6-(2,6-Dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazine-3(2H)-one (35a). NaOAc (126.20 mg, 1.54 mmol) was added to a solution of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazine (31c) (150 mg, 307.69 μmol) in AcOH (3 mL). The mixture was stirred at 120 °C for 16 hours. LCMS showed complete depletion of 31c and detection of the desired mass. The reaction mixture was concentrated under reduced pressure to remove AcOH. The crude product was wet-milled at 20 °C with H₂O (5 mL) for 15 minutes, followed by wet-milling at 20 °C with petroleum ether:ethyl acetate = 20:1 (5 mL) for 30 minutes to give obtained 35a as a white solid. Regarding [M+1] + (C 14 H 11 The MS quality requirement value (m / z) calculated by Cl2IN2O4 is 468.9, and the experimental value (m / z) of LCMS is also 468.9.

[0629] 6-(2,6-dichloro-4-iodophenoxy)-2-methyl-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazin-3(2H)-one (35b). A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazin-3(2H)-one (35a) (80 mg, 170.55 μmol), K₂CO₃ (47.14 mg, 341.11 μmol), and CH₃I (29.05 mg, 204.67 μmol, 12.74 μL) in ACN (5 mL) was degassed and purged three times with N₂, and then stirred at 25 °C under N₂ atmosphere for 1 h. LCMS showed complete depletion of 35a and detection of the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was wet-milled with 5 mL of H₂O and stirred at 20 °C for 1 hour. The mixture was then filtered to collect the solid. The solid was wet-milled with 5 mL of a solution of petroleum ether:ethyl acetate = 5:1 and filtered to give 35b. (For [M+1]) + (C 15 H 13 The MS quality requirement value (m / z) calculated by Cl2IN2O4 is 482.9, and the experimental value (m / z) of LCMS is 483.0.

[0630] 4-Acetyl-6-(2,6-dichloro-4-iodophenoxy)-2-methylpyridazin-3(2H)-one (35c). HCl (4M, 2 mL) was added to a solution of 6-(2,6-dichloro-4-iodophenoxy)-2-methyl-4-(2-methyl-1,3-dioxocyclopentan-2-yl)pyridazin-3(2H)-one (35b) (70 mg, 144.90 μmol) in dioxane (2 mL). The mixture was stirred at 80 °C for 16 hours. LCMS indicated complete depletion of 35b and the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was wet-milled with a solution of petroleum ether:ethyl acetate and stirred at 20 °C for 1 hour. The mixture was filtered to give 35c. [M+1] + (C 13 The MS quality requirement value (m / z) calculated by H9Cl2IN2O3 is 438.9, and the experimental value (m / z) of LCMS is also 438.9. 1 H NMR (400MHz, MeOH-d4) δ7.89(s,2H),7.78(s,1H),3.54(s,3H),2.66(s,3H).

[0631] 4-Acetyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-2-methylpyridazin-3(2H)-one (35d). Pd(dppf)Cl2 (10.00 mg, 13.67 μmol) and KOAc (67.06 mg, 683.32 μmol) were added to a solution of 4-acetyl-6-(2,6-dichloro-4-iodophenoxy)-2-methylpyridazin-3(2H)-one (35c) (60 mg, 136.66 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (104.11 mg, 409.99 μmol) in dioxane (3 mL) under N2 conditions. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. LCMS indicated a retention of approximately 40% of 35d and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with ethyl acetate (10 mL × 3). The combined organic layers were washed with H₂O (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate) to give 35d. [M+1] + (C 19 H 21 The MS quality requirement value (m / z) calculated by BCl2N2O5 is 439.1, and the experimental value (m / z) of LCMS is also 439.1. 1H NMR (400MHz, CDCl3) δ7.80(s,2H),7.71(s,1H),3.56-3.60(m,3H),2.75-2.77(m,3H),1.34-1.39(m,12H).

[0632] 6-(4-((5-acetyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazin-3,5(2H,4H)-dione (35). Under N2, the 4-acetyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)-2-methylpyridazin-3(2H) -one (35d) (40 mg, 91.10 μmol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (34.98 mg, 182.19 μmol) in a solution of THF (2 mL) and H2O (0.5 mL) were added with Pd(dppf)Cl2 (5.94 mg, 9.11 μmol) and K3PO4 (38.67 mg, 182.19 μmol). The mixture was stirred at 80 °C for 5 hours under a N2 atmosphere. LCMS indicated that 35d was completely depleted and the desired mass was detected. The suspension was filtered through a diatomaceous earth pad and the pad cake was washed with ethyl acetate (10 mL × 3). The combined filtrates were concentrated under vacuum. The residue was purified by preparative HPLC (column: Ultimate C18 100 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]) to give 35. For [M+1] + (C 16 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 424.0, and the experimental value (m / z) for LCMS is also 424.0. 1 H NMR (400MHz, MeOH-d4) δ8.18-8.21(m,2H),7.79(s,1H),3.54(s,3H),3.50-3.51(m,1H),2.67(s,3H).

[0633] Biological Example: Biological Screening

[0634] Example B1: Time-of-flight fluorescence resonance energy transfer (TR-FRET) analysis for screening thyroid receptor agonists

[0635] LanthaScreen TM TR-FRET Thyroid Receptor Alpha Coactivator Assay Kit (ThermoFisher) and LanthaScreen TMThe TR-FRET Thyroid Receptor β Co-activator Assay Kit (ThermoFisher) was used for agonist compound screening. Compounds in DMSO were serially diluted in duplicate at 10-point 3-fold series to 384 plates (5 μM final maximum concentration) using an ECHO liquid processor (Labcyte Inc.). Buffer C (ThermoFisher) was added to each well, followed by a 4-fold mixture of fluorescein-SCR2-2 co-activator (200 nM final concentration), terbium-labeled anti-GST antibody (2 nM final concentration), and either THRα-LBD (0.4 nM final concentration) or THRβ-LBD (1.0 nM final concentration). After incubation in the dark at room temperature for 2 hours, the TR-FRET signal was measured on an EnVision plate reader (PerkinElmer) with excitation at 340 nm and dual emission readouts at 495 and 520 nm, a delay of 100 μs, and an integration time of 200 μs. Using GraphPadPrism (GraphPad Software), the ratio of the transmitted signals at 520 and 495 was used to calculate EC. 50 In each batch of compound screening, T3 (L-3,3',5-triiodothyronine sodium salt >95%) (Calbiochem) was used as a reference compound. The EC50 of T3 was measured. 50 Within three times the reference values ​​provided by the analytical kit manufacturer (ThermoFisher Scientific). The Z' factor, measured in each batch of screening using T3 as a higher percentage effect (HPE) control and 0.5% DMSO as a zero percentage effect (ZPE) control, ranged from 0.5 to 0.8. The THR-β selectivity values ​​for the compounds in Table 2 were obtained from T3 selectivity-normalized data. Data obtained using TR-FRET analysis of some of the compounds disclosed herein are listed in Table 2.

[0636] Table 2.

[0637]

[0638]

[0639] *Compound 4 is not within the scope of formula (I) and is provided for comparative purposes only. a All compounds were tested in duplicate multiple times, and average data were reported.

[0640] All disclosures mentioned in this specification, including patents, patent applications and scientific objects, are incorporated herein by full reference for all purposes, to the extent that each individual publication, including patents, patent applications or scientific papers, is specifically and individually indicated as incorporated by reference.

[0641] While the invention has been described in considerable detail by way of illustration and examples for purposes of clarity, it will be apparent to those skilled in the art that minor changes and modifications can be made based on the foregoing teachings. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound of Formula (I), wherein: R1is C1-C6alkyl or C3-C6cycloalkyl, each of which is optionally substituted with 1 substituent selected from the group consisting of -OH, oxo, -CN, and halo; R2is H or unsubstituted C1-C6alkyl; R3is H; R4is H or linear C1-C3alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2alkyl); L is -O-, -C(O)-, or -C(R5)(R6)-; R5and R6are independently H; M1and M2are independently halo or unsubstituted C1-C6alkyl; and M3is H, halo, or unsubstituted C1-C6alkyl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1is cyclopropyl, isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R2is H or methyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R4is H or linear C1-C3alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of oxo, -CN, halo, and -O(C1-C2alkyl).

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R4is H, methyl, ethyl, -CH2C(O)OCH2CH3, -CH2CF3, -CH2CN, or -CH2CHF2.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: M1and M2are independently halo or methyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: M1and M2are each chloro.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: M1and M2are each methyl.

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: M3is H, F, or methyl.

10. A compound selected from the following table: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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