Thyroid hormone receptor beta-agonist compounds

Abstract

To provide thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.SOLUTION: For example, the following compound (example 2) is illustrated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 722,312 filed on 24 August 2018 and U.S. Provisional Application No. 62 / 867,117 filed on 26 June 2019, and the entirety of the disclosures of the aforementioned applications is incorporated into this application by reference for all purposes. Technical field The present invention relates to compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, methods for producing the same, as well as methods for agonizing THR beta and methods for treating THR beta-mediated disorders. [Background technology]

[0002] The beneficial effects of treating patients with hyperthyroidism or hypothyroidism with T3 / T4 endogenous ligands or early analogs of these endogenous ligands have been documented in the literature (Richardson Hill Jr., S. et al., J. Clin. Invest. 1960, 39, 523-533). These early studies, and similar follow-ups, have established the heart as the primary organ for the development of side effects in both hyperthyroidism and hypothyroidism (Klein, I. et al., Circulation, 2007, 1725-1735). In particular, tachycardia, hypertrophy, atrial arrhythmias, and atrial fibrillation are serious problems. Furthermore, it has been noted that increased bone turnover can lead to decreased bone mineral density. Negative effects in both the heart and bone are associated with agonism of the THR alpha isoform, while beneficial effects of THR agonism in the liver are primarily associated with the THR beta isoform (Sinha, RA et al., Nat. Rev. Endocrinology 2018, 14, 259-269). [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] Diseases or disorders associated with THR beta include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. For example, there is a need for thyroid hormone analogs, such as THR beta agonists, for the treatment of patients with non-alcoholic steatohepatitis (NASH), preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism and maintain the beneficial effects of thyroid hormones. For example, there is a need to develop novel thyroid hormone analogs, particularly those that are selective agonists of THR beta, for the treatment of patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia, preferably those that avoid the undesirable effects associated with THR alpha agonism and maintain the beneficial effects of thyroid hormones for therapeutic purposes. [Means for solving the problem]

[0004] overview In one embodiment, this specification uses formula (I): [ka] (I) [In the formula, Ring A, which has a carbonyl (keto) group within it, forms a five-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, where the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl groups or C3-C4 cycloalkyl groups, where the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 This is a C1-C4 alkyl, C3-C5 cycloalkyl, CON(R) molecule optionally substituted with 1 to 5 halo or hydroxyl groups. 10 )2, or NR 10 COR 10 is; R2 is H or C1-C3 alkyl; L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 )CN, CHR 11 , or C(R 11 )R 11 ; R 3 and R 4 are independently Cl, Br, methyl, or ethyl; R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl; alternatively R 5 is such that together with R 4 and intervening atoms forms a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 or 2 heteroatoms; X is absent, O, NR 12 , C(O)NR 12 , NR 12 C(O), CR 12 R 12 , OCR 12 R 12 , CR 12 R 12 O, NR 12 CR 12 R 12 , CR 12 R 12 NR 12 , SO2NR 12 , or NR 12 SO2; each R 10 is independently C1-C3 alkyl or H; each R 11 is independently optionally substituted C1-C2 alkyl with 1 to 5 halos, or two R 11 groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring; and each R 12 is independently H or methyl] To provide a compound represented by or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the compound is of formula (IIA) or (IIB): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 X and L are equivalent to those in equation (I). It is a compound represented by [the formula shown].

[0006] In some embodiments, the compound is of formula (VD): [ka] (VD) [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 This is equivalent to equation (I). It is a compound represented by [the formula shown].

[0007] In some embodiments, R 1 R is a C1-C4 alkyl or C3-C5 cycloalkyl group optionally substituted with one or two halo or hydroxyl groups. In some embodiments, R 1 isopropyl, t-butyl, HO-CH(CH3)-, HO-CH(CH2CH3)-, HO-C(CH3)2-, HO-CH2CH(CH3)-, cyclopropyl, or [ka] That is the case.

[0008] In some embodiments, R 2 This is either H or -CH3. In some embodiments, R 3 It is chloro or -CH3.

[0009] In some embodiments, R 4is chloro or -CH3; or R 5 R 4 And together with the intervening atoms, they form a 5-6 member cycloalkyl group. In some embodiments, R 5 R 4 and together with intervening atoms, they form cyclopentyl. In some embodiments, R 5 It is either H or fluoro.

[0010] In some embodiments, X is a bond. In some embodiments, X is NR 12 C(O), OCR 12 R 12 , or NR 12 CR 12 R 12 and each R 12 X is independently H or methyl. In some embodiments, X is -OCH2-, -NHCH2-, -NHC(O)-, -N(CH3)CH2-, or -N(H)CH(CH3)-.

[0011] In some embodiments, L is O, CH2, SO2, CO, CHR 11 , or C(R 11 )R 11 and each R 11 L is independently methyl or ethyl. In some embodiments, L is O, CH2, SO2, or CO.

[0012] In some embodiments, this specification provides compounds selected from the compounds listed in Table 1, or pharmaceutically acceptable salts thereof.

[0013] In one embodiment, this specification provides a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient.

[0014] In one embodiment, this specification provides a method for agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of either a compound provided herein or a pharmaceutical composition provided herein.

[0015] In one embodiment, this specification provides a method for treating a patient's THR beta-mediated disorder, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH). [Modes for carrying out the invention]

[0016] Detailed description definition When used herein, unless otherwise specified, the following definitions shall apply. Furthermore, if a term or symbol used herein is not defined as described below, it shall have its ordinary meaning in the art.

[0017] "Contains" is intended to mean that the compositions and methods described include the elements described, but do not exclude others. When used to define compositions and methods, "essentially consists of" shall mean that other elements that are essentially important to the combination are excluded. For example, a composition consisting essentially of the elements defined herein would not exclude other elements that do not substantially affect the basic and novel features of the claimed invention. "Consists of" shall mean that amounts greater than trace amounts of, for example, other components described and substantial method steps are excluded. Embodiments defined by any of these linking phrases are within the scope of the invention.

[0018] The “effective amount” or dose of a compound or composition means that amount of the compound or composition that produces the desired intended result based on the disclosure herein. The effective amount is the amount obtained by standard pharmaceutical procedures in cell culture or experimental animals, for example, but not limited to, LD 50 This can be determined by determining the lethal dose (50% of the population) and the ED50 (the dose that is therapeutically effective for 50% of the population).

[0019] As used herein, the term “excipient” means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals, such as tablets, containing the compounds of the present invention as active ingredients. The term “excipient” may include, but is not limited to, substances used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavorings, suspending / gelling agents, or wet granulating agents. Binders include, for example, Carbopol, povidone, and xanthan gum; coatings include, for example, cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coatings; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; combined with aspartame, cellulose, or microcrystalline cellulose as needed), starch dc, and sucrose; disintegrants include, for example, croscarmellose sodium, gellan gum, and sodium starch glycolate; creams or lotions include, for example, maltodextrin. This includes todextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate; chewable tablet ingredients include, for example, dextrose, fructose dc, lactose (monohydrate, combined with aspartame or cellulose as needed); suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose.

[0020] "Patient" refers to a mammal, including humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient means human.

[0021] "Pharmacologically acceptable" means that it is preferably safe and non-toxic in vivo, and more preferably safe and non-toxic for human administration.

[0022] "Pharmacologically acceptable salt" means a pharmaceutically acceptable salt. The compounds described herein may be administered as pharmaceutically acceptable salts.

[0023] A “prodrug” means a compound that, after administration, is metabolized or otherwise converted into a compound (or drug) that is biologically active or more active in respect of at least one property. Compared to a drug, a prodrug is chemically modified to be less active or inactive compared to the drug, but the chemical modification is such that the corresponding drug is produced by metabolism or other biological processes after the prodrug is administered. Compared to an active drug, a prodrug may have altered metabolic stability or transport properties, reduced side effects or toxicity, or improved flavor (see, for example, Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388–392, reference incorporated herein by reference). Prodrugs can be synthesized using reactants other than those using the corresponding drug. For illustrative purposes, and not limited to these, prodrugs include carboxyesters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, and the aryl and heteroaryl moieties may be optionally substituted).

[0024] "Salt" refers to an ionic compound formed between an acid and a base. Where the compounds provided herein contain acidic functional groups, such salts include, but are not limited to, alkali metals, alkaline earth metals, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include ammonium cations based on Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and naturally occurring amino acids. Where the compounds used herein contain basic functional groups, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, as well as mineral acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalates, maleates, acetates, propions, succinates, tartrates, chlorides, sulfates, bisulfates, monobasic, dibasic, and tribasic phosphates, mesylates, tosylates, and the like.

[0025] The “therapeutic effective dose” or dosage of a compound or composition refers to the amount of the compound or composition that results in the reduction or inhibition of a patient’s symptoms or the extension of survival. Results may require multiple doses of the compound or composition.

[0026] To “treat” or “treat” a patient’s illness means 1) preventing the onset of the illness in a patient who is predisposed to the illness or who has not yet shown symptoms of the illness; 2) inhibiting the illness or stopping its progression; or 3) causing improvement or regression of the illness. As used herein, “treat” or “treat” is an approach to obtain a beneficial or desirable outcome, including clinical outcomes. For the purposes of the present invention, beneficial or desirable outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the illness or disability; reducing the severity of the illness or disability; stabilizing the illness or disability (e.g., preventing or delaying the worsening of the illness or disability); delaying the onset or recurrence of the illness or disability; slowing or delaying the progression of the illness or disability; improving the state of the illness or disability; providing remission (partial or total) of the illness or disability; reducing the dose of one or more other drugs required to treat the illness or disability; enhancing the effect of another drug used to treat the illness or disability; slowing the progression of the illness or disability; improving the quality of life; and / or extending the patient’s survival. "Treatment" also includes the reduction of pathological consequences of a disease or disorder. The methods of the present invention aim to achieve one or more of these aspects of treatment.

[0027] An "isotopomer" of a compound is a compound in which one or more atoms of the compound are replaced by isotopes of the same atoms. For example, H may be replaced by D or T, or 12 C 11 Replaced with C, or 14 N 15 It was replaced with N. For example, substitution with D, though not limited to it, may in some cases lead to a decrease in metabolic rate and therefore a longer half-life. Replacing H with T may provide a radioligand that could be useful for binding studies. 12 C is a short-lived isotope 11 Replacing it with C can provide a ligand useful for positron emission tomography (PET) scans.14 N 15 If we replace it with N, 15 Compounds that can be detected / monitored by NNMR spectroscopy are obtained. For example, the isotopomer of a compound containing -CH2CH3 is the same compound, but it contains -CD2CD3 instead of -CH2CH3.

[0028] Unless a specific isotope of an element is shown in the formula, this disclosure does not include, for example, deuterated derivatives of a compound (H is 2 This includes all isotopes of the compounds disclosed herein, such as H (which can be D). The isotopologs may have isotopic substitutions at any or all locations in the structure, or may have atoms present at any or all locations in the structure in natural abundance.

[0029] "Stereoisomers" or "stereoisomers" refer to compounds that differ in the stereoforming properties of their constituent atoms, such as in the chirality of one or more stereocenters, or in relation to the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds, although this is not an exhaustive definition. Stereoiomers include enantiomers and diastereomers.

[0030] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, and tautomers of heteroaryl groups containing ring atoms bonded to both the ring-NH- and ring-N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0031] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group that has x carbon atoms.

[0032] "Alkenyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and at least 1, preferably 1 to 2 vinyl (>C=C<) unsaturated moieties. Such groups are exemplified, for example, by vinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers or mixtures thereof. x An alkenyl refers to an alkenyl group with x carbon atoms.

[0033] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and at least 1, preferably 1 to 2 acetylene (-C≡C-) unsaturated moieties. Examples of such groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH). x Alkynyl refers to an alkynyl group with x carbon atoms.

[0034] "Substituting alkyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cyclo This means an alkyl group having 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2 substituents, selected from the group consisting of alkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio (where the substituents are defined herein).

[0035] "Substituted alkenyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo This means an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of hydroxy, substituted cycloalkyl, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio (wherein the substituents are defined herein, except that any hydroxy or thiol substitution is not bonded to a vinyl (unsaturated) carbon atom).

[0036] "Substituted alkynyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyano This means an alkekyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of chloroalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio (where the substituents are as defined herein, except that any hydroxyl or thiol substitutions are not bonded to the acetylene carbon atom).

[0037] "Alkoxy" means an -O-alkyl group, where alkyl is defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0038] "Replacement alkoxy" means an -O-(replacement alkyl) group where the replacement alkyl is defined herein. Preferred replacement alkyl groups in -O-(replacement alkyl) include alkyl halide groups and, in particular, methyl halide groups such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0039] "Acyl" denotes H-C(O)-, alkyl-C(O)-, replacement alkyl-C(O)-, alkenyl-C(O)-, replacement alkenyl-C(O)-, alkynyl-C(O)-, replacement alkynyl-C(O)-, cycloalkyl-C(O)-, replacement cycloalkyl-C(O)-, aryl-C(O)-, replacement aryl-C(O)-, heteroaryl-C(O)-, replacement heteroaryl-C(O)-, heterocyclic-C(O)-, and replacement heterocyclic-C(O)- groups, where alkyl, replacement alkyl, alkenyl, replacement alkenyl, alkoxy, replacement alkoxy, alkynyl, replacement alkynyl, cycloalkyl, replacement cycloalkyl, aryl, replacement aryl, heteroaryl, replacement heteroaryl, heterocyclic, and replacement heterocyclic are as defined herein. Acyl includes the "acetyl" group: CH3C(O)-.

[0040] "Acylamino" is -NR 30 C(O)alkyl, -NR 30 C(O)replacement alkyl, -NR 30 C(O)cycloalkyl, -NR 30 C(O)replacement cycloalkyl, -NR 30 C(O)alkenyl, -NR 30 C(O)replacement alkenyl, alkoxy, replacement alkoxy-NR 30 C(O)alkynyl, -NR 30 C(O)replacement alkynyl, -NR 30 C(O)aryl, -NR 30 C(O)replacement aryl, -NR 30 C(O)heteroaryl, -NR 30 C(O)replacement heteroaryl, -NR 30 C(O)heterocyclic, and -NR 30 C(O)replacement heterocyclic group, where R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein 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.

[0041] "acyloxy" means an 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-, heterocycle-C(O)O-, and substituted heterocycle-C(O)O-group, wherein 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.

[0042] "amino" means a -NH2 group.

[0043] "substituted amino" means a -NR 31 R 32 group, wherein R 31 and R 32R is 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, heterocyclic, substituted heterocyclic, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamino, and substituted sulfonyl, and here, R 31 and R 32 They may optionally form a heterocycle or a substituted heterocycle group together with the nitrogen atoms bonded to them, provided that R 31 and R 32 Each is defined herein as having at least one hydrogen atom, and thereafter, 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 defined herein. 31 is hydrogen, R 32 If it is alkyl, the substituted amino group may mean alkylamino. 31 and R 32 If it is alkyl, the substituted amino group may mean dialkylamino. If it means monosubstituted amino, R 31 or R 32 This means that one of them is hydrogen, but not both. If it means a disubstituted amino acid, R 31 or R 32 This means that none of them are hydrogen.

[0044] "Aminocarbonyl" is -C(O)NR 33 R 34 It means base, and here, R 33 and R 34R is 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, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0045] "Aminothiocarbonyl" is -C(S)NR 33 R 34 It means base, and here, R 33 and R 34 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0046] "Aminocarbonylamino" is -NR 30 C(O)NR 33 R 34 It means base, and here, R 30is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0047] "Aminothiocarbonylamino" is -NR 30 C(S)NR 33 R 34 It means base, and here, R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0048] "Aminocarbonyloxy" is -OC(O)NR 33 R 34 , here, R 33 and R 34 R independently represents hydrogen, alkyl, oscillating group, and is selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0049] "Aminosulfonyl" is -SO2NR 33 R 34 It means base, and here, R 33 and R 34 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0050] "Aminosulfonyloxy" is -O-SO2NR 33 R 34 It means base, and here, R 33 and R 34 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0051] "Aminosulfonylamino" is -NR 30 -SO2NR 33 R 34 It means base, and here, R 30 This includes hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34R is 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, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0052] "Amidino" is -C(=NR 35 )NR 33 R 34 It means base, and here, R 33 , R 34 , and R 35 R is 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, heterocyclic, and substituted heterocyclic, and here, R 33およびR34 These may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, where 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.

[0053] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple fused rings (e.g., naphthyl or anthryl), where the fused ring may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl), but the bond site is located on the aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0054] "Substituting aryl" includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino This means an aryl group substituted with 1 to 5 substituents, preferably 1 to 3, or more preferably 1 to 2 substituents (wherein the substituents are as defined herein) selected from the group consisting of carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0055] "Aryloxy" means an -O-aryl group, where aryl is as defined herein, with examples including phenoxy and naphthoxy.

[0056] "Substituting aryloxy" means an -O-(substituted aryl) group, where substituted aryl is as defined herein.

[0057] "Arylthio" means an -S-aryl group, where aryl is as defined herein.

[0058] "Substituting arylthio" means an -S-(substituted aryl) group, where substituted aryl is as defined herein.

[0059] "Arylamino" is -NR 37 (aryl) group means, where aryl is as defined herein, and R 37 is hydrogen, alkyl, or substituted alkyl.

[0060] "Substituting arylamino" is -NR 37 (substituted aryl) group, where R 37 is hydrogen, alkyl, or substituted alkyl, where substituted aryl is as defined herein.

[0061] "Carbonyl" refers to a divalent group, -C(O)-, which is synonymous with -C(=O)-.

[0062] "Carboxylate" or "carboxyl" means -COOH or a salt thereof.

[0063] "Carboxyester" or "carboxyester" means -C(O)O-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, and -C(O)O-substituted heterocyclic group, where 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.

[0064] "(carboxyl ester)amino" is -NR 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O-substituted alkenyl, -NR 30 -C(O)O-alkynyl, -NR 30 -C(O)O-substituted alkynyl, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O- Substitute Arial, -NR 30 -C(O)O-cycloalkyl, -NR 30 -C(O)O-substituted cycloalkyl, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O- substituted heteroaryl, -NR 30 -C(O)O- heterocycle, and -NR 30 -C(O)O- substituted heterocyclic group, where R 30is alkyl or hydrogen, and here 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.

[0065] "(carboxyl ester)oxy" means -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic group, where 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.

[0066] "Cyano" means -C≡N group.

[0067] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group having monocyclic or polycyclic groups such as condensation, crosslinking, and spirocyclic systems, comprising 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. xCycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, however the bonding site is non-aromatic, non-heterocyclic saturated carbon ring. "Substituting cycloalkyl" includes oxo, thion, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo This means a cycloalkyl group having 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of chloroalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio (where the substituents are as defined herein).

[0068] "Cycloalkyloxy" means -O-cycloalkyl.

[0069] "Substituting cycloalkyloxy" means -O- (substituted cycloalkyl).

[0070] "Cycloalkylamino" is -NR 37 (cycloalkyl) group, where R 37 is hydrogen, alkyl, or substituted alkyl.

[0071] "Substituting cycloalkylamino" is -NR 37 (substituted cycloalkyl) group, where R 37 is hydrogen, alkyl, or substituted alkyl, where substituted cycloalkyl is as defined herein.

[0072] "Cycloalkylthio" means -S-cycloalkyl.

[0073] "Substituting cycloalkylthio" means -S- (substituted cycloalkyl).

[0074] "Guanidino" refers to the -NHC (=NH)NH2 group.

[0075] "Substituting guanidino" is -NR 36 C(=NR 36 )N(R 36 ) means 2, where each R 36 The elements are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and two R atoms bonded to a common guanidino nitrogen atom. 36 The groups may optionally combine with the nitrogen atoms bonded to them to form a heterocyclic or substituted heterocyclic group, provided that at least one R is present. 36 This is not hydrogen, and here, the substituent is as defined herein.

[0076] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine, preferably fluoro or chloro.

[0077] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0078] "Heteroalkylenes" are compounds in which one or more carbon atoms are -O-, -S-, SO2, -NR Q -, [ka] This refers to an alkylene group that can be partially replaced, where R Q is H or C1-C6 alkyl. "Substitutive heteroalkylene" means a heteroalkylene group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylenes.

[0079] "Heteroaryl" means an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups may have a monocyclic (e.g., pyridinyl or furyl) or a plurality of fused rings (e.g., indolidinyl or benzothienyl), where the fused ring may or may not be aromatic and / or contain heteroatoms, provided that the bonding sites are mediated by atoms 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 heteroaryls include 5 or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9 or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0080] "Substituting heteroaryl" means a heteroaryl group substituted with 1 to 5 substituents, preferably 1 to 3, or more preferably 1 to 2, selected from the group consisting of substituents in the same group as those defined for substituted aryls.

[0081] "Heteroaryloxy" means -O-heteroaryl.

[0082] "Substituting heteroaryloxy" means -O-(substituted heteroaryl) group.

[0083] "Heteroarylthio" means -S-heteroaryl group.

[0084] "Substituting heteroarylthio" means -S- (substituted heteroaryl) group.

[0085] "Heteroarylamino" is -NR 37 (heteroaryl) group, where R 37 is hydrogen, alkyl, or substituted alkyl.

[0086] "Substituting heteroarylamino" is -NR 37 (substituted heteroaryl) group, where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heteroaryl is as defined herein.

[0087] "Heterocycle," "heterocyclic," "heterocycloalkyl," or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms, and more preferably 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. x A heterocycloalkyl group refers to a heterocycloalkyl group having x ring heteroatoms. Heterocycles include monocycles or multiple fused rings, such as condensed, bridged, and spirocycle systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, but the bonding site is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0088] "Heterocyclylene" refers to a divalent, saturated or partially saturated, but non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. "Substitutive heterocyclylene" refers to a heterocyclylene group substituted with 1 to 5, or preferably 1 to 3, substituents of the same substituents defined for substituted cycloalkyl groups.

[0089] "Substituting heterocycle," "substituted heterocycloalkyl," or "substituted heterocyclyl" means a heterocyclyl group substituted with 1 to 5, or preferably 1 to 3, substituents of the same substituents defined for substituted cycloalkyls.

[0090] "Heterocyclyloxy" means -O-heterocyclyl group.

[0091] "Substituting heterocyclyloxy" means -O-(substituted heterocyclyl) group.

[0092] "Heterocyclilthio" means -S-heterocyclyl group.

[0093] "Substituting heterocyclylthio" means -S- (substituted heterocyclyl) group.

[0094] "Heterocyclylamino" is -NR 37 (heterocyclyl) group, where R 37 is hydrogen, alkyl, or substituted alkyl.

[0095] "Substituting heterocyclylamino" is -NR 37 (substituted heterocyclyl) group, where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heterocyclyl is as defined herein.

[0096] Examples of heterocyclyls and heteroaryls include azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolidyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylkyrdinyl, pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carborinyl, phenanthridine, acridinyl, phenanthrolinyl, isothiazolyl, phenadinyl, isoxa This includes, but is not limited to, zolyl, phenoxadinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophering, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranil.

[0097] "Nitro" refers to the -NO2 group.

[0098] "Oxo" means atom (=O) or (O).

[0099] A "spiro ring system" refers to a bicyclic ring system that has a single ring carbon atom common to both rings.

[0100] "Sulfinyl" refers to a divalent group: -S(O)- or -S(=O)-.

[0101] "Sulfonyl" refers to a divalent group: -S(O)2- or -S(=O)2-.

[0102] "Substituting sulfonyl" means -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, and -SO2-substituted heterocyclic groups, where 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. Substituting sulfonyls include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on substituted alkyl-SO2- include halogenated alkyl groups, and in particular halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0103] "Substituting sulfinyl" means -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, and -SO-substituted heterocyclic groups, where 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. Substituting sulfinyls include groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on substituted alkyl-SO- include halogenated alkyl groups, and in particular trifluoromethyl, difluoromethyl, and fluoromethyl.

[0104] "Sulfonyloxy" or "substituted sulfonyloxy" means -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 group, where 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.

[0105] "Sulfonylamino" is -NR 37 (substituted sulfonyl) group, where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted sulfonyl is as defined herein.

[0106] "Thioacyl" means a group such as s 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.

[0107] "Mercapto" or "thiol" refers to the -SH group.

[0108] "Formyl" refers to the -C(O)H group.

[0109] "Thiocaunal" refers to a divalent group, -C(S)-, which is synonymous with -C(=S)-.

[0110] "Thion" means atom (=S).

[0111] "Alkylthio" means -S-alkyl, where alkyl is as defined herein.

[0112] "Substituting alkylthio" means an -S-(substituted alkyl) group, where substituted alkyl is as defined herein. Preferred substituted alkyl groups on the -S-(substituted alkyl) include halogenated alkyl groups and, in particular, halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0113] "Vinyl" refers to the unsaturated hydrocarbon radical -CH=CH2 derived from ethylene.

[0114] As used throughout this specification, the terms “optional” or “optionally” mean that the event or situation described thereafter may occur but is not required to occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not. For example, “the nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety” means that the nitrogen atom may be oxidized but is not required to be oxidized, and that the description includes both cases in which the nitrogen atom is not oxidized and cases in which the nitrogen atom is oxidized.

[0115] The term "optionally substituted" means substituted or non-substituted. A substituent may be substituted with one or more substituents, such as 1, 2, 3, 4, or 5 substituents. Preferably, the substituent is selected from the functional groups provided herein. In certain more preferred embodiments, the substituent may be oxo, halo, -CN, NO2, -CO2R 100 , -OR 100 , -SR 100 -SOR 100 , -SO2R100 , -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-C 10 Heterocyclyl, C6-C 14 Aryl and C5-C 12 Selected from heteroaryls, where each R 100 These are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocycline; C6-C 14 Aryl; or C2-C 12 The substituents are heteroaryl groups; where each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted with 1 to 3 halo, 1 to 3 C1-C6 alkyl, 1 to 3 C1-C6 haloalkyl, or 1 to 3 C1-C6 alkoxy groups. More preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0116] R 101 and R 102 These are independently C1-C8 alkyl, C1-C6 alkoxy, oxo, and -CR molecules optionally substituted with hydrogen;-CO2H or its esters. 103 =C(R 103 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 14 Aryl, or C2-C 12 It is a heteroaryl C1-C8 alkyl, where each R 103 These are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10Heterocycline; C6-C 14 Aryl; or C2-C 12 It is a heteroaryl group; where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R 101 and R 102 These, together with the nitrogen atom to which they are bonded, form a 5-7 membered heterocycle.

[0117] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is obtained by naming the terminal portion of the functional group, followed by the functional groups adjacent to the bond site. For example, the substituent "alkoxycarbonylalkyl" means (alkoxy)-C(O)-(alkyl)- group.

[0118] It is understood that polymers obtained by defining substituents that have further substituents themselves (for example, substituted aryls having a substituted aryl group as a substituent that itself is substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substituents is 3. That is, each of the above definitions is constrained by the restriction that, for example, the substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0119] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substitutions with four fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0120] For clarity, it is understood that certain features of the Invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the Invention described in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables are specifically covered by the Invention and are disclosed herein as if each and all combinations were individually and explicitly disclosed, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of chemical groups described in embodiments illustrating such variables are also specifically covered by the Invention and are disclosed herein as if all such subcombinations of chemical groups were individually and explicitly disclosed herein.

[0121] compound In one embodiment, this specification uses formula (I): [ka] (I) [In the formula, Ring A, having a carbonyl (keto) group, forms a five-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, where the heterocycle is optionally substituted with 1 to 2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, where the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 C1-C4 alkyl; C1-C4 alkyl; C3-C5 cycloalkyl, optionally substituted with 1-5 halo, preferably fluoro, or hydroxyl groups, CON(R 10 )2, or NR 10 COR 10 And here, each R 10 These are independently C1-C3 alkyl or H; R2 is H or C1-C3 alkyl; L is C(R) such as O, CH2, S, SO, SO2, CO, CHF, CF2, C(Me)CN, etc. 11 )CN, CHR 11 , or C(R 11 )R 11 Here, each R 11 These are 1 to 5 halos, preferably fluoro, optionally substituted C1-C2 alkyls, or 2 R 11 The groups, together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl ring; R 3 and R 4 Each of these is independently Cl, Br, Me, or ethyl; R 5 is H, halo, C1-C4 alkyl, preferably CH3, or C3-C4 cycloalkyl, or R 5 R 4 and together with intervening atoms, they form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycle containing 1-2 heteroatoms; and X is either absent (i.e., X is conjugated) or O, NR 12 , C(O)NR 12 , NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O,NR 12 CR 12 R 12 CR 12 R 12 NR 12 、 SO2NR 12 , or NR 12 SO2, where each R 12 [It is independently H or methyl] The present invention provides the compound represented by, or its tautomer or N-oxide, or their respective isotopomers, or the respective prodrugs, or the stereoisomers, or the respective pharmaceutically acceptable salts, or the respective solvates.

[0122] In some embodiments, the compound represented by formula (I) is a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the compound represented by formula (I) is represented by formula (IIA): [ka] (IIA) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0124] In one embodiment, the compound represented by formula (I) is represented by formula (IIB): [ka] (IIB) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0125] In one embodiment, the compound represented by formula (I) is represented by formula (IIIA): [ka] (IIIA) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0126] In one embodiment, the compound represented by formula (I) is represented by formula (IIIB): [ka] (IIIB) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown]. In one embodiment, the compound represented by formula (I) is represented by formula (IIIC): [ka] (IIIC) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0127] In one embodiment, the compound represented by formula (I) is represented by formula (IIID): [ka] (IIID) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0128] In one embodiment, the compound represented by formula (I) is represented by formula (IVA): [ka] (IVA) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0129] In one embodiment, the compound represented by formula (I) is represented by formula (IVB): [ka] (IVB) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0130] In one embodiment, the compound represented by formula (I) is represented by formula (IVC): [ka] (IVC) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0131] In one embodiment, the compound represented by formula (I) is represented by formula (IVD): [ka] (IVD) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0132] In one embodiment, the compound represented by formula (I) is represented by formula (VA): [ka] (VA) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0133] In one embodiment, the compound represented by formula (I) is represented by formula (VB): [ka] (VB) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0134] In one embodiment, the compound represented by formula (I) is formula (VC): [ka] (VC) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0135] In one embodiment, the compound represented by formula (I) is represented by formula (VD): [ka] (VD) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0136] In one embodiment, the compound represented by formula (I) is represented by formula (VIA): [ka] (VIA) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0137] In one embodiment, the compound represented by formula (I) is represented by formula (VIB): [ka] (VIB) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0138] In one embodiment, the compound represented by formula (I) is represented by formula (VIC): [ka] (VIC) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0139] In one embodiment, the compound represented by formula (I) is represented by formula (VID): [ka] (VID) [In the formula, the variable group is equivalent to that in formula (I)] It is a compound represented by [the formula shown].

[0140] In one embodiment, the compound represented by formula (I) is represented by formula (VIIA): [ka] (VIIA) [In the formula, R 2[wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0141] In one embodiment, the compound represented by formula (I) is represented by formula (VIIB): [ka] (VIIB) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0142] In one embodiment, the compound represented by formula (I) is represented by formula (VIIC): [ka] (VIIC) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0143] In one embodiment, the compound represented by formula (I) is represented by formula (VIID): [ka] (VIID) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0144] In one embodiment, the compound represented by formula (I) is represented by formula (VIIIA): [ka] (VIIIA) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0145] In one embodiment, the compound represented by formula (I) is represented by formula (VIIIB): [ka] (VIIIB) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0146] In one embodiment, the compound represented by formula (I) is represented by formula (VIIIC): [ka] (VIIIC) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0147] In one embodiment, the compound represented by formula (I) is represented by formula (VIIID): [ka] (VIIID) [In the formula, R 2 [wherein it is H or methyl, and the variable group is equivalent to formula (I)] It is a compound represented by [the formula shown].

[0148] In one embodiment, the compound represented by formula (I) is (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF): [ka] [In the formula, the variable group is equivalent to that in formula (I)] The compound is represented by the formula (IXA). In some embodiments, the compound is represented by the formula (IXB). In some embodiments, the compound is represented by the formula (IXC). In some embodiments, the compound is represented by the formula (IXD). In some embodiments, the compound is represented by the formula (IXE). In some embodiments, the compound is represented by the formula (IXF).

[0149] In one embodiment, ring A having a carbonyl (keto) group forms a five-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, where the keto group is not adjacent to the atom bonded to X. In one embodiment, ring A having a carbonyl (keto) group forms a five-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, where the heterocycle is substituted with 1 to 2 C1-C3 alkyl or C3-C4 cycloalkyl groups, where the keto group is not adjacent to the atom bonded to X. In one embodiment, the five-membered heterocycle contains 1 to 3 ring heteroatoms selected from the group consisting of N and O. In some embodiments, ring A, together with the carbonyl (keto) group within the ring, [ka] In some embodiments, ring A combines with a carbonyl (keto) group within the ring, [ka] That is the case.

[0150] In one embodiment, R 1 is a C1-C4 alkyl group. In some embodiments, R 1 R is methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In some embodiments, R 1 is a C3-C4 alkyl group. In one embodiment, R 1is isopropyl. In some embodiments, R 1 is t-butyl. In one embodiment, R 1 R is 1 to 5 halos, preferably fluoro, and optionally substituted C1-C4 alkyl groups. In some embodiments, R 1 R is a C1-C4 alkyl optionally substituted with one or two halos such as fluoro or chloro. In one embodiment, R 1 is a C1-C4 alkyl group optionally substituted with 1 to 5 halo or hydroxyl groups. In some embodiments, R 1 is a C2-C4 alkyl group optionally substituted with 1 to 5 halo or hydroxyl groups. In some embodiments, R 1 is a C1-C4 alkyl group optionally substituted with one or two halo or hydroxyl groups. In one embodiment, R 1 is a C1-C4 alkyl group optionally substituted with 1 to 5 hydroxyl groups. In some embodiments, R 1 is a C1-C4 alkyl group optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 1 is a C1-C4 alkyl group substituted with one hydroxyl group. In some embodiments, R 1 is a C1-C4 alkyl group optionally substituted with one or two halo or hydroxyl groups. In some embodiments, R 1 is HO-CH(CH3)-. In some embodiments, R 1 It is HO-CH(CH2CH3)-. In some embodiments, R 1 is HO-C(CH3)2-. In some embodiments, R 1 It is HO-CH2CH(CH3)-. In one embodiment, R 1 is a C3-C5 cycloalkyl group. In some embodiments, R 1 It is a monocyclic C3-C5 cycloalkyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 1is cyclopropyl. In some embodiments, R 1 It is a condensed bicyclic C3-C5 cycloalkyl. In some embodiments, R 1 is a crosslinked bicyclic C3-C5 cycloalkyl. In some embodiments, R 1 teeth, [ka] In one embodiment, R 1 CON(R 10 )2. In one embodiment, R 1 , NR 10 COR 10 That is the case.

[0151] In one embodiment, each R 10 R is independently a C1-C3 alkyl group. In some embodiments, each R 10 R is independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments, each R 10 is methyl. In one embodiment, each R 10 is H. In some embodiments, one R 10 H is H, and the other R is R 10 is a C1-C3 alkyl group. In some embodiments, one R 10 H is H, and the other R is R 10 It is methyl.

[0152] In one embodiment, R 2 is H. In one embodiment, R 2 is a C1-C3 alkyl group. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 This is either H or -CH3.

[0153] In one embodiment, L is O. In one embodiment, L is CH2. In one embodiment, L is S. In one embodiment, L is SO. In one embodiment, L is SO2. In one embodiment, L is CO. In one embodiment, L is CHF. In one embodiment, L is CF2. In one embodiment, L is C(R) 11 )CN. In one embodiment, L is C(Me)CN. In one embodiment, L is CHR 11 or C(R 11 )R 11 And here, each R 11 These are independently 1 to 5 halos, preferably fluoro, optionally substituted C1-C2 alkyls, or 2 R 11 The groups, together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl ring. In one embodiment, L is CHR 11 In one embodiment, L is C(R 11 )R 11 In one embodiment, each R 11 R is independently a C1-C2 alkyl group, i.e., methyl or ethyl. In one embodiment, each R 11 These are independently 1 to 5 halo, preferably fluoro-substituted C1-C2 alkyl groups. In one embodiment, two R 11 The groups, together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl ring. In some embodiments, L is O, CH2, SO2, CO, CHR 11 , or C(R 11 )R 11 and each R 11 L is independently methyl or ethyl. In some embodiments, L is O, CH2, SO2, or CO.

[0154] In one embodiment, R 3 is Cl. In one embodiment, R 3 is Br. In one embodiment, R 3 is Me. In one embodiment, R3 is ethyl. In some embodiments, R 3 is Cl or -CH3. In one embodiment, R 4 is Cl. In one embodiment, R 4 is Br. In one embodiment, R 4 is Me. In one embodiment, R 4 is ethyl. In one embodiment, R 3 and R 4 These are Cl, respectively. In some embodiments, R 3 and R 4 Each of these is methyl. In some embodiments, R 3 Cl is, and R 4 is methyl. In some embodiments, R 3 It is methyl, and R 4 It is Cl.

[0155] In one embodiment, R 5 is H. In one embodiment, R 5 is a halo. In some embodiments, R 5 is fluoro, chloro, or bromo. In some embodiments, R 5 is fluoro. In one embodiment, R 5 is a C1-C4 alkyl group. In some embodiments, R 5 is a C1-C3 alkyl group. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In one embodiment, R 5 is CH3. In some embodiments, R 5 is H or -CH3. In one embodiment, R 5 is a C3-C4 cycloalkyl group. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is cyclobutyl. In one embodiment, R 4 R 5And together with the intervening atoms, they form a 5-7 membered cycloalkyl group. In some embodiments, R 4 R 5 and together with intervening atoms, they form cyclopentyl or cyclohexyl. In some embodiments, R 4 R 5 And together with the intervening atoms, it is cyclopentyl. In one embodiment, R 4 R 5 Together with intervening atoms, they form a 5-7 membered heterocycle containing 1-2 ring heteroatoms. Preferred heteroatoms include one or more N, O, and S atoms.

[0156] In one embodiment, X is absent (i.e., X is joined). In one embodiment, X is O. In one embodiment, X is NR 12 In one embodiment, X is C(O)NR 12 In one embodiment, X is NR 12 C(O). In one embodiment, X is NR 12 It is SO2. In one embodiment, X is SO2NR 12 In one embodiment, X is NR 12 C(O). In one embodiment, X is CR 12 R 12 In one embodiment, X is OCR 12 R 12 In one embodiment, X is CR 12 R 12 O. In one embodiment, X is CR 12 R 12 It is NH. In one embodiment, X is NR 12 CR 12 R 12 In some embodiments, X is NR 12 C(O), OCR 12 R 12 , or NR 12 CR 12 R 12 And each R 12X is independently H or methyl. In some embodiments, X is N(CH3)CH2. In one embodiment, X is CR 12 R 12 NR 1 2. In one embodiment, X is NH. In one embodiment, X is CH2. In one embodiment, X is OCH2. In one embodiment, X is CH2O. In one embodiment, X is NHCH2. In one embodiment, X is CH2NH. In one embodiment, X is NHC(O). In one embodiment, X is C(O)NH. In one embodiment, X is SO2NH. In one embodiment, X is NHSO2. In some embodiments, X is OCH2, NHCH2, NHC(O), N(CH3)CH2, or N(H)CH(CH3). In one embodiment, R 12 is H. In one embodiment, R 12 is methyl. In some embodiments, all R 12 The basis is OCR 12 R 12 In certain parts such as, H. In some embodiments, all R 12 The basis is OCR 12 R 12 In certain parts such as, R 12 The basis is OCR 12 R 12 In certain parts, such as those mentioned above, the combination is H and methyl.

[0157] In one embodiment, a compound represented by formula (I) is provided having one or more of the following characteristics: (I) Ring A, which is coupled with a carbonyl group within the ring, (i) [ka] ;or (ii) [ka] is; (II)R 1 but, (iii) A C1-C4 alkyl group optionally substituted with 1 to 5 halo or hydroxyl groups; or (iv) It is a C3-C5 cycloalkyl; (III)R 2 However, it is H or C1-C3 alkyl; (IV)R 3 However, it is either Cl or methyl; (V)R 4 However, it is either Cl or methyl; (VI)R 5 However, it is H, halo, or C1-C4 alkyl; (VII)R 5 However, R 4 Together with intervening atoms, they form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycle containing 1-2 heteroatoms; (VIII)X is, (v) bond; or (vi)NR 12 C(O), OCR 12 R 12 , or NR 12 CR 12 R 12 And here, each R 12 is independently H or methyl; and (IX)L is O, CH2, SO2, or CO.

[0158] In one modification, apply (I). In another modification, apply (II). In another modification, apply (III). In another modification, apply (IV). In another modification, apply (V). In another modification, apply (VI). In another modification, apply (VII). In another modification, apply (VIII). In another modification, apply (IX). In one aspect of this modification, apply (I), (II), (III), (IV), (V), (VI), (VIII), and (IX). In yet another aspect of this modification, apply (I), (II), (III), (IV), (VII), (VIII), and (IX). In one modification, apply (i), (iii), and (vi). In another modification, apply (ii), (iii), and (v). In another modification, apply (i), (iii), and (vi). In one variation, apply (i), (iv), and (vi). In another variation, apply (i), (iii), (VII), and (vi).

[0159] In some embodiments, the compound represented by formula (I) is an agonist of THR beta. In some embodiments, the compound represented by formula (I) is an agonist of THR beta and is more selective than to THR alpha. In some embodiments, the compound represented by formula (I) has at least twice the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least five times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least ten times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least twenty times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least fifty times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least seventy times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has at least 100 times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound represented by formula (I) has 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 the selectivity for THR beta compared to THR alpha. In any such embodiment, in one aspect, the selectivity is evaluated via a biochemical assay such as the TR-FRET assay described in Example B1.

[0160] In this specification, it is understood that all descriptions, variations, embodiments, or aspects of a part can be combined with all descriptions, variations, embodiments, or aspects of the other parts, as if each description and all combinations of descriptions were specifically and individually listed. For example, all descriptions, variations, embodiments, or aspects provided herein with respect to ring A part of formula (I) can be combined with all descriptions of the other parts, as if each description and all combinations of descriptions were specifically and individually listed. 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 All descriptions, variations, embodiments, or aspects of formula (I) can be combined with all descriptions, variations, embodiments, or aspects of X, and L. It is also understood that all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to and described with respect to other formulas detailed herein, where applicable, as if each and every description, variation, embodiment, or aspect were specifically and individually listed for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to and described with respect to any formulas detailed herein, such as formulas (IIA), (IIB), (IIIA)-(IIID), (IVA)-(IVD), (VA)-(VD), (VIA)-(VID), (VIIA)-(VIID), (VIIIA)-(VIIID), and (IXA)-(IXF), where applicable, as if each and every description, variation, embodiment, or aspect were specifically and individually listed for all formulas.

[0161] In some embodiments, compounds selected from the compounds in Table 1 or their pharmaceutically acceptable salts are provided. While certain compounds described in this disclosure, including Table 1, are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any or all stereochemical forms, including any enantiomer or diastereomer forms of any compound in this disclosure, including Table 1, and any tautomers or other forms, are also described herein.

[0162] In one embodiment, this specification provides compounds selected from the compounds summarized in Table 1 below, or their tautomers or N-oxides, or their respective isotopomers, or the respective prodrugs, or the respective stereoisomers, or the respective pharmaceutically acceptable salts, or the respective solvates: Table 1 [Table 1] [Table 2] [Table 3]

[0163] In some embodiments, this specification provides compounds selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0164] The present invention also includes all salts, such as pharmaceutically acceptable salts, of the compounds referred to herein. The present invention also includes any stereochemical form, including any enantiomer, diastereomer, any tautomer, other form such as N-oxide, solvate, prodrug, or isotopomer of the described compounds. Unless the stereochemistry is expressly indicated by the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the compound depicted. Furthermore, if a particular stereochemical form is indicated, it is understood that other stereochemical forms are also included in the present invention. All forms of the compound, such as crystalline or amorphous forms, are also included in the present invention. Compositions containing the compounds of the present invention, for example, compositions of substantially pure compounds containing a particular stereochemical form of that compound, are also intended. Compositions containing mixtures of the compounds of the present invention in any ratio, such as mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, including racemic, non-racemic, enantiorich, and scalmic mixtures of the compounds, are also included in the present invention.

[0165] Synthesis method Scheme 1: General synthetic biaryl-ether core [ka] [Here, R 1 , R 3 , R 4 , and R 5 [ is synonymous with the compound represented by formula (I); T is Br, CN, or NH2; and PG and G are appropriate protecting groups.]

[0166] The biaryl-ether cores of the compounds disclosed herein can be prepared as outlined in Scheme 1. 3,6-Dichloropyridazine and the general formula R 1 -The reaction of the CO2H compound with ammonium persulfate produces R 1 -A substituted dichloropyridazine compound is obtained, which is then reacted with a phenol derivative, hydrolyzed, and optionally nitrogen-protected to obtain the desired intermediate compound.

[0167] Scheme 1': Another pyridazine synthesis [ka] [Here, R 1 This is synonymous with the compound represented by formula (I).

[0168] Scheme 1' provides another synthesis of pyridazine used in the preparation of the compound represented by formula (I) disclosed herein. 3,6-dichloro-1,2,4,5-tetrazine and R 1 -The reaction of substituted acetylenes, R 1 - Substituting dichloropyridazine compounds are obtained.

[0169] Scheme 1a: G = alkyl and T = NH 2 Reaching [ka] [Here, R 1 , R 3 , R 4 , and R 5 [ is synonymous with the compound represented by formula (I); and G is a suitable protecting group.]

[0170] Scheme 1a outlines a synthesis in which G is an alkyl group and T is NH2. Compounds having a biaryl ether core with an amine moiety can be modified by phthalimide protection, N-alkylation, and subsequent deprotection to provide desired intermediates.

[0171] Scheme 2: [ka] [Here, R 1 , R 3 , R 4 , R 5 , and R 12 [ is synonymous with the compound represented by formula (I); and PG, G, and G1 are appropriate protecting groups.]

[0172] Scheme 2 outlines the synthesis of a compound represented by a specific formula (I) disclosed herein. As provided in Scheme 1a, a compound having a biaryl-ether core and an amine moiety can be subjected to N-alkylation and secondary amine derivatization, followed by reaction with NH2OH, treatment with a carbonyl transfer reagent, and optional deprotection to obtain the desired compound.

[0173] Scheme 2a: [ka] [Here, R 1 , R 3 , R 4 , R 5 , and R 12 [ is synonymous with the compound represented by formula (I); and PG and G1 are appropriate protecting groups.]

[0174] Scheme 2a outlines the synthesis of a compound represented by a specific formula (I) disclosed herein. A compound having a biaryl-ether core and an amine moiety can be subjected to N-alkylation, protection of the amine group, reaction with NH2OH, treatment with a carbonyl transfer agent, and optional deprotection or hydrolysis to obtain the desired compound.

[0175] Scheme 3: [ka] [Here, R 1 , R 3 , R 4 , R 5 Ring A is synonymous with the compound represented by formula (I); and G and G1 are appropriate protecting groups.

[0176] Scheme 3 shows the synthesis of a compound represented by a specific formula (I). The reaction of a biaryl-ether derivative having an amine moiety with a carboxylic acid derivative of ring A provides an amide bond to form the desired compound.

[0177] Scheme 4: [ka] [Here, R 1 , R 3 , R 4 , R 5 , and R 12 [ is synonymous with the compound represented by formula (I); and G and PG are appropriate protecting groups.]

[0178] Scheme 4 shows the synthesis of a compound represented by a specific formula (I). Palladium-mediated hydroxylation of a biaryl-ether derivative containing a bromo group, followed by O-alkylation, reaction with NH2OH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis, provides the desired compound.

[0179] Scheme 5: [ka] [Here, R 1 , R 3 , R 4 , and R 5 [ is synonymous with the compound represented by formula (I); and G is a suitable protecting group.]

[0180] Scheme 5 shows the synthesis of a compound represented by a specific formula (I). Treatment of a biaryl-ether derivative having a cyano group with NH2OH, followed by treatment with a carbonyl transfer reagent, provides the desired compound.

[0181] Scheme 6: [ka] [Here, R 1 , R 3 , R 4 , and R 5 This is synonymous with the compound represented by formula (I).

[0182] Scheme 6 shows the synthesis of a compound represented by a specific formula (I). Treatment of a biaryl-ether derivative having a cyano group with NH2OH, followed by treatment with a carbonyl transfer reagent and hydrolysis, provides the desired compound.

[0183] Scheme 7: [ka] [Here, R 1 , R 3 , R 4 , and R 5 [ is synonymous with the compound represented by formula (I); and G is a suitable protecting group.]

[0184] Scheme 7 shows the synthesis of a compound represented by a specific formula (I). Diazotation / iodonation of a biaryl-ether derivative having an amino group, followed by sonogashira coupling and reaction with NH2OH, and subsequently optional deprotection, provides the desired compound.

[0185] The synthesis of the specific compounds provided herein is schematically shown above and provided in the Examples section below. The variables listed in the scheme above are synonymous with the compound represented by formula (I), or any variant, embodiment, or aspect. The synthesis of other compounds provided herein will be apparent to those skilled in the art, based on the guidance provided herein and on synthesis methods well known to those skilled in the art.

[0186] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or dividing enantiomers. For example, a diastereomer derivative can be produced by the reaction of a mixture of enantiomers, e.g., a racemate, with a suitable chiral compound. The diastereomer can then be separated by any convenient means, e.g., crystallization, to recover the desired enantiomer. In another division process, the racemate can be separated using chiral high-performance liquid chromatography. Alternatively, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes, if necessary.

[0187] Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products if it is desired to obtain specific isomers of a compound or otherwise purify the products of a reaction.

[0188] Solvates and / or polymorphs of the compounds provided herein, as well as their pharmaceutically acceptable salts, are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Polymorphs contain the same elemental composition of the compound but with different crystalline packing configurations. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline shapes, optical and electrical properties, stability, and / or solubility. Single crystals may be dominant due to various factors such as the recrystallization solvent, crystallization rate, and storage temperature.

[0189] It is understood that the synthesis processes disclosed herein can be modified to arrive at various compounds of the present invention by selecting appropriate reagents and starting materials. It is also understood that, if protection of a specific active or incompatible group (e.g., an amine or carboxylic acid) is required, the formulas of the schemes provided herein, for example, are intended to include compounds in which such active or incompatible groups are appropriately protected. For a general description of protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4. th See edition, Wiley-Interscience, New York, 2006.

[0190] Pharmaceutical compositions and formulations Any pharmaceutical composition of any of the compounds detailed herein is included in the present invention. Accordingly, the present invention includes pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. In one embodiment, 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 present invention can be in a form suitable for oral, buccal, parenteral, intranasal, topical or rectal administration, or in a form suitable for inhalation administration.

[0191] In one embodiment, the compounds detailed herein may be in a purified form, and compositions comprising the compounds in a purified form are detailed herein. Compositions comprising the compounds or salts thereof, as detailed herein, are provided, such as substantially pure compositions of the compounds. In some embodiments, the compositions comprising the compounds or salts thereof described herein are in a substantially pure form. In one variation, “substantially pure” means a composition with no more than 35% impurities, where impurities mean compounds other than the compound or salts thereof that constitute the majority of the composition. For example, a substantially pure composition of a compound selected from the compounds in Table 1 is intended to be a composition with no more than 35% impurities, where impurities indicate compounds other than the compound or salts thereof. In one variation, a substantially pure composition of the compound or salt thereof is provided, which contains no more than 25% impurities. In another variation, a substantially pure composition of the compound or salt thereof is provided, which contains 20% or less impurities. In yet another variation, a substantially pure composition of the compound or salt thereof is provided, which contains 10% or less impurities. In a further variation, a substantially pure composition of the compound or salt thereof is provided, which contains 5% or less impurities. Another variation provides a substantially pure composition of the compound or a salt thereof, the composition containing 3% or less impurities. Yet another variation provides a substantially pure composition of the compound or a salt thereof, the composition containing 1% or less impurities. A further variation provides a substantially pure composition of the compound or a salt thereof, the composition containing 0.5% or less impurities. In yet another variation, a substantially pure composition of the compound means that the composition contains 15% or less, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and most preferably 1% or less impurities, where these impurities may be compounds of different stereochemical forms. For example, without limitation, a substantially pure composition of the (S) compound means that the composition contains 15% or less, or 10% or less, or 5% or less, or 3% or less, or 1% or less of the (R) type compound.

[0192] In one variation, the compounds described herein are synthetic compounds prepared for administration to an organism such as a human. In another variation, a composition comprising a substantially pure form of the compound is provided. In yet another variation, the present invention encompasses a pharmaceutical composition comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In yet another variation, a method for administering the compound is provided. The purified form, pharmaceutical composition, and method for administering the compound are suitable for any of the compounds or forms detailed herein.

[0193] The compound may be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, cheek, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound may be formulated with a suitable carrier to provide delivery forms, including, but not limited to, tablets, caplets, capsules (such as rigid or flexible gelatin capsules), cachets, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0194] One or more compounds described herein can be used in the preparation of pharmaceutical formulations, such as medical formulations, by combining one or more compounds as active ingredients with pharmaceutically acceptable carriers as described above. Depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet), the carrier may be in various forms. Furthermore, the medical formulation may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, modifiers, salts for osmotic pressure adjustment, buffers, coatings, or antioxidants. The formulation containing the compounds may also contain other substances having valuable therapeutic properties. The medical formulation can be prepared by known medical methods. For example, see Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st This can be found in ed. (2005), which is incorporated into this application by reference.

[0195] The compounds described herein can be administered to an individual (e.g., a human) in the form of commonly accepted oral compositions such as tablets, coated tablets, and hard-shell or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used in the preparation of such compositions include lactose, corn starch or its derivatives, talc, stearate or its salts. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, modifiers, salts for osmotic pressure adjustment, buffers, coatings, or antioxidants.

[0196] Any of the compounds described herein can be formulated into tablets of any of the dosage forms described.

[0197] Compositions containing the compounds provided herein are also described. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, a substantially pure composition of the compound is provided.

[0198] How to use / treat Compounds and compositions detailed herein, such as compounds of any formula provided herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising pharmaceutically acceptable carriers or excipients, may be used in administration and therapeutic methods provided herein. Compounds and compositions may also be used in in vitro methods, such as in vitro methods for administering the compound or composition to cells for screening purposes and / or for performing quality control assays.

[0199] In one embodiment, this specification provides a method for agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with either an effective amount of a compound provided herein or an effective amount of a pharmaceutical composition provided herein.

[0200] In one embodiment, this specification provides a method for treating a patient's THR beta-mediated disorder, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0201] Disorders mediated by THR beta, including but not limited to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, as well as methods for treating their respective symptoms and signs, are well known to those skilled in the art and can be adapted to treat such disorders with compounds or compositions provided herein.

[0202] In one embodiment, the Specified provides a method for agonizing thyroid hormone receptor beta (THRbeta), comprising contacting THRbeta with an effective amount of any of the compounds provided herein, or salts thereof such as pharmaceutically acceptable salts, or an effective amount of any of the pharmaceutical compositions provided herein. In one embodiment, the Specified provides a method for selectively agonizing THRbeta more than THRalpha, comprising contacting THRbeta with any of the compounds provided herein, or salts thereof such as pharmaceutically acceptable salts, or an effective amount of any of the pharmaceutical compositions provided herein. In one such embodiment, the method selectively agonizes THRbeta more than THRalpha by 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. In such embodiments, in one aspect, selectivity is evaluated via a biochemical assay such as the TR-FRET assay described in Example B1.

[0203] In one embodiment, the Specified provides a method for treating a THR beta-mediated disease or disorder in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one embodiment, the disease or disorder is a liver disease or liver disorder. In one embodiment, the Specified provides a method for treating a liver disease or liver disorder associated with suboptimal THR beta agonism in a patient in need, comprising administering to the patient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof that selectively agonizes THR beta rather than THR alpha.

[0204] In one aspect, this specification provides a method for treating non-alcoholic fatty liver disease in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for treating non-alcoholic steatohepatitis (NASH) in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for treating metabolic syndrome in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for treating dyslipidemia in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for treating hypertriglyceridemia in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one embodiment, the Specified provides a method for treating hypercholesterolemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0205] In any of the embodiments described herein, patients with a disease or disorder related to THR betaagonism may include, but are not limited to, patients with underlying hypothyroidism.

[0206] In another embodiment, a method is provided for delaying the onset and / or progression of a THR beta-mediated disease or disorder in a patient (such as a human) at risk of developing the disease or disorder. It is understood that delaying onset may include prevention if the individual does not develop the disease or disorder. In one embodiment, an individual at risk of developing a THR beta-mediated disease or disorder has one or more risk factors for developing the disease or disorder, such as age, increased waist circumference, high body mass index, or the presence of associated comorbidities.

[0207] In one aspect, this specification provides a method for delaying the onset and / or progression of non-alcoholic fatty liver disease in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for delaying the onset and / or progression of non-alcoholic steatohepatitis (NASH) in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for delaying the onset and / or progression of metabolic syndrome in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one aspect, this specification provides a method for delaying the onset and / or progression of dyslipidemia in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. In one embodiment, the Specified provides a method for delaying the onset and / or progression 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 embodiment, the Specified provides a method for delaying the onset and / or progression of hypercholesterolemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein.

[0208] In one embodiment, this specification provides a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for therapeutic use. In several embodiments, this specification provides a pharmaceutical composition comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt, for use in the treatment of non-alcoholic fatty liver disease. In several embodiments, this specification provides a pharmaceutical composition comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt, for use in the treatment of non-alcoholic steatohepatitis (NASH). In several embodiments, this specification provides a pharmaceutical composition comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt, for use in the treatment of metabolic syndrome. In several embodiments, this specification provides a pharmaceutical composition comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt, for use in the treatment of dyslipidemia. In some embodiments, this specification provides pharmaceutical compositions for use in the treatment of hypertriglyceridemia, comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt. In some embodiments, this specification provides pharmaceutical compositions for use in the treatment of hypercholesterolemia, comprising a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or such a compound or pharmaceutically acceptable salt.

[0209] In another embodiment, this specification provides a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical for the treatment of non-alcoholic fatty liver disease. In yet another embodiment, this specification provides a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical for the treatment of non-alcoholic steatohepatitis (NASH). In yet another embodiment, this specification provides a compound represented by formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical for the treatment of metabolic syndrome. In some embodiments, the pharmaceutical is for the treatment of dyslipidemia. In some embodiments, the pharmaceutical is for the treatment of hypertriglyceridemia. In some embodiments, the pharmaceutical is for the treatment of dyslipidemia. In some embodiments, the pharmaceutical is for the treatment of hypercholesterolemia.

[0210] 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 about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old, or any of the above about 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 about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old, or any of the above about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old.

[0211] Medication and administration methods The dose of any compound described herein, or its stereoisomers, tautomers, solvates, or salts, administered to an individual (such as a human) varies depending on the specific compound or salt thereof, the method of administration, and the specific disease 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.

[0212] The compounds or salts thereof provided herein can be administered to an individual via various routes, such as intravenous, intramuscular, subcutaneous, oral, or transdermal.

[0213] In one embodiment, the effective dose of the compound may be a dose between about 0.01 and about 100 mg / kg. The effective dose or amount of the compound of this disclosure can be determined by routine methods such as modeling, dose escalation, or clinical trials, taking into account routine factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, the patient's health status, physical condition, and body weight. Exemplary doses range from about 0.7 mg to 7 g per day, or about 7 mg to 350 mg, or about 350 mg to 1.75 g, or about 1.75 to 7 g.

[0214] In one embodiment, any of the methods provided herein may involve administering to an individual a pharmaceutical composition comprising an effective amount of the compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.

[0215] The compounds or compositions provided herein can be administered to an individual for a desired time or period, 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, according to an effective dosage plan, and in some variations, may extend to the individual's lifetime. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered to an individual continuously over a period of time (e.g., at least once a day). The dosage frequency can also be less than once a day, for example, once a week. The dosage frequency can be once or more a day, for example, twice or three times a day. The dosage frequency can also be intermittent, including “drug-free periods” (e.g., once a day for seven days followed by seven days of no dosage, repeated for any 14-day period, for example, about two months, about four months, about six months or longer). Any dosage frequency can be used with any of the compounds described herein, in conjunction with any of the dosages described herein.

[0216] Products and Kits This disclosure further provides products comprising the compounds or salts thereof described herein, the compositions described herein, or one or more unit doses described herein in appropriate packaging. In certain embodiments, the product is intended for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, wide-mouthed bottles, flexible packaging, etc. The product may be further sterilized and / or sealed.

[0217] This disclosure further provides a kit for carrying out the method of this disclosure, comprising one or more compounds described herein or a composition comprising one or more compounds described herein. The kit may use any of the compounds disclosed herein. In one variation, the kit may use one of the compounds described herein or a pharmaceutically acceptable salt thereof. The kit may be used for any one or more of the uses described herein and may therefore include instructions for the treatment of any disease, or for example, one of the diseases described herein, such as non-alcoholic steatohepatitis (NASH).

[0218] The kit generally includes appropriate packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if there are multiple components) may be packaged in a separate container, or several components may be combined in one container, as long as cross-reactivity and shelf life permit.

[0219] The kit may be a unit dose, a bulk package (e.g., a multi-dose package), or a subunit dose. For example, a kit may be provided that contains a sufficient dose of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for the disease detailed herein, and that provides effective treatment for an individual for an extended period such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. The kit may contain multiple unit doses of the compound and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (such as a hospital pharmacy or a compounding pharmacy).

[0220] The kit may optionally include a set of instructions, generally written instructions, although an electronic storage medium (e.g., a magnetic diskette or optical disc) containing instructions is also acceptable in connection with the use of the components of the method of this disclosure. Instructions included in the kit generally include information about the components and their administration to an individual.

[0221] Exemplary Embodiments This disclosure is further illustrated by the following embodiments. Features of each embodiment can be combined with any other embodiment that is appropriate and practical.

[0222] Embodiment 1. Formula (Ia): [ka] (Ia) [In the formula, Ring A, having a carbonyl (keto) group within it, forms a five-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, where the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl or C3-C4 cycloalkyl groups, where the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 The C1-C4 alkyl and C3-C5 cycloalkyl groups consist of 1 to 5 halos, preferably fluoro, and optionally substituted with C1-C4 alkyl and C3-C5 cycloalkyl groups, CON(R 10 )2, or NR 10 COR 10 And here, each R 10 These are independently C1-C3 alkyl or H; R 2 is H or C1-C3 alkyl; L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 )CN, CHR 11 , or C(R 11 )R 11 And each R 11 These are independently 1 to 5 halos, preferably fluoro, optionally substituted C1-C2 alkyls, or 2 R 11 The groups, together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl ring; R 3 and R 4 Each of these is independently Cl, Br, methyl, or ethyl; R 5 is either H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R5 R 4 Together with intervening atoms, they form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycle containing 1-2 heteroatoms; X is either absent (i.e., X is conjugated) or O, NR 12 , C(O)NR 12 , NR 12 C(O), CR 12 R 12 OCR 12 R 12 , CR 12 R 12 O,NR 12 CR 12 R 12 , CR 12 R 12 NR 12 SO2NR 12 , NR 12 SO2, where each R 12 [It is independently H or methyl] The compound represented by or its tautomer or N-oxide, or their respective isotopomers, or the respective prodrugs, or the stereoisomers, or the respective pharmaceutically acceptable salts, or the respective solvates.

[0223] Embodiment 2. Formulas (IIA), (IIB), (IIIA), (IIIB), (IIIC), (IVA), (IVB), (IVC), (IVA), (VB), (VC), (VIA), (VIB), or (VIC): [ka] (IIA) (IIB) [ka] (IIIA) (IIIB) (IIIC) [ka] (IVA) (IVB) (IVC) [ka] (VA) (VB) (VC) [ka] (VIA) (VIB) (VIC) [In the formula, the variable group has the same meaning as in Embodiment 1.] The compound of Embodiment 1 shown.

[0224] Embodiment 3. Formulas (VIIA), (VIIB), (VIIC), (VIIIA), (VIIIB), or (VIIIC): [ka] (VIIA) (VIIB) (VIIC) [ka] (VIIIA) (VIIIB) (VIIIC) [In the formula, R 2 [wherein it is H or methyl, and the variable group is the same as in Embodiment 1] The compound of Embodiment 1 shown.

[0225] Embodiment 4.R 1 The compound of Embodiment 1, wherein isopropyl. Embodiment 5.R 2 The compound of Embodiment 1, wherein is H. Embodiment 6.R 3 The compound of Embodiment 1, wherein is chloro. Embodiment 7.R 4 The compound of Embodiment 1, wherein is chloro. Embodiment 8.R 5 The compound of Embodiment 1, wherein the compound is hydrogen. Embodiment 9. The compound of Embodiment 1, wherein the X is a bond.

[0226] Embodiment 10.X is CHR 11 , OCHR 11 , NR 11 CHR 11 , NR 11CH2, CHR 11 NH, CHR 11 NR 11 NHCR 11 R 11 , C(O)NR 12 , NR 12 C(O), SO2NR 12 , or NR 12 It is SO2, and here, R 12 The compound of Embodiment 1, wherein the same meaning applies as in Embodiment 1. Implementation 11.X is NH, CH 2、 The compound of Embodiment 1, which is OCH2, CH2O, NHCH2, CH2NH, C(O)NH, NHC(O), SO2NH, or NHSO2. Embodiment 12. The compound of Embodiment 1, wherein -X- is -NH-CH2-, -NHC(O)-, or -O-CH2-. Embodiment 13. The compound of Embodiment 1, wherein -L- is O.

[0227] Embodiment 14. A compound selected from the compounds listed in Table 1. Embodiment 15. A pharmaceutical composition comprising the compound of Embodiment 1 and at least one pharmaceutically acceptable anti-aging agent.

[0228] Embodiment 16. A method for agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of the compound of Embodiment 1 or an effective amount of the composition of Embodiment 15.

[0229] Embodiment 17. A method for treating a patient's THR beta-mediated disorder, comprising administering to the patient a therapeutically effective amount of the compound of Embodiment 1, or a therapeutically effective amount of the composition of Embodiment 15. [Examples]

[0230] This disclosure is made for illustrative purposes only, and it is understood that numerous changes in the combination and arrangement of parts can be reclassified by those skilled in the art without departing from the true intent and scope of this disclosure.

[0231] The chemical reactions in the described examples can be readily adapted to prepare many other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. The synthesis of non-exemplary compounds according to this disclosure can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by utilizing other suitable reagents known to those skilled in the art other than those described, or by routinely changing reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of this disclosure.

[0232] The following abbreviations may be relevant to this application. Abbreviation Ac: Acetyl ACN: Acetonitrile Boc: Tertiary butyloxycarbonyl Bu: Butyl DBA: Dibenzylideneacetone DMAP: Dimethylaminopyridine DMF: Dimethylformamide DMF-DMA: Dimethylformamide Dimethylacetal DMSO: Dimethyl sulfoxide DSC: Disco Synimidyl Carbonate Et: Ethyl Me: Methyl Pr: Propyl Py or Pyr: pyridine rt: room temperature SEMCl:2-(trimethylsilyl)ethoxymethylchloride SFC: Supercritical Fluid Chromatography TEA: Triethylamine THF: Tetrahydrofuran TFA: Trifluoroacetic acid t-Bu Xphos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0233] Synthesis example Scheme A: 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (compound 1e)

[0234] [ka]

[0235] 3,6-Dichloro-4-isopropylpyridazine (1a) Sulfuric acid (19.75 g, 201.37 mmol, 10.73 mL) was added at 60°C to a mixture of 3,6-dichloropyridazine (10 g, 67.12 mmol), 2-methylpropanoic acid (6.21 g, 70.48 mmol, 6.54 mL), and AgNO3 (5.70 g, 33.56 mmol, 5.64 mL) in H2O (200 mL). Next, a solution of ammonium persulfate (45.95 g, 201.37 mmol) in H2O (100 mL) was added dropwise to the mixture at 75°C, and the resulting mixture was stirred at 75°C for 30 minutes. TLC indicated completion of the reaction. After cooling, the mixture was adjusted to pH 9-10 with NH3·H2O, extracted with ethyl acetate (200 mL x 2), washed the organic phase with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain 1a. The product was used directly in the next step. Calculated MS mass: [M+1] + (C7H8Cl2N2) m / z 191.1, LCMS measured value: m / z 191.1; 1 H NMR (400MHZ, CDCl3) δ 7.38 (s, 1H), 3.24 - 3.31 (m, 1H), 1.31 (d, J=6.8 HZ, 6H).

[0236] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline(1b) 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), K2CO3 (9.32 g, 67.41 mmol) and CuI (1.93 g, 10.11 mmol) were added. The mixture was then degassed, purged three times with N2, and stirred at 90°C for 16 hours under a nitrogen atmosphere. TLC and LCMS showed that the starting materials were completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned into ethyl acetate (1000 mL × 2) and H2O (500 mL). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1~3:1, TLC) to obtain 1b. Calculated MS mass: [M+1] + (C 13 H 12 Cl3N3O) m / z 332.0, LCMS measured value: m / z 332.0; 1 H NMR (400MHZ, DMSO) δ 7.66(s, 1H), 6.67 - 6.76(m, 2H), 5.67(s, 2H), 3.11 - 3.21(m, 1H), 1.28(d, J=6.85 HZ, 6H).

[0237] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-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-isopropylpyridazine-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 that the starting materials were completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCO3 solution (10 mL). The mixture was then partitioned into ethyl acetate (30 mL x 2) and H2O (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was diluted with ethyl acetate (10 mL), and then petroleum ether (50 mL) was gradually added to the mixture. The mixture was filtered to collect the solid. The solid was dried to obtain 1c. Calculated MS mass: [M+1] + (C 21 H 15 Cl2N3O4) m / z 444.0, LCMS measured value: m / z 444.1; 1 H NMR(400MHZ, DMSO)δ 12.21(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).

[0238] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoindoline-1,3-dione(1d) A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)iso-indoline-1,3-dione (1c) (500 mg, 1.13 mmol) in DMF-DMA (4 mL) was stirred at 110°C for 2.5 hours. TLC showed that the starting material was completely consumed and two new spots were formed. The mixture was concentrated under reduced pressure. The residue was partitioned into ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1d. The product was used directly in the next step without purification.

[0239] 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 butan-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 LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R f The sample was purified using the method (=0.6) to obtain 1e. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O2) m / z 328.1, LCMS measured value: m / z 328.2; 1 H NMR (400MHZ, CD3OD)δ 7.22(s, 1 H)6.70(s, 1 H)3.52(s, 3 H)3.17(dt, J=13.81, 7.13 Hz, 1 H)1.43(s, 2 H)1.25(d, J=6.58 Hz, 6 H).

[0240] Example 1: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0241] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)-acetonitrile(1f) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (240 mg, 731.28 uL) in ACN (4 mL), 2-bromoacetonitrile (438.58 mg, 3.66 mmol, 243.65 uL), NaI (219.23 mg, 1.46 mmol), and K2CO3 (202.13 mg, 1.46 mmol) were added. The mixture was then sealed in a tube and stirred at 100°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad was washed with siRNA (5 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was subjected to preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R f Purified using (=0.5), 1f was obtained as a yellow oily substance. Calculated MS mass: [M+1] + (C 16 H 16 Cl2N4O2) m / z 367.1, LCMS measured value: m / z 366.8; 1 H NMR(400MHZ, CDCl3)δ 7.04(s, 1H), 6.72(s, 2H), 4.13(d, J=6.85 HZ, 2H), 3.54(s, 3H), 3.21 - 3.28(m, 1H), 1.26(d, J=6.85 HZ, 5H).

[0242] Tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-phenyl)carbamate (1g) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)acetonitrile (1f) (210 mg, 571.85 umol) in THF (3 mL), Boc2O (374.41 mg, 1.72 mmol, 394.12 uL) and DMAP (69.86 mg, 571.85 umol) were added. The mixture was stirred at 40°C for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1, P1:R) f LC-MS (=0.9) and LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned twice into ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was prepared using TLC (SiO2, petroleum ether:ethyl acetate = 3:1, P1:R f Purified using the method (=0.5), yielding 1 g. Calculated MS mass: [M+1] + (C 21 H 24 Cl2N4O4) m / z 467.1, LCMS measured value: m / z 467.0; 1 H NMR(400MHZ, CDCl3)δ 7.45(s, 2H), 4.61(s, 2H), 3.43(s, 3H), 3.13(dt, J=13.8, 6.8 HZ, 1H), 1.45(s, 9H), 1.22(d, J=6.8 HZ, 6H).

[0243] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate(1h) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate (1 g) (250 mg, 534.94 umol) in DMF (3 mL), NH2OH·HCl (297.39 mg, 4.28 mmol) and NaOAc (351.06 mg, 4.28 mmol) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was partitioned into ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1h (260 mg, crude) as a yellow solid. The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 21 H 27 Cl2N5O5) m / z 500.1, LCMS measured value: m / z 500.1.

[0244] tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(1i) To a solution of (Z / E)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-carbamate (1h) (260 mg, 519.61 uL) in THF (3 mL), DSC (173.04 mg, 675.49 uL, 1.3 equivalents) and TEA (105.16 mg, 1.04 mmol, 144.65 uL) were added. The mixture was stirred at 60°C for 16 hours. TLC (dichloromethane:methanol = 10:1, P1:R) fLC-MS (=0.3) and LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned into ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was prepared using TLC (SiO2, DCM:MeOH = 10:1, P1:R f 1i was obtained by purification using the method (=0.3). Calculated MS mass: [M+1] + (C 22 H 25 Cl2N5O6) m / z 526.1, LCMS measured value: m / z 526.2; 1 H NMR (400MHZ, CD3OD)δ 7.54(s, 2H), 7.32(s, 1H), 4.77(s, 2H), 3.48(s, 3H), 3.18(dt, J=13.6, 6.84 HZ, 1H), 1.46(s, 9H), 1.27(d, J=6.8 HZ, 6H).

[0245] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H),-one (Example 1) A solution of tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (1i) (170 mg, 322.97 umol) in HCl / siRNA (2 mL) was stirred at 25°C for 2 hours. LC-MS and HPLC showed that the starting material was completely consumed and the desired MS was detected. The mixture was diluted with water (0.5 mL) and the pH was adjusted to 8 with NaHCO3 (5 mL). The mixture was then divided twice into 10 mL of ethyl acetate. The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using a preparative HPLC (FA) column: Luna C18 100×30 5u; mobile phase: [water (0.2% FA)-ACN]; B%: 25%-60%, 12 min] to obtain Example 1. Calculated MS mass: [M+1] + (C 17 H 17Cl2N5O4) m / z 426.1, LCMS measured value: m / z 426.0; 1 H NMR (400 MHZ, CD3OD) δ 7.23(s, 1H), 6.76(s, 2H), 4.88(s, 139H), 4.28(s, 2H), 3.50(s, 3H), 3.12 - 3.21(m, 1H), 1.25(d, J=7.06 HZ, 6H).

[0246] Example 2: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0247] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)amino)acetonitrile(2a) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)acetonitrile (1f) (50 mg, 136.15 uL) in THF (2 mL), Cs2CO3 (66.54 mg, 204.23 uL) and MeI (193.26 mg, 1.36 mmol, 84.76 uL) were added. The mixture was placed in a sealed tube and stirred at 100°C for 16 hours. TLC and LCMS showed that approximately 30% of the reaction product 1f remained, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad was washed with siRNA (5 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 2a. Calculated MS mass: [M+1] + (C 17 H 18 Cl2N4O2) m / z 381.1, LCMS measured value: m / z 381.0. 1 H NMR (400 MHZ, CDCl3)δ 7.03(d, J=0.7 HZ, 1H), 6.82(s, 2H), 4.19(s, 2H), 3.54(s, 3H), 3.28 - 3.20(m, 1H), 3.05(s, 3H), 1.27 - 1.25(m, 6H).

[0248] (Z)-2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)-amino)-N'-hydroxyacetoimidamide(2b) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)amino)acetonitrile (2a) (52 mg, 136.39 umol) in DMF (2 mL), NH2OH·HCl (75.82 mg, 1.09 mmol) and NaOAc (89.51 mg, 1.09 mmol) were added. The mixture was stirred at 80°C for 6 hours. TLC showed that reactant 2a was completely consumed, and LCMS showed one major peak with the desired MS. The suspension was filtered through a Celite pad, and the pad was washed with RINKAN (5 mL × 3). The combined filtrate was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1, TLC) to obtain 2b. Calculated MS mass: [M+1] + (C 17 H 21 Cl2N5O3) m / z 414.1, LCMS measured value: m / z 414.1.

[0249] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 2) To a solution of (Z / E)-2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(methyl)amino)-N'-hydroxyacetoimidamide (2b) (30 mg, 65.17 uL) in THF (2 mL), DSC (21.70 mg, 84.72 uL) and TEA (33.97 mg, 335.75 uL, 46.73 uL) were added. The mixture was stirred at 80°C for 2 hours. TLC and LCMS showed that 2b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC, and then purified by preparative HPLC (column: Waters Atlantis T3 150×30×5um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 13 min) to obtain Example 2. Calculated MS mass: [M+1]+ (C 18 H 19 Cl2N5O4) m / z 440.1, LCMS measured value: m / z 0.440.1. 1 H NMR (400MHZ, CD3OD)δ 7.24(s, 1H), 6.92(s, 2H), 4.48(s, 2H), 3.49(s, 3H), 3.17(td, J=7.2, 13.9 HZ, 1H), 3.05(s, 3H), 1.26(d, J=6.8 HZ, 6H).

[0250] Example 3: P1 and P2: 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0251] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)propanenitrile(3a) A mixture of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (0.2 g, 609.40 umol, 1 equivalent), K2CO3 (168.44 mg, 1.22 mmol), NaI (182.69 mg, 1.22 mmol), and 2-bromopropannitrile (816.44 mg, 6.09 mmol) in CH3CN (5 mL) was placed in a sealed tube and heated at 90°C for 16 hours. LC-MS showed the desired MS and STM for 1e. The mixture was filtered and washed with ethyl acetate (10 mL x 2). The combined filtrate was washed with brine (20 mL), and the organic phase was concentrated to obtain 3a (0.25 g, crude). The crude product was used directly in the next step. Calculated MS mass: [M+1] + (C 17 H 18 Cl2N4O2) m / z 381.1, LCMS measured value: m / z 381.0.

[0252] Tert-butyl(1-cyanoethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate(3b) A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)propanenitrile (3a) (0.25 g, 655.73 umol), Boc2O (429.33 mg, 1.97 mmol, 451.93 uL), and DMAP (80.11 mg, 655.73 umol) in THF (5 mL) was heated at 50°C for 1 hour. LC-MS showed the desired MS, and TLC showed novel spots. The mixture was concentrated, and the residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to obtain 3b. Calculated MS mass: [M+1] + (C 22 H 26 Cl2N4O4) m / z 481.1, LCMS measured value: m / z 481.3; 1 H NMR (400MHz, CDCl3)δ 7.31(s, 2H), 7.07(s, 1H), 3.51(s, 3H), 3.30 - 3.23(m, 1H), 3.20(q, J=7.0 Hz, 1H), 2.03(s, 3H), 1.75(d, J=7.0 Hz, 3H), 1.57(s, 4H), 1.51 - 1.43(m, 9H), 1.28(d, J=6.8 Hz, 6H).

[0253] (Z / E)-tert-butyl(1-amino-1-(hydroxyimino)propan-2-yl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate(3c) A mixture of tert-butyl(1-cyanoethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate (3b) (80 mg, 166.19 ml), NH2OH·HCl (92.39 mg, 1.33 mmol), and NaOAc (109.07 mg, 1.33 mmol) in DMF (3 mL) was heated at 80°C for 5 hours. LC-MS showed the desired MS, and TLC (petroleum ether:ethyl acetate = 1:1, R) was used. f(=0.47) showed a new spot. The mixture was filtered, washed with ethyl acetate (10 mL × 2), the filtrate was washed with brine (10 mL × 2), the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 3c. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O5) m / z 514.2, LCMS measured value: m / z 514.0;

[0254] Tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)ethyl)carbamate(3d) A mixture of (Z / E)-tert-butyl(1-amino-1-(hydroxyimino)propan-2-yl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate (3c) (39 mg, 75.82 umol), DSC (25.25 mg, 98.56 umol), and TEA (15.34 mg, 151.63 umol, 21.11 uL) in THF (4 mL) was heated at 60°C for 2 hours. The mixture was then heated under reflux for a further 4 hours. TLC (petroleum ether:ethyl acetate = 1:1, R) f =0) indicates completion of the reaction, and the mixture was concentrated to obtain 3d (70 mg, crude), which was used directly in the next step. Calculated mass of MS: [M+1] + (C 23 H 27 Cl2N5O6) m / z 540.1, LCMS measured value: m / z 540.2;

[0255] 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazole-5(4H)-one (Example 3) To a solution of tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)ethyl)carbamate (3d) (70 mg, 129.53 umol) in DCM (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at 25°C for 50 minutes. LC-MS indicated completion of the reaction and detection of the desired MS. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) (column: Waters Atlantis T3 150×30×5um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-80%, 13 min) to obtain 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazole-5(4H)-one (Example 3). Calculated MS mass: [M+1] + (C 18 H 19 Cl2N5O4) m / z 440.0, LCMS measured value: m / z 440.1; 1 H NMR (400MHz, CD3OD)δ 7.25(d, J=0.8 Hz, 1H), 6.78(s, 2H), 4.55(q, J=6.8 Hz, 1H), 3.52(s, 3H), 3.23 - 3.13(m, 1H), 1.60(d, J=6.8 Hz, 3H), 1.27(d, J=7.0 Hz, 6H).

[0256] SFC Separation: 3-(1-((3,5-Dichloro-4-((5-Isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-Oxadiazole-5(4H)-one (Example 3) (17.17 mg, 39.00 umol, 1 equivalent) was separated by SFC ([Monitoring] Instrument: Thar SFC80 Preparative SFC; Column: Chiralpak AS-H, 250 × 30 mm id10u; Mobile Phase: A for CO2 and B for MeOH (0.1% ammonia); Gradient: B%=40%; Flow Rate: 70 g / min; Wavelength: 220 nm; Column Temperature: 40°C; System Back Pressure: 100 bar) in Example-P1; Calculated MS Mass: [M+1] + (C 18 H 19 Cl2N5O4) m / z 440.1, LCMS measured value: m / z 440.0; 1 H NMR (400MHz, CD3OD)δ 7.23(d, J=0.8 Hz, 1H), 6.75(s, 2H), 4.48(q, J=6.8 Hz, 1H), 3.51(s, 3H), 3.17(td, J=6.6, 13.6 Hz, 1H), 1.58(d, J=6.8 Hz, 3H), 1.26 (d, J=7.2 Hz, 6H) and Example-P2; Calculated value of MS mass: [M+1] + (C 18 H 19 Cl2N5O4) m / z 440.1, LCMS measured value: m / z 440.0; 1 H NMR (400MHz, CD3OD)δ 7.23(s, 1H), 6.75(s, 2H), 4.48(q, J=6.8 Hz, 1H), 3.51(s, 3H), 3.17(quin, J=6.8 Hz, 1H), 1.58(d, J=6.8 Hz, 3H), 1.26(d, J=6.8 Hz, 6H) was obtained.

[0257] Example 4: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0258] (Z / E)-Ethyl 2-amino-2-(hydroxyimino)acetate (4a) To a solution of ethyl carbonocyanide (2.5 g, 25.23 mmol, 2.48 mL) in EtOH (25 mL), NH2OH·HCl (2.63 g, 37.85 mmol) and Na2CO3 (2.67 g, 25.23 mmol) were added. The mixture was stirred at 25°C for 2 hours. TLC indicated completion of the reaction. LCMS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (5 mL) and extracted with RINKAN (20 mL × 5). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified at 70°C by recrystallization from MTBE:petroleum ether = 1:1 (20 mL) to obtain 4a. Calculated MS mass: [M+1] + (C4H8N2O3) m / z 133.1, LCMS measured value: m / z 133.1; 1 H NMR(400MHz, CDCl3)δ 8.90(br s, 1H), 5.12(br s, 2H), 4.34(q, J=7.1 Hz, 2H), 1.36(t, J=7.2 Hz, 3H)

[0259] (Z)-Ethyl 2-amino-2-(((ethoxycarbonyl)oxy)imino)acetate(4b) To a solution of (Z / E)-ethyl 2-amino-2-(hydroxyimino)acetate (4a) (1 g, 7.57 mmol) in DCM (5 mL), TEA (2.30 g, 22.71 mmol, 3.16 mL) and ethyl carbonochloride (903.56 mg, 8.33 mmol, 792.59 μL) were added. The mixture was stirred at 0°C for 1 hour. TLC showed that 5a was completely consumed and one new spot was formed. The reaction product was clean by TLC. The reaction mixture was concentrated under reduced pressure to obtain 4b (1.34 g, crude). 1 H NMR (400MHz, CDCl3)δ 5.44(br s, 2H), 4.40(q, J=7.2 Hz, 2H), 4.34(q, J=7.2 Hz, 2H), 1.42 - 1.38(m, 3H), 1.38 - 1.34(m, 3H).

[0260] 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate ethyl(4c) A solution of (Z / E)-ethyl 2-amino-2-(((ethoxycarbonyl)oxy)imino)acetate (4b) (1.34 g, 6.56 mmol) in AcOH (5 mL) was degassed, purged three times with nitrogen, and the mixture was stirred under a nitrogen atmosphere at 120°C for 10 hours. LC-MS showed that 4b was completely consumed and one major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH, and then 4c (1.03 g, crude) was obtained. The crude product was used in the next step without further purification. Calculated MS mass: [M-1] - (C5H6N2O4) m / z 157.0, LCMS measured value: m / z 157.0.

[0261] 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (4d) To a solution of ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (4c) (200 mg, 1.26 mmol, 1 equivalent) in MeOH (1 mL) and H2O (0.2 mL), LiOH (36.35 mg, 1.52 mmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 1 hour. TLC showed that reactant 4 was completely consumed and a novel spot was formed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with HCl (1 M, 5 mL) to adjust the pH to 4-6, and then extracted with ELISA (5 mL × 4). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4d (114 mg, crude). The crude product was used in the next step without further purification. Calculated MS mass: [M+1] + (C5H6N2O4) m / z 159.0, LCMS measured value: m / z not available; 1 H NMR (400MHz, DMSO) δ 4.35 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).

[0262] 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) To a solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (4d) (110 mg, 845.77 uL) in THF (3 mL), (COCl)2 (128.82 mg, 1.01 mmol, 88.84 uL) and DMF (6.18 mg, 84.58 uL, 6.51 uL) were added. The mixture was stirred at 25°C for 1 hour. For monitoring, a few drops of the reaction mixture were quenched with MeOH. TLC showed that 4d was completely consumed and one new spot was formed, and the mixture was concentrated under reduced pressure to obtain 4e (155 mg, crude). The crude product was used in the next step without further purification.

[0263] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 4) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (20 mg, 60.94 umol) in THF (3 mL), TEA (18.50 mg, 182.82 umol, 25.45 uL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.57 mg, 91.41 umol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that 1e was completely consumed and the desired MS was detected. The reaction mixture was quenched with MeOH (1 mL) at 25°C, and then concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and purified by preparative HPLC (column: Xtimate C18 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%-55%, 10 min) to obtain Example 4. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.0, LCMS measured value: m / z 440.0. 1 H NMR (400MHz, CD3OD) δ 7.93(s, 2H), 7.31(s, 1H), 3.51(s, 3H), 3.19(quind, J=7.0, 13.8 Hz, 1H), 1.27(d, J=6.8 Hz, 6H).

[0264] Example 5: 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0265] 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)amino)acetonitrile(5a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline (1b) (180 mg, 432.94 umol) and 2-bromoacetonitrile (259.65 mg, 2.16 mmol, 144.25 uL) in ACN (2 mL), K2CO3 (119.67 mg, 865.87 umol) and NaI (129.79 mg, 865.87 umol) were added. The mixture was placed in a sealed tube and stirred at 100°C for 16 hours. LC-MS showed that reactant 1b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 4a. Calculated MS mass: [M+1] + (C 15 H 13 Cl3N4O) m / z 371.0, LCMS measured value: m / z 0.371.0. 1 H NMR (400MHz, CD3Cl)δ 7.25(s, 1H), 6.66(s, 2H), 4.83 - 4.77(m, 1H), 4.05(d, J=6.4 Hz, 2H), 3.29(td, J=6.8, 13.6 Hz, 1H), 1.37(d, J=6.8 Hz, 6H).

[0266] Tert-butyl(cyanomethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)carbamate(5b) To a solution of 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)amino)acetonitrile (5a) (172 mg, 379.50 uL) in THF (10 mL), DMAP (51.00 mg, 417.45 uL) and Boc2O (248.48 mg, 1.14 mmol, 261.55 uL) were added. The mixture was stirred at 40°C for 2 hours. TLC showed that reactant 5a was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 5b. Calculated MS mass: [M+1] + (C 20 H 21 Cl3N4O3) m / z 471.1, LCMS measured value: m / z 471.1. 1 H NMR (400MHz, CDCl) δ 7.38(s, 2H), 7.24(s, 1H), 4.48(s, 2H), 3.29(td, J=6.7, 13.6 Hz, 1H), 1.53(s, 9H), 1.37(d, J=6.8 Hz, 6H).

[0267] (Z / E)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)carbamate(5c) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)carbamate (5b) (145 mg, 307.36 ml) in DMF (2 mL), NH2OH·HCl (170.87 mg, 2.46 mmol) and NaOAc (201.70 mg, 2.46 mmol) were added. The mixture was stirred at 80°C for 6 hours. TLC showed that the reaction product 5b was completely consumed. LCMS showed one major peak with the desired MS. The suspension was filtered through a Celite pad, and the pad was washed with RINKAN (5 mL × 3). The combined filtrate was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 5c. Calculated MS mass: [M+1]+ (C 20 H 24 Cl3N5O4) m / z 504.1, LCMS measured value: m / z 504.1. 1 H NMR (400MHz, CD3Cl)δ 7.37(s, 2H), 7.21(s, 1H), 5.11(br s, 2H), 4.23(s, 2H), 3.28(td, J=7.0, 13.8 Hz, 1H), 2.09(s, 1H), 1.49(s, 9H), 1.36(d, J=6.8 Hz, 6H).

[0268] Tert-butyl(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(5d) To a solution of (Z / E)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl) carbamate (5c) (50 mg, 89.15 umol) in THF (2 mL), DSC (29.69 mg, 115.89 umol) and TEA (33.97 mg, 335.75 umol, 46.73 uL) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed that 5c was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1, by TLC) to obtain 5d. Calculated MS mass: [M+1] + (C 21 H 22 Cl3N5O5) m / z 530.1, LCMS measured value: m / z 530.1.

[0269] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 5) To a solution of (tert-butyl(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate) 5d (68 mg, 115.30 umol) in AcOH (3 mL), NaOAc (75.66 mg, 922.40 umol) was added. The mixture was stirred at 110°C for 3 hours. LC-MS showed that the reaction product 5d was consumed and the desired MS was obtained. The reaction mixture was concentrated under reduced pressure to remove AcOH, and then the residue was obtained. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-65%, 13 min) to obtain Example 5. Calculated MS mass: [M+1] + (C 16 H 15 Cl2N5O4) m / z 412.0, LCMS measured value: m / z 412.0. 1 H NMR (400MHz, DMSO) δ 12.11(s, 1H), 7.31(s, 1H), 6.79(s, 2H), 6.66(br t, J=6.0 Hz, 1H), 4.27(d, J=6.2 Hz, 2H), 3.02(td, J=7.0, 13.6 Hz, 1H), 1.17(d, J=6.8 Hz, 6H).

[0270] Example 6: 3-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0271] 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-isopropylpyridazine(6a) A mixture of 4-bromo-2,6-dichlorophenol (3.04 g, 12.56 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (2 g, 10.47 mmol) in pyridine (10 mL) was stirred in a 100 mL autoclave at 130°C for 48 hours. LC-MS showed that the starting material 1a was completely consumed and the desired MS was obtained. The mixture was diluted in 10 mL (30 mL) and concentrated under reduced pressure. The residue was partitioned into ethyl acetate (30 mL × 2) and H₂O (10 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 1:0~100:1) to obtain 6a. Calculated MS mass: [M+1] + (C 13 H 10 BrCl3N2O) m / z 394.9, LCMS measured value: m / z 394.9. 1 H NMR (400MHz, DMSO) δ ppm 7.98 - 8.04 (m, 1 H) 7.92 - 7.97 (m, 1 H) 7.84 (s, 1 H) 3.11 - 3.29 (m, 1 H) 1.23 - 1.47 (m, 6 H).

[0272] 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one(6b) A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-isopropylpyridazine (6a) (1 g, 2.52 mmol) and NaOAc (827.59 mg, 10.09 mmol) in AcOH (10 mL) was stirred at 120°C for 18 hours. LC-MS showed that the starting materials were completely consumed and the desired MS was obtained. The mixture was concentrated under reduced pressure. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCO3 (2 mL). The mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6b. The product was used directly in the next step without further purification. [M+1] + (C 13 H 11(BrCl2N2O2) m / z 376.9, LCMS measured value: m / z 376.9. 1 H NMR(400MHz, DMSO)δ ppm 12.22(br s, 1 H)7.91 - 8.02(m, 2 H)7.39(s, 1 H)2.97 - 3.11(m, 1 H)2.87 - 2.95(m, 1 H)1.29(d, J=6.72 Hz, 1 H)1.15 - 1.23(m, 6H).

[0273] 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one(6c) A mixture of 3-(4-bromo-2,6-dichlorophenoxy)-5-isopropyl-1H-pyridazin-6-one (6b) (500 mg, 1.32 mmol) in DMF-DMA (22.42 g, 188.19 mmol, 25.00 mL) was stirred at 105°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned into ethyl acetate (10 mL × 2) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1:0~30:1) to obtain 6c. [M+1] + (C 14 H 13 (BrCl2N2O2) m / z 391.0, LCMS measured value: m / z 391.0. 1 H NMR (400MHz, DMSO) δ ppm 7.96(s, 2 H)7.41(s, 1 H)3.32(s, 1 H)3.08(dt, J=13.67, 6.84 Hz, 1 H)2.50(br d, J=3.53 Hz, 8 H)1.18(d, J=7.06 Hz, 5 H)1.23(br s, 1 H).

[0274] 6-(2,6-dichloro-4-hydroxyphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one(6d) A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (6c) (170 mg, 433.59 umol), KOH (31.63 mg, 563.67 umol), t-Bu Xphos (27.62 mg, 65.04 umol), and Pd2(dba)3 (39.70 mg, 43.36 umol) in dioxane (8 mL) and H2O (8 mL) was degassed, purged three times with nitrogen, and then stirred at 100°C under a nitrogen atmosphere for 3.5 hours. TLC showed that 6c was completely consumed, and LCMS detected the desired MS. The suspension was filtered through a Celite pad, and the pad was washed with ELISA (5 mL x 3). The combined filtrate was concentrated to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 1:1, by TLC) to obtain 6d. Calculated MS mass: [M+1] + (C 14 H 14 Cl2N2O3) m / z 329.0, MS actual value: m / z 329.0. 1H NMR (400MHz, CDCl3) δ 7.06 (s, 1H), 6.93 (s, 2H), 6.45 (br s, 1H), 3.55 (s, 3H), 3.25 (td, J=6.8, 13.6 Hz, 1H), 1.27(d, J=6.8 Hz, 6H).

[0275] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)acetonitrile(6e) To a solution of 6-(2,6-dichloro-4-hydroxyphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (6d) (40 mg, 121.51 umol) in acetone (2 mL), K2CO3 (50.38 mg, 364.54 umol) and 2-bromoacetonitrile (21.86 mg, 182.27 umol, 12.15 uL) were added. The mixture was stirred at 20°C for 2 hours. TLC showed that 6d was completely consumed and a novel spot was formed. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL × 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 1:1) to obtain 6e as a yellow solid. Calculated MS mass: [M+1] + (C 16 H 15 Cl2N3O3) m / z 368.0, MS measured value: m / z 368.0. 1 H NMR (400MHz, CDCl3)δ 7.04(s, 3H), 4.80(s, 2H), 3.53(s, 3H), 3.25(td, J=6.8, 13.4 Hz, 1H), 1.27(d, J=6.8 Hz, 6H).

[0276] ( Z / E)-2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)-N'-hydroxyacetoimidamide(6f) To a solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)acetonitrile (6e) (38 mg, 103.20 umol) in DMF (2 mL), NH2OH·HCl (57.37 mg, 825.61 umol) and NaOAc (67.72 mg, 825.61 umol) were added. The mixture was stirred at 80°C for 6 hours. TLC showed that 6e was completely consumed, and LCMS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was diluted with brine (5 mL) and extracted with RINKAN (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6f (66.3 mg, crude). The product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 16 H 18 Cl2N4O4) m / z 401.0, LCMS measured value: m / z 401.2.

[0277] 3-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 6) To a solution of (Z / E)-2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenoxy)-N'-hydroxyacetoimidamide (6f) (66.3 mg, 132.19 uL) in THF (2 mL), DSC (44.02 mg, 171.85 uL) and TEA (26.75 mg, 264.38 uL, 36.80 uL) were added. The mixture was stirred at 60°C for 4 hours. LC-MS showed that 6f was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×30 5u; mobile phase: [water (0.04%NH3H2O)-ACN]; B%: 5%-35%, 10 min) to obtain Example 6. Calculated MS mass: [M+1] + (C 17 H 16Cl2N4O5) m / z 427.1, LCMS measured value: m / z 427.1. 1 H NMR (400MHz, CD3OD) δ 7.30(s, 1H), 7.24(s, 2H), 5.10(s, 2H), 3.49(s, 3H), 3.19(quind, J=7.0, 13.8 Hz, 1H), 1.27(d, J=6.8 Hz, 6H).

[0278] Example 7: 5-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one [ka]

[0279] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one(7a) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (50 mg, 152.35 umol) in HCl (5 M, 304.70 uL), NaNO2 (12.61 mg, 182.82 umol) was added at 0°C. The mixture was then stirred at 0°C for 0.5 hours. Next, a solution of KI (50.58 mg, 304.70 umol) in H2O (1.5 mL) was added to the mixture, and the mixture was stirred for a further 16 hours at 20°C. TLC showed that reactant 1e was completely consumed. LCMS showed that reactant 1e was completely consumed and that one major peak with the desired MS was formed. The reaction mixture was extracted with siRNA (5 mL × 4). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Residue prepared as TLC (SiO2, petroleum ether:ethyl acetate = 1:1, product R f Purified by TLC (=0.80) to obtain 7a. Calculated MS mass: [M+1] + (C 14 H 12 Cl2N2O2) m / z 438.9, LCMS measured value: m / z 438.9. 1H NMR (400MHz, CDCl3)δ 7.71(s, 2H), 7.04(s, 1H), 3.52(s, 3H), 3.25(td, J=7.0, 13.4 Hz, 1H), 1.26(d, J=6.8 Hz, 6H).

[0280] 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)propiolate ethyl(7b) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (7a) (25 mg, 56.94 umol), ethyl propiolate (12.29 mg, 125.26 umol), Pd(PPh3)2Cl2 (4.00 mg, 5.69 umol), CuI (2.17 mg, 11.39 umol), and Cs2CO3 (37.10 mg, 113.88 umol) in THF (5 mL) was degassed and purged three times with nitrogen. The mixture was then stirred under microwave at 110°C for 0.5 hours. TLC showed that the reaction product 7a was completely consumed and many spots were formed. The suspension was filtered through a Celite pad and the pad was washed with siRNA (5 mL x 3). The combined filtrate was concentrated to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, by TLC) to obtain 7b. Calculated MS mass: [M+1] + (C 19 H 18 Cl2N2O4) m / z 409.1, LCMS measured value: m / z 409.1. 1 H NMR (400MHz, CDCl3)δ 7.61(s, 2H), 7.06(s, 1H), 4.32(q, J=7.0 Hz, 2H), 3.51(s, 3H), 3.25(quind, J=6.8, 13.8 Hz, 1H), 1.37(t, J=7.2 Hz, 3H), 1.27(d, J=6.8 Hz, 6H).

[0281] 5-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one (Example 7) To a solution of ethyl 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)propiolate (7b) (27 mg, 48.56 umol) in MeOH (3 mL), NH2OH·HCl (13.50 mg, 194.22 umol) and KOH (16.35 mg, 291.33 umol) were added. The mixture was stirred at 25°C for 16 hours. TLC showed that reaction product 7b was completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with RINKAN (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×30 5u; mobile phase: [water (0.04%NH3H2O)-ACN]; B%: 5%-35%, 10 min) to obtain Example 7. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N3O4) m / z 396.0, LCMS measured value: m / z 396.0. 1 H NMR (400MHz, CDCl3)δ 7.76(s, 2H), 7.08(s, 1H), 6.25(s, 1H), 3.52(s, 3H), 3.31 - 3.22(m, 1H), 1.28(d, J=6.8 Hz, 6H).

[0282] Example 8: 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one [ka]

[0283] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)acetamide(8a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline (1b) (1 g, 3.01 mmol) in AcOH (10 mL), NaOAc (863.18 mg, 10.52 mmol) was added. The mixture was stirred at 100°C for 16 hours. LC-MS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (20 mL) and pH was adjusted to 9-10 by adding 1N NaOH. The suspension was extracted with RINKAN (10 mL x 4), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8a (1.55 g, crude). The product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 15 H 15 Cl2N3O3) m / z 356.1, LCMS measured value: m / z 356.1.

[0284] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one(8b) To a solution of N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)acetamide (8a) (1.55 g, 3.48 mmol) in MeOH (20 mL), aqueous NaOH (1 M, 21.26 mL) was added. The mixture was stirred at 120°C for 4 hours. LC-MS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (20 mL) and extracted with RINKAN (10 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1~1:5, TLC) to obtain 8b. Calculated MS mass: [M+1] + (C 13 H 13 Cl2N3O2) m / z 314.0, LCMS measured value: m / z 314.0. 1H NMR (400MHz, DMSO) δ 12.11(s, 1H), 7.25(s, 1H), 6.64(s, 2H), 5.60(s, 2H), 3.07 - 2.94(m, 1H), 1.19 - 1.12(m, 7H).

[0285] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazine-3(2H)-one(8c) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (8b) (250 mg, 795.76 umol) in HCl (967.11 mg, 7.96 mmol, 948.14 μL, 30% purity), NaNO2 (65.89 mg, 954.91 umol) was added at 0°C, and the mixture was stirred for 0.5 hours. Next, a solution of KI (264.19 mg, 1.59 mmol) in H2O (5 mL) was added to the mixture. The mixture was then stirred for a further 16 hours at 20°C. LC-MS showed one major peak with the desired MS. The reaction mixture was extracted with siRNA (10 mL × 4). The combined organic layers were washed, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Residue prepared as TLC (SiO2, petroleum ether:ethyl acetate = 3:1, product R f Purified by TLC (=0.60) to obtain 8c. Calculated MS mass: [M+1] + (C 13 H 11 Cl2IN2O2) m / z 424.9, LCMS measured value: m / z 424.9. 1 H NMR (400 MHz, CDCl3)δ 10.50 - 10.29 (m, 1H), 7.75 - 7.69 (m, 2H), 7.13 - 7.08 (m, 1H), 3.30 - 3.14 (m, 1H), 1.28 - 1.25 (m, 6H).

[0286] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one(8d) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazine-3(2H)-one (8c) (50 mg, 117.63 umol) and DIPEA (30.41 mg, 235.27 umol, 40.98 uL) in DMF (4 mL) was mixed with 2-(chloromethoxy)ethyl-trimethyl-silane (58.84 mg, 352.90 umol, 62.46 uL). The mixture was degassed, purged three times with nitrogen, and stirred under a nitrogen atmosphere at 25°C for 2 hours. TLC showed that 8c was completely consumed. LCMS showed one major peak with the desired MS. The reaction mixture was quenched with water (5 mL) and then extracted with siRNA (6 mL × 3). The combined organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, by TLC) to obtain 8d. Calculated MS mass: [M+1] + (C 19 H 25 Cl2IN2O3Si) m / z 555.0, LCMS measured value: m / z 555.0. 1 H NMR (400 MHz, CD3OD)δ 7.78 - 7.61(m, 2H), 7.13 - 7.00(m, 1H), 5.28 - 5.16(m, 2H), 3.58 - 3.50(m, 2H), 3.32 - 3.18(m, 1H), 1.31 - 1.23(m, 6H), 0.91 - 0.83(m, 2H), 0.01 - 0.11(m, 9H).

[0287] Ethyl 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)oxy)phenyl)propiolate (8e) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (8d) (18 mg, 32.41 umol), ethyl propiolate (7.00 mg, 71.31 umol, 7.00 uL), Pd(PPh3)2Cl2 (2.28 mg, 3.24 umol), CuI (1.23 mg, 6.48 umol), and Cs2CO3 (21.12 mg, 64.83 umol) in THF (4 mL) was degassed, purged three times with nitrogen, and then stirred at 110°C for 0.5 hours under microwave. TLC showed that 8d was completely consumed and many spots were formed. LCMS showed that one major peak with the desired MS was formed. The suspension was filtered through a Celite pad, and the pad was washed with Â10 (5 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 8:1, by TLC) to obtain 8e. Calculated MS mass: [M+1] + (C 24 H 30 Cl2N2O5Si) m / z 525.1, LCMS measured value: m / z 525.1. 1 H NMR (400 MHz, CD3OD)δ 7.61 - 7.57(m, 2H), 7.08 - 7.06(m, 1H), 5.19 - 5.17(m, 2H), 4.35 - 4.28(m, 2H), 3.57 - 3.50(m, 2H), 3.31 - 3.19 (m, 1H), 1.38 - 1.34 (m, 3H), 1.28 - 1.25 (m, 6H), 0.89 - 0.84 (m, 2H), -0.03 - 0.06 (m, 9H).

[0288] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one(8f) To a solution of ethyl 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)oxy)phenyl)propiolate (8e) (5 mg, 9.51 umol) in MeOH (2 mL), NH2OH·HCl (2.64 mg, 38.06 umol) and KOH (3.20 mg, 57.09 umol) were added. The mixture was stirred at 25°C for 5 hours. TLC showed that 8e was completely consumed. LCMS showed the formation of one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with RINKAN (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:2, by TLC) to obtain 8f. Calculated MS mass: [M+1] + (C 22 H 27 Cl2N3O5Si) m / z 512.1, LCMS measured value: m / z 512.1. 1 H NMR (400 MHz, CD3OD)δ 7.78 - 7.73(m, 2H), 7.12 - 7.08(m, 1H), 6.29 - 6.24(m, 1H), 5.23 - 5.20(m, 2H), 3.59 - 3.52(m, 2H), 3.33 - 3.22 (m, 1H), 1.30 - 1.27 (m, 6H), 0.90 - 0.85 (m, 2H), -0.05 - 0.10 (m, 9H).

[0289] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one (Example 8) A solution of 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoxazole-3(2H)-one (8f) (4 mg, 7.81 umol) in TFA (2 mL) was stirred at 25°C for 4 hours. LC-MS showed that 8f was completely consumed and the desired MS was detected. The mixture was then concentrated under reduced pressure. The residue was checked by HPLC and purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.2% FA)-ACN]; B%: 30%-60%, 12 min) to obtain Example 8. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N3O4) m / z 382.0, LCMS measured value: m / z 382.0. 1 H NMR (400 MHz, CD3OD) δ 7.91 - 7.86 (m, 2H), 7.37 - 7.35 (m, 1H), 6.48 - 6.46 (m, 1H), 3.20 - 3.14 (m, 1H), 1.33 - 1.24 (m, 6H).

[0290] Example 9: 3-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine-3-yl)oxy]phenyl]-4H-1,2,4-oxadiazole-5-one [ka]

[0291] 3,5-Dichloro-4-(6-chloro-5-isopropylpyridazine-3-yl)oxy-benzonitrile (9a) A mixture of 3,5-dichloro-4-hydroxy-benzonitrile (1a) (100 mg, 531.88 umol) and 3,6-dichloro-4-isopropyl-pyridazine (101.62 mg, 531.88 umol) in Py (3 mL) was stirred at 130°C for 36 hours. LC-MS showed that 1a was completely consumed and the desired MS was detected. The mixture was diluted in Tol. (5 mL × 3) and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to obtain 9a. Calculated MS mass: [M+1] + (C 14 H10 Cl3N3O) m / z 342.0, LCMS measured value: m / z 342.1; 1 HNMR(400MHZ, CD3OD)δ 8.02(s, 2H), 7.67(s, 1H), 3.47 - 3.50(m, 1H), 3.32 - 3.39(m, 1H), 1.37(d, J=6.84 HZ, 6H).

[0292] (Z / E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)-N'-hydroxybenzimidamide(9b) To a solution of 3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxybenzonitrile (9a) (60 mg, 175.13 mmol) in DMF (2 mL), NH2OH·HCl (97.36 mg, 1.40 mmol) and NaOAc (114.93 mg, 1.40 mmol) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was partitioned into ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to obtain 9b. Calculated MS mass: [M+1] + (C 14 H 13 Cl3N4O2) m / z 375.0, LCMS measured value: m / z 375.0.

[0293] 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)-1,2,4-oxadiazole-5(4H),-one(9c) To a solution of (Z / E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)-N'-hydroxybenzimidamide (9b) (60 mg, 159.73 uL) in THF (3 mL), DSC (53.19 mg, 207.65 uL) and TEA (32.33 mg, 319.46 uL, 44.46 uL) were added. The mixture was stirred at 60°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure to obtain 9c (60 mg, crude). The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 15 H 11 Cl3N4O3) m / z 401.0, LCMS measured value: m / z 401.0.

[0294] 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-1,2,4-oxadiazole-5(4H),-one (Example 9) To a solution of 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)phenyl)-1,2,4-oxadiazole-5(4H),-one(9c) (60 mg, 149.39 umol) in HOAc (3 mL), NaOAc (49.02 mg, 597.56 umol) was added. The mixture was stirred at 120°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150 × 30 × 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-75%, 13 min) to obtain Example 9. Calculated MS mass: [M+1] + (C 15 H 12 Cl2N4O4) m / z 383.0, LCMS measured value: m / z 383.0; 1 H NMR (400MHZ, CD3OD) δ 7.93(s, 2H), 7.38(d, J=0.8 HZ, 1H), 3.17(spt, J=6.8 HZ, 1H), 1.29(d, J=6.8 HZ, 6H).

[0295] Example 10: 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-1,2,4-oxadiazole-5(4H),-one [ka]

[0296] 3,5-Dichloro-4-((5-Isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzonitrile (10a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)benzonitrile (9a) (40 mg, 116.75 umol) in HOAc (4 mL), NaOAc (38.31 mg, 467.01 umol) was added. The mixture was stirred at 120°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was obtained. The mixture was concentrated under reduced pressure. The solid was dissolved in water and the pH was adjusted to 9 with NaHCO3 (4 mL). The mixture was then divided twice into 10 mL of ethyl acetate. The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10a (34 mg, crude). Calculated MS mass: [M+1] + (C 14 H 11 Cl2N3O2) m / z 324.0, LCMS measured value: m / z 324.2; 1 H NMR (400MHZ, DMSO) δ 12.28(s, 1H), 8.27 - 8.35(m, 2H), 7.44(s, 1H), 3.27 - 3.44(m, 25H), 2.98 - 3.10(m, 1H), 1.15 - 1.23(m, 6H).

[0297] 3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzonitrile(10b) A mixture of 3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzonitrile (10a) (34 mg, 104.89 umol) in DMF-DMA (2 mL) was stirred under reflux at 110°C for 5 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to obtain 10b. Calculated MS mass: [M+1] + (C 15 H 13 Cl2N3O2) m / z 338.0, LCMS measured value: m / z 338.0; 1 H NMR (400MHZ, CD3OD)δ 8.00(s, 2H), 7.38(s, 1H), 3.48(s, 3H), 3.14 - 3.25(m, 1H), 1.28(d, J=6.85 HZ, 6H).

[0298] (Z)-3,5-Dichloro-N'-Hydroxy-4-((5-Isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzimidamide(10c) To a solution of 3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzonitrile (10b) (25 mg, 73.92 umol) in DMF (2 mL), NH2OH·HCl (41.10 mg, 591.39 umol) and NaOAc (48.51 mg, 591.39 umol) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed that 10b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was partitioned into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10c (25 mg, crude). The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 15 H 16Cl2N4O3) m / z 371.1, LCMS measured value: m / z 371.2.

[0299] 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-1,2,4-oxadiazole-5(4H),-one (Example 10) To a solution of (Z)-3,5-dichloro-N'-hydroxy-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)benzimidamide (10c) (25 mg, 67.35 umol) in THF (3 mL), DSC (22.43 mg, 87.55 umol) and TEA (13.63 mg, 134.69 umol, 18.75 uL) were added. The mixture was stirred at 60°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150×30×5um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-70%, 13 min) to obtain Example 10. Calculated MS mass: [M+1] + (C 16 H 14 Cl2N4O 4) m / z 397.0, LCMS measured value: m / z 397.0; 1 H NMR (400MHZ, CD3OD)δ 7.92 - 7.98(m, 2H), 7.37(d, J=0.73 HZ, 1H), 3.48(s, 3H), 3.12 - 3.26(m, 1H), 1.28(d, J=6.85 HZ, 6H).

[0300] Scheme B: 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (compound 11d) [ka]

[0301] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)-2-methylaniline(11a) A mixture of 4-amino-2,6-dichloro-3-methylphenol (0.2 g, 1.04 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (198.97 mg, 1.04 mmol) in DMSO (5 mL) was mixed with K2CO3 (575.75 mg, 4.17 mmol) and CuI (119.01 mg, 624.86 mmol) at 25°C. The mixture was then stirred at 90°C for 16 hours. The mixture was added to H2O (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was washed with petroleum ether (5 mL) and filtered. The filtered cake was concentrated under reduced pressure to obtain 11a.

[0302] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2-methylphenyl)isoindoline-1,3-dione(11b) A mixture of 3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxy-2-methylaniline (11a) (0.4 g, 1.15 mmol) and isobenzofuran-1,3-dione (170.92 mg, 1.15 mmol) in AcOH (10 mL) was mixed with NaOAc (378.63 mg, 4.62 mmol) at 25°C. The mixture was then stirred at 120°C for 12 hours. LC-MS indicated completion of the reaction. The mixture was concentrated to obtain a residue, to which H2O (20 mL) was added and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with MTBE (5 mL) and filtered. The filtered cake was concentrated to obtain 11b. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O4) m / z 458.1, LCMS measured value: m / z 458.1.

[0303] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)isoindoline-1,3-dione(11c) A mixture of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]isoindoline-1,3-dione (11b) (0.37 g, 807.34 umol) in DMF-DMA (5 mL) was stirred at 105°C for 4 hours. LC-MS indicated completion of the reaction. The mixture was added to H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11c. The crude substance was used directly in the next step. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O4) m / z 472.1, LCMS measured value: m / z 472.1.

[0304] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one(11d) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxy-2-methylphenyl]isoindoline-1,3-dione (11c) (440 mg, 931.57 umol) in MeOH (1 mL), butan-1-amine (2 M, 1.40 mL) was added at 70°C. The mixture was stirred at 70°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain 11d. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O4) m / z 342.1, LCMS measured value: m / z 342.1. 1 H NMR (400 MHz, CD3OD) δ 7.22(s, 1H), 6.77(s, 1H), 3.50(s, 3H), 3.20 - 3.14(m, 1H), 2.20(s, 3H), 1.25(d, J=6.8 Hz, 6H).

[0305] Example 11: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2-methylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0306] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2-methylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 11) To a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (11d) (20.85 mg, 60.94 umol) in THF (3 mL), TEA (18.50 mg, 182.82 umol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.57 mg, 91.41 umol) were added. The mixture was stirred at 25°C for 0.5 hours. TLC showed that 11d was consumed. The reaction mixture was quenched with MeOH (1 mL) at 25°C, and then concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Xtimate C18 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain Example 11. Calculated MS mass: [M+1] + (C 18 H 17 Cl2N5O5) m / z 454.1, LCMS measured value: m / z 454.1; 1 H NMR (400 MHz, CD3OD) δ 7.77(s, 1H), 7.31(d, J=0.7 Hz, 1H), 3.49(s, 3H), 3.23 - 3.11(m, 1H), 2.38(s, 3H), 1.27(d, J=6.8 Hz, 6H).

[0307] Example 12: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2-methylphenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0308] 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxy-2-methyl-anilino]acetonitrile (12a) To a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (11d) (50 mg, 146.10 umol) in ACN (1 mL), 2-bromoacetonitrile (87.62 mg, 730.52 umol, 48.68 uL), NaI (43.80 mg, 292.21 umol), and K2CO3 (40.39 mg, 292.21 umol) were added. The mixture was stirred at 100°C for 16 hours. The suspension was filtered through a Celite pad, and the pad was washed with siRNA (5 mL x 3). The combined filtrate was concentrated to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain (12a). 1 HNMR (400MHz, CDCl3)δ 7.04(s, 1H), 6.71(s, 1H), 4.20(d, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 1H), 4.08 - 4.01(m, 1H), 3.53(s, 3H), 3.31 - 3.16(m, 1H), 2.27(s, 3H), 1.59(br s, 4H), 1.38 - 1.15(m, 8H).

[0309] tert-butyl N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxy-2-methylphenyl]carbamate (12b) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxy-2-methylanilino]acetonitrile (12a) (55 mg, 144.26 umol) in THF (1 mL), Boc2O (94.45 mg, 432.78 umol, 99.42 uL) and DMAP (17.62 mg, 144.26 umol) were added. The mixture was stirred at 40°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain 12b. Calculated MS mass: [M+1] + (C 22H 26 Cl2N4O 4) m / z 481.1, LCMS measured value: m / z 481.1; 1 H NMR (400MHz, CDCl3)δ 7.04(d, J=1.0 Hz, 1H), 4.57 - 4.27(m, 2H), 3.48(br s, 3H), 3.28 - 3.16(m, 1H), 2.29(s, 3H), 1.66 - 1.47(m, 10H), 1.38(br s, 6H).

[0310] tert-butyl N-[(2Z)-2-amino-2-hydroxyiminoethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxy-2-methylphenyl]carbamate(12c) To a solution of tert-butyl N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxy-2-methylphenyl]carbamate (12b) (40 mg, 83.10 umol) in DMF (1 mL), NH2OH·HCl (46.19 mg, 664.77 umol) and NaOAc (54.53 mg, 664.77 umol) were added. The mixture was stirred at 80°C for 1 hour. The residue was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 12c. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 514.2, LCMS measured value: m / z 514.2; 1 H NMR (400MHz, CDCl3)δ 7.16(s, 1H), 7.05(d, J=1.0 Hz, 1H), 5.27(br s, 2H), 3.50(s, 3H), 3.33 - 3.17(m, 1H), 2.25(s, 4H), 1.39(s, 8H), 1.28 - 1.26(m, 7H).

[0311] tert-butyl N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxy-2-methylphenyl]-N-[(5-oxo-4H-1,2,4-oxadiazole-3-yl)methyl]carbamate (12d) To a solution of tert-butyl N-[(2Z)-2-amino-2-hydroxyiminoethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxy-2-methylphenyl]carbamate (12c) (40 mg, 77.76 umol) in THF (1 mL), DSC (25.90 mg, 101.09 umol) and TEA (15.74 mg, 155.52 umol, 21.65 uL) were added. The mixture was stirred at 60°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 5:1) to obtain 12d. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 540.1, LCMS measured value: m / z 540.1.

[0312] 3-[[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxy-2-methylanilino]methyl]-4H-1,2,4-oxadiazole-5-one (Example 12) To a solution of tert-butyl N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxy-2-methylphenyl]-N-[(5-oxo-4H-1,2,4-oxadiazole-3-yl)methyl]carbamate (12d) (30 mg, 55.51 uL) in 1 mL of HCl, HCl / HCl (2 M, 27.76 uL) was added at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (HCl conditions) to obtain Example 12. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 440.1, LCMS measured value: m / z 440.2. 1H NMR (400MHz, CD3OD) δ 7.24(s, 1H), 6.72(s, 1H), 4.37(s, 2H), 3.48(s, 3H), 3.23 - 3.11(m, 1H), 2.29(s, 3H), 1.26(d, J=6.8 Hz, 6H).

[0313] Scheme C: 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (compound 13e) [ka]

[0314] 2-Cyano-2-(2,6-dichloro-4-nitrophenyl)ethyl acetate (13a) To a suspension of NaH (1.41 g, 35.33 mmol, 60% purity) in DMSO (40 mL), 2-ethyl cyanoethyl (4.00 g, 35.33 mmol) was added dropwise at 0°C and stirred at 15°C for 30 minutes. Then, 1,2,3-trichloro-5-nitrobenzene (4 g, 17.66 mmol) was added, and the resulting mixture was stirred at 15°C for 16 hours. Next, the mixture was quenched with water (100 mL) and the pH was adjusted to 1 with 1 M HCl. The white precipitate was then filtered and dried under reduced pressure. The solid was washed with petroleum ether (40 mL) and dried under reduced pressure to obtain 13a. 1 H NMR (400 MHz, CDCl3)δ 8.32(s, 2H), 5.72(s, 1H), 4.38(q, J=7.1 Hz, 2H), 1.37(t, J=7.2 Hz, 3H).

[0315] 2-(2,6-dichloro-4-nitrophenyl)acetonitrile (13b) A mixture of 2-cyano-2-(2,6-dichloro-4-nitrophenyl)ethyl acetate (13a) (1.7 g, 5.61 mmol) and LiCl (285.33 mg, 6.73 mmol) in DMSO (6 mL) and H2O (2.5 mL) was heated at 165°C for 1 hour. After cooling, the mixture was quenched with water (50 mL), extracted with ethyl acetate (20 mL x 2), washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 13b. 1H NMR (400 MHz, CDCl3) δ 8.21(s, 2H), 4.03(s, 2H).

[0316] 2-(4-amino-2,6-dichlorophenyl)acetonitrile(13c) A mixture of 2-(2,6-dichloro-4-nitrophenyl)acetonitrile (13b) (1 g, 4.33 mmol) and Fe (1.21 g, 21.64 mmol) in HOAc (10 mL) was heated at 15°C for 1 hour. TLC showed novel spots. The mixture was filtered, water (100 mL) was added to the filtrate, and it was extracted with ethyl acetate (50 mL). The organic phase was neutralized with saturated NaHCO3 (20 mL × 2), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated to obtain 13c. 1 H NMR (400 MHz, CDCl3) δ 6.67 (s, 2H), 3.88 (s, 4H).

[0317] 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazine-3-yl)acetonitrile (13d) To a solution of 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c) (0.43 g, 2.14 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (408.62 mg, 2.14 mmol) in THF (5 mL), t-BuOK (1 M, 4.28 mL) was added dropwise at 60°C, and the resulting mixture was heated at 60°C for 40 minutes. After cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 13d. Calculated MS mass: [M+1] + (C 15 H 13 Cl3N4) m / z 355.0, LCMS measured value: m / z 0.355.1; 1 H NMR (400 MHz, CDCl3)δ 7.60(s, 1H), 6.69(s, 2H), 6.33(s, 1H), 3.99(br s, 2H), 3.33(td, J=6.8, 13.6 Hz, 1H), 1.32(dd, J=4.0, 6.8 Hz, 6H).

[0318] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one(13e) A solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (13d) (0.15 g, 421.76 umol) in HOAc (0.6 mL), H2O (0.6 mL), and concentrated HCl (2.4 mL) was heated at 120°C for 32 hours. LC-MS showed the desired mass. After cooling, the mixture was adjusted to pH ~7 with 4M NaOH at 0°C, the solid was filtered, and dried to obtain 13e as an off-white solid, which was used directly in the next step. Calculated mass of MS: [M+1] + (C 14 H 15 Cl2N3O) m / z 311.0, LCMS measured value: m / z 0.311.1.

[0319] Example 13: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0320] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 13) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (13e) (20 mg, 64.06 umol) in THF (3 mL), TEA (19.45 mg, 192.19 umol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (14.27 mg, 96.09 umol, 1.5 equivalents) were added. The mixture was stirred at 25°C for 0.5 hours. TLC showed that 13e was completely consumed. The reaction mixture was quenched with MeOH (1 mL) at 25°C, and then concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150×25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%-35%, 10 min) to obtain Example 13. Calculated MS mass: [M+1] + (C 17 H 15Cl2N5O4) m / z 424.0, LCMS measured value: m / z 424.0. 1 H NMR (400 MHz, CD3OD) δ 7.87 (s, 2H), 7.23 (s, 1H), 4.30 (s, 2H), 3.16 - 3.04 (m, 1H), 1.20 (d, J=7.1 Hz, 6H).

[0321] Example 14: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0322] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one(14a) To a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (13d) (1.5 g, 4.22 mmol) in concentrated HCl (16 mL) and HOAc (2 mL), H2O (2 mL) was added. The mixture was stirred at 120°C for 72 hours. LC-MS showed the desired mass. The mixture was adjusted to pH=7 by adding 6 M sodium hydroxide aqueous solution. The suspension was stirred for 15 minutes. The resulting solid was filtered and washed with H2O and petroleum ether. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain 14a. 1 HNMR (400 MHz, DMSO-d6)δ 12.59(s, 1H), 7.12 - 7.10(m, 1H), 6.62(s, 2H), 5.60(s, 2H), 3.99(s, 2H), 2.96(td, J=6.9, 13.5 Hz, 1H), 1.11(d, J=6.8 Hz, 6H).

[0323] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione(14b) A solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (14a) (450 mg, 1.44 mmol) in AcOH (5 mL) was added to isobenzofuran-1,3-dione (213.50 mg, 1.44 mmol). The mixture was stirred at 130°C for 4 hours. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to remove AcOH. This mixture was extracted with water (50 mL) and ethyl acetate (50 mL), then washed with NaHCO3 (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14b. The product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O3) m / z 442.1, LCMS measured value: m / z 442.1.

[0324] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione(14c) A mixture of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione (14b) (600 mg, 1.36 mmol) and DMF-DMA (5 mL) was heated at 105°C for 3 hours. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to obtain 14c. The product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 23 H 19 Cl2N3O3) m / z 456.1, LCMS measured value: m / z 456.1.

[0325] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazine-3(2H)-one(14d) A solution of N-butylamine (981.11 mg, 6.57 mmol) and 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione (14c) (600 mg, 1.31 mmol) in MeOH (3 mL) was heated at 70°C for 3 hours. TLC indicated completion of the reaction. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1~2:1) to obtain 14d. Calculated MS mass: [M+1] + (C 18 H 17 Cl2N5O4) m / z 326.1, LCMS measured value: m / z 326.0. 1 H NMR (400 MHz, CD3OD) δ 7.08 - 7.04 (m, 1H), 6.72 - 6.69 (m, 2H), 4.13 (s, 2H), 3.70 (s, 3H), 3.14 - 3.06 (m, 1H), 1.15 (d, J=6.8 Hz, 6H).

[0326] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 14) A solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazine-3(2H)-one (14d) (19.43 mg, 59.78 umol) in DCM (2 mL) was added to TEA (18.15 mg, 179.33 umol, 3 eq) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.88 mg, 59.78 umol). The mixture was degassed, purged three times with nitrogen, and stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (NH4CO3) to obtain Example 14. Calculated MS mass: [M+1]+(C18H17Cl2N5O4) m / z 438.1, LCMS actual value: m / z 438.0; 1H NMR (400 MHz, CD3OD) δ 7.89(s, 2H), 7.18(s, 1H), 4.30(s, 2H), 3.69 - 3.63(m, 3H), 3.13(td, J=7.0, 13.8 Hz, 1H), 1.19(d, J=6.8 Hz, 6H).

[0327] Example 15: 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0328] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one(15a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (13e) (200 mg, 640.63 umol) in DMF (5 mL), PMB-Cl (120.39 mg, 768.75 umol) and K2CO3 (106.25 mg, 768.75 umol) were added. The mixture was stirred at 20°C for 16 hours. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC to obtain 15a. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (d, J=8.6 Hz, 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, 13.5 Hz, 1H), 1.07(d, J=7.1 Hz, 6H).

[0329] 2-((3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)acetonitrile(15b) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15a) (150 mg, 346.95 umol) and 2-bromoacetonitrile (416.16 mg, 3.47 mmol) in DMF (10 mL), K2CO3 (57.54 mg, 416.34 umol) and KI (28.80 mg, 173.47 umol) were added. The mixture was stirred at 100°C for 6 hours. The reaction mixture was quenched with 5 mL of water and then extracted with siRNA (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 15b. 1 H NMR (400 MHz, DMSO-d6)δ 7.15(d, J=8.6 Hz, 2H), 7.12(s, 1H), 6.87(s, 2H), 6.83(d, J=8.8 Hz, 2H), 6.76(t, J=6.7 Hz, 1H), 5.00(s, 2H), 4.37(d, J=6.6 Hz, 2H), 4.08(s, 2H), 3.71(s, 3H), 2.99(td, J=6.7, 13.7 Hz, 1H), 1.08(d, J=6.8 Hz, 6H).

[0330] tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate(15c) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)acetonitrile (15 b) (133 mg, 282.15 umol) in THF (3 mL), DMAP (34.47 mg, 282.15 umol) and Boc2O (184.74 mg, 846.45 umol) were added. The mixture was stirred at 20°C for 1 hour. The reaction product was clean by TLC. LC-MS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to obtain 15 c. Calculated MS mass: [M+1] + (C 29 H 32 Cl2N4O4) m / z 571.2, LCMS measured value: m / z 471.1 / 571.1; 1 HNMR (400 MHz, CD3Cl)δ 7.35 - 7.33(m, 2H), 7.31(s, 1H), 6.91(s, 1H), 6.82(d, J=8.8 Hz, 2H), 5.13(s, 2H), 4.49(s, 2H), 4.24(s, 2H), 3.78(s, 3H), 3.16(quin, J=6.9 Hz, 1H), 1.51(s, 9H), 1.15(d, J=6.6 Hz, 6H).

[0331] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate(15d) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate (15c) (100 mg, 174.98 umol) in DMF (3 mL), NH2OH·HCl (97.27 mg, 1.40 mmol) and NaOAc (114.83 mg, 1.40 mmol) were added. The mixture was stirred at 80°C for 6 hours. LC-MS showed one major peak with the desired MS. The suspension was filtered through a Celite pad, and the pad was washed with ELISA (5 mL × 3). The combined filtrate was washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 15d as an off-white gum-like substance, which was used in the next step without further purification. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O2) m / z 604.2, LCMS measured value: m / z 504.2 / 604.2; 1 H NMR (400 MHz, DMSO-d6)δ 9.15(s, 1H), 7.51(s, 2H), 7.18(s, 1H), 7.11(d, J=8.6 Hz, 2H), 6.82(d, J=8.6 Hz, 2H), 5.40(s, 2H), 4.96(s, 2H), 4.21(s, 2H), 4.19(s, 2H), 3.71(s, 3H), 2.99(td, J=6.8, 13.5 Hz, 1H), 1.38(s, 9H), 1.09(d, J=6.8 Hz, 6H).

[0332] tert-butyl(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(15e) To a solution of (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate (15d) (40.00 mg, 66.17 umol) in THF (3 mL), TEA (13.39 mg, 132.34 umol) and DSC (22.04 mg, 86.02 umol) were added at 0°C. The mixture was stirred at 65°C for 16 hours. LC-MS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain 15e. Calculated MS mass: [M+1] + (C 30 H 33 Cl2N5O6) m / z 630.1, LCMS measured value: m / z 630.1.

[0333] tert-butyl(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(15f) To a solution of tert-butyl(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (15e) (17 mg, 21.57 umol) in ACN (2 mL) and H2O (0.5 mL), CAN (47.30 mg, 86.28 umol) was added. The mixture was stirred at 20°C for 4 hours. TLC showed that approximately 10% of 15e remained and a novel spot was formed. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with 5 mL of brine and extracted with 30 mL (10 mL × 3) of ethyl acetate. The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 15f. Calculated MS mass: [M+1] + (C 22 H 25 Cl2N5O5) m / z 510.1, LCMS measured value: m / z 510.1.

[0334] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 15) A solution of tert-butyl(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (15f) (33 mg, 64.66 uL) in HCl / siRNA (2 mL, 161.65 uL) was stirred at 20°C for 1 hour. TLC showed that the starting material was completely consumed and a novel spot was formed. LCMS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove siRNA. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.04%HCl)-ACN]; B%: 25%-50%, 12 min) to obtain Example 15. Calculated MS mass: [M+1] + (C 17 H 17 Cl2N5O3) m / z 410.0, LCMS measured value: m / z 410.0. 1 H NMR (400 MHz, CD3OD) δ 7.12(s, 1H), 6.76(s, 2H), 4.28(s, 2H), 4.17(s, 2H), 3.08(td, J=6.9, 13.6 Hz, 1H), 1.17(d, J=6.8 Hz, 6H).

[0335] Example 16: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0336] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)acetonitrile(16a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazine-3(2H)-one (14d) (150 mg, 459.81 umol) and 2-bromoacetonitrile (551.53 mg, 4.60 mmol) in DMF (5 mL), KI (38.16 mg, 229.91 umol) and K2CO3 (76.26 mg, 551.77 umol) were added. The mixture was stirred at 100°C for 8 hours. LC-MS showed the desired mass. After cooling, the reaction mixture was partitioned into ethyl acetate (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to obtain 16a. 1 HNMR (400 MHz, DMSO-d6)δ 7.10(s, 1H), 6.85(s, 2H), 6.75(t, J=6.7 Hz, 1H), 4.35(d, J=6.6 Hz, 2H), 4.07(s, 2H), 3.53(s, 3H), 3.01(td, J=7.0, 13.7 Hz, 1H), 1.10(d, J=6.8 Hz, 6H).

[0337] tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate(16b) A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)acetonitrile (16a) (20 mg, 54.76 umol), DMAP (6.69 mg, 54.76 umol), and Boc2O (119.50 mg, 547.56 umol) in THF (2 mL) was stirred at 20°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to obtain 16b. 1H NMR (400 MHz, CD3OD)δ 7.45(s, 2H), 7.22 - 7.19(m, 1H), 4.67 - 4.64(m, 2H), 4.35 - 4.32(m, 2H), 3.66 - 3.62(m, 3H), 3.17 - 3.09(m, 1H), 1.51 - 1.47 (m, 9H), 1.19 (d, J=7.0 Hz, 6H).

[0338] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate(16c) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate (16b) (50 mg, 107.44 umol) in DMF (2 mL), NH2OH·HCl (37.33 mg, 537.20 umol) and NaOAc (44.07 mg, 537.20 umol) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed the desired mass. The reaction mixture was partitioned into ethyl acetate (20 mL) and H2O (20 mL). The organic phase was separated, washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 16c without further purification. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O4) m / z 498.2, LCMS measured value: m / z 498.2.

[0339] tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(16d) To a solution of (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)carbamate (16c) (26 mg, 52.17 umol) in THF (2 mL), DSC (17.37 mg, 67.82 umol) and TEA (10.56 mg, 104.33 umol) were added. The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain 16d. Calculated MS mass: [M+1] + (C 23 H 27 Cl2N5O5) m / z 524.1, LCMS measured value: m / z 524.1.

[0340] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 16) To a solution of tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (16d) (24 mg, 45.77 uL) in 1 mL of ethylethanol, ethylethanol / HCl (4 M, 11.44 uL) was added. The mixture was stirred at 20°C for 2 hours. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA) to obtain Example 16. Calculated MS mass: [M+1] + (C 18 H 19 Cl2N5O3) m / z 424.1, LCMS measured value: m / z 424.1. 1 H NMR (400 MHz, CD3OD)δ 7.10 - 7.06(m, 1H), 6.76(s, 2H), 4.27(s, 2H), 4.16(s, 2H), 3.70 - 3.67(m, 3H), 3.14 - 3.06(m, 1H), 1.15(d, J=6.8 Hz, 6H).

[0341] Example 17: N-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0342] (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyridazine-3-yl)methanone (17a) To a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (13d) (0.9 g, 2.53 mmol) in CH3CN (20 mL), t-BuOK (1 M, 2.40 mL) was added at 20°C. The mixture was then stirred at 20°C for 0.5 hours. Next, the mixture was cooled to 0°C, and H2O2 (573.85 mg, 5.06 mmol, 486.31 μL, 30% purity) was added dropwise. The mixture was then stirred at 0°C for 0.5 hours, followed by stirring at 20°C for a further 2 hours. Next, saturated Na2SO3 solution (5 mL) was added to the mixture, and the mixture was stirred at 20°C for 1 hour. Finally, the mixture was concentrated under reduced pressure to remove CH3CN. The residue was extracted with ELISA (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column silica gel chromatography (petroleum ether:ethyl acetate = 30:1-5:1) to obtain 17a. Calculated MS mass: [M+1] + (C 14 H 12 Cl3N3O) m / z 344.0, LCMS measured value: m / z 344.0 / 346.0; 1 HNMR (400 MHz, DMSO-d6) δ 8.24 (s, 1 H) 6.67 (s, 2 H) 6.21 (s, 2 H) 3.18 - 3.31 (m, 1 H) 2.50 (br s, 5 H) 1.27 - 1.39 (m, 6 H).

[0343] 2-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione(17b) To a solution of (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyridazin-3-yl)methanone (17a) (260 mg, 797.11 umol) in HOAc (10 mL), NaOAc (326.94 mg, 3.99 mmol) and isobenzofuran-1,3-dione (129.87 mg, 876.82 umol) were added. The mixture was stirred at 120°C for 1 hour. LCMS showed the desired mass. The mixture was concentrated under reduced pressure, and the residue was dissolved in H2O (50 mL × 2) and NaHCO₃⁻. 3( The mixture was diluted in 50 mL x 2. Next, the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC to obtain 17b. Calculated MS mass: [M+1] + (C 22 H 15 Cl2N3O4) m / z 456.0, LCMS measured value: m / z 456.0.

[0344] 2-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione(17c) The mixture was stirred at 110°C for 3.5 hours in a solution of 2-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione (17b) (250 mg, 547.91 umol) in DMF-DMA (30 mL). LC-MS showed the desired mass. The reaction mixture was partitioned into two 30 mL H2O solutions and two 30 mL siRNA solutions. The organic phase was concentrated under reduced pressure to obtain 17c. The crude product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 23 H 17 Cl2N3O4) m / z 470.1, LCMS measured value: m / z 470.1.

[0345] 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazine-3(2H)-one(17d) To a solution of 2-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione (17c) (200 mg, 425.26 uL) in MeOH (2 mL), N-butylamine (190.39 mg, 1.28 mmol, 204.72 uL) was added. The mixture was stirred at 70°C for 0.5 hours. LC-MS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to obtain 17d. Calculated MS mass: [M+1] + (C 15 H 15 Cl2N3O2) m / z 340.1, LCMS measured value: m / z 340.1; 1 HNMR (400 MHz, CD3OD) δ 7.85 (d, J=0.9 Hz, 1H), 6.64 (s, 2H), 3.76 - 3.72 (m, 4H), 3.22 - 3.14 (m, 1H), 1.29 - 1.26 (m, 7H).

[0346] N-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 17) To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazine-3(2H)-one (17d) (20 mg, 58.79 umol) in THF (5 mL), TEA (17.85 mg, 176.36 umol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.10 mg, 88.18 umol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that the desired MS was detected. The reaction mixture was quenched with 1 mL of MeOH at 25°C, and then concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150×25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-40%, 10 min) to obtain Example 17. Calculated MS mass: [M+1]+(C18H15Cl2N5O5) m / z 452.0, measured LCMS mass: m / z 452.0; 1H NMR (400 MHz, CD3OD) δ 7.94 (br s, 2H), 7.93 (br d, J=2.9 Hz, 1H), 3.73 (s, 3H), 3.26 - 3.11 (m, 1H), 1.30 (br d, J=6.7 Hz, 6H).

[0347] Example 18: 3-(((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0348] 2-((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)acetonitrile (18a) To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazine-3(2H)-one (72 mg, 211.64 umol) (17d) in MeCN (2 mL), 2-bromoacetonitrile (126.93 mg, 1.06 mmol, 70.52 μL), NaI (63.45 mg, 423.28 umol), and K2CO3 (58.50 mg, 423.28 umol) were added. The mixture was stirred at 100°C for 13 hours. The reaction mixture was extracted with ethyl acetate (20 mL × 2) and H2O (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 18a. Calculated MS mass: [M+1] + (C 17 H 16 Cl2N4O2) m / z 379.1, LCMS measured value: m / z 379.2; 1 H NMR (400 MHz, CDCl3)δ 7.84(d, J=0.7 Hz, 1H), 6.68(s, 2H), 4.16(d, J=6.8 Hz, 2H), 3.77(s, 3H), 3.27 - 3.19(m, 1H), 1.28(d, J=6.8 Hz, 6H).

[0349] tert-butyl(cyanomethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)carbamate(18b) To a solution of 2-((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)acetonitrile (18a) (53 mg, 139.75 uL) in THF (3 mL), DMAP (17.07 mg, 139.75 uL) and Boc2O (274.51 mg, 1.26 mmol, 288.95 uL) were added. The mixture was stirred at 25°C for 5 minutes. The mixture was partitioned into ethyl acetate (10 mL x 2) and H2O (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 18b. 1 H NMR (400 MHz, CDCl3)δ 7.87 - 7.84(m, 1H), 7.35(s, 2H), 4.52(s, 2H), 3.75(s, 3H), 3.28 - 3.19(m, 1H), 1.54(s, 9H), 1.29(d, J=7.0 Hz, 6H).

[0350] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)carbamate(18c) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)carbamate (18b) (32 mg, 66.76 umol) in DMF (3 mL), NH2OH·HCl (37.11 mg, 534.05 umol) and NaOAc (27.38 mg, 333.78 umol) were added. The mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18c. The product was used directly in the next step without further purification.

[0351] tert-butyl(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(18d) To a solution of (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl) carbamate (32 mg, 62.45 umol) (18c) in THF (3 mL), DSC (20.80 mg, 81.19 umol) and TEA (12.64 mg, 124.91 umol, 17.39 uL) were added. The mixture was stirred at 60°C for 13 hours. LCMS showed the desired mass. The reaction mixture was extracted with 20 mL x 2 of ethyl acetate and 20 mL x 2 of H2O. The combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18d as a yellow solid. The crude product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 23 H 25 Cl2N5O6) m / z 538.1, LCMS measured value: m / z 438.2 / 538.2.

[0352] 3-(((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 18) A solution of tert-butyl(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (18d) (22 mg, 40.86 umol) in siRNA / HCl (2 M, 2 mL). The mixture was stirred at 25°C for 1 hour. LC-MS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to obtain Example 18. Calculated MS mass: [M+1] + (C 18 H 17 Cl2N5O4) m / z 438.1, LCMS measured value: m / z 438.2; 1 H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.78 - 6.71 (m, 2H), 4.32 (s, 2H), 3.72 (s, 3H), 3.18 (td, J=6.8, 13.7 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).

[0353] Scheme D: 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazine-3(2H)-one(19h) [ka]

[0354] O-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19a) To a solution of 2,6-dichloro-4-nitrophenol (1 g, 4.81 mmol) in DMF (20 mL), NaH (288.44 mg, 7.21 mmol, 60% purity) was added. The mixture was then stirred at 20°C for 1 hour. Next, a mixture of N,N-dimethylcarbamotioil chloride (950.81 mg, 7.69 mmol) was added. The mixture was stirred at 20°C for 16 hours. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column silica gel chromatography (petroleum ether:ethyl acetate = 20:1~5:1) to obtain 19a. 1 HNMR (400MHz, CDCl3) δ 8.28 (s, 2H) 3.50 (s, 3H) 3.44 (s, 3H).

[0355] S-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19b) O-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19a) (0.9 g, 3.05 mmol) was added to the flask and stirred at 200°C for 4 hours. LC-MS showed the desired MS. The mixture was cooled to 20°C to obtain 19b. The crude reaction product was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H) 3.13 (br s, 3H) 2.95 (br s, 3H).

[0356] O-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19c) To a solution of S-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19b) (0.8 g, 2.71 mmol) in AcOH (10 mL), 2-propanol (20 mL), and H2O (10 mL), Fe (1.06 g, 18.97 mmol) was added. The mixture was then stirred at 95°C for 2 hours. The mixture was cooled to 20°C, saturated NaHCO3 solution was added to the mixture until the pH was 8-9, and the mixture was filtered. The filtrate was then concentrated under reduced pressure to remove most of the solvent. The residue was then extracted with H2O (50 mL) and siRNA (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 19c. The product was used directly in the next step. 1 HNMR (400 MHz, CDCl3) δ 6.73 (s, 2H) 3.98 (br s, 2H) 2.90 - 3.25 (m, 6H).

[0357] 4-amino-2,6-dichlorobenzenethiol (19d) To a solution of O-(2,6-dichloro-4-nitrophenyl)dimethylcarbamothioate (19c) (0.7 g, 2.64 mmol) in EtOH (20 mL), KOH (3 M, 20 mL) was added. The mixture was then refluxed at 100°C for 16 hours. LC-MS indicated completion of the reaction. The mixture was cooled to 20°C, and HCl solution (1 M) was added until the pH was 2-3. The mixture was extracted with ELISA (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 19d. The product was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.27 (s, 2H) 6.70 (s, 2H) 4.23 (s, 1H) 3.70 (br s, 2H).

[0358] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)thio)aniline(19e) To a solution of 4-amino-2,6-dichlorobenzenethiol (19d) (520 mg, 2.68 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (511.90 mg, 2.68 mmol) in DMSO (15 mL), K2CO3 (1.11 g, 8.04 mmol) was added. The mixture was then stirred at 95°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to obtain 19e. 1 H NMR (400 MHz, CDCl3) δ ppm 7.01 (s, 1H) 6.78 (s, 2H) 4.10 (br s, 2H) 3.14 - 3.27 (m, 1H) 1.23 (d, J=6.84 Hz, 6H).

[0359] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)isoindoline-1,3-dione(19f) NaOAc (1.18 g, 14.34 mmol) was added to a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)thio)aniline (19e) (1 g, 2.87 mmol) and isobenzofuran-1,3-dione (424.79 mg, 2.87 mmol) in HOAc (8 mL). The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with NaHCO3 (10 mL). The mixture was then divided twice into ethyl acetate (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was stirred in ethyl acetate (10 mL) and petroleum ether (50 mL), then filtered and dried to obtain 19f. The product was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 8.00 - 8.05 (m, 2 H) 7.93 - 7.97 (m, 2 H) 7.84 (s, 2 H) 7.32 (d, J=0.86 Hz, 1 H) 3.01 (quin, J=6.79 Hz, 1 H) 1.14 (d, J=6.85 Hz, 6 H).

[0360] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)-phenyl)isoindoline-1,3-dione (19g) A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)isoindoline-1,3-dione (19f) (955 mg, 2.07 mmol) in DMF-DMA (8 mL) was stirred at 120°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was divided twice into ethyl acetate (10 mL) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 19 g. The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O3S) m / z 474.0, LCMS measured value: m / z 474.0.

[0361] 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazine-3(2H)-one(19h) A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)isoindoline-1,3-dione (19 g) (980 mg, 2.07 mmol) and butan-1-amine (453.29 mg, 6.20 mmol, 612.55 μL) in MeOH (2 mL) was stirred at 70°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 19H. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3OS) m / z 344.0, LCMS measured value: m / z 344.1; 1H NMR (400 MHz, CD3OD) δ 6.85(d, J=0.73 Hz, 1 H)6.80(s, 2 H)3.64(s, 3 H)3.09(qd, J=7.01, 6.48 Hz, 1 H)1.12(d, J=6.97 Hz, 6 H).

[0362] Example 19: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0363] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)amino)acetonitrile(19i) To a solution of 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazine-3(2H)-one (19h) (420 mg, 1.22 mmol) in ACN (3 mL), 2-bromoacetonitrile (731.69 mg, 6.10 mmol, 406.49 μL), K2CO3 (337.23 mg, 2.44 mmol), and NaI (365.75 mg, 2.44 mmol) were added. The mixture was stirred at 100°C for 16 hours. The suspension was filtered through a Celite pad, and the pad cake was washed with siRNA (10 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 19i. Calculated MS mass: [M+1] + (C 16 H 16 Cl2N4OS) m / z 383.3, LCMS measured value: m / z 383.0; 1 H NMR (400 MHz, CDCl3)δ 6.82(s, 2H)6.79(d, J=0.73 Hz, 1H)4.39(d, J=6.85 Hz, 1H)4.12 - 4.24(m, 2H)3.77(s, 1H)3.67(s, 3H)3.11 - 3.20(m, 1H)1.16(d, J=6.85 Hz, 6H).

[0364] tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)carbamate(19j) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)amino)acetonitrile (19i) (420 mg, 1.10 mmol) in THF (3 mL), DMAP (133.87 mg, 1.10 mmol) and Boc2O (717.45 mg, 3.29 mmol) were added at 25°C. The mixture was stirred at 25°C for 20 minutes. The mixture was divided twice into 10 mL of ethyl acetate and 3 mL of H2O. The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain 19j. 1 H NMR (400 MHz, CDCl3) δ 7.46 (s, 2H) 6.84 (s, 1H) 4.53 (s, 2H) 3.64 (s, 3H) 3.18 (dt, J=13.66, 6.80 Hz, 1H) 1.53 (s, 9H) 1.18 (d, J=6.85 Hz, 6H).

[0365] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)carbamate(19k) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)carbamate (19j) (250 mg, 517.16 ml, 1 equivalent) in DMF (3 mL), NH2OH·HCl (287.50 mg, 4.14 mmol, 8 equivalents) and NaOAc (339.38 mg, 4.14 mmol, 8 equivalents) were added at 25°C. The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, twice). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 19K. 11H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H) 7.60 (s, 2H) 7.05 (d, J = 0.66 Hz, 1H) 4.31 (s, 2H) 3.59 (s, 3H) 3.11 (dt, J = 13.67, 6.84 Hz, 1H) 1.49 (s, 9H) 1.17 (d, J = 7.06 Hz, 6H).

[0366] tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (19L) To a solution of (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)carbamate (19k) (220 mg, 425.99 μmol) in THF (4 mL) was added DSC (141.86 mg, 553.79 μmol) and TEA (86.21 mg, 851.99 μmol, 118.59 μL). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to give 19l. Calculated MS mass: [M+1] + (C 22 H 25 Cl2N5O5S) m / z 542.4, LCMS found: m / z 542.1; 1 1H NMR (400 MHz, CD3OD) δ 7.63 (s, 2H) 7.04 (d, J = 0.73 Hz, 1H) 4.82 (s, 2H) 3.58 (s, 3H) 3.07 - 3.15 (m, 1H) 1.48 (s, 9H) 1.16 (d, J = 6.85 Hz, 6H).

[0367] tert-butyl(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (19m) A solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (19l) (20 mg, 36.87 umol) in DCM (2 mL) was added with m-CPBA (37.43 mg, 184.35 umol, 85% purity). Next, the mixture was stirred at 60 °C for 48 h. Na2SO3 (23 mg) was added to the reaction mixture at 20 °C to quench it, and the mixture was stirred for 30 min. Next, the mixture was concentrated under reduced pressure to obtain 19m. Calculated MS mass: [M+1] + (C 22 H 25 Cl2N5O7S) m / z 574.4, LCMS found: m / z 574.1. The product was used directly in the next step without further purification.

[0368] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 19) A solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (19m) (20 mg, 34.82 umol) in HCl / EtOAc (4 M, 2 mL) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%-50%, 11 min) to obtain Example 19. Calculated MS mass: [M+1] + (C 17 H 17 Cl2N5O5 S ) m / z 474.3, LCMS found: m / z 474.0; 1 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H) 6.83 (s, 2H) 4.38 (s, 2H) 3.72 (s, 3H) 3.13 (br d, J = 1.71 Hz, 1H) 1.24 (d, J = 6.85 Hz, 6H).

[0369] Example 20: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0370] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(20a) To a mixture of 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazine-3(2H)-one (19h) (20 mg, 58.10 umol) in DCM (5 mL), TEA (29.39 mg, 290.48 uml, 40.43 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.63 mg, 58.10 umol) were added, and the mixture was stirred at 25°C for 0.2 hours. The reaction mixture was partitioned into H2O (5 mL) and siRNA (5 mL). The organic phase was separated, washed with brine (5 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (0.1% FA conditions) to obtain 20a. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O4S) m / z 456.0, LCMS measured value: m / z 456.1; 1 H NMR (400 MHz, CD3OD) δ 7.94 - 8.14 (m, 2H) 7.07 (s, 1H) 3.52 - 3.64 (m, 3H) 3.05 - 3.18 (m, 1H) 1.17 (d, J=6.85 Hz, 6H).

[0371] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)-phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 20) N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)thio)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (20a) (8 mg, 17.53 umol) in DCM (1 mL) was mixed with MCPBA (21.36 mg, 105.19 umol, 85% purity), and the mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (aqueous acetonitrile w / TFA) to obtain Example 20. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O6S) m / z 488.0, LCMS measured value: m / z 488.1; 1 HNMR (400 MHz, DMSO) δ 11.40 - 11.66 (m, 1 H) 8.09 - 8.13 (m, 2 H) 7.72 - 7.75 (m, 1 H) 3.62 - 3.65 (m, 3 H) 3.08 - 3.11 (m, 1 H) 1.16 - 1.21 (m, 6 H).

[0372] Scheme E: 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazine-3(2H)-one(21e) [ka]

[0373] 3,6-Dichloro-4-cyclopropylpyridazine (21a) H2SO4 (9.88 g, 100.69 mmol) was added at 60°C to a solution of 3,6-dichloropyridazine (5 g, 33.56 mmol), cyclopropanecarboxylic acid (2.89 g, 33.56 mmol), and AgNO3 (5.70 g, 33.56 mmol) in H2O (100 mL). Next, ammonium persulfate (22.98 g, 100.69 mmol) in H2O (100 mL) was added to the mixture at 70°C. The resulting mixture was stirred at 70°C for 30 minutes. The mixture was extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified with MPLC (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain 21a. 1 HNMR (400 MHz, CD3Cl) δ 6.94 (s, 1H), 2.27 - 2.14 (m, 1H), 1.37 - 1.23 (m, 2H), 0.91 - 0.77 (m, 2H).

[0374] 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazine-3-yl)acetonitrile (21b) To a solution of 3,6-dichloro-4-cyclopropylpyridazine (21a) (0.4 g, 2.12 mmol) and 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c) (467.96 mg, 2.33 mmol) in THF (10 mL), t-BuOK (1 M, 4.23 mL) was added dropwise at 60°C, and the resulting mixture was stirred at 60°C for 40 minutes. After cooling, the mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL), the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 21b. 1 H NMR (400 MHz, DMSO-d6)δ 7.00(s, 1H), 6.71 - 6.68(m, 2H), 6.46(s, 1H), 6.02(s, 2H), 2.22 - 2.14(m, 1H), 1.25 - 1.19(m, 2H), 0.88 - 0.75(m, 2H).

[0375] 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyridazine-3(2H)-one(21c) To a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazin-3-yl)acetonitrile (21b) (365 mg, 1.03 mmol) in dioxane (5 mL) and H2O (10 mL), KOH (1.16 g, 20.64 mmol) was added. The mixture was stirred under O2 at 100°C for 16 hours. LC-MS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove the dioxane. The residue was diluted with 2M aqueous HCl to adjust the pH to 5-7 and extracted with siRNA (20 mL x 4). The combined organic layers were washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 21c. Calculated MS mass: [M+1] + (C 14 H 11 Cl2N3O2) m / z 324.0, LCMS measured value: m / z 324.1.

[0376] 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazine-3(2H)-one(21d) To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyridazine-3(2H)-one (21c) (100 mg, 308.49 umol) in MeOH (5 mL), NaBH4 (116.70 mg, 3.08 mmol) was added at 0°C. The mixture was stirred at 15°C for 16 hours. LC-MS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (5 mL) and extracted with siRNA (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 2:1, TLC) to obtain 21d. Calculated MS mass: [M+1] + (C 14 H 13 Cl2N3O2) m / z 326.1, LCMS measured value: m / z 326.1; 1H NMR (400 MHz, DMSO-d6)δ 12.58(s, 1H), 7.16(s, 1H), 6.54(s, 2H), 6.07 - 6.05(m, 1H), 6.02 - 6.00(m, 1H), 5.64(s, 2H), 2.12 - 2.07(m, 1H), 1.01(br dd, J=2.8, 8.5 Hz, 2H), 0.81(br t, J=6.0 Hz, 2H).

[0377] 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazine-3(2H)-one(21e) To a solution of 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazine-3(2H)-one (21d) (50 mg, 153.29 umol) in TFA (1 mL) and DCE (5 mL), Et3SiH (89.12 mg, 766.46 umol) was added. The mixture was stirred at 50°C for 6 hours. LC-MS showed one major peak with the desired MS. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 2:1; TLC) to obtain 21e. Calculated MS mass: [M+1]+(C 14 H 13 Cl2N3O) m / z 310.0, LCMS actual value: m / z 310.1;1H NMR (400 MHz, CDCl3)δ 10.39(br s, 2H), 6.68(s, 2H), 6.64(s, 1H), 4.10(s, 2H), 2.19 - 2.14(m, 1H), 1.12 - 1.06(m, 2H), 0.85 - 0.79(m, 2H).

[0378] Example 21: N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0379] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 21) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazine-3(2H)-one (21e) (16 mg, 51.58 umol) in DCM (2 mL), TEA (15.66 mg, 154.75 umol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (11.49 mg, 77.37 umol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-40%, 10 min) to obtain Example 21. Calculated MS mass: [M+1] + (C 17 H 13 Cl2N5O4) m / z 422.0, LCMS measured value: m / z 422.0; 1 H NMR (400 MHz, CD3OD) δ 7.86(s, 2H), 6.88(s, 1H), 4.23(s, 2H), 2.15 - 2.06(m, 1H), 1.10 - 1.04(m, 2H), 0.85 - 0.79(m, 2H).

[0380] Example 22: N-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0381] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione(22a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazine-3(2H)-one (21e) (44 mg, 141.85 umol) in AcOH (3 mL), isobenzofuran-1,3-dione (22.06 mg, 148.95 umol) was added. The mixture was stirred at 120°C for 2 hours. TLC showed the formation of a novel spot. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with 2 mL of water and saturated aqueous solution of NaHCO3 was added to adjust the pH to 9-10. The suspension was extracted with 20 mL (5 mL x 4) of siRNA, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 22a, a yellow oily substance, which was used in the next step without further purification. Calculated MS mass: [M+1] + (C 22 H 15 Cl2N3O3) m / z 440.1, LCMS measured value: m / z 440.1.

[0382] 2-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione(22b) A solution of 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione (22a) (70 mg, 158.99 umol) in DMF-DMA (5 mL) was degassed, purged three times with nitrogen, and the mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. LC-MS showed that 22a was completely consumed and one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove DMF-DMA, and the mixture was then obtained as a residue. The residue was diluted with 5 mL of H2O and extracted with 20 mL (5 mL × 4) of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 22b, which was used in the next step without further purification as a bright yellow gum. Calculated MS mass: [M+1] + (C 23 H 17 Cl2N3O3) m / z 454.1, LCMS measured value: m / z 454.0.

[0383] 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazine-3(2H)-one(22c) To a solution of 2-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)isoindoline-1,3-dione (22b) (100 mg, 154.08 umol) in MeOH (3 mL), N-butylamine (33.81 mg, 462.24 umol) was added. The mixture was stirred at 70°C for 0.5 hours. LC-MS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate; TLC) to obtain 22c. Calculated MS mass: [M+1] + (C 15 H 15 Cl2N3O) m / z 324.1, LCMS measured value: m / z 324.0; 1 H NMR (400 MHz, CDCl3)δ 6.70 - 6.65(m, 2H), 6.48(s, 1H), 4.07(s, 2H), 3.79(br s, 2H), 3.74(s, 3H), 2.24 - 2.13(m, 1H), 1.07 - 0.99(m, 2H), 0.75 - 0.66(m, 2H).

[0384] N-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 22) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazine-3(2H)-one (22c) (10 mg, 30.84 umol) in DCM (2 mL), TEA (9.36 mg, 92.53 umol, 12.88 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (6.87 mg, 46.27 umol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150×25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%-35%, 14 min) to obtain Example 22 as a white solid. Calculated MS mass: [M+1] + (C18 H 15 Cl2N5O4) m / z 436.0, LCMS measured value: m / z 436.0; 1 H NMR (400 MHz, CD3OD) δ 7.87(s, 2H), 6.85(s, 1H), 4.24(s, 2H), 3.65(s, 3H), 2.20 - 2.09(m, 1H), 1.11 - 1.04(m, 2H), 0.83 - 0.75(m, 2H).

[0385] Example 23: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0386] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 23) To a solution of 3-(4-amino-2,6-dichlorophenoxy)-5-isopropyl-1H-pyridazin-6-one (8b) (13.7 g, 43.61 mmol) in THF (140 mL), TEA (13.24 g, 130.82 mmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (9.71 g, 65.41 mmol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed a peak with the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was triturated with HCl (100 mL) at 80°C for 30 minutes, and then cooled to 20°C. The suspension was filtered, the filter cake was washed with HCl (5 mL × 3), and concentrated to dryness to obtain Example 23. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O5) m / z 426.0, LCMS measured value: m / z 426.0; 1 H NMR (400 MHz, CD3OD) δ 7.92 (s, 2H), 7.33 (d, J=0.9 Hz, 1H), 3.21 - 3.13 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).

[0387] Example 24: N-(6-chloro-7-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0388] 6-Chloro-7-(6-Chloro-5-isopropylpyridazine-3-yl)oxyindan-4-amine(24a) 7-amino-5-chloroindan-4-ol (0.39 g, 2.12 mmol), 3,6-dichloro-4-isopropylpyridazine (1a) (405.77 mg, 2.12 mmol), CuI (40.45 mg, 212.38 mmol), and K2CO3 (440.28 mg, 3.19 mmol) in DMA (15 mL) were degassed with N2, and then heated under N2 at 100°C for 16 hours. LC-MS indicated the completion of the reaction and the detection of the desired MS. The mixture was filtered through a Celite pad and washed with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 24a. Calculated MS mass: [M+1] + (C 16 H 17 Cl2N3O) m / z 338.1, LCMS measured value: m / z 338.1. 1 HNMR (400 MHz, DMSO-d6)δ 7.53(s, 1H), 6.56(s, 1H), 5.15(br s, 2H), 3.14(td, J=6.8, 13.6 Hz, 1H), 2.68(br t, J=7.3 Hz, 2H), 2.60(br t, J=7.4 Hz, 2H), 2.03 - 1.95(m, 2H), 1.27(d, J=6.7 Hz, 6H).

[0389] 2-[6-chloro-7-[(5-isopropyl-6-oxo-1H-pyridazine-3-yl)oxy]indan-4-yl]isoindorin-1,3-dione(24b) AcOH (1 mL) was added to a mixture of 6-chloro-7-(6-chloro-5-isopropylpyridazin-3-yl)oxyindan-4-amine (24a) (120 mg, 354.79 mmol) and isobenzofuran-1,3-dione (52.55 mg, 354.79 mmol) in NaOAc (101.87 mg, 1.24 mmol). The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the AcOH. The solid was dissolved in water and the pH was adjusted to 9 with NaHCO3 (10 mL). The mixture was then divided twice into ethyl acetate (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 24b. The product was used directly in the next step without purification. Calculated MS mass: [M+1] + (C 24 H 20 ClN3O4) m / z 450.1, LCMS measured value: m / z 450.2.

[0390] 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxopyridazine-3-yl)oxyindan-4-yl]isoindorin-1,3-dione(24c) A solution of 2-[6-chloro-7-[(5-isopropyl-6-oxo-1H-pyridazine-3-yl)oxy]indan-4-yl]isoindorin-1,3-dione (24b) (150 mg, 333.42 umol) in DMFDMA (2 mL) was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was divided twice into 10 mL of ethyl acetate and 3 mL of H2O. The combined filtrate was washed with water (20 mL), and the organic phase was concentrated to obtain 24c, which was used directly in the next step. Calculated MS mass: [M+1] + (C 25 H 22 ClN3O4) m / z 464.1, LCMS measured value: m / z 464.2.

[0391] 6-(7-amino-5-chloroindan-4-yl)oxy-4-isopropyl-2-methylpyridazine-3-one(24d) A mixture of 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxopyridazin-3-yl)oxyindan-4-yl]isoindorin-1,3-dione (24c) (100 mg, 215.56 umol) and N-butylamine (15.77 mg, 215.56 umol) in MeOH (2 mL) was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain 24d. Calculated MS mass: [M+1] + (C 17 H 20 ClN3O2) m / z 334.1, LCMS measured value: m / z 334.1.

[0392] N-(6-chloro-7-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 24) To a solution of 24d (10 mg, 29.96 umol, 1 equivalent) in THF (5 mL), TEA (9.09 mg, 89.87 umol, 12.51 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (6.67 mg, 44.94 umol) were added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched with MeOH (1 mL) at 25°C, and then concentrated under reduced pressure to obtain the residue. The residue was checked by HPLC and then purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 35%-60%, 12 min) to obtain Example 24. Calculated MS mass: [M+1] + (C 20 H 20 ClN5O5) m / z 446.1, LCMS measured value: m / z 446.2; 1 H NMR (400 MHz, CD3OD)δ 7.55(s, 1H), 7.27(s, 1H), 3.50(s, 3H), 3.20 - 3.12(m, 1H), 2.94(br t, J=7.4 Hz, 2H), 2.87(br t, J=7.3 Hz, 2H), 2.17 - 2.12 (m, 2H), 1.27 (d, J=6.8 Hz, 6H).

[0393] Example 25: N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chem.

[0394] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazine-3-yl)oxy)aniline(25a) 3,6-Dichloro-4-cyclopropyl-pyridazine (1 g, 5.29 mmol) (21a), 4-amino-2,6-dichloro-phenol (941.67 mg, 5.29 mmol), K2CO3 (1.10 g, 7.93 mmol) and CuI (201.49 mg, 1.06 mmol) in DMA (5 mL) were degassed and then heated at 100 °C for 16 h under N2. The solid was filtered off, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to give 25a. Calculated MS mass: [M+1] + (C 13 H 10 Cl3N3O) m / z 330.0, LCMS found: m / z 329.9 / 331.9;

[0395] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(25b) A solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (11.80 mg, 90.75 μmol) in THF (2 mL) was added a drop of DMF, then (COCl)2 (11.52 mg, 90.75 μmol, 7.94 μL, 1.5 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. The solution was added to a mixture of 3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline (25a) (20 mg, 60.50 μmol) and TEA (18.37 mg, 181.50 μmol, 25.26 μL) in DCM (3 mL) at 25 °C, and the resulting mixture was stirred at 25 °C for 30 min. The mixture was concentrated, and the residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to give 25b. Calculated MS mass: [M+1]+ (C 16 H 10 Cl3N5O4) m / z 442.0, LCMS measured value: m / z 442.0.

[0396] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 25) A mixture of N-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (25b) (30 mg, 67.78 umol) and NaOAc (33.36 mg, 406.65 umol) in HOAc (3 mL) was heated at 110°C for 16 hours. The mixture was concentrated. The residue was purified using preparative HPL (neutral) C to obtain Example 25. Calculated MS mass: [M+1] + (C 16 H 11 Cl2N5O5) m / z 424.2, LCMS measured value: m / z 424.2; 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 2H), 7.03 (s, 1H), 2.28 - 2.18 (m, 1H), 1.23 - 1.14 (m, 2H), 1.04 - 0.94 (m, 2H).

[0397] Example 26: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0398] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one(26a) To a suspension of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3-one (1e) (20 g, 60.94 mmol) in CH3CN (200 mL) and THF (60 mL), NaHCO3 (15.36 g, 182.82 mmol) was added under a nitrogen atmosphere. To the resulting solution, Select F (21.59 g, 60.94 mmol) was added gradually over 30 minutes. The mixture was stirred at 20°C for 16 hours. The reaction mixture was partitioned into 200 mL of H2O and 300 mL of siRNA. The organic phase was separated, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1~1 / 1; TLC) to obtain 26a. Calculated MS mass: [M+1] + (C 14 H 14 Cl2FN3O2) m / z 346.0, LCMS measured value: m / z 346.0; 1 HNMR (400 MHz, CDCl3)δ 7.02(s, 1H), 6.80(d, J=8.8 Hz, 1H), 3.89(br s, 2H), 3.53(s, 3H), 3.24(quind, J=6.8, 13.5 Hz, 1H), 1.26(d, J=6.8 Hz, 6H).

[0399] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 26) To a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazine-3-one (26a) (13 g, 37.55 mmol) in THF (130 mL), TEA (11.40 g, 112.66 mmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.37 g, 56.33 mmol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed peaks with the desired MS. The mixture was diluted with 1 M HCl to change the pH to 6-7 and extracted with ethyl acetate in 300 mL (100 mL x 3). The combined organic layers were washed with 150 mL of brine, dried over anhydrous sodium sulfate, and filtered to obtain a bright yellow liquid. The bright yellow liquid was concentrated under reduced pressure to remove the solvent until the solid dissolved. The mixture was stirred at 20°C for 1 hour and filtered to obtain Example 26. Calculated MS mass: [M+1] + (C 17 H 14 Cl2FN5O5) m / z 458.0, LCMS measured value: m / z 458.0; 1 H NMR (400 MHz, CD3OD) δ 8.30 (d, J=7.5 Hz, 1H), 7.35 (s, 1H), 3.51 (s, 3H), 3.24 - 3.12 (m, 1H), 1.28 (d, J=6.8 Hz, 6H).

[0400] Example 27: 3-(((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one [ka]

[0401] 2-((3,5-Dichloro-2-fluoro-4-((5-Isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)acetonitrile(27a) To a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (26a) (20 mg, 57.77 umol) in ACN (2 mL), 2-bromoacetonitrile (52.26 mg, 435.72 umol, 29.03 uL), K2CO3 (24.09 mg, 174.29 umol), and NaI (26.12 mg, 174.29 umol) were added. The mixture was stirred at 100°C for 20 hours. The suspension was filtered through a Celite pad, and the pad was washed with siRNA (5 mL x 3). The combined filtrate was concentrated to dryness to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 27a. Calculated MS mass: [M+1] + (C 16 H 15 Cl2FN4O2) m / z 385.2, LCMS measured value: m / z 385.0; 1 HNMR(400 MHz, CDCl3)δ 7.04(s, 1H)6.81(d, J=8.16 Hz, 1H)4.38 - 4.50(m, 1H)4.21(d, J=7.06 Hz, 2H)3.54(s, 3H)3.24(dt, J=13.62, 6.75 Hz, 1H)1.26 - 1.28(m, 6H).

[0402] tert-butyl(cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate(27b) To a solution of 2-((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)acetonitrile (27a) (20 mg, 51.92 umol) in THF (3 mL), DMAP (6.34 mg, 51.92 umol) and Boc2O (33.99 mg, 155.76 umol, 35.78 uL) were added at 20°C. The mixture was stirred at 20°C for 20 minutes. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1) to obtain 27b. Calculated MS mass: [M+1] + (C 21 H 23Cl2FN4O4) m / z 485.3, LCMS measured value: m / z 485.2; 1 H NMR (400 MHz, CDCl3) δ 7.43 (br s, 1H) 7.07 (s, 1H) 4.52 (br s, 2H) 3.52 (s, 3H) 3.26 (dt, J=13.66, 6.92 Hz, 1H) 1.25 - 1.47 (m, 15H).

[0403] (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate(27c) To a solution of tert-butyl(cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)carbamate (27b) (20 mg, 41.21 umol) in DMF (2 mL), NH2OH·HCl (22.91 mg, 329.67 umol) and NaOAc (27.04 mg, 329.67 umol) were added at 20°C. The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was divided twice into 10 mL of ethyl acetate and 5 mL of H2O. The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 27c. Calculated MS mass: [M+1] + (C 21 H 26 Cl2FN5O5) m / z 518.4, LCMS measured value: m / z 518.0.

[0404] tert-butyl(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate(27d) To a solution of (Z)-tert-butyl(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydrop-yridazin-3-yl)oxy)phenyl)carbamate (27c) (20 mg, 38.58 umol) in THF (3 mL), DSC (12.85 mg, 50.16 umol) and TEA (7.81 mg, 77.17 umol, 10.74 uL) were added. The mixture was stirred at 60°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was then prepared using TLC (SiO2, DCM:MeOH = 10:1, P1:R) f Purified using the method (=0.3), 27d was obtained. Calculated MS mass: [M+1] + (C 22 H 24 Cl2FN5O6) m / z 544.4, LCMS measured value: m / z 544.0.

[0405] 3-(((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazole-5(4H)-one (Example 27) A solution of tert-butyl(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)methyl)carbamate (27d) (8 mg, 14.70 umol) in HCl / siRNA (2 mL) was stirred at 20°C for 1.5 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.04%HCl)-ACN]; B%: 30%-60%, 12 min) to obtain Example 27. Calculated MS mass: [M+1] + (C 17 H 16 Cl2FN5O4) m / z 444.2, LCMS measured value: m / z 444.0; 1 H NMR (400 MHz, CD3OD) δ 7.27 (s, 1H) 6.91 (d, J = 8.33 Hz, 1H) 4.38 (s, 2H) 3.49 (s, 3H) 3.13 - 3.21 (m, 1H) 1.26 (d, J = 7.02 Hz, 6H).

[0406] Example 28: N-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0407] 4-((5-(tert-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline(28a) To a solution of 4-(tert-butyl)-3,6-dichloropyridazine (200 mg, 0.975 mmol) in DMSO (5 mL), 4-amino-2,6-dichlorophenol (173.61 mg, 0.975 mmol), K2CO3 (404.34 mg, 2.93 mmol), and CuI (111.44 mg, 0.585 mmol) were added, and the mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. The solvent was diluted with SiO2 (10 mL) and H2O (10 mL), extracted with EA (10 mL × 2), washed with brine (20 mL × 2), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to obtain 28a. Calculated MS mass: [M+1] + (C 14 H 14 Cl3N3O) m / z 346.6, LCMS measured value: m / z 346.6; 1 H NMR (400 MHz, CDCl3) δ 1.51 (s, 9H), 6.67 (s, 2H), 7.24 (s, 1H).

[0408] N-(4-((5-(tert-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(28b) To a mixture of 4-((5-(tert-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (28a) (100 mg, 288.48 mmol) in THF (2 mL), TEA (87.58 mg, 865.45 mmol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (64.26 mg, 432.73 mmol) in DCM (2 mL) were added under a nitrogen atmosphere. The mixture was stirred under N2 at 20°C for 0.5 hours. The mixture was poured into H2O (10 mL), and the resulting mixture was extracted with siRNA (10 mL × 3). The organic layer was washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product 28c. The crude product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 17 H 14 Cl3N5O4) m / z 458.1, LCMS measured value: m / z 458.1.

[0409] N-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 28) NaOAc (125.19 mg, 1.53 mmol) was added to a mixture of N-(4-((5-(tert-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (140 mg, 305.2 µmol) in HOAc (10 mL). The mixture was then stirred at 120°C for 16 hours. The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (CH3CN in H2O, 40%) to obtain Example 28 (9.9 mg, 7.4% yield). Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.2, LCMS measured value: m / z 440.2; 1 H NMR (400 MHz, CD3OD) δ 1.44 (s, 9H), 7.32 (s, 1H), 7.92 (s, 2H).

[0410] Example 29 (P1 and P2): N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0411] 1-(3,6-dichloropyridazine-4-yl)ethanol (29a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (500 mg, 3.31 mmol) in Tol (3 mL), buto-3-in-2-ol (278.59 mg, 3.97 mmol) was added. The mixture was placed in a sealed tube and stirred at 110°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, TLC) to obtain 29a. 1 H NMR (400 MHz, CDCl3) δ 7.82 (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).

[0412] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine(29b) To a solution of 1-(3,6-dichloropyridazin-4-yl)ethanol (29a) (300 mg, 1.55 mmol) and DHP (653.68 mg, 7.77 mmol, 710.52 μL) in DCM (10 mL), TsOH (13.38 mg, 77.71 μL) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1, by TLC) to obtain 29b. 1 H NMR (400 MHz, CDCl3)δ 7.77(s, 1H), 7.63(s, 1H), 5.10(q, J=6.5 Hz, 1H), 4.98(q, J=6.6 Hz, 1H), 4.81(br d, J=4.6 Hz, 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=6.4 Hz, 3H), 1.46 (d, J=6.4 Hz, 3H).

[0413] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)aniline(29c) To a solution of 4-amino-2,6-dichlorophenol (167.00 mg, 938.13 umol) and 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (29b) (200 mg, 721.64 umol) in DMSO (5 mL), K2CO3 (299.21 mg, 2.16 mmol) and CuI (82.46 mg, 432.98 umol) were added, the mixture was degassed, purged three times with nitrogen, and then stirred at 90°C for 2 hours under a nitrogen atmosphere. LC-MS detected one peak with the desired MS. The reaction mixture was diluted with 5 mL of H2O and extracted with 30 mL (10 mL x 3) of ethyl acetate. The combined organic layer was washed with 10 mL of brine and dried on anhydrous sodium sulfate. 、 The residue was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, TLC) to obtain 29c. 1 H NMR (400 MHz, CDCl3)δ 7.55(s, 1H), 7.37(s, 1H), 6.68(s, 4H), 5.10(q, J=6.6 Hz, 1H), 5.00(q, J=6.4 Hz, 1H), 4.90 - 4.85(m, 1H), 4.52(t, J=3.6 Hz, 1H), 3.96 (ddd, J=3.8, 7.5, 11.2 Hz, 1H), 3.81 (br d, J=2.4 Hz, 4H), 3.65 (ddd, J=3.2, 8.0, 11.3 Hz, 1H), 3.61 - 3.54 (m, 1H), 3.47 - 3.40(m, 1H), 1.96 - 1.60(m, 12H), 1.55(d, J=6.5 Hz, 3H), 1.49(d, J=6.4 Hz, 3H).

[0414] N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(29d) To a solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)aniline (29c) (250 mg, 597.08 umol) in DCM (5 mL), TEA (181.26 mg, 1.79 mmol, 249.32 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (133.00 mg, 895.63 umol) were added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1, by TLC) to obtain 29d. Calculated MS mass: [M+1] + (C 20 H 18 Cl3N5O6) m / z 530.0, LCMS measured value: m / z 529.9.

[0415] 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)ethyl acetate (29e) To a solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (29d) (60 mg, 90.44 umol) in AcOH (3 mL), NaOAc (37.09 mg, 452.19 umol) was added. The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH, and then 29e was obtained, which was used in the next step without further purification. Calculated MS mass: [M+1] + (C 17 H 13 Cl2N5O7) m / z 470.0, LCMS measured value: m / z 470.0.

[0416] N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29) To a solution of 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)ethyl acetate (29 e) (105 mg, 223.30 umol) in MeOH (3 mL) and H2O (0.5 mL), LiOH.H2O (18.74 mg, 446.60 umol) was added. The mixture was stirred at 25°C for 1 hour. LC-MS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with 6 M HCl to change the pH to 6-8, extracted with ELISA (5 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 1%-40%, 12 min) to obtain Example 29. Calculated MS mass: [M+1] + (C 15 H 11 Cl2N5O6) m / z 428.0, LCMS measured value: m / z 428.0; 1 H NMR (400 MHz, DMSO-d6)δ 12.28(s, 1H), 11.31(s, 1H), 7.99(s, 2H), 7.40(d, J=1.1 Hz, 1H), 5.49(br s, 1H), 4.70(q, J=6.1 Hz, 1H), 1.33(d, J=6.4 Hz, 3H).

[0417] (R)-N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29-P1) and (S)-N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29-P2) N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29) was checked and purified by chiral SFC (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3 × H2O MeOH]; B%: 40%-40%, 10 min) to obtain Examples 29-P1 and 29-P2.

[0418] Example 29-P1: Calculated value of MS mass: [M+1] + (C 15 H 11 Cl2N5O6) m / z 428.0, LCMS measured value: m / z 428.0; 1 H NMR (400 MHz, DMSO-d6)δ 12.26(s, 1H), 10.71(br s, 1H), 8.06(s, 2H), 7.39(d, J=1.3 Hz, 1H), 5.49(br d, J=4.4 Hz, 1H), 4.74 - 4.66 (m, 1H), 1.33 (d, J=6.6 Hz, 3H).

[0419] Example 29-P2: Calculated mass of MS: [M+1]+(C15H11Cl2N5O6) m / z 428.0, measured mass of LCMS: m / z 427.9; 1 H NMR (400 MHz, DMSO-d6)δ 12.26(s, 1H), 10.74(br s, 1H), 8.05(s, 2H), 7.39(d, J=1.3 Hz, 1H), 5.49(br d, J=4.4 Hz, 1H), 4.75 - 4.66 (m, 1H), 1.33 (d, J=6.4 Hz, 3H).

[0420] Example 30: N-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0421] 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene (30a) To a solution of (4-bromo-2,6-dimethylphenyl)methanol in DCM (30 mL), PPh3 (1.83 g, 6.97 mmol) was added. The mixture was then cooled to 0-5°C. Next, CBr4 (2.31 g, 6.97 mmol) was gradually added to the mixture. The mixture was then stirred under N2 at 15°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~10:1, TLC) to obtain 30a. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H) 4.50 (s, 2H) 2.39 (s, 6H).

[0422] 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (30b) To a solution of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene (30a) (1.26 g, 4.53 mmol) in DMF (30 mL), NaCN (244.35 mg, 4.99 mmol) was added at 15°C. The mixture was then stirred at 15°C for 16 hours. The mixture was divided twice into ethyl acetate (50 mL) and aqueous NH4Cl solution (20 mL). The combined organic phases were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1~3:1, TLC) to obtain 30b. 1 H NMR (400 MHz, CD3OD) δ 7.28 (s, 2H) 3.79 (s, 2H) 2.38 (s, 6H).

[0423] 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazine-3-yl)acetonitrile (30c) To a solution of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (30b) (800 mg, 3.57 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (682.05 mg, 3.57 mmol) in THF (10 mL), t-BuOK (1 M, 7.14 mL, 2 equivalents) was added dropwise at 60°C, and the resulting mixture was heated at 60°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL, 2x). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1~3:1, TLC) to obtain 30c. Calculated MS mass: [M+1] + (C 17 H 17 BrClN3) m / z 378.0, LCMS measured value: m / z 378.2; 1H NMR (400 MHz, CD3OD)δ 7.34(s, 3H)7.21(s, 1H)6.28(s, 1H)3.01(dt, J=13.54, 6.74 Hz, 1H)2.89(dt, J=13.72, 6.89 Hz, 1H)2.27(s, 6H)1.27 - 1.30(m, 6H).

[0424] 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one(30d) A solution of 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (30c) (1 g, 2.78 mmol), H2O (10 mL), and HCl (40 mL) in AcOH (10 mL) was heated at 120°C for 48 hours. LC-MS showed that the starting material was consumed and the desired MS was obtained. The mixture was adjusted to pH ~7 with 3M NaOH at 15°C, the solid was filtered, and dried to obtain 30d. The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 16 H 19 BrN2O) m / z 335.1, LCMS measured value: m / z 335.2; 1 H NMR (400 MHz, DMSO) δ 12.56 (s, 1H) 7.24 (s, 2H) 7.11 (s, 1H) 3.90 (s, 2H) 2.97 (quin, J = 6.82 Hz, 1H) 2.21 (s, 6H) 1.11 (d, J = 6.85 Hz, 6H).

[0425] 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one(30e) To a solution of 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30d) (100 mg, 298.30 umol) and benzophenone imine (54.06 mg, 298.30 umol, 50.06 uL) in dioxane (5 mL), t-BuONa (43.00 mg, 447.44 umol), Pd2(dba)3 (27.32 mg, 29.83 umol), and xanthophos (17.26 mg, 29.83 umol) were added. The mixture was degassed, purged three times with nitrogen, and stirred at 80°C for 16 hours. The mixture was partitioned into DCM (20 mL) and saturated NH4Cl aqueous solution (10 mL), and a second extraction was performed with DCM. The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 30e. Calculated mass of MS: [M+1] + (C 29 H 29 N3O) m / z 436.2, LCMS measured value: m / z 436.4. The residue was used directly in the next step without further purification.

[0426] 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one(30f) A solution of 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30e) (100 mg, 229.59 umol) in HCl / siRNA (5 mL) was stirred at 15°C for 16 hours. LC-MS showed detection of the desired MS. The mixture was diluted with 5 mL of water and the pH was adjusted to 9-10 with saturated NaHCO3 aqueous solution. The suspension was extracted with siRNA (15 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain 30f. Calculated MS mass: [M+1] + (C 16 H 21 N3O) m / z 272.2, LCMS measured value: m / z 272.3; 1H NMR (400 MHz, CD3OD) δ 6.89 (s, 1H) 6.48 (s, 2H) 3.89 (s, 2H) 3.04 (dt, J=13.69, 6.72 Hz, 1H) 2.18 (s, 5H) 1.11 (d, J=6.97 Hz, 6H).

[0427] N-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 30) To a mixture of 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30f) (10 mg, 36.85 umol) in THF (1 mL), TEA (14.92 mg, 147.41 umol, 20.52 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (10.95 mg, 73.70 umol) were added at 15°C. The mixture was stirred at 15°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 × 30 mm 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 12 min) to obtain Example 30. Calculated MS mass: [M+1] + (C 19 H 21 N5O4) m / z 384.2, LCMS measured value: m / z 384.2; 1 H NMR (400 MHz, CD3OD) δ 7.41 (s, 2H) 7.02 (s, 1H) 4.86 (s, 19H) 4.02 (s, 2H) 3.07 (dt, J = 13.72, 6.77 Hz, 1H) 2.30 (s, 6H) 1.15 (d, J = 6.85 Hz, 6H).

[0428] Example 31: N-(4-((5-(bicyclo[1,1,1]pentan-1-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0429] 4-(bicyclo[1.1.1]pentan-1-yl)-3,6-dichloropyridazine(31a) To a mixture of 3,6-dichloropyridazine (170 mg, 1.14 mmol) and bicyclo[1.1.1]pentane-1-carboxylic acid (134.35 mg, 1.20 mmol) in H2O (5 mL), AgNO3 (193.84 mg, 1.14 mmol), ammonium persulfate (286.44 mg, 1.26 mmol), and H2SO4 (335.75 mg, 3.42 mmol, 182.48 μL in H2O (2.5 mL)) were added all at once under nitrogen at 60°C. The mixture was stirred at 70°C for 20 minutes. After cooling, the mixture was extracted with ethyl acetate (5 mL × 2), the organic phase was washed with NaHCO3 (2 mL) and brine (5 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1) to obtain 31a. 1 H NMR (400 MHz, CD3OD) δ 7.62 (s, 1H), 2.66 (s, 1H), 2.34 (s, 6H).

[0430] 4-((5-(Bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline(31b) 4-(bicyclo[1.1.1]pentan-1-yl)-3,6-dichloropyridazine (31a) (150 mg, 697.42 umol) and 4-amino-2,6-dichlorophenol (124.15 mg, 697.42 umol) were added in DMSO (9 mL) to a single addition of K2CO3 (385.55 mg, 2.79 mmol) and CuI (79.69 mg, 418.45 umol) under nitrogen at 25°C. The mixture was stirred at 90°C for 16 hours. The residue was partitioned into ethyl acetate (20 mL) and H2O (5 mL x 2). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to obtain 31b. Calculated MS mass: [M+1] + (C 15 H 12 Cl3N3O) m / z 356.0, LCMS measured value: m / z 355.9.

[0431] N-(4-((5-(Bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl-)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(31c) To a mixture of 4-((5-(bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (31b) (30 mg, 84.12 umol) in DCM (5 mL), TEA (25.54 mg, 252.36 umol, 35.13 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (18.74 mg, 126.18 umol) were added all at once under nitrogen at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. The residue was diluted with water (5 mL) and extracted with DCM (10 mL, 2x). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 31c.

[0432] N-(4-((5-(Bicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 31) NaOAc (15.75 mg, 192.03 umol) was added all at once to a mixture of N-(4-((5-(bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl-)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (31c) (18 mg, 38.41 umol) in AcOH (3 mL). The mixture was then stirred under nitrogen at 120°C for 16 hours. The mixture was concentrated. The residue was purified by preparative HPL (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 45%-75%, 10 min) to obtain Example 31. Calculated MS mass: [M+1] + (C 18 H 13 Cl2N5O5) m / z 450.0, LCMS measured value: m / z 450.0; 1 H NMR (400 MHz, CD3OD) δ 7.91 (s, 2H), 7.19 (s, 1H), 2.60 (s, 1H), 2.25 (s, 6H).

[0433] Example 32: N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0434] 1-(3,6-dichloropyridazine-4-yl)propan-1-ol(32a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1 g, 6.62 mmol) in 10 mL of tol, pent-1-in-3-ol (1.11 g, 13.25 mmol, 1.14 mL) was added at 20°C. The mixture was placed in a sealed tube and stirred at 110°C for 16 hours. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 32a. Calculated MS mass: [M+1] + (C7H8Cl2N2O) m / z 207.1, LCMS measured value: m / z 207.0; 1 H NMR(400 MHz, CDCl3)δ 7.79(s, 1H)4.94(dt, J=7.73, 3.77 Hz, 1H)2.72(d, J=4.03 Hz, 1H)1.94(dqd, J=14.52, 7.39, 7.39, 7.39, 3.55 Hz, 1H)1.60 - 1.72 (m, 1H) 1.06 (t, J=7.34 Hz, 3H).

[0435] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxypropyl)pyridazine(32b) To a solution of 1-(3,6-dichloropyridazine-4-yl)propan-1-ol (32a) (140 mg, 676.14 uL) and DHP (284.37 mg, 3.38 mmol, 309.10 uL) in DCM (5 mL), TsOH (5.82 mg, 33.81 uL) was added. The mixture was stirred at 20°C for 1 hour. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1, TLC) to obtain 32b. Calculated MS mass: [M+1] + (C 12 H 16Cl2N2O2) m / z 291.2, LCMS measured value: m / z 291.1; 1 H NMR (400 MHz, CDCl3)δ 7.71(s, 1H)7.56(s, 1H)4.95 - 5.00(m, 1H)4.78(dd, J=7.06, 3.97 Hz, 1H)4.69(dd, J=5.40, 2.09 Hz, 1H)4.40(t, J=3.42 Hz, 1H)3.85 - 4.03(m, 2H)3.54 - 3.55(m, 1H)3.45 - 3.62(m, 2H)3.33 - 3.41(m, 1H)2.04 - 2.10(m, 1H)1.47 - 1.94(m, 24H)1.05(t, J=7.39 Hz, 3H)0.95(t, J=7.39 Hz, 3H).

[0436] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine-3-yl)oxy)aniline(32c) To a solution of 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (32b) (130 mg, 446.47 umol) and 4-amino-2,6-dichlorophenol (79.48 mg, 446.47 umol) in DMSO (5 mL), K2CO3 (246.83 mg, 1.79 mmol) and CuI (51.02 mg, 267.88 umol) were added, the mixture was degassed, purged three times with nitrogen, and then stirred at 90°C under a nitrogen atmosphere for 16 hours. LC-MS showed the desired MS. The mixture was diluted with siRNA (5 mL), filtered, and the filtrate was partitioned into ethyl acetate (5 mL) and H2O (3 mL). The organic phase was separated, and the aqueous phase was extracted with siRNA (5 mL). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to obtain 32c. Calculated MS mass: [M+1] + (C 18 H 20 Cl3N3O3) m / z 432.7, LCMS measured value: m / z 432.1; 1H NMR (400 MHz, CDCl3)δ 7.48(s, 1H)7.29(s, 1H)6.68(s, 2H)4.97(dd, J=7.46, 3.79 Hz, 1H)4.76 - 4.83(m, 1H)4.46(t, J=3.30 Hz, 1H)3.93 - 4.02 (m, 1H) 3.80 (br s, 2H) 3.54 - 3.62 (m, 1H) 3.33 - 3.41 (m, 1H) 1.85 - 1.99 (m, 2H) 1.66 - 1.83 (m, 4H) 1.06 (t, J=7.34 Hz, 2H)0.96(t, J=7.34 Hz, 2H).

[0437] N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(32d) To a solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)aniline (32c) (110 mg, 254.20 umol) in DCM (5 mL), TEA (77.17 mg, 762.60 umol, 106.15 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (56.63 mg, 381.30 umol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 32d. Calculated MS mass: [M+1] + (C 21 H 20 Cl3N5O6) m / z 544.8, LCMS measured value: m / z 544.6; 1 H NMR (400 MHz, CD3OD)δ 7.97(s, 2H)7.64(s, 1H)4.83(dd, J=8.05, 3.20 Hz, 1H)3.92(s, 1H)1.87 - 1.97(m, 2H)1.59 - 1.69(m, 1H)1.06(t, J=7.28 Hz, 3H).

[0438] 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propyl acetate (32e) To a solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32d) (130 mg, 238.63 umol, 1 equivalent) in HOAc (5 mL), NaOAc (97.88 mg, 1.19 mmol) was added. The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and AcOH was removed to obtain 32e. Calculated MS mass: [M+1] + (C 18 H 15 Cl2N5O7) m / z 484.2, LCMS measured value: m / z 484.1. The crude product was used in the next step without further purification.

[0439] N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32) To a solution of 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propylacetate (32e) (115 mg, 237.48 uL) in MeOH (3 mL) and H2O (0.5 mL), LiOH.H2O (1 M, 474.97 uL) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with 5 mL of water. The suspension was extracted with ELISA (30 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 10 min) to obtain Example 32. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.2, LCMS measured value: m / z 442.0; 1H NMR(400 MHz, CD3OD)δ 7.92(s, 2H)7.47(s, 1H)4.85(s, 29H)4.74(br d, J=4.77 Hz, 1H)1.88 - 2.02(m, 1H)1.51 - 1.64(m, 1H)1.02(t, J=7.40 Hz, 3H).

[0440] Examples 32-P1 and P2: N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0441] N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(32f) A solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32d) (160 mg, 293.70 umol) in TFA (1 mL) and DCM (3 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 35%-65%, 10 min) to obtain 32f. Calculated MS mass: [M+1] + (C 16 H 12 Cl3N5O5) m / z 460.0, LCMS measured value: m / z 460.1.

[0442] SFC separation: N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f) (95 mg, 206.23 umol) was separated by SFC (column: DAIEL CHIRALCEL OJ (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH3 × H2O MeOH]; B%: 30%-30%, 5 min) to obtain 32f-P1 and 32f-P2.

[0443] (R)-N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32-P1) A solution of (R)-N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f-P1) (10.00 mg, 21.71 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-50%, 12 min) to obtain Example 32-P1. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.0, LCMS measured value: m / z 442.0; 1 H NMR(400 MHz, CD3OD)δ 7.92(s, 2H)7.47(d, J=0.98 Hz, 1H)4.87(s, 40H)4.73(br d, J=4.03 Hz, 1H)1.90 - 1.98(m, 1H)1.58(dt, J=14.15, 7.29 Hz, 1H)1.02(t, J=7.40 Hz, 3H).

[0444] (S)-N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32-P2) A solution of (S)-N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f-P2) (10.00 mg, 21.71 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-50%, 10 min) to obtain Example 32-P2. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.0, LCMS measured value: m / z 442.0; 1 H NMR (400 MHz, CD3OD)δ 7.91(s, 2H)7.47(d, J=1.10 Hz, 1H)4.87(s, 19H)4.73(dd, J=7.09, 3.06 Hz, 1H)1.95(ddd, J=13.91, 7.43, 3.48 Hz, 1H)1.52 - 1.63(m, 1H) 1.02(t, J=7.34 Hz, 3H).

[0445] Example 33: N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0446] 2-(3,6-dichloropyridazine-4-yl)propan-2-ol(33a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (500 mg, 3.31 mmol) in 5 mL, 2-methylbuto-3-in-2-ol was added at 20°C. The mixture was placed in a sealed tube and stirred at 115°C for 16 hours. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1~4:1, TLC) to obtain 33a. Calculated MS mass: [M+1] +(C7H8Cl2N2O) m / z 207.0, LCMS measured value: m / z 207.0; 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H) 2.17 (s, 1H) 1.77 (s, 6H).

[0447] 3,6-Dichloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazine(33b) To a solution of 2-(3,6-dichloropyridazine-4-yl)propan-2-ol (33a) (70 mg, 338.07 umol) in DCM (5 mL), DHP (142.19 mg, 1.69 mmol, 154.56 uL) and PPTS (16.99 mg, 67.61 umol) were added. The mixture was stirred at 20°C for 16 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, 2x). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, TLC) to obtain 33b. Calculated MS mass: [M+1] + (C 12 H 16 Cl2N2O2) m / z 291.1, LCMS measured value: m / z 291.1; 1 H NMR (400 MHz, CDCl3)δ 7.85(s, 1H)4.84(dd, J=5.62, 2.81 Hz, 1H)4.01 - 4.08(m, 1H)3.88 - 3.95(m, 1H)3.57(dt, J=11.13, 5.44 Hz, 1H)3.47(dt, J=11.37, 5.69 Hz, 1H)1.83 - 1.96(m, 2H)1.78(s, 3H)1.75(s, 3H)1.56 - 1.73(m, 6H).

[0448] 3,5-Dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazine-3-yl)oxy)aniline(33c) To a solution of 3,6-dichloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazine (33b) (40 mg, 137.38 umol) and 4-amino-2,6-dichlorophenol (24.45 mg, 137.38 umol) in DMSO (4 mL), K2CO3 (75.94 mg, 549.50 umol) and CuI (15.70 mg, 82.43 umol) were added, the mixture was degassed, purged three times with nitrogen, and then stirred at 90°C under a nitrogen atmosphere for 16 hours. LC-MS showed the desired MS. The mixture was diluted with siRNA (5 mL) and filtered. The filtrate was partitioned into ethyl acetate (5 mL) and H2O (3 mL). The organic phase was separated, and the aqueous phase was extracted with siRNA (5 mL). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to obtain 33c. Calculated MS mass: [M+1] + (C 18 H 20 Cl3N3O3) m / z 432.1, LCMS measured value: m / z 432.1.

[0449] N-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(33d) To a solution of 3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazin-3-yl)oxy)aniline (33c) (25 mg, 57.77 umol) in DCM (1.5 mL), TEA (17.54 mg, 173.32 umol, 24.12 uL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (12.87 mg, 86.66 umol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain 33d. Calculated MS mass: [M+1] + (C 21 H 20Cl3N5O6) m / z 544.0, LCMS measured value: m / z 544.1; 1 H NMR (400 MHz, CD3OD)δ 7.98(s, 2H)7.76(s, 1H)4.36 - 4.41(m, 6H)3.93(s, 3H)3.83 - 3.89(m, 1H)3.62 - 3.65(m, 2H)3.59(t, J=6.60 Hz, 5H) 3.48 (dt, J=7.73, 6.22 Hz, 9H) 1.92 (dt, J=6.14, 3.10 Hz, 4H) 1.78 - 1.88 (m, 16H) 1.66 - 1.75 (m, 9H).

[0450] N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 33) A solution of N-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (33d) (25 mg, 45.89 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-55%, 12 min) to obtain Example 33. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.0, LCMS actual value: m / z 441.9; 1H NMR (400 MHz, CD3OD) δ 7.91 (s, 2H) 7.58 (s, 1H) 4.85 (br s, 126H) 1.62 (s, 6H).

[0451] Example 34: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0452] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropylpyridazine-3(2H)-one(34a) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (8b) (300 mg, 954.91 uL) in CH3CN (10 mL) and THF (10 mL), NaHCO3 (240.66 mg, 2.86 mmol, 111.41 uL) was added. Next, Select F (372.11 mg, 1.05 mmol) was added to the mixture all at once at 20°C. The mixture was then stirred at 20°C for 2 hours. The mixture was diluted with siRNA (30 mL) and H2O (30 mL). The organic layer was washed with brine (10 mL) and dried under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain 34a. 1 H NMR (400 MHz, CD3OD) δ 7.29 (d, J=0.86 Hz, 1H) 6.89 (d, J=8.44 Hz, 1H) 3.10 - 3.23 (m, 1H) 1.25 - 1.33 (m, 6H).

[0453] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 34) To a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropylpyridazine-3(2H)-one (34a) (100 mg, 301.06 umol) in DCM (4 mL), TEA (91.39 mg, 903.19 umol, 125.71 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (67.06 mg, 451.59 umol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain the desired substance. The desired compound was re-purified by preparative HPLC (column: Phenomenex Luna C18 200×40mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 12 min) to obtain Example 34. Calculated MS mass: [M+1] + (C16H12Cl2FN5O5) m / z 444.0, LCMS measured value: m / z 443.9; 1H NMR (400 MHz, CD3OD) δ 7.97 (br d, J=6.72 Hz, 1H) 7.37 (s, 1H) 4.87 (br s, 13H) 3.12 - 3.22 (m, 1H) 1.28 (br d, J=6.60 Hz, 6H).

[0454] Scheme F: 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (compound 35c) [ka]

[0455] 2-(3,6-dichloropyridazine-4-yl)propan-1-ol(35a) To 25 mL of H2O, TFA (4.97 g, 43.63 mmol, 3.23 mL) was added at 50°C. Then, 2-methylpropane-1,3-diol (6.65 g, 73.8 mmol, 6.59 mL) was added to the mixture. Next, 3,6-dichloropyridazine (5 g, 33.6 mmol) and AgNO3 (7.70 g, 45.3 mmol) were added. Next, a solution of ammonium thiothiosulfate (15.3 g, 67.1 mmol, 14.6 mL) in 15 mL of H2O was gradually added to the mixture at 50°C. The resulting mixture was stirred at 50°C for 0.5 hours. The reaction mixture was partitioned into 45 mL of H2O and 50 mL of toluene. The organic phase was separated, washed with 3 x 50 mL of H2O, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate) to obtain 35a. Calculated MS mass: [M+1] + (C7H8Cl2N2O) m / z 207.0, LCMS measured value: m / z 207.0; 1 H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 3.93 - 3.84 (m, 2H), 3.45 - 3.30 (m, 1H), 1.35 (d, J=7.2 Hz, 3H).

[0456] 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,6-dichloropyridazine(35b) To a solution of 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (35a) (3.4 g, 16.4 mmol) and tert-butyl-chlorodimethyl-silane (2.47 g, 16.4 mmol, 2.01 mL) in DMF (25 mL), imidazole (1.34 g, 19.7 mmol) was added. The mixture was stirred under a nitrogen atmosphere at 25°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with RINKAN (100 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35b. The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 13 H 22 Cl2N2OSi) m / z 321.1, LCMS measured value: m / z 321.0; 1 H NMR(400 MHz, CDCl3)δ 7.48(s, 1H), 3.77(d, J=4.4 Hz, 2H), 3.38 - 3.29(m, 1H), 1.32(d, J=6.8 Hz, 3H), 0.88 - 0.79(m, 9H), 0.04 - 0.02(m, 3H), 0.02 - 0.08(m, 3H).

[0457] 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline(35c) To a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,6-dichloropyridazine (35b) (1 g, 3.11 mmol) in DMSO (15 mL), 4-amino-2,6-dichlorophenol (752.84 mg, 3.11 mmol), K2CO3 (1.29 g, 9.34 mmol), and CuI (355.63 mg, 1.87 mmol) were added. The mixture was stirred at 90°C for 5 hours under a nitrogen atmosphere. The suspension was filtered through a Celite pad, and the pad cake was washed with HCl (50 mL). The reaction mixture was quenched with H2O (30 mL), then extracted with ethyl acetate (50 mL), and then extracted with HCl (50 mL x 5). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 35c. Calculated MS mass: [M+1] + (C 19 H 26 Cl3N3O2Si) m / z 462.1, LCMS measured value: m / z 462.1.

[0458] Example 35: N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0459] 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindorin-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propylacetate(35d) To a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (35c) (510 mg, 1.10 mmol) in HOAc (8 mL), isobenzofuran-1,3-dione (244.8 mg, 1.65 mmol) and NaOAc (271.2 mg, 3.31 mmol) were added. The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with H2O (30 mL) and extracted with ELISA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate) to obtain 35d. Calculated MS mass: [M+1] + (C 23 H 17 Cl2N3O6) m / z 502.0, LCMS measured value: m / z 502.1.

[0460] 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindorin-2-yl)phenoxy)-2-methyl-3-oxo-2,3-dihydropyridazine-4-yl)propylacetate(35e) In a solution of 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindorin-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propylacetate (35d) (230 mg, 457.9 umol) in DMF (3 mL), K2CO2 was added. 3( 107.6 mg (778.4 uL) and MeI (130.0 mg (915.8 uL, 57.0 uL)) were added. The mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with H2O (15 mL) at 25°C, and then extracted with RINKAN (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35e. The mixture was used in the next step without further purification. Calculated MS mass: [M+1] + (C 24 H 19 Cl2N3O6) m / z 516.1, LCMS measured value: m / z 516.1.

[0461] 6-(4-amino-2,6-dichlorophenoxy)-4-(1-hydroxypropan-2-yl)-2-methylpyridazine-3(2H)-one(35f) To a solution of 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindolin-2-yl)phenoxy)-2-methyl-3-oxo-2,3-dihydropyridazine-4-yl)propyl acetate (35e) (223 mg, 431.89 umol) in MeOH (5 mL), butan-1-amine (1.11 g, 15.2 mmol, 1.5 mL) was added. The mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the MeOH. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain 35f. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O3) m / z 344.0, LCMS measured value: m / z 344.0.

[0462] N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 35) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-(1-hydroxypropan-2-yl)-2-methylpyridazine-3(2H)-one (35f) (50 mg, 145.3 umol) in THF (3 mL), TEA (44.1 mg, 435.8 umol, 60.7 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (32.4 mg, 217.9 umol) were added. The mixture was stirred at 25°C for 5 minutes. TLC and LCMS showed that 35f was completely consumed and the desired mass + Ac was detected. The reaction mixture was quenched by adding MeOH (5 mL) at 25°C. Then, the pH was adjusted to LiOH . The mixture was adjusted to 10-12 with H2O, and the resulting mixture was stirred at 25°C for 1 hour. LC-MS showed that the desired mass was found in the major peak. Next, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [water (10mM NH4HCO3)-MeCN]) to obtain Example 35. Calculated mass of MS: [M+1] + (C 17 H15 Cl2N5O6) m / z 456.0, LCMS measured value: m / z 456.1; 1 H NMR (400 MHz, CD3OD)δ 7.93(s, 2H), 7.34(s, 1H), 3.80(dd, J=6.0, 10.6 Hz, 1H), 3.73 - 3.66(m, 1H), 3.51(s, 3H), 3.29 - 3.23(m, 1H), 1.29(d, J=7.0 Hz, 3H).

[0463] Example 36: N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0464] N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropan-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide(36a) To a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (35c) (50 mg, 108.0 umol) in THF (2 mL), TEA (32.8 mg, 324.0 umol, 45.1 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (24.1 mg, 162.0 umol) were added. The mixture was stirred at 25°C for 5 minutes. The reaction mixture was quenched with MeOH (25 mL) at 25°C, and the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to obtain 36a. Calculated MS mass: [M+1] + (C 16 H 12 Cl3N5O5) m / z 460.0, LCMS measured value: m / z 460.0.

[0465] 2 -(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propylformate(36b) A solution of N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropan-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (36a) (40 mg, 86.8 umol) in HCOOH (5 mL) was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove HCOOH. The residue was purified by preparative TLC (SiO2, ethyl acetate: petroleum ether) to obtain 36b. Calculated MS mass: [M+1] + (C 17 H 13 Cl2N5O7) m / z 470.0, LCMS measured value: m / z 470.0.

[0466] N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 36) To a solution of 2-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)phenoxy)-3-oxo-2,3-dihydropyridazine-4-yl)propyl formate (36b) (35 mg, 74.4 umol) in MeOH (4 mL), LiOH.H2O (3.8 mg, 89.3 umol)H2O (1 mL) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]) to obtain Example 36. Calculated MS mass: [M+1] + (C16H13Cl2N5O6) m / z 442.0, LCMS measured value: m / z 442.1 1 H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.36 (s, 1H), 3.84 - 3.78 (m, 1H), 3.73 - 3.67 (m, 1H), 3.26 - 3.20 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).

[0467] Example 37: N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0468] 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)...

Claims

【Request Item 1】 【Chemistry 1】 A compound selected from the above, or its tautomers, N-oxides, isotopic isomers, or stereoisomers, or any pharmaceutically acceptable salt thereof.

2. The compound, 【Chemistry 2】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound, 【Transformation 3】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

4. The compound, 【Chemistry 4】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

5. The compound, 【Transformation 5】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The compound, 【Transformation 6】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. The compound, 【Transformation 7】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The compound, 【Transformation 8】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

9. The compound, 【Chemistry 9】 The compound according to claim 1, which is either a tautomer thereof, an N-oxide, an isotopic isomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a tautomer thereof, an N-oxide, an isotope isomer, or a stereoisomer, or any pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition for agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of the compound described in any one of claims 1 to 9, or a tautomer, N-oxide, isotope isomer, or stereoisomer thereof, or any pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition for treating THR beta-mediated disorders, comprising an effective amount of the compound described in any one of claims 1 to 9, or a tautomer, N-oxide, isotope isomer, or stereoisomer thereof, or any pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, wherein the disorder is non-alcoholic steatohepatitis (NASH).

Images