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 TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 722,312, filed August 24, 2018, and U.S. Provisional Application No. 62 / 867,117, filed June 26, 2019, the entire disclosures of each of which are incorporated herein by reference for all purposes. Technical Field The present invention relates to compounds, preferably thyroid hormone receptor beta (THRbeta) agonist compounds, compositions thereof, and methods for their preparation, as well as methods for agonizing THRbeta and treating disorders mediated by THRbeta. [Background technology]

[0002] The beneficial effects of treating patients with hyperthyroidism or hypothyroidism with endogenous T3 / T4 ligands or early analogs of these endogenous ligands have been documented (Richardson Hill Jr., S. et al., J. Clin. Invest. 1960, 39, 523-533). These early studies, and similar follow-up studies, established the heart as the primary organ for the manifestation of side effects of both hyperthyroidism and hypothyroidism (Klein, I. et al., Circulation, 2007, 1725-1735). Tachycardia, hypertrophy, atrial arrhythmias, and atrial fibrillation are particularly serious problems. Furthermore, increased bone turnover has been shown to lead to decreased bone mineral density. Negative effects at both the heart and bone sites are associated with agonism of the THR alpha isoform, whereas 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). Summary of the Invention [Problem to be solved by the invention]

[0003] The diseases or disorders related to 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 analogues, such as THR beta agonists, preferably avoiding the undesirable effects of hyperthyroidism and hypothyroidism and maintaining the beneficial effects of thyroid hormones, for the treatment of patients with non-alcoholic steatohepatitis (NASH).For example, there is a need for developing novel thyroid hormone analogues, particularly as selective agonists of THR beta, preferably avoiding the undesirable effects related to the agonism of THR alpha and maintaining the beneficial effects of thyroid hormones for the treatment of patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia or hypercholesterolemia. [Means for solving the problem]

[0004] overview In one aspect, the present description provides a compound of formula (I): [ka] (I) [In the formula, Ring A having a carbonyl (keto) group therein forms a 5-membered heterocycle containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl groups or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 is C1-C4 alkyl, C3-C5 cycloalkyl, CON(R 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 is; R 3 and R 4 is independently Cl, Br, methyl, or ethyl; R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl; Or R 5 is R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; X is absent, O, NR 12 , C(O)NR 12 , N.R. 12 C(O), CR 12 R 12 , OCR 12 R 12 , C.R. 12 R 12 O, NR 12 CR 12 R 12 , C.R. 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 C1-C2 alkyl optionally substituted with 1 to 5 halo, or The Two R's 11 groups, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclobutyl ring; and Each R 12 are independently H or methyl] or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the compound has formula (IIA) or (IIB): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, and L are as defined in formula (I). It is a compound represented by the formula:

[0006] In some embodiments, the compound has formula (VD): [ka] (VD) [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 has the same meaning as in formula (I). It is a compound represented by the formula:

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

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

[0009] In some embodiments, R 4is chloro or -CH3; or R 5 is R 4 and together with the intervening atoms form a 5- to 6-membered cycloalkyl. In some embodiments, R 5 is R 4 and together with the intervening atoms form cyclopentyl. In some embodiments, R 5 is 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 is independently H or methyl. In some embodiments, X is —OCH—, —NHCH—, —NHC(O)—, —N(CH)CH—, or —N(H)CH(CH)—.

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

[0012] In some embodiments, the present disclosure provides a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0013] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient.

[0014] In one aspect, the description provides a method of agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of a compound provided herein, or an effective amount of any of the pharmaceutical compositions provided herein.

[0015] In one aspect, the present disclosure provides a method for treating a THR beta-mediated disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a therapeutically effective amount of a composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH). DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description definition As used herein, the following definitions apply unless otherwise stated. Furthermore, if a term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0017] "Comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude others. When used to define compositions and methods, "consisting essentially of" is intended to mean excluding other elements that are essential to the combination. For example, a composition consisting essentially of the elements defined herein would not exclude other elements that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding more than trace amounts of, for example, other recited components and substantial method steps. Embodiments defined by any of these conjunctions are within the scope of the present invention.

[0018] An "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. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, LD 50 This can be determined by determining the ED50 (the dose that is therapeutically effective in 50% of the population) and the ED50 (the dose that is lethal to 50% of the population).

[0019] As used herein, the term "excipient" refers to an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains a compound of the invention as an active ingredient. A variety of substances may be included within the term excipient, including, but not limited to, substances used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, chewable tablet materials, sweeteners or flavoring agents, suspending / gelling agents, or wet granulation agents. Binders include, for example, carbopol, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[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 refers to a human being.

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

[0022] "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. The compounds described herein can be administered as a pharmaceutically acceptable salt.

[0023] A "prodrug" refers to a compound that, after administration, is metabolized or otherwise converted into a compound (or drug) that is biologically active or more active in at least one property. Compared to a drug, a prodrug is chemically modified to be less active or inactive, 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, e.g., Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). Prodrugs can be synthesized using reactants other than those used in the corresponding drug. By way of illustration, and without limitation, prodrugs include carboxy esters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxy group is part of an aryl or heteroaryl moiety, and the aryl and heteroaryl can be optionally substituted), and the like.

[0024] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include salts containing protonated and alkylated nitrogen bases. Exemplary, non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds used herein contain a basic functional group, such salts include, but are not limited to, salts of organic acids such as carboxylic and sulfonic acids, and mineral acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Exemplary, non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic, and tribasic phosphates, mesylate, tosylate, and the like.

[0025] A "therapeutically effective amount" or dose of a compound or composition means that amount of the compound or composition that results in the reduction or inhibition of symptoms or a prolongation of survival in a patient. This result may require multiple administrations of the compound or composition.

[0026] "Treating" or "treatment" of a disease in a patient means 1) preventing the disease from occurring in a patient who is predisposed to the disease or who does not yet exhibit symptoms of the disease; 2) inhibiting the disease or halting its progression; or 3) causing an improvement or regression of the disease. As used herein, "treating" or "treatment" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms resulting from the disease or disorder, reducing the severity of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the state of the disease or disorder, providing remission (partial or total) of the disease or disorder, reducing the dose of one or more other medications required to treat the disease or disorder, increasing the effectiveness of another medication used to treat the disease or disorder, slowing the progression of the disease or disorder, improving the quality of life, and / or prolonging the survival of a patient. "Treatment" also includes the reduction of the pathological consequences of a disease or disorder. The methods of the invention contemplate any 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 an isotope of those same atoms. For example, H is replaced by D or T, or 12 C is 11 replaced by C, or 14 N 15 Substitution with N. For example, but not limited to, substitution with D may in some cases lead to a slower metabolic rate and therefore a longer half-life. Substitution of H with T can provide a radioligand that may be useful for binding studies. 12 C as a short-lived isotope 11 When substituted with C, it can provide a useful ligand for positron emission tomography (PET) scans.14 N 15 Substituting for N, 15 This results in a compound that can be detected / monitored by NNMR spectroscopy. For example, an isotopomer of a compound containing -CH2CH3 would be that compound but containing -CD2CD3 instead of -CH2CH3.

[0028] Unless a specific isotope of an element is indicated in a formula, the disclosure also includes, for example, deuterated derivatives of a compound (wherein H is 2 H, i.e., D). Isotopologues can have isotopic substitutions at any or all of the positions within the structure, or can have atoms present at natural abundance at any or all of the positions within the structure.

[0029] "Stereoisomers" or "stereoisomers" mean compounds that differ in the stereogenicity of their constituent atoms, such as, but not limited to, the chirality of one or more stereocenters, or in relation to the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0030] "Tautomer" means alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, and tautomeric forms of heteroaryl groups that contain ring atoms attached to both the ring -NH- and ring =N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[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 way of example, straight-chain 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 means an alkyl group having x carbon atoms.

[0032] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, and preferably 2 to 4 carbon atoms, and having at least 1, and preferably 1 to 2, sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers. C x Alkenyl means an alkenyl group having x carbon atoms.

[0033] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, and preferably 2 to 3 carbon atoms, and having at least 1, and preferably 1 to 2, sites of acetylenic (-C≡C-) unsaturation. Examples of such groups include acetylenyl (-C≡CH), and propargyl (-CHC≡CH). x Alkynyl means an alkynyl group having x carbon atoms.

[0034] "Substituted alkyl" includes 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, cyclo means an alkyl group having 1 to 5, preferably 1 to 3, and 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, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0035] "Substituted alkenyl" includes 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, cycloalkylamino ...

[0033] The term "alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein, with the proviso that any hydroxy or thiol substitutions are not attached to a vinyl (unsaturated) carbon atom.

[0036] "Substituted alkynyl" includes 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 ... means an alkoxy group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein, with the proviso that any hydroxyl or thiol substitutions are not attached to an acetylenic carbon atom.

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

[0038] "Substituted alkoxy" refers to the group -O-(substituted alkyl), where substituted alkyl is defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0039] "Acyl" refers to the HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocycle-C(O)-, and substituted heterocycle-C(O)- groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkynyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Acyl includes the "acetyl" group: CHC(O)-.

[0040] "Acylamino" is -NR 30 C(O) alkyl, -NR 30 C(O) substituted alkyl, -NR 30 C(O)cycloalkyl, -NR 30 C(O)-substituted cycloalkyl, -NR 30 C(O)alkenyl, -NR 30 C(O) substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O)alkynyl, -NR 30 C(O) substituted alkynyl, -NR 30 C(O)aryl, -NR 30 C(O) substituted aryl, -NR 30 C(O)heteroaryl, -NR 30 C(O)-substituted heteroaryl, -NR 30 C(O) heterocycle, and -NR 30 represents a C(O)-substituted heterocyclic group, where R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and where 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 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- groups where 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" refers to the group -NH2.

[0043] "Substituted amino" is -NR 31 R 32 means a group, where R 31 and R 32is 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 wherein R 31 and R 32 optionally, together with the nitrogen to which they are attached, form a heterocyclic or substituted heterocyclic group, with the proviso that R 31 and R 32 and at least one is not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are defined herein. 31 is hydrogen and R 32 When R is alkyl, the substituted amino group may refer to alkylamino. 31 and R 32 When R is alkyl, the substituted amino group may refer to dialkylamino. When R is monosubstituted amino, 31 or R 32 When referring to a disubstituted amino, R 31 or R 32 means that none of the groups is hydrogen.

[0044] "Aminocarbonyl" is -C(O)NR 33 R 34 means a group, where R 33 and R 34is 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 cycloalkylheteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 33 and R 34 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 wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 30is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 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 wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 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 wherein R 33 and R 34optionally, together with the nitrogen bound thereto, 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 , where R 33 and R 34 are 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 wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 33 and R 34 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 wherein R 33 and R 34optionally, together with the nitrogen bound thereto, 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 means a group, where R 33 and R 34 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 wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34is 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 wherein R 33 and R 34 optionally, together with the nitrogen bound thereto, 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 means a group, where R 33 , R 34 , and R 35 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 wherein R 33およびR34 optionally, together with the nitrogen bound thereto, 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" means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl), which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0054] "Substituted 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, and substituted heterocyclylamino. means an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents 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, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0055] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein, and includes, by way of example, phenoxy and naphthoxy.

[0056] "Substituted aryloxy" refers to the group --O-(substituted aryl), where substituted aryl is as defined herein.

[0057] "Arylthio" refers to the group --S-aryl, where aryl is as defined herein.

[0058] "Substituted arylthio" refers to the group --S-(substituted aryl), where substituted aryl is as defined herein.

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

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

[0061] "Carbonyl" means the divalent group --C(O)--, which is synonymous with --C(.dbd.O)--.

[0062] "Carboxy" or "carboxyl" means --COOH or salts thereof.

[0063]

[0033] A "carboxy ester" or "carboxy ester" means the groups -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-heterocycle, and -C(O)O-substituted heterocycle, where 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.

[0064] "(Carboxy 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-substituted aryl, -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 means a —C(O)O-substituted heterocyclic group, where R 30is alkyl or hydrogen, and where 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] "(Carboxy ester)oxy" means the groups -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-heterocycle, and -OC(O)O-substituted heterocycle, where 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.

[0066] "Cyano" refers to the radical -C≡N.

[0067] "Cycloalkyl" refers to saturated or unsaturated, but non-aromatic, cyclic alkyl groups of 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having monocyclic or polycyclic groups including fused, bridged, and spirocyclic systems. 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 of the rings can be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is a non-aromatic, non-heterocyclic saturated carbocyclic ring. "Substituted cycloalkyl" includes oxo, thione, 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, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, ...

[0033] The term "cycloalkyl group" means a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0068] "Cycloalkyloxy" refers to -O-cycloalkyl.

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

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

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

[0072] "Cycloalkylthio" refers to -S-cycloalkyl.

[0073] "Substituted cycloalkylthio" refers to --S-(substituted cycloalkyl).

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

[0075] "Substituted guanidino" is -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 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 bonded to the common guanidino nitrogen atom 36 The groups may optionally, together with the nitrogen to which they are attached, form a heterocyclic or substituted heterocyclic group, provided that at least one R 36 is not hydrogen, and wherein said substituents are as defined herein.

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

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

[0078] "Heteroalkylene" refers to a heteroalkyl group in which one or more carbon atoms are -O-, -S-, SO2, or -NR Q -, [ka] means an alkylene group substituted with a moiety, where R Q is H or C1-C6 alkyl. "Substituted heteroalkylene" means a heteroalkynylene group having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

[0079] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), where the condensed rings may or may not be aromatic and / or may or may not contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. 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] The term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0081] "Heteroaryloxy" refers to -O-heteroaryl.

[0082] "Substituted heteroaryloxy" refers to the group --O-(substituted heteroaryl).

[0083] "Heteroarylthio" refers to the group --S-heteroaryl.

[0084] "Substituted heteroarylthio" refers to the group --S-(substituted heteroaryl).

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

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

[0087] "Heterocycle" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" means a saturated or partially saturated, but not 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 Heterocycloalkyl refers to a heterocycloalkyl group having x ring heteroatoms. Heterocycles include single or multiple condensed rings, such as fused, bridged, or spiro ring systems. In condensed ring systems, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0088] "Heterocyclylene" means a divalent saturated or partially saturated, but not 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. "Substituted heterocyclylene" means a heterocyclylene group substituted with 1 to 5, or preferably 1 to 3, of the same substituents defined for substituted cycloalkyl.

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

[0090] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0091] "Substituted heterocyclyloxy" refers to the group --O-(substituted heterocyclyl).

[0092] "Heterocyclylthio" refers to the group -S-heterocyclyl.

[0093] "Substituted heterocyclylthio" refers to the group --S-(substituted heterocyclyl).

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

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

[0096] Examples of heterocyclyl and heteroaryl include azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylsilyl, pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isothiazolyl, phenazinyl, isoxazinyl, and benzoyl. These include, but are not limited to, zolyl, phenoxazinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

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

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

[0099] "Spirocyclic ring system" means a bicyclic ring system having 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 the divalent group: -S(O)2- or -S(=O)2-.

[0102] "Substituted sulfonyl" refers to -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic 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. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on the substituted alkyl-SO2- include halogenated alkyl groups, and particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0103] "Substituted sulfinyl" refers to -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic 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. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups, and in particular trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0104] "Sulfonyloxy" or "substituted sulfonyloxy" means an -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, or -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" refers to the groups 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)-, heterocycle-C(S)-, and substituted heterocycle-C(S)-, where 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.

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

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

[0109] "Thiocarbonyl" means a divalent group: -C(S)-, which is synonymous with -C(=S)-.

[0110] "Thione" refers to the atom (=S).

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

[0112] "Substituted alkylthio" refers to the group -S-(substituted alkyl), where substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups, and particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0113] "Vinyl" means an unsaturated hydrocarbon radical derived from ethylene: -CH=CH2.

[0114] As used throughout this specification, the term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "a nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety" means that the nitrogen atom may, but need not, be oxidized, and that the description includes cases where the nitrogen atom is not oxidized and cases where the nitrogen atom is oxidized.

[0115] The term "optionally substituted" means a substituted or unsubstituted group. A substituent can be substituted with one or more substituents, such as, for example, 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituents are oxo, halo, -CN, NO, -COR. 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 heteroaryl, wherein each R 100 are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocyclyl; C6-C 14 aryl; or C2-C 12 and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl 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 are independently hydrogen; C1-C8 alkyl, C1-C6 alkoxy, oxo, -CR optionally substituted with -COH or its ester. 103 =C(R 103 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 14 Aryl, or C2-C 12 heteroarylC1-C8 alkyl, where each R 103 are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10Heterocyclyl; C6-C 14 aryl; or C2-C 12 heteroaryl; wherein 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 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle.

[0117] Unless otherwise stated, the nomenclature for substituents not explicitly defined herein is obtained by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0118] For all of the substituents defined above, it is understood that polymers arrived at by defining a substituent that itself has further substituents (e.g., a substituted aryl having a substituted aryl group as a substituent that is itself substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is constrained by the restriction that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0119] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substitution with four fluoro groups), such impermissible substitution patterns being well known to those of skill in the art.

[0120] It is understood that certain features of the invention that are, for clarity, 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 that are 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 embraced by the present invention and are disclosed herein as if each and every combination 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 describing such variables are also specifically embraced by the present invention and are disclosed herein as if all such subcombinations of chemical groups were individually and explicitly disclosed herein.

[0121] compound In one aspect, the present description provides a compound of formula (I): [ka] (I) [In the formula, Ring A bearing the carbonyl (keto) group forms a 5-membered heterocycle containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1-2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1 to 5 halo, preferably fluoro, or hydroxyl groups; C3-C5 cycloalkyl, CON(R 10 )2, or NR 10 COR 10 where each R 10 is 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 11 )CN, CHR 11 , or C(R 11 )R 11 , where each R 11 is C1-C2 alkyl optionally substituted with 1 to 5 halo, preferably fluoro, or two R 11 the groups, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclobutyl ring; R 3 and R 4 each is independently Cl, Br, Me, or ethyl; R 5 is H, halo, C1-C4 alkyl, preferably CH3, or C3-C4 cycloalkyl, or R 5 is R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; and X is absent (i.e., X is a bond), or O, NR 12 , C(O)NR 12 , N.R. 12 C(O), CR 12 R 12 , OCR 12 R 12 , C.R. 12 R 12 O, NR 12 CR 12 R 12 , C.R. 12 R 12 NR 12 、 SO2NR 12 , or NR 12 SO2, where each R 12 are independently H or methyl] or a tautomer or N-oxide thereof, or each isotopomer thereof, or a prodrug of each of the above, or a stereoisomer of the above, or a pharmaceutically acceptable salt of each of the above, or a solvate of each of the above.

[0122] In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the compound of formula (I) has formula (IIA): [ka] (IIA) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0124] In one embodiment, the compound of formula (I) has formula (IIB): [ka] (IIB) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0125] In one embodiment, the compound of formula (I) has the formula (IIIA): [ka] (IIIA) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0126] In one embodiment, the compound of formula (I) has formula (IIIB): [ka] (IIIB) wherein the variables are as defined in formula (I). It is a compound represented by the formula: In one embodiment, the compound of formula (I) has formula (IIIC): [ka] (IIIC) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0127] In one embodiment, the compound of formula (I) has formula (IIID): [ka] (IIID) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0128] In one embodiment, the compound of formula (I) has the formula (IVA): [ka] (IVA) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0129] In one embodiment, the compound of formula (I) has formula (IVB): [ka] (IVB) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0130] In one embodiment, the compound of formula (I) has the formula (IVC): [ka] (IVC) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0131] In one embodiment, the compound of formula (I) has the formula (IVD): [ka] (IVD) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0132] In one embodiment, the compound of formula (I) has the formula (VA): [ka] (VA) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0133] In one embodiment, the compound of formula (I) has the formula (VB): [ka] (VB) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0134] In one embodiment, the compound of formula (I) has the formula (VC): [ka] (VC) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0135] In one embodiment, the compound of formula (I) has the formula (VD): [ka] (VD) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0136] In one embodiment, the compound of formula (I) has the formula (VIA): [ka] (VIA) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0137] In one embodiment, the compound of formula (I) has formula (VIB): [ka] (VIB) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0138] In one embodiment, the compound of formula (I) has the formula (VIC): [ka] (VIC) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0139] In one embodiment, the compound of formula (I) has the formula (VID): [ka] (VID) wherein the variables are as defined in formula (I). It is a compound represented by the formula:

[0140] In one embodiment, the compound of formula (I) has formula (VIIA): [ka] (VIIA) [In the formula, R 2is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0141] In one embodiment, the compound of formula (I) has formula (VIIB): [ka] (VIIB) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0142] In one embodiment, the compound of formula (I) has formula (VIIC): [ka] (VIIC) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0143] In one embodiment, the compound of formula (I) has the formula (VIID): [ka] (VIID) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0144] In one embodiment, the compound of formula (I) has formula (VIIIA): [ka] (VIIIA) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0145] In one embodiment, the compound of formula (I) has formula (VIIIB): [ka] (VIIIB) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0146] In one embodiment, the compound of formula (I) has formula (VIIIC): [ka] (VIIIC) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0147] In one embodiment, the compound of formula (I) has formula (VIIID): [ka] (VIIID) [In the formula, R 2 is H or methyl, and the variables are as defined in formula (I). It is a compound represented by the formula:

[0148] In one embodiment, the compound of formula (I) has the formula (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF): [ka] wherein the variables are as defined in formula (I). In some embodiments, the compound is a compound of formula (IXA). In some embodiments, the compound is a compound of formula (IXB). In some embodiments, the compound is a compound of formula (IXC). In some embodiments, the compound is a compound of formula (IXD). In some embodiments, the compound is a compound of formula (IXE). In some embodiments, the compound is a compound of formula (IXF).

[0149] In one embodiment, ring A bearing the carbonyl (keto) group forms a 5-membered heterocycle containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein the keto group is not adjacent to the atom bonded to X. In one embodiment, ring A bearing the carbonyl (keto) group forms a 5-membered heterocycle containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl, and wherein the keto group is not adjacent to the atom bonded to X. In one embodiment, the 5-membered heterocycle contains 1-3 ring heteroatoms selected from the group consisting of N and O. In some embodiments, ring A, taken together with the carbonyl (keto) group in the ring, forms [ka] In some embodiments, ring A together with the carbonyl (keto) group in the ring is: [ka] is.

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

[0151] In one embodiment, each R 10 is independently C1-C3 alkyl. In some embodiments, each R 10 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 is H, and the other R 10 is C1-C3 alkyl. In some embodiments, one R 10 is H, and the other R 10 is methyl.

[0152] In one embodiment, R 2 is H. In one embodiment, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is 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 where each R 11 are independently C1-C2 alkyl optionally substituted with 1 to 5 halo, preferably fluoro, or two R 11 In one embodiment, L is CHR 11 In one embodiment, L is C(R 11 )R 11 In one embodiment, each R 11 is independently C1-C2 alkyl, i.e., methyl or ethyl. In one embodiment, each R 11 are independently C1-C2 alkyl substituted with 1 to 5 halo, preferably fluoro. In one embodiment, two R 11 The groups, taken together with the carbon atoms to which they are attached, form a cyclopropyl or cyclobutyl ring. In some embodiments, L is O, CH, SO, CO, CHR 11 , or C(R 11 )R 11 and each R 11 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 are each Cl. In some embodiments, R 3 and R 4 are each methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is methyl and R 4 is Cl.

[0155] In one embodiment, R 5 is H. In one embodiment, R 5 is halo. In some embodiments, R 5 is fluoro, chloro, or bromo. In some embodiments, R 5 is fluoro. In one embodiment, R 5 is C1-C4 alkyl. In some embodiments, R 5 is C1-C3 alkyl. 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 C-C cycloalkyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is cyclobutyl. In one embodiment, R 4 is R 5and together with the intervening atoms form a 5- to 7-membered cycloalkyl. In some embodiments, R 4 is R 5 and together with the intervening atoms form cyclopentyl or cyclohexyl. In some embodiments, R 4 is R 5 and together with the intervening atoms is cyclopentyl. In one embodiment, R 4 is R 5 and together with the intervening atoms form a 5-7 membered heterocyclic ring containing 1-2 ring heteroatoms. Preferred heteroatoms include one or more of N, O, and S.

[0156] In one embodiment, X is absent (i.e., X is a bond). 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 In one embodiment, X is SONR 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 In one embodiment, X is CR 12 R 12 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 12are 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 CH. In one embodiment, X is OCH. In one embodiment, X is CHO. In one embodiment, X is NHCH. In one embodiment, X is CHNH. In one embodiment, X is NHC(O). In one embodiment, X is C(O)NH. In one embodiment, X is SONH. In one embodiment, X is NHSO. In some embodiments, X is OCH, NHCH, NHC(O), N(CH)CH, or N(H)CH(CH). In one embodiment, R 12 is H. In one embodiment, R 12 is methyl. In some embodiments, all R 12 Based on OCR 12 R 12 In some embodiments, all R 12 Based on OCR 12 R 12 In some embodiments, R 12 Based on OCR 12 R 12 and the like are combinations of H and methyl in certain moieties.

[0157] In one embodiment, compounds of formula (I) are provided having one or more of the following features: (I) Ring A, which is combined with a carbonyl group in the ring, is (i) [ka] ;or (ii) [ka] is; (II)R 1 but, (iii) C1-C4 alkyl optionally substituted with 1 to 5 halo or hydroxyl groups; or (iv) C3-C5 cycloalkyl; (III)R 2 is H or C1-C3 alkyl; (IV)R 3 is Cl or methyl; (V)R 4 is Cl or methyl; (VI)R 5 is H, halo, or C1-C4 alkyl; (VII)R 5 But R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; (VIII) X is (v) bonding; or (vi)NR 12 C(O), OCR 12 R 12 , or NR 12 CR 12 R 12 where each R 12 is independently H or methyl; and (IX) L is O, CH2, SO2, or CO.

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

[0159] In some embodiments, the compound of Formula (I) is a THR beta agonist. In some embodiments, the compound of Formula (I) is a THR beta agonist and is more selective than THR alpha. In some embodiments, the compound of Formula (I) is at least 2-fold more selective for THR beta than THR alpha. In some embodiments, the compound of Formula (I) is at least 5-fold more selective for THR beta than THR alpha. In some embodiments, the compound of Formula (I) is at least 10-fold more selective for THR beta than THR alpha. In some embodiments, the compound of Formula (I) is at least 20-fold more selective for THR beta than THR alpha. In some embodiments, the compound of Formula (I) is at least 50-fold more selective for THR beta than THR alpha. In some embodiments, the compound of Formula (I) is at least 75-fold more selective for THR beta than THR alpha. In some embodiments, compounds of Formula (I) are at least 100-fold more selective for THR beta than THR alpha. In some embodiments, compounds of Formula (I) are 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-fold more selective for THR beta than THR alpha. In any such embodiment, in one aspect, selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example B1.

[0160] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of any other moiety, as if each and every combination of descriptions were specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to the Ring A moiety of Formula (I) can be combined with R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , X, and L. It is also understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally to, and are equally described, other formulas detailed herein, where applicable, as if each and every description, variation, embodiment, or aspect were specifically and individually listed for every formula. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to, and are equally described, any formula detailed herein, where applicable, 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 every formula.

[0161] In some embodiments, a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof, is provided. While certain compounds described in this disclosure, including in Table 1, are presented as particular stereoisomers and / or non-stereochemical forms, it is understood that any and all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any compound of this disclosure, including in Table 1, are described herein.

[0162] In one embodiment, the present disclosure provides a compound selected from the compounds summarized in Table 1 below, or a tautomer or N-oxide thereof, or each isotopomer thereof, or a prodrug of each of the above, or a stereoisomer of the above, or a pharmaceutically acceptable salt of each of the above, or a solvate of each of the above: Table 1 [Table 1] [Table 2] [Table 3]

[0163] In some embodiments, the present disclosure provides a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt 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 enantiomeric, diastereomeric, tautomeric, other forms such as N-oxides, solvates, prodrugs, or isotopomers, of the described compounds. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. Furthermore, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also included in the present invention. All forms of the compounds, including crystalline or amorphous forms of the compounds, are also included in the present invention. Compositions containing the compounds of the present invention, for example, compositions of substantially pure compounds containing a specific stereochemical form, are also contemplated. 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, enantioenriched, and scaemic mixtures of the compounds, are also included in the present invention.

[0165] Synthesis method Scheme 1: General synthesis of biaryl-ether cores [ka] [where R 1 , R 3 , R 4 , and R 5 is defined as a compound of formula (I); T is Br, CN, or NH; and PG and G are suitable protecting groups.

[0166] The biaryl-ether core of the compounds disclosed herein can be prepared as outlined in Scheme 1. 3,6-dichloropyridazine and compounds of general formula R 1 The reaction of the compound -COH with ammonium persulfate gives R 1 -substituted dichloropyridazine compounds are obtained which can then be reacted with phenol derivatives, hydrolyzed and optionally N-protected to give the desired intermediate compounds.

[0167] Scheme 1': Alternative pyridazine synthesis [ka] [where R 1 has the same meaning as the compound represented by formula (I).

[0168] Scheme 1' provides an alternative synthesis of the pyridazines used to prepare compounds of formula (I) disclosed herein. 1 -Substituted acetylenes react to give R 1 -substituted dichloropyridazine compounds are obtained.

[0169] Scheme 1a: G=Alkyl and T=NH 2 Reaching [ka] [where R 1 , R 3 , R 4 , and R 5 is defined as in the compound of formula (I); and G is a suitable protecting group.

[0170] Scheme 1a outlines the synthesis where G is an alkyl group and T is NH. Compounds with a biaryl ether core bearing an amine moiety can be subjected to phthalimide protection, N-alkylation, and subsequent deprotection to provide the desired intermediates.

[0171] Scheme 2: [ka] [where R 1 , R 3 , R 4 , R 5 , and R 12 is defined as in the compound of formula (I); and PG, G, and G1 are suitable protecting groups.

[0172] Scheme 2 outlines the synthesis of certain compounds of Formula (I) disclosed herein. As provided in Scheme 1a, compounds bearing a biaryl-ether core and an amine moiety can be subjected to N-alkylation and secondary amine derivatization, followed by reaction with NHOH, treatment with a carbonyl transfer reagent, and optional deprotection to afford the desired compounds.

[0173] Scheme 2a: [ka] [where R 1 , R 3 , R 4 , R 5 , and R 12 is defined as in the compound of formula (I); and PG and G1 are suitable protecting groups.

[0174] Scheme 2a outlines the synthesis of certain compounds of Formula (I) disclosed herein. Compounds bearing a biaryl-ether core and an amine moiety can be subjected to N-alkylation, protection of the amine group, reaction with NHOH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis to provide the desired compounds.

[0175] Scheme 3: [ka] [where R 1 , R 3 , R 4 , R 5 and ring A is as defined in the compound of formula (I); and G and G1 are suitable protecting groups.

[0176] Scheme 3 illustrates the synthesis of certain compounds of formula (I). Reaction of a biaryl-ether derivative bearing an amine moiety with a carboxylic acid derivative of ring A provides an amide bond to form the desired compound.

[0177] Scheme 4: [ka] [where R 1 , R 3 , R 4 , R 5 , and R 12 is defined as in the compound of formula (I); and G and PG are suitable protecting groups.

[0178] Scheme 4 illustrates the synthesis of certain compounds of formula (I). Palladium-mediated hydroxylation of biaryl-ether derivatives containing a bromo group, followed by O-alkylation, reaction with NHOH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis provides the desired compounds.

[0179] Scheme 5: [ka] [where R 1 , R 3 , R 4 , and R 5 is defined as in the compound of formula (I); and G is a suitable protecting group.

[0180] Scheme 5 illustrates the synthesis of certain compounds of formula (I). Treatment of a cyano-containing biaryl-ether derivative with NH2OH, followed by treatment with a carbonyl transfer reagent, provides the desired compound.

[0181] Scheme 6: [ka] [where R 1 , R 3 , R 4 , and R 5 has the same meaning as the compound represented by formula (I).

[0182] Scheme 6 illustrates the synthesis of certain compounds of formula (I). Treatment of a cyano-containing biaryl-ether derivative with NH2OH, followed by treatment with a carbonyl transfer reagent and hydrolysis provides the desired compound.

[0183] Scheme 7: [ka] [where R 1 , R 3 , R 4 , and R 5 is defined as in the compound of formula (I); and G is a suitable protecting group.

[0184] Scheme 7 illustrates the synthesis of certain compounds of formula (I). Diazotization / iodination of an amino-bearing biaryl-ether derivative, followed by Sonogashira coupling, reaction with NHOH, and subsequent optional deprotection provide the desired compounds.

[0185] The synthesis of certain compounds provided herein is outlined above and provided in the Examples section below. The variables listed in the above schemes are synonymous with the compounds shown in Formula (I), or any variant, embodiment, or aspect thereof. The synthesis of other compounds provided herein will be apparent to those of skill in the art based on the guidance provided herein and on synthetic methods known to those of skill in the art.

[0186] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with an appropriate chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer is recovered. In another resolution process, chiral high-performance liquid chromatography can be used to separate the racemate. Alternatively, if necessary, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described.

[0187] Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0188] Solvates and / or polymorphs of the compounds provided herein, as well as pharmaceutically acceptable salts thereof, are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during crystallization. Hydrates form when the solvent is water, or alcoholates form when the solvent is alcohol. Polymorphs include different crystalline packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and / or solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, may result in the predominance of a single crystal.

[0189] It is understood that the synthetic processes disclosed herein can be modified to arrive at a variety of compounds of the invention by selecting appropriate reagents and starting materials. Where protection of a particular reactive or incompatible group (e.g., amine or carboxylic acid) is required, it is also understood that the formulae of the schemes provided herein contemplate and include compounds in which such reactive or incompatible group is in an appropriately protected form. For a general description of protecting groups and their use, see PGM Wuts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis 4" (2004). th edition, Wiley-Interscience, New York, 2006.

[0190] Pharmaceutical Compositions and Formulations Any pharmaceutical composition of the compounds detailed herein is included in the present invention.Accordingly, the present invention includes a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.In one embodiment, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic acid or an organic acid.The pharmaceutical composition 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 administration by inhalation.

[0191] In one aspect, the compounds described herein may be in purified form, and compositions comprising the compounds in purified form are described herein. Compositions comprising the compounds described herein or salts thereof, such as compositions of substantially pure compounds, are provided. In some embodiments, compositions comprising the compounds described herein or salts thereof are in substantially pure form. In one variation, "substantially pure" refers to a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or its salts that make up the majority of the composition. For example, a composition of a substantially pure compound selected from the compounds of Table 1 contemplates a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or its salts. In one variation, a composition of a substantially pure compound or salt thereof is provided, where the composition contains 25% or less impurities. In another variation, a composition of a substantially pure compound or salt thereof is provided, where the composition contains 20% or less impurities. In yet another variation, a composition of a substantially pure compound or salt thereof is provided, where the composition contains 10% or less impurities. In a further variation, a composition of a substantially pure compound or salt thereof is provided, where the composition contains 5% or less impurities. In another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 3% or less of impurities. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 1% or less of impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 0.5% or less of impurities. In yet another variation, a substantially pure composition of a 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 of impurities, which may be compounds of different stereochemical forms. For example, without limitation, a substantially pure (S) compound composition 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) form of the compound.

[0192] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual, such as a human. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the present invention encompasses pharmaceutical compositions containing the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods for administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods for administering compounds are suitable for any of the compounds or forms thereof detailed herein.

[0193] The compounds may be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds may be formulated with a suitable carrier to provide a delivery form including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, pastilles, 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 to prepare formulations, such as pharmaceutical formulations, by combining one or more compounds as active ingredients with a pharmaceutically acceptable carrier, as described above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in a variety of forms. In addition, pharmaceutical formulations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also include other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is incorporated herein by reference.

[0195] The compounds described herein can be administered to individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coated tablets, and hard- or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearates or salts thereof, etc. Acceptable carriers for soft-shell gel capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

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

[0197] Also described herein is a composition comprising the compound provided herein.In one variation, this composition comprises the compound and a pharmaceutically acceptable carrier or excipient.In another variation, a composition of substantially pure compound is provided.

[0198] How to use / treat The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, can be used in the administration and treatment methods provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control assays.

[0199] In one aspect, the description provides a method of agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of a compound provided herein, or an effective amount of any of the pharmaceutical compositions provided herein.

[0200] In one aspect, the present disclosure provides a method for treating a THR beta-mediated disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a therapeutically effective amount of a composition provided herein.

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

[0202] In one embodiment, the present disclosure provides a method for agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of a compound provided herein, or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of any of the pharmaceutical compositions provided herein. In one embodiment, the present disclosure provides a method for selectively agonizing THR beta over THR alpha, comprising contacting THR beta with an effective amount of a compound provided herein, or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of any of the pharmaceutical compositions provided herein. In one such embodiment, the method selectively agonizes THR beta over THR alpha 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 assessed via a biochemical assay, such as the TR-FRET assay described in Example B1.

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

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

[0205] In any of the embodiments described herein, patients having a disease or disorder associated with THR beta agonism can 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 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 can include prevention, where the individual does not develop the disease or disorder.In one embodiment, the individual at risk of developing 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 related comorbidities.

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

[0208] In one aspect, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in therapy. In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt, for use in treating non-alcoholic fatty liver disease. In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt, for use in treating non-alcoholic steatohepatitis (NASH). In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt, for use in treating metabolic syndrome. In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt, for use in treating dyslipidemia. In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, for use in the treatment of hypertriglyceridemia. In some embodiments, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof, for use in the treatment of hypercholesterolemia.

[0209] In another embodiment, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating non-alcoholic fatty liver disease. In another embodiment, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH). In another embodiment, the present disclosure provides a compound of Formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating metabolic syndrome. In some embodiments, the medicament is for the treatment of dyslipidemia. In some embodiments, the medicament is for the treatment of hypertriglyceridemia. In some embodiments, the medicament is for the treatment of dyslipidemia. In some embodiments, the medicament 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 is about any of 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 is about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old.

[0211] Dosage and Administration The dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual (such as a human) will vary depending on the particular compound or salt thereof, the method of administration, and the particular 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 a stereoisomer, tautomer, solvate, or salt thereof, is a therapeutically effective amount.

[0212] The compounds provided herein, or salts thereof, can be administered to an individual by a variety of routes, such as, for example, intravenous, intramuscular, subcutaneous, oral, or transdermal.

[0213] In one embodiment, an effective amount of a compound can be a dose between about 0.01 and about 100 mg / kg. Effective amounts or doses of compounds of the present disclosure can be ascertained 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 agent, the severity and course of the disease being treated, and the patient's health, physical condition, and weight. Exemplary doses range from about 0.7 mg to 7 g daily, or from about 7 mg to 350 mg, or from about 350 mg to 1.75 g, or from about 1.75 to 7 g.

[0214] In one embodiment, any of the methods provided herein can include administering to an individual a pharmaceutical composition comprising an effective amount of a 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 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months, or even longer, according to an effective dosing regimen, and in some variations, can be for 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 (e.g., at least once daily) for a period of time. The dosing frequency can also be less than once daily, for example, about once weekly. The dosing frequency can also be more than once daily, for example, twice or three times daily. The dosing frequency can also be intermittent, including "drug holidays" (e.g., 7 days of once-daily dosing followed by 7 days without dosing, repeated for any 14-day period, for example, about 2 months, about 4 months, about 6 months, or more). Any of the dosing frequencies, along with any of the dosages described herein, can be used with any of the compounds described herein.

[0216] Products and Kits The present disclosure further provides a product comprising a compound or salt thereof described herein, a composition described herein, or one or more unit doses described herein in suitable packaging. In certain embodiments, the product is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The product can be further sterilized and / or sealed.

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

[0218] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if 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 kits can be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits can be provided that contain sufficient doses of a compound as disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment for an individual for an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kits can also include multiple unit doses of the compound and instructions for use, and can be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy or a compounding pharmacy).

[0220] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are acceptable relating to the use of the components of the disclosed methods. The instructions included with the kit generally include information regarding the components and their administration to an individual.

[0221] Exemplary Embodiments The present disclosure is further illustrated by the following embodiments, the features of each of which may be combined with any of the other embodiments where appropriate and practical.

[0222] Embodiment 1. Formula (Ia): [ka] (Ia) [In the formula, Ring A having a carbonyl (keto) group therein forms a 5-membered heterocycle containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl groups or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 is C1-C4 alkyl optionally substituted with 1 to 5 halo, preferably fluoro; C3-C5 cycloalkyl, CON(R 10 )2, or NR 10 COR 10 where each R 10 is 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 are independently C1-C2 alkyl optionally substituted with 1 to 5 halo, preferably fluoro, or two R 11 groups, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclobutyl ring; R 3 and R 4 each is independently Cl, Br, methyl, or ethyl; R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R5 is R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; X is absent (i.e., X is a bond), or O, NR 12 , C(O)NR 12 , N.R. 12 C(O), CR 12 R 12 , OCR 12 R 12 , C.R. 12 R 12 O, NR 12 CR 12 R 12 , C.R. 12 R 12 NR 12 , SO2NR 12 , N.R. 12 SO2, where each R 12 are independently H or methyl] or a tautomer or N-oxide thereof, or each isotopomer thereof, or each prodrug of the above, or a stereoisomer of the above, or each pharmaceutically acceptable salt of the above, or each solvate of the above.

[0223] Embodiment 2. Formula (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) wherein the variables are as defined in embodiment 1. 2. The compound of embodiment 1, wherein:

[0224] Embodiment 3. Formula (VIIA), (VIIB), (VIIC), (VIIIA), (VIIIB), or (VIIIC): [ka] (VIIA) (VIIB) (VIIC) [ka] (VIIIA) (VIIIB) (VIIIC) [In the formula, R 2 is H or methyl, and the variables are as defined in embodiment 1. 2. The compound of embodiment 1, wherein:

[0225] Embodiment 4.R 1 The compound of embodiment 1, wherein is 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 is hydrogen. Embodiment 9. The compound of embodiment 1, wherein X is a bond.

[0226] Embodiment 10. X is CHR 11 , OCHR 11 , N.R. 11 CHR 11 , N.R. 11CH2, CHR 11 N.H., C.H.R. 11 NR 11 , NHCR 11 R 11 , C(O)NR 12 , N.R. 12 C(O), SO2NR 12 , or NR 12 SO2, where R 12 is as defined in embodiment 1. Embodiment 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 set forth in Table 1. Embodiment 15. A pharmaceutical composition comprising a compound of embodiment 1 and at least one pharmaceutically acceptable anti-aging agent.

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

[0229] Embodiment 17. A method of treating a disorder mediated by THR beta in a patient, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a therapeutically effective amount of a composition of embodiment 15. [Example]

[0230] It will be understood that this disclosure has been made by way of example only, and that numerous changes in the combination and arrangement of parts can be rearranged by those skilled in the art without departing from the true spirit and scope of the 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 compounds of the present disclosure are considered to be within the scope of the present disclosure. Synthesis of non-exemplified compounds according to the present disclosure can be successfully carried out by modifications apparent to those skilled in the art, for example, by appropriate protection of 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 the present 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 dimethyl acetal DMSO: dimethyl sulfoxide DSC: Disuccinimidyl carbonate Et: Ethyl Me: Methyl Pr: Propyl Py or Pyr: pyridine rt: room temperature SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride 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-methylpyridazin-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 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 AgNO (5.70 g, 33.56 mmol, 5.64 mL) in HO (200 mL) at 60 °C. Then, a solution of ammonium persulfate (45.95 g, 201.37 mmol) in HO (100 mL) was added dropwise to the mixture at 75 °C, and the resulting mixture was stirred at 75 °C for 30 min. TLC indicated the reaction was complete. After cooling, the mixture was adjusted to pH 9-10 with NH3·H2O, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to give 1a. The product was used directly in the next step. MS mass calculated: [M+1] + (C7H8Cl2N2) m / z 191.1, LCMS observed: 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-isopropylpyridazin-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) was added K2CO3 (9.32 g, 67.41 mmol) and CuI (1.93 g, 10.11 mmol). The mixture was then degassed and purged with N2 three times and stirred at 90 °C under a nitrogen atmosphere for 16 h. TLC and LCMS indicated complete consumption of the starting material and the desired MS were detected. The mixture was concentrated under reduced pressure. The residue was partitioned between 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 (SiO, petroleum ether / ethyl acetate = 10:1 to 3:1, by TLC) to give 1b. MS mass calculated: [M+1] + (C 13 H 12 Cl3N3O) m / z 332.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1c) To a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (2.6 g, 7.82 mmol) and isobenzofuran-1,3-dione (1.16 g, 7.82 mmol) in HOAc (5 mL) was added NaOAc (3.21 g, 39.08 mmol). The mixture was stirred at 120 °C for 6 h. LCMS showed complete consumption of the starting material 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 between ethyl acetate (30 mL × 2) and HO (30 mL). The combined organic phase was washed with brine (10 mL × 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 added portionwise to the mixture. The mixture was filtered to collect the solid. The solid was dried to give 1c. Calculated MS mass: [M+1] + (C 21 H 15 Cl2N3O4) m / z 444.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1d) A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)iso-indoline-1,3-dione (1c) (500 mg, 1.13 mmol) in DMF-DMA (4 mL) was stirred at 110 °C for 2.5 h. TLC showed complete consumption of the starting material and the formation of two new spots. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 mL × 2) and HO (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 give 1d. The product was used directly in the next step without purification.

[0239] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H),-one (1e) A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-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 h. TLC (petroleum ether:ethyl acetate=1:1, P1:R f = 0.6) and LCMS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R f =0.6) to give 1e. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O2) m / z 328.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0241] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)-acetonitrile (1f) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) (240 mg, 731.28 umol) in ACN (4 mL) was added 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). The mixture was then sealed in a tube and stirred at 100 °C for 16 h. LCMS indicated complete consumption of the starting material and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (5 mL × 3). The combined filtrate was concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R f Purification by HCl (HCl = 0.5) gave 1f as a yellow oil. MS mass calculated: [M+1] + (C 16 H 16 Cl2N4O2) m / z 367.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)-phenyl)carbamate (1g) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (1f) (210 mg, 571.85 umol) in THF (3 mL) was added BocO (374.41 mg, 1.72 mmol, 394.12 uL) and DMAP (69.86 mg, 571.85 umol). The mixture was stirred at 40 °C for 3 h. TLC (petroleum ether:ethyl acetate = 1:1, P1:R f =0.9) and LCMS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned twice between 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 give a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, P1:R f =0.5) to give 1 g. Calculated MS mass: [M+1] + (C 21 H 24 Cl2N4O4) m / z 467.1, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)carbamate (1g) (250 mg, 534.94 umol) in DMF (3 mL) was added NH2OH·HCl (297.39 mg, 4.28 mmol) and NaOAc (351.06 mg, 4.28 mmol). The mixture was stirred at 80 °C for 1 h. LCMS showed complete consumption of the starting material and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between 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 give 1h (260 mg, crude) as a yellow solid. The product was used directly in the next step without further purification. MS mass calculated: [M+1] + (C 21 H 27 Cl2N5O5) m / z 500.1, LCMS observed: m / z 500.1.

[0244] tert-Butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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-dihydropyridazin-3-yl)oxy)phenyl)carbamate (1h) (260 mg, 519.61 umol) in THF (3 mL) was added DSC (173.04 mg, 675.49 umol, 1.3 equiv) and TEA (105.16 mg, 1.04 mmol, 144.65 uL). The mixture was stirred at 60° C. for 16 h. TLC (dichloromethane:methanol=10:1, P1:R f=0.3) and LCMS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned between 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 give a residue. The residue was analyzed by preparative TLC (SiO2, DCM:MeOH = 10:1, P1:R f Purification by HCl (HCl = 0.3) gave 1i. Calculated MS mass: [M+1] + (C 22 H 25 Cl2N5O6) m / z 526.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H),-one (Example 1) A solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (1i) (170 mg, 322.97 umol) in HCl / EtOAc (2 mL) was stirred at 25° C. for 2 hours. LCMS and HPLC showed complete consumption of the starting material and the desired MS was detected. The mixture was diluted with water (0.5 mL), and the pH was adjusted to 8 with NaHCO (5 mL). The mixture was then partitioned twice with 10 mL of ethyl acetate. The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) column: Luna C18 100x30 5u; mobile phase: [water (0.2% FA)-ACN]; B%: 25%-60%, 12 min] to give Example 1. Calculated MS mass: [M+1] + (C 17 H 17Cl2N5O4) m / z 426.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0247] 2-((3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (1f) (50 mg, 136.15 umol) in THF (2 mL) was added Cs2CO3 (66.54 mg, 204.23 umol) and MeI (193.26 mg, 1.36 mmol, 84.76 uL). The mixture was placed in a sealed tube and stirred at 100 °C for 16 h. TLC and LCMS showed that ~30% of reactant 1f remained and the desired MS was detected. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (5 mL × 3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to give 2a. Calculated MS mass: [M+1] + (C 17 H 18 Cl2N4O2) m / z 381.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)(methyl)-amino)-N'-hydroxyacetimidamide (2b) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)acetonitrile (2a) (52 mg, 136.39 umol) in DMF (2 mL) was added NHOH·HCl (75.82 mg, 1.09 mmol) and NaOAc (89.51 mg, 1.09 mmol). The mixture was stirred at 80 °C for 6 h. TLC showed complete consumption of reactant 2a, and LCMS showed one major peak with the desired MS. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (5 mL × 3). The combined filtrate was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1, by TLC) to give 2b. MS mass calculated: [M+1] + (C 17 H 21 Cl2N5O3) m / z 414.1, LCMS observed: m / z 414.1.

[0249] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 2) To a solution of (Z / E)-2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)-N'-hydroxyacetimidamide (2b) (30 mg, 65.17 umol) in THF (2 mL) was added DSC (21.70 mg, 84.72 umol) and TEA (33.97 mg, 335.75 umol, 46.73 uL). The mixture was stirred at 80°C for 2 hours. TLC and LCMS showed complete consumption of 2b and the desired MS were detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was checked by HPLC and then purified by preparative HPLC (column: Waters Atlantis T3 150 x 30 x 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 13 min) to give Example 2. Calculated MS mass: [M+1]+ (C 18 H 19 Cl2N5O4) m / z 440.1, LCMS observed: m / z 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-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one [ka]

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

[0252] Tert-butyl(1-cyanoethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)carbamate (3b) A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)propanenitrile (3a) (0.25 g, 655.73 umol), BocO (429.33 mg, 1.97 mmol, 451.93 uL) and DMAP (80.11 mg, 655.73 umol) in THF (5 mL) was heated to 50° C. for 1 h. LCMS showed the desired MS and TLC showed a new spot. The mixture was concentrated and the residue was purified by preparative TLC (petroleum ether:ethyl acetate=3:1) to give 3b. MS mass calculated: [M+1] + (C 22 H 26 Cl2N4O4) m / z 481.1, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)carbamate (3b) (80 mg, 166.19 umol), NHOH HCl (92.39 mg, 1.33 mmol), and NaOAc (109.07 mg, 1.33 mmol) in DMF (3 mL) was heated to 80 °C for 5 h. LCMS showed the desired product, and TLC (petroleum ether:ethyl acetate = 1:1, R f=0.47) showed a new spot, the mixture was filtered and 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 give 3c. MS mass calculated: [M+1] + (C 22 H 29 Cl2N5O5) m / z 514.2, LCMS observed: 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-oxadiazol-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-dihydropyridazin-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 to 60° C. for 2 hours. The mixture was then heated to reflux for an additional 4 hours. TLC (petroleum ether:ethyl acetate=1:1, R f = 0) indicated completion of the reaction, and the mixture was concentrated to give 3d (70 mg, crude), which was used directly in the next step. MS mass calculated: [M+1] + (C 23 H 27 Cl2N5O6) m / z 540.1, LCMS observed: m / z 540.2;

[0255] 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one (Example 3) To a solution of 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-oxadiazol-3-yl)ethyl)carbamate (3d) (70 mg, 129.53 umol) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at 25° C. for 50 minutes. LCMS showed the reaction was complete and the desired MS was detected. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) (column: Waters Atlantis T3 150 x 30 x 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-80%, 13 min) to give 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one (Example 3). MS mass calculated: [M+1] + (C 18 H 19 Cl2N5O4) m / z 440.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one (Example 3) (17.17 mg, 39.00 umol, 1 equiv.) was separated by SFC ([Monitoring] Instrument: Thar SFC80 Preparative SFC; Column: Chiralpak AS-H, 250 x 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) to give Example-P1; Calculated MS Mass: [M+1] + (C 18 H 19 Cl2N5O4) m / z 440.1, LCMS observed: 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 observed: 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-dihydropyridazin-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) was added NHOH·HCl (2.63 g, 37.85 mmol) and NaCO (2.67 g, 25.23 mmol). The mixture was stirred at 25 °C for 2 h. TLC showed the reaction was complete. 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 EtOAc (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 give a residue. The residue was purified by recrystallization from MTBE:petroleum ether = 1:1 (20 mL) at 70 °C to give 4a. Calculated MS mass: [M+1] + (C4H8N2O3) m / z 133.1, LCMS observed: 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) was added TEA (2.30 g, 22.71 mmol, 3.16 mL) and ethyl carbonochloridate (903.56 mg, 8.33 mmol, 792.59 uL). The mixture was stirred at 0 °C for 1 h. TLC showed complete consumption of 5a and the formation of one new spot. The reaction was clean by TLC. The reaction mixture was concentrated under reduced pressure to give 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] Ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (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 and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 120° C. for 10 h. LCMS 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, 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 observed: 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 equiv.) in MeOH (1 mL) and HO (0.2 mL) was added LiOH (36.35 mg, 1.52 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 1 h. TLC showed that reactant 4 was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HCl (1 M, 5 mL) and adjusted to pH 4-6, then extracted with EtOAc (5 mL × 4). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4d (114 mg, crude). The crude product was used in the next step without further purification. MS mass calculated: [M+1] + (C5H6N2O4) m / z 159.0, LCMS observed: no m / z; 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 umol) in THF (3 mL) was added (COCl) (128.82 mg, 1.01 mmol, 88.84 uL) and DMF (6.18 mg, 84.58 umol, 6.51 uL). The mixture was stirred at 25 °C for 1 h. For monitoring, a few drops of the reaction mixture were quenched with MeOH. TLC showed that 4d was completely consumed and one new spot had formed. The mixture was concentrated under reduced pressure to give 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-dihydropyridazin-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-methylpyridazin-3(2H)-one (1e) (20 mg, 60.94 umol) in THF (3 mL) was added 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). The mixture was stirred at 25° C. for 0.5 h. LCMS showed complete consumption of 1e 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 give a residue. The residue was checked by HPLC and purified by preparative HPLC (Column: Xtimate C18 150 x 25 mm x 5 um; Mobile phase: [Water (10 mM NH4HCO3)-ACN]; B%: 30%-55%, 10 min) to give Example 4. MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0265] 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)acetonitrile (5a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-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) was added K2CO3 (119.67 mg, 865.87 umol) and NaI (129.79 mg, 865.87 umol). The mixture was placed in a sealed tube and stirred at 100 °C for 16 h. LCMS showed complete consumption of reactant 1b and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to give 4a. MS mass calculated: [M+1] + (C 15 H 13 Cl3N4O) m / z 371.0, LCMS observed: m / z .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-isopropylpyridazin-3-yl)oxy)phenyl)carbamate (5b) To a solution of 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)acetonitrile (5a) (172 mg, 379.50 umol) in THF (10 mL) was added DMAP (51.00 mg, 417.45 umol) and BocO (248.48 mg, 1.14 mmol, 261.55 uL). The mixture was stirred at 40 °C for 2 h. TLC showed complete consumption of reactant 5a and the formation of one new spot. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1, by TLC) to give 5b. MS mass calculated: [M+1] + (C 20 H 21 Cl3N4O3) m / z 471.1, LCMS observed: 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-isopropylpyridazin-3-yl)oxy)phenyl)carbamate (5b) (145 mg, 307.36 umol) in DMF (2 mL) was added NHOH·HCl (170.87 mg, 2.46 mmol) and NaOAc (201.70 mg, 2.46 mmol). The mixture was stirred at 80 °C for 6 h. TLC showed that reactant 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 EtOAc (5 mL × 3). The combined filtrate was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1, by TLC) to give 5c. Calculated MS mass: [M+1]+ (C 20 H 24 Cl3N5O4) m / z 504.1, LCMS observed: 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-isopropylpyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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) was added DSC (29.69 mg, 115.89 umol) and TEA (33.97 mg, 335.75 umol, 46.73 uL). The mixture was stirred at 80° C. for 1 hour. LCMS showed complete consumption of 5c and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol=10:1, by TLC) to give 5d. Calculated MS mass: [M+1] + (C 21 H 22 Cl3N5O5) m / z 530.1, LCMS observed: m / z 530.1.

[0269] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 5) To a solution of (tert-butyl(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate) 5d (68 mg, 115.30 umol) in AcOH (3 mL) was added NaOAc (75.66 mg, 922.40 umol). The mixture was stirred at 110° C. for 3 hours. LCMS showed that reactant 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 150x30 5u; Mobile phase: [water (0.225% FA)-ACN]; B%: 30%-65%, 13 min) to give Example 5. MS mass calculated: [M+1] + (C 16 H 15 Cl2N5O4) m / z 412.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0271] 6-(4-Bromo-2,6-dichlorophenoxy)-3-chloro-4-isopropylpyridazine (6a) A mixture of 4-bromo-2,6-dichloro-phenol (3.04 g, 12.56 mmol) and 3,6-dichloro-4-isopropyl-pyridazine (1a) (2 g, 10.47 mmol) in pyridine (10 mL) was stirred at 130 °C for 48 h in a 100 mL autoclave. LCMS showed that starting material 1a was completely consumed and the desired MS was found. The mixture was diluted with Tol (30 mL) and concentrated under reduced pressure. The residue was partitioned between 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 to 100:1) to give 6a. Calculated MS mass: [M+1] + (C 13 H 10 BrCl3N2O) m / z 394.9, LCMS observed: 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-isopropylpyridazin-3(2H)-one (6b) A mixture of 6-(4-bromo-2,6-dichloro-phenoxy)-3-chloro-4-isopropyl-pyridazine (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 h. LCMS showed that the starting material was completely consumed and the desired MS was found. 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 give 6b. The product was used directly in the next step without further purification. [M+1] + (C 13 H 11BrCl2N2O2) m / z 376.9, LCMS observed: 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-methylpyridazin-3(2H)-one (6c) A mixture of 3-(4-bromo-2,6-dichloro-phenoxy)-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 h. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned between 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 to 30:1) to give 6c. [M+1] + (C 14 H 13 BrCl2N2O2) m / z 391.0, LCMS observed: 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-methylpyridazin-3(2H)-one (6d) A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6c) (170 mg, 433.59 umol), KOH (31.63 mg, 563.67 umol), t-BuXphos (27.62 mg, 65.04 umol), and Pd(dba) (39.70 mg, 43.36 umol) in dioxane (8 mL) and HO (8 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C under a nitrogen atmosphere for 3.5 h. TLC showed complete consumption of 6c, and LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (5 mL × 3). The combined filtrates were concentrated to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:petroleum ether=1:1 by TLC) to give 6d. MS mass calculated: [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-dihydropyridazin-3-yl)oxy)phenoxy)acetonitrile (6e) To a solution of 6-(2,6-dichloro-4-hydroxyphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6d) (40 mg, 121.51 umol) in acetone (2 mL) was added K2CO3 (50.38 mg, 364.54 umol) and 2-bromoacetonitrile (21.86 mg, 182.27 umol, 12.15 uL). The mixture was stirred at 20 °C for 2 h. TLC showed that 6d was completely consumed and one new 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 give a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 1:1) to give 6e as a yellow solid. MS mass calculated: [M+1] + (C 16 H 15 Cl2N3O3) m / z 368.0, MS observed: 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-dihydropyridazin-3-yl)oxy)phenoxy)-N'-hydroxyacetimidamide (6f) To a solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)acetonitrile (6e) (38 mg, 103.20 umol) in DMF (2 mL) was added NHOH·HCl (57.37 mg, 825.61 umol) and NaOAc (67.72 mg, 825.61 umol). The mixture was stirred at 80 °C for 6 h. 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 DMF. The residue was diluted with brine (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 observed: m / z 401.2.

[0277] 3-((3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 6) To a solution of (Z / E)-2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)-N'-hydroxyacetimidamide (6f) (66.3 mg, 132.19 umol) in THF (2 mL) was added DSC (44.02 mg, 171.85 umol) and TEA (26.75 mg, 264.38 umol, 36.80 uL). The mixture was stirred at 60°C for 4 hours. LCMS showed complete consumption of 6f and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150x30 5u; Mobile phase: [water (0.04% NH3H2O)-ACN]; B%: 5%-35%, 10 min) to give Example 6. MS mass calculated: [M+1] + (C 17 H 16Cl2N4O5) m / z 427.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one [ka]

[0279] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (7a) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) (50 mg, 152.35 umol) in HCl (5 M, 304.70 uL) was added NaNO (12.61 mg, 182.82 umol) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. A solution of KI (50.58 mg, 304.70 umol) in HO (1.5 mL) was then added to the mixture, and the mixture was stirred at 20 °C for an additional 16 h. TLC showed that reactant 1e was completely consumed. LCMS showed that reactant 1e was completely consumed and one major peak with the desired MS was formed. The reaction mixture was extracted with EtOAc (5 mL × 4). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1, product R f =0.80 by TLC) to give 7a. Calculated MS mass: [M+1] + (C 14 H 12 Cl2N2O2) m / z 438.9, LCMS observed: 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] Ethyl 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)propiolate (7b) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazin-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 with nitrogen three times. The mixture was then stirred at 110 °C for 0.5 h under microwave irradiation. TLC showed that reactant 7a was completely consumed and many spots had formed. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (5 mL × 3). The combined filtrate was concentrated to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=3:1, by TLC) to give 7b. MS mass calculated: [M+1] + (C 19 H 18 Cl2N2O4) m / z 409.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (Example 7) To a solution of ethyl 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)propiolate (7b) (27 mg, 48.56 umol) in MeOH (3 mL) was added NHOH·HCl (13.50 mg, 194.22 umol) and KOH (16.35 mg, 291.33 umol). The mixture was stirred at 25 °C for 16 h. TLC showed that reactant 7b was completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with HO (5 mL) and extracted with EtOAc (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 give a residue. The residue was checked by HPLC and purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150x30 5u; Mobile phase: [water (0.04% NH3H2O)-ACN]; B%: 5%-35%, 10 min) to give Example 7. MS mass calculated: [M+1] + (C 17 H 15 Cl2N3O4) m / z 396.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one [ka]

[0283] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)acetamide (8a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (1 g, 3.01 mmol) in AcOH (10 mL) was added NaOAc (863.18 mg, 10.52 mmol). The mixture was stirred at 100° C. for 16 h. LCMS 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 adjusted to pH=9-10 by adding 1N NaOH. The suspension was extracted with EtOAc (10 mL×4). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 observed: m / z 356.1.

[0284] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (8b) To a solution of N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)acetamide (8a) (1.55 g, 3.48 mmol) in MeOH (20 mL) was added aqueous NaOH (1 M, 21.26 mL). The mixture was stirred at 120 °C for 4 h. LCMS 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 EtOAc (10 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5:1 to 1:5, by TLC) to give 8b. MS mass calculated: [M+1] + (C 13 H 13 Cl2N3O2) m / z 314.0, LCMS observed: 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-isopropylpyridazin-3(2H)-one (8c) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (8b) (250 mg, 795.76 umol) in HCl (967.11 mg, 7.96 mmol, 948.14 uL, 30% purity) was added NaNO (65.89 mg, 954.91 umol) at 0 °C, and the mixture was stirred for 0.5 h. Next, a solution of KI (264.19 mg, 1.59 mmol) in HO (5 mL) was added to the mixture. The mixture was then stirred at 20 °C for an additional 16 h. LCMS showed one major peak with the desired MS. The reaction mixture was extracted with EtOAc (10 mL × 4). The combined organic layers were washed, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 3:1, product R f =0.60 by TLC) to give 8c. Calculated MS mass: [M+1] + (C 13 H 11 Cl2IN2O2) m / z 424.9, LCMS observed: 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)pyridazin-3(2H)-one (8d) To a mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazin-3(2H)-one (8c) (50 mg, 117.63 umol), DIPEA (30.41 mg, 235.27 umol, 40.98 uL) in DMF (4 mL) was added 2-(chloromethoxy)ethyl-trimethyl-silane (58.84 mg, 352.90 umol, 62.46 uL). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 25 °C for 2 h. 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 EtOAc (6 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=5:1, by TLC) to give 8d. MS mass calculated: [M+1] + (C 19 H 25 Cl2IN2O3Si) m / z 555.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)propiolate (8e) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-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 and purged with nitrogen three times, and then the mixture was stirred at 110 °C under microwave irradiation for 0.5 h. TLC showed that 8d was completely consumed and many spots had formed. LCMS showed that one major peak with the desired MS had formed. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (5 mL x 3). The combined filtrate was concentrated to dryness to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 8:1, by TLC) to give 8e. MS mass calculated: [M+1] + (C 24 H 30 Cl2N2O5Si) m / z 525.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-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-dihydropyridazin-3-yl)oxy)phenyl)propiolate (8e) (5 mg, 9.51 umol) in MeOH (2 mL) was added NH2OH·HCl (2.64 mg, 38.06 umol) and KOH (3.20 mg, 57.09 umol). The mixture was stirred at 25 °C for 5 h. TLC showed that 8e was completely consumed. LCMS showed that one major peak with the desired MS was formed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with HO (5 mL) and extracted with EtOAc (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 give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=3:2, by TLC) to give 8f. MS mass calculated: [M+1] + (C 22 H 27 Cl2N3O5Si) m / z 512.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (Example 8) A solution of 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (8f) (4 mg, 7.81 umol) in TFA (2 mL) was stirred at 25° C. for 4 hours. LCMS 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 give Example 8. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N3O4) m / z 382.0, LCMS observed: 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-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-oxadiazol-5-one [ka]

[0291] 3,5-Dichloro-4-(6-chloro-5-isopropyl-pyridazin-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. LCMS showed that 1a was completely consumed and the desired MS was detected. The mixture was diluted with Toluene (5 mL×3) and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=5:1) to give 9a. Calculated MS mass: [M+1] + (C 14 H10 Cl3N3O) m / z 342.0, LCMS observed: 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-isopropylpyridazin-3-yl)oxy)-N'-hydroxybenzimidamide (9b) To a solution of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-benzonitrile (9a) (60 mg, 175.13 umol) in DMF (2 mL) was added NHOH·HCl (97.36 mg, 1.40 mmol) and NaOAc (114.93 mg, 1.40 mmol). The mixture was stirred at 80° C. for 1 hour. LCMS showed complete consumption of the starting material and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between 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 give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=5:1) to give 9b. Calculated MS mass: [M+1] + (C 14 H 13 Cl3N4O2) m / z 375.0, LCMS observed: m / z 375.0.

[0293] 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H),-one (9c) To a solution of (Z / E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-N'-hydroxybenzimidamide (9b) (60 mg, 159.73 umol) in THF (3 mL) was added DSC (53.19 mg, 207.65 umol) and TEA (32.33 mg, 319.46 umol, 44.46 uL). The mixture was stirred at 60°C for 16 hours. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was concentrated under reduced pressure to give 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 observed: m / z 401.0.

[0294] 3-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H),-one (Example 9) To a solution of 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H),-one (9c) (60 mg, 149.39 umol) in HOAc (3 mL) was added NaOAc (49.02 mg, 597.56 umol). The mixture was stirred at 120° C. for 16 hours. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Waters Atlantis T3 150×30×5 um; Mobile phase: [water (0.225% FA)-ACN]; B%: 35%-75%, 13 min) to give Example 9. Calculated MS mass: [M+1] + (C 15 H 12 Cl2N4O4) m / z 383.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H),-one [ka]

[0296] 3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10a) To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)benzonitrile (9a) (40 mg, 116.75 umol) in HOAc (4 mL) was added NaOAc (38.31 mg, 467.01 umol). The mixture was stirred at 120° C. for 16 hours. LCMS showed that the starting material was completely consumed and the desired MS was found. 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 partitioned twice with 10 mL of ethyl acetate. The combined organic phase was washed with brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 10a (34 mg, crude). Calculated MS mass: [M+1] + (C 14 H 11 Cl2N3O2) m / z 324.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)benzonitrile (10b) A mixture of 3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10a) (34 mg, 104.89 umol) in DMF-DMA (2 mL) was stirred at reflux at 110° C. for 5 hours. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned twice between 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 give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 10b. Calculated MS mass: [M+1] + (C 15 H 13 Cl2N3O2) m / z 338.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)benzimidamide (10c) To a solution of 3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10b) (25 mg, 73.92 umol) in DMF (2 mL) was added NHOH·HCl (41.10 mg, 591.39 umol) and NaOAc (48.51 mg, 591.39 umol). The mixture was stirred at 80 °C for 1 h. LCMS showed that 10b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL) and HO (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 give 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 observed: m / z 371.2.

[0299] 3-(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H),-one (Example 10) To a solution of (Z)-3,5-dichloro-N'-hydroxy-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzimidamide (10c) (25 mg, 67.35 umol) in THF (3 mL) was added DSC (22.43 mg, 87.55 umol) and TEA (13.63 mg, 134.69 umol, 18.75 uL). The mixture was stirred at 60°C for 16 hours. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150 x 30 x 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-70%, 13 min) to give Example 10. Calculated MS mass: [M+1] + (C 16 H 14 Cl2N4O 4) m / z 397.0, LCMS observed 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-methylpyridazin-3(2H)-one (compound 11d) [ka]

[0301] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-2-methylaniline (11a) To a mixture of 4-amino-2,6-dichloro-3-methyl-phenol (0.2 g, 1.04 mmol) and 3,6-dichloro-4-isopropyl-pyridazine (1a) (198.97 mg, 1.04 mmol) in DMSO (5 mL) was added KCO (575.75 mg, 4.17 mmol) and CuI (119.01 mg, 624.86 umol) at 25 °C. The mixture was then stirred at 90 °C for 16 h. The mixture was added to HO (25 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was washed with petroleum ether (5 mL) and filtered. The filter cake was concentrated under reduced pressure to give 11a.

[0302] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)isoindoline-1,3-dione (11b) To a mixture of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-2-methyl-aniline (11a) (0.4 g, 1.15 mmol) and isobenzofuran-1,3-dione (170.92 mg, 1.15 mmol) in AcOH (10 mL) was added NaOAc (378.63 mg, 4.62 mmol) at 25 °C. The mixture was then stirred at 120 °C for 12 hours. LCMS showed the completion of the reaction. The mixture was concentrated to give a residue, to which HO (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 filter cake was concentrated to give 11b. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O4) m / z 458.1, LCMS observed: m / z 458.1.

[0303] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-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-methyl-phenyl]isoindoline-1,3-dione (11b) (0.37 g, 807.34 umol) in DMF-DMA (5 mL) was stirred at 105° C. for 4 hours. LCMS showed the reaction was complete. The mixture was added to HO (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 11c. The crude material was used directly in the next step. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O4) m / z 472.1, LCMS observed: m / z 472.1.

[0304] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (11d) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]isoindoline-1,3-dione (11c) (440 mg, 931.57 umol) in MeOH (1 mL) was added butan-1-amine (2 M, 1.40 mL) at 70 °C. The mixture was stirred at 70 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 1:1) to give 11d. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O4) m / z 342.1, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-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-methylpyridazin-3(2H)-one (11d) (20.85 mg, 60.94 umol) in THF (3 mL) was added 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). The mixture was stirred at 25° C. for 0.5 h. 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 give a residue. The residue was purified by preparative HPLC (Column: Xtimate C18 150 x 25 mm x 5 um; Mobile phase: [Water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to give Example 11. Calculated MS mass: [M+1] + (C 18 H 17 Cl2N5O5) m / z 454.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)-2-methylphenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0308] 2-[3,5-Dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-anilino]acetonitrile (12a) To a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (11d) (50 mg, 146.10 umol) in ACN (1 mL) was added 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). The mixture was stirred at 100 °C for 16 h. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (5 mL × 3). The combined filtrate was concentrated to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give 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-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate (12b) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-anilino]acetonitrile (12a) (55 mg, 144.26 umol) in THF (1 mL) was added BocO (94.45 mg, 432.78 umol, 99.42 uL) and DMAP (17.62 mg, 144.26 umol). The mixture was stirred at 40 °C for 1 h. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was partitioned twice between ethyl acetate (10 mL) and HO (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 give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=3:1) to give 12b. MS mass calculated: [M+1] + (C 22H 26 Cl2N4O 4) m / z 481.1, LCMS observed 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-hydroxyimino-ethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate (12c) To a solution of tert-butyl N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate (12b) (40 mg, 83.10 umol) in DMF (1 mL) was added NHOH·HCl (46.19 mg, 664.77 umol) and NaOAc (54.53 mg, 664.77 umol). The mixture was stirred at 80 °C for 1 h. The residue was partitioned twice between ethyl acetate (10 mL) and HO (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 preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give 12c. MS mass calculated: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 514.2, LCMS observed: 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-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]-N-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)methyl]carbamate (12d) To a solution of tert-butyl N-[(2Z)-2-amino-2-hydroxyimino-ethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate (12c) (40 mg, 77.76 umol) in THF (1 mL) was added DSC (25.90 mg, 101.09 umol) and TEA (15.74 mg, 155.52 umol, 21.65 uL). The mixture was stirred at 60 °C for 16 h. LCMS showed complete consumption of the starting material and the desired MS was detected. The mixture was partitioned twice between ethyl acetate (10 mL) and HO (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 give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=5:1) to give 12d. MS mass calculated: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 540.1, LCMS observed value: m / z 540.1.

[0312] 3-[[3,5-Dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-anilino]methyl]-4H-1,2,4-oxadiazol-5-one (Example 12) To a solution of tert-butyl N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]-N-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)methyl]carbamate (12d) (30 mg, 55.51 umol) in EtOAc (1 mL) was added HCl / EtOAc (2 M, 27.76 uL) at 25° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl condition) to give Example 12. Calculated MS mass: [M+1] + (C 22 H 29 Cl2N5O 5) m / z 440.1, LCMS observed 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-isopropylpyridazin-3(2H)-one (compound 13e) [ka]

[0314] Ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetate (13a) To a suspension of NaH (1.41 g, 35.33 mmol, 60% purity) in DMSO (40 mL), ethyl 2-cyanoacetate (4.00 g, 35.33 mmol) was added dropwise at 0° C. and stirred at 15° C. for 30 min. 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 h. The mixture was then quenched with water (100 mL) and adjusted to pH=1 with 1 M HCl. The white precipitate was then collected by filtration and dried under vacuum. The solid was washed with petroleum ether (40 mL) and dried under vacuum to give 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 ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetate (13a) (1.7 g, 5.61 mmol) and LiCl (285.33 mg, 6.73 mmol) in DMSO (6 mL), HO (2.5 mL) was heated to 165 °C for 1 h. After cooling, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 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 to 15 °C for 1 h. TLC showed a new spot, the mixture was filtered, and the filtrate was added with water (100 mL) and 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 give 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-isopropylpyridazin-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) was added t-BuOK (1 M, 4.28 mL) dropwise at 60 °C, and the resulting mixture was heated to 60 °C for 40 min. 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, and concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to give 13d. MS mass calculated: [M+1] + (C 15 H 13 Cl3N4) m / z 355.0, LCMS observed value: m / z 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-isopropylpyridazin-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), HO (0.6 mL), and concentrated HCl (2.4 mL) was heated to 120° C. for 32 h. LCMS showed the desired MS. After cooling, the mixture was adjusted to pH 7 with 4 M NaOH at 0° C., and the solid was filtered and dried to give 13e as an off-white solid, which was used directly in the next step. Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O) m / z 311.0, LCMS observed: m / z 311.1.

[0319] Example 13: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-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-dihydropyridazin-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-isopropylpyridazin-3(2H)-one (13e) (20 mg, 64.06 umol) in THF (3 mL) was added 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 equiv.). The mixture was stirred at 25° C. for 0.5 h. 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 give a residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%-35%, 10 min) to give Example 13. MS mass calculated: [M+1] + (C 17 H 15Cl2N5O4) m / z 424.0, LCMS observed: 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-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0322] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-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) was added HO (2 mL). The mixture was stirred at 120 °C for 72 h. LCMS showed the desired mass. The mixture was adjusted to pH = 7 by the addition of 6 M aqueous sodium hydroxide solution. The suspension was stirred for 15 min. The resulting solid was filtered and washed with HO and petroleum ether. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to give 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-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14b) A solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-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. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to remove AcOH. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL), then washed with NaHCO3 (20 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 14b. The product was used in the next step without further purification. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O3) m / z 442.1, LCMS observed: m / z 442.1.

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

[0325] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d) A solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14c) (600 mg, 1.31 mmol) in N-butylamine (981.11 mg, 6.57 mmol) and MeOH (3 mL) was heated to 70° C. for 3 h. TLC showed the reaction was complete. LCMS 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 to 2:1) to give 14d. MS mass calculated: [M+1] + (C 18 H 17 Cl2N5O4) m / z 326.1, LCMS observed: 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-dihydropyridazin-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-methylpyridazin-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 and purged with nitrogen three times and stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (NH4CO3) to give 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-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0328] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3(2H)-one (15a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (13e) (200 mg, 640.63 umol) in DMF (5 mL) was added PMB-Cl (120.39 mg, 768.75 umol) and K2CO3 (106.25 mg, 768.75 umol). The mixture was stirred at 20 °C for 16 h. 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 give a residue. The residue was purified by preparative TLC to give 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-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (15b) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3(2H)-one (15a) (150 mg, 346.95 umol) and 2-bromoacetonitrile (416.16 mg, 3.47 mmol) in DMF (10 mL) was added K2CO3 (57.54 mg, 416.34 umol) and KI (28.80 mg, 173.47 umol). The mixture was stirred at 100 °C for 6 h. The reaction mixture was quenched by adding 5 mL of water and then extracted with EtOAc (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 give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, by TLC) to give 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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (15c) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (15b) (133 mg, 282.15 umol) in THF (3 mL) was added DMAP (34.47 mg, 282.15 umol) and BocO (184.74 mg, 846.45 umol). The mixture was stirred at 20°C for 1 hour. The reaction was clean by TLC. LCMS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1, by TLC) to give 15c. Calculated MS mass: [M+1] + (C 29 H 32 Cl2N4O4) m / z 571.2, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (15c) (100 mg, 174.98 umol) in DMF (3 mL) was added NH2OH·HCl (97.27 mg, 1.40 mmol) and NaOAc (114.83 mg, 1.40 mmol). The mixture was stirred at 80 °C for 6 h. LCMS showed one major peak with the desired MS. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (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 give 15d as an off-white gum, which was used in the next step without further purification. MS mass calculated: [M+1] + (C 14 H 15 Cl2N3O2) m / z 604.2, LCMS observed: 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-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (15d) (40.00 mg, 66.17 umol) in THF (3 mL) at 0° C. was added TEA (13.39 mg, 132.34 umol) and DSC (22.04 mg, 86.02 umol). The mixture was stirred at 65° C. for 16 hours. LCMS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give 15e. Calculated MS mass: [M+1] + (C 30 H 33 Cl2N5O6) m / z 630.1, LCMS observed: m / z 630.1.

[0333] tert-Butyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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-oxadiazol-3-yl)methyl)carbamate (15e) (17 mg, 21.57 umol) in ACN (2 mL) and HO (0.5 mL) was added ACN (47.30 mg, 86.28 umol). The mixture was stirred at 20 °C for 4 h. TLC showed that 15e remained at ∼10% and one new 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 of EtOAc (10 mL × 3). The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 15f. MS mass calculated: [M+1] + (C 22 H 25 Cl2N5O5) m / z 510.1, LCMS observed: m / z 510.1.

[0334] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 15) A solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (15f) (33 mg, 64.66 umol) in EtOAc (2 mL) and HCl / EtOAc (2 M, 161.65 uL) was stirred at 20° C. for 1 h. TLC showed complete consumption of the starting material and the formation of one new spot. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to remove EtOAc. 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 give Example 15. Calculated MS mass: [M+1] + (C 17 H 17 Cl2N5O3) m / z 410.0, LCMS observed: 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-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0336] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (16a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d) (150 mg, 459.81 umol) and 2-bromoacetonitrile (551.53 mg, 4.60 mmol) in DMF (5 mL) was added KI (38.16 mg, 229.91 umol) and K2CO3 (76.26 mg, 551.77 umol). The mixture was stirred at 100 °C for 8 h. LCMS showed the desired mass. After cooling, the reaction mixture was partitioned between 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 give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to give 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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (16b) A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (16a) (20 mg, 54.76 umol), DMAP (6.69 mg, 54.76 umol), and BocO (119.50 mg, 547.56 umol) in THF (2 mL) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=2:1) ​​to give 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-dihydropyridazin-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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (16b) (50 mg, 107.44 umol) in DMF (2 mL) was added NH2OH·HCl (37.33 mg, 537.20 umol) and NaOAc (44.07 mg, 537.20 umol). The mixture was stirred at 80 °C for 1 h. LCMS showed the desired mass. The reaction mixture was partitioned between ethyl acetate (20 mL) and HO (20 mL). The organic phase was separated, washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 16c without further purification. MS mass calculated: [M+1] + (C 22 H 29 Cl2N5O4) m / z 498.2, LCMS observed: m / z 498.2.

[0339] tert-Butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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-dihydropyridazin-3-yl)methyl)phenyl)carbamate (16c) (26 mg, 52.17 umol) in THF (2 mL) was added DSC (17.37 mg, 67.82 umol) and TEA (10.56 mg, 104.33 umol). 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 give 16d. MS mass calculated: [M+1] + (C 23 H 27 Cl2N5O5) m / z 524.1, LCMS observed: m / z 524.1.

[0340] 3-(((3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 16) To a solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (16d) (24 mg, 45.77 umol) in EtOAc (1 mL) was added EtOAc / HCl (4 M, 11.44 uL). The mixture was stirred at 20° C. for 2 hours. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) to give Example 16. MS mass calculated: [M+1] + (C 18 H 19 Cl2N5O3) m / z 424.1, LCMS observed: 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-isopropylpyridazin-3-yl)methanone (17a) To a solution of 2-(4-amino-2,6-dichloro-phenyl)-2-(6-chloro-5-isopropyl-pyridazin-3-yl)acetonitrile (13d) (0.9 g, 2.53 mmol) in CHCN (20 mL) was added t-BuOK (1 M, 2.40 mL) at 20 °C. The mixture was then stirred at 20 °C for 0.5 h. The mixture was then cooled to 0 °C, and HO (573.85 mg, 5.06 mmol, 486.31 uL, 30% purity) was added dropwise to the mixture. The mixture was then stirred at 0 °C for 0.5 h and at 20 °C for an additional 2 h. Saturated NaSO solution (5 mL) was then added to the mixture, and the mixture was stirred at 20 °C for 1 h. The mixture was then concentrated under reduced pressure to remove CHCN. The residue was extracted with EtOAc (10 mL × 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 chromatography on silica gel (petroleum ether:ethyl acetate=30:1 to 5:1) to give 17a. MS mass calculated: [M+1] + (C 14 H 12 Cl3N3O) m / z 344.0, LCMS observed: 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) was added NaOAc (326.94 mg, 3.99 mmol) and isobenzofuran-1,3-dione (129.87 mg, 876.82 umol). The mixture was stirred at 120 °C for 1 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure, and the residue was diluted with HO (50 mL × 2) and NaHCO 3( The mixture was diluted with ethyl acetate (50 mL x 2). The mixture was then extracted with ethyl acetate (30 mL x 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC to give 17b. MS mass calculated: [M+1] + (C 22 H 15 Cl2N3O4) m / z 456.0, LCMS observed: 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) To 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) was added and the mixture was stirred at 110° C. for 3.5 hours. LCMS showed the desired mass. The reaction mixture was partitioned between 2×30 mL of H2O and 2×30 mL of EtOAc. The organic phase was concentrated under reduced pressure to give 17c. The crude product was used in the next step without further purification. MS mass calculated: [M+1] + (C 23 H 17 Cl2N3O4) m / z 470.1, LCMS observed: m / z 470.1.

[0345] 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazin-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 umol) in MeOH (2 mL) was added N-butylamine (190.39 mg, 1.28 mmol, 204.72 uL). The mixture was stirred at 70° C. for 0.5 h. LCMS showed the desired mass. The mixture was concentrated in vacuo. The residue was purified by preparative TLC to give 17d. MS mass calculated: [M+1] + (C 15 H 15 Cl2N3O2) m / z 340.1, LCMS observed: 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-methylpyridazin-3(2H)-one (17d) (20 mg, 58.79 umol) in THF (5 mL) was added 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). The mixture was stirred at 25° C. for 0.5 h. LCMS showed 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 give a residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-40%, 10 min) to give Example 17. MS mass calculated: [M+1]+(C18H15Cl2N5O5) m / z 452.0, LCMS observed: 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-oxadiazol-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-methylpyridazin-3(2H)-one (72 mg, 211.64 umol) (17d) in MeCN (2 mL) was added 2-bromoacetonitrile (126.93 mg, 1.06 mmol, 70.52 uL), NaI (63.45 mg, 423.28 umol), and K2CO3 (58.50 mg, 423.28 umol). The mixture was stirred at 100 °C for 13 h. The reaction mixture was extracted with ethyl acetate (20 mL × 2) and HO (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 18a. Calculated MS mass: [M+1] + (C 17 H 16 Cl2N4O2) m / z 379.1, LCMS observed: 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 umol) in THF (3 mL) was added DMAP (17.07 mg, 139.75 umol) and BocO (274.51 mg, 1.26 mmol, 288.95 uL). The mixture was stirred at 25 °C for 5 min. The mixture was partitioned between ethyl acetate (10 mL × 2) and HO (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 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) was added NHOH·HCl (37.11 mg, 534.05 umol) and NaOAc (27.38 mg, 333.78 umol). The mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned twice between ethyl acetate (10 mL) and HO (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 give 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-oxadiazol-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) was added DSC (20.80 mg, 81.19 umol) and TEA (12.64 mg, 124.91 umol, 17.39 uL). The mixture was stirred at 60 °C for 13 h. LCMS showed the desired mass. The reaction mixture was extracted with 20 mL ethyl acetate and 20 mL H2O. The combined organic layers were washed with 20 mL brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 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 observed: 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-oxadiazol-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-oxadiazol-3-yl)methyl)carbamate (18d) (22 mg, 40.86 umol) in EtOAc / HCl (2 M, 2 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to give Example 18. MS mass calculated: [M+1] + (C 18 H 17 Cl2N5O4) m / z 438.1, LCMS observed: 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-methylpyridazin-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) was added NaH (288.44 mg, 7.21 mmol, 60% purity). The mixture was then stirred at 20 °C for 1 h. Next, a mixture of N,N-dimethylcarbamothioyl chloride (950.81 mg, 7.69 mmol) was added. The mixture was stirred at 20 °C for 16 h. The mixture was extracted with EtOAc (20 mL × 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 silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give 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. LCMS showed the desired MS. The mixture was cooled to 20° C. to give 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 HO (10 mL) was added Fe (1.06 g, 18.97 mmol). The mixture was then stirred at 95 °C for 2 h. The mixture was cooled to 20 °C, and saturated NaHCO solution was added to the mixture until the pH reached 8–9 and filtered. The filtrate was then concentrated under reduced pressure to remove most of the solvent. The residue was then extracted with HO (50 mL) and EtOAc (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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) was added KOH (3 M, 20 mL). The mixture was then refluxed at 100° C. for 16 h. LCMS showed the reaction was complete. The mixture was cooled to 20° C., and HCl solution (1 M) was added to the mixture until the pH reached 2-3. The mixture was extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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-isopropylpyridazin-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) was added KCO (1.11 g, 8.04 mmol). The mixture was then stirred at 95 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 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 give 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-dihydropyridazin-3-yl)thio)phenyl)isoindoline-1,3-dione (19f) To a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-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) was added NaOAc (1.18 g, 14.34 mmol). The mixture was stirred at 120 °C for 16 h. 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 NaHCO (10 mL). The mixture was then partitioned twice with ethyl acetate (30 mL). The combined organic phases were washed with brine (10 mL × 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 give 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-dihydropyridazin-3-yl)thio)-phenyl)isoindoline-1,3-dione (19g) A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-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 h. The mixture was concentrated under reduced pressure to give a residue. The residue was partitioned twice between ethyl acetate (10 mL) and HO (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 give 19 g. The product was used directly in the next step without further purification. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O3S) m / z 474.0, LCMS observed: m / z 474.0.

[0361] 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)-phenyl)isoindoline-1,3-dione (19g) (980 mg, 2.07 mmol) and butan-1-amine (453.29 mg, 6.20 mmol, 612.55 uL) in MeOH (2 mL) was stirred at 70° C. for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give 19h. MS mass calculated: [M+1] + (C 14 H 15 Cl2N3OS) m / z 344.0, LCMS observed: 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-dihydropyridazin-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0363] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)amino)acetonitrile (19i) To a solution of 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) (420 mg, 1.22 mmol) in ACN (3 mL) was added 2-bromoacetonitrile (731.69 mg, 6.10 mmol, 406.49 uL), K2CO3 (337.23 mg, 2.44 mmol), and NaI (365.75 mg, 2.44 mmol). The mixture was stirred at 100 °C for 16 h. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOAc (10 mL × 3). The combined filtrate was concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 19i. MS mass calculated: [M+1] + (C 16 H 16 Cl2N4OS) m / z 383.3, LCMS observed: 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-dihydropyridazin-3-yl)thio)phenyl)carbamate (19j) To a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)amino)acetonitrile (19i) (420 mg, 1.10 mmol) in THF (3 mL) was added DMAP (133.87 mg, 1.10 mmol) and BocO (717.45 mg, 3.29 mmol) at 25 °C. The mixture was stirred at 25 °C for 20 min. The mixture was partitioned twice between 10 mL of ethyl acetate and 3 mL of HO. 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 preparative TLC (SiO, petroleum ether:ethyl acetate = 3:1) to give 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-dihydropyridazin-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-dihydropyridazin-3-yl)thio)phenyl)carbamate (19j) (250 mg, 517.16 umol, 1 equiv) in DMF (3 mL) was added NHOH·HCl (287.50 mg, 4.14 mmol, 8 equiv) and NaOAc (339.38 mg, 4.14 mmol, 8 equiv) at 25 °C. The mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, 2 times). The combined organic phase was washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1) to give 19k. 1H 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-dihydropyridazin-3-yl)thio)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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 umol) in THF (4 mL) was added DSC (141.86 mg, 553.79 umol) and TEA (86.21 mg, 851.99 umol, 118.59 uL). The mixture was stirred at 60°C for 16 hours. 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. MS mass calculated: [M+1] + (C 22 H 25 Cl2N5O5S) m / z 542.4, LCMS observed: m / z 542.1; 1 H 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-dihydropyridazin-3-yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (19m) To 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 m-CPBA (37.43 mg, 184.35 umol, 85% purity). The mixture was then stirred at 60°C for 48 hours. The reaction mixture was quenched with NaSO (23 mg) at 20°C and stirred for 30 minutes. The mixture was then concentrated under reduced pressure to provide 19m. MS mass calculated: [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-dihydropyridazin-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-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 hours. The mixture was concentrated under reduced pressure to give 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 give Example 19. MS mass calculated: [M+1] + (C 17 H 17 Cl2N5O5 S ) m / z 474.3, LCMS observed value: m / z 474.0; 1 HNMR (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-dihydropyridazin-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-dihydropyridazin-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-methylpyridazin-3(2H)-one (19h) (20 mg, 58.10 umol) in DCM (5 mL) was added 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), and the mixture was stirred at 25 °C for 0.2 h. The reaction mixture was partitioned between HO (5 mL) and EtOAc (5 mL). The organic phase was separated, washed with brine (5 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to give 20a. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O4S) m / z 456.0, LCMS observed: 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-dihydropyridazin-3-yl)sulfonyl)-phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 20) To N-(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-oxadiazole-3-carboxamide (20a) (8 mg, 17.53 umol) in DCM (1 mL) was added 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 give a residue. The residue was purified by preparative HPLC (aqueous acetonitrile with TFA) to give Example 20. MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O6S) m / z 488.0, LCMS observed: 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-cyclopropylpyridazin-3(2H)-one (21e) [ka]

[0373] 3,6-Dichloro-4-cyclopropylpyridazine (21a) H2SO4 (9.88 g, 100.69 mmol) was added 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 HO (100 mL) at 60 °C. Then, ammonium persulfate (22.98 g, 100.69 mmol) in HO (100 mL) was added to the mixture at 70 °C. The resulting mixture was stirred at 70 °C for 30 min. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by MPLC (silica gel, petroleum ether:ethyl acetate = 5:1) to give 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-cyclopropylpyridazin-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) was added dropwise t-BuOK (1 M, 4.23 mL) 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) and washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=2:1) ​​to give 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-cyclopropylpyridazin-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 HO (10 mL) was added KOH (1.16 g, 20.64 mmol). The mixture was stirred at 100 °C under O for 16 h. LCMS showed one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with 2M aqueous HCl, adjusted to pH = 5-7, and extracted with EtOAc (20 mL × 4). The combined organic layer was washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21c. Calculated MS mass: [M+1] + (C 14 H 11 Cl2N3O2) m / z 324.0, LCMS observed: m / z 324.1.

[0376] 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazin-3(2H)-one (21d) To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyridazin-3(2H)-one (21c) (100 mg, 308.49 umol) in MeOH (5 mL) was added NaBH (116.70 mg, 3.08 mmol) at 0 °C. The mixture was stirred at 15 °C for 16 h. LCMS showed 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 EtOAc (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 give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:petroleum ether = 2:1, TLC) to give 21d. Calculated MS mass: [M+1] + (C 14 H 13 Cl2N3O2) m / z 326.1, LCMS observed: 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-cyclopropylpyridazin-3(2H)-one (21e) To a solution of 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazin-3(2H)-one (21d) (50 mg, 153.29 umol) in TFA (1 mL) and DCE (5 mL) was added EtSiH (89.12 mg, 766.46 umol). The mixture was stirred at 50 °C for 6 h. LCMS showed one major peak with the desired MS. The reaction mixture was diluted with saturated NaHCO (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 give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:petroleum ether = 2:1; TLC) to give 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-dihydropyridazin-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-dihydropyridazin-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-cyclopropylpyridazin-3(2H)-one (21e) (16 mg, 51.58 umol) in DCM (2 mL) was added 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). The mixture was stirred at 25°C for 0.5 hours. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Xtimate C18 150 x 25 mm x 5 um; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-40%, 10 min) to give Example 21. Calculated MS mass: [M+1] + (C 17 H 13 Cl2N5O4) m / z 422.0, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e) (44 mg, 141.85 umol) in AcOH (3 mL) was added isobenzofuran-1,3-dione (22.06 mg, 148.95 umol). The mixture was stirred at 120 °C for 2 h. TLC showed the formation of one new spot. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with 2 mL of water and saturated aqueous NaHCO3 was added to pH = 9-10. The suspension was extracted with 20 mL of EtOAc (5 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 22a as a yellow oil, which was used in the next step without further purification. MS mass calculated: [M+1] + (C 22 H 15 Cl2N3O3) m / z 440.1, LCMS observed: m / z 440.1.

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

[0383] 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazin-3(2H)-one (22c) To a solution of 2-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22b) (100 mg, 154.08 umol) in MeOH (3 mL) was added N-butylamine (33.81 mg, 462.24 umol). The mixture was stirred at 70 °C for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate; TLC) to give 22c. Calculated MS mass: [M+1] + (C 15 H 15 Cl2N3O) m / z 324.1, LCMS observed: 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-dihydropyridazin-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-methylpyridazin-3(2H)-one (22c) (10 mg, 30.84 umol) in DCM (2 mL) was added 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). The mixture was stirred at 25° C. for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was checked by HPLC and purified by preparative HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%-35%, 14 min) to give Example 22 as a white solid. MS mass calculated: [M+1] + (C18 H 15 Cl2N5O4) m / z 436.0, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-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-dichloro-phenoxy)-5-isopropyl-1H-pyridazin-6-one (8b) (13.7 g, 43.61 mmol) in THF (140 mL) was added 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). The mixture was stirred at 20° C. for 0.5 hours. LCMS showed a peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with EtOAc (100 mL) at 80° C. for 30 minutes and then cooled to 20° C. The suspension was filtered, and the filter cake was washed with EtOAc (5 mL×3) and concentrated to dryness to give Example 23. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O5) m / z 426.0, LCMS observed: 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-dihydropyridazin-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-isopropyl-pyridazin-3-yl)oxy-indan-4-amine (24a) 7-Amino-5-chloro-indan-4-ol (0.39 g, 2.12 mmol), 3,6-dichloro-4-isopropyl-pyridazine (1a) (405.77 mg, 2.12 mmol), CuI (40.45 mg, 212.38 umol), and K2CO3 (440.28 mg, 3.19 mmol) in DMA (15 mL) was degassed with N2 and then heated to 100 °C under N2 for 16 h. LCMS indicated the reaction was complete and the desired MS was detected. The mixture was filtered through a Celite pad and washed with ethyl acetate (20 mL × 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 give 24a. MS mass calculated: [M + 1] + (C 16 H 17 Cl2N3O) m / z 338.1, LCMS observed: 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-pyridazin-3-yl)oxy]indan-4-yl]isoindoline-1,3-dione (24b) To a mixture of 6-chloro-7-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-indan-4-amine (24a) (120 mg, 354.79 umol) and isobenzofuran-1,3-dione (52.55 mg, 354.79 umol) in NaOAc (101.87 mg, 1.24 mmol) was added AcOH (1 mL). The mixture was stirred at 120 °C for 16 h. 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 NaHCO (10 mL). The mixture was then partitioned twice with ethyl acetate (30 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 24b. The product was used directly in the next step without purification. MS mass calculated: [M+1] + (C 24 H 20 ClN3O4) m / z 450.1, LCMS observed: m / z 450.2.

[0390] 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-indan-4-yl]isoindoline-1,3-dione (24c) A solution of 2-[6-chloro-7-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]indan-4-yl]isoindoline-1,3-dione (24b) (150 mg, 333.42 umol) in DMFDMA (2 mL) was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned twice between 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 give 24c, which was used crude in the next step directly. MS mass calculated: [M+1] + (C 25 H 22 ClN3O4) m / z 464.1, LCMS observed: m / z 464.2.

[0391] 6-(7-amino-5-chloro-indan-4-yl)oxy-4-isopropyl-2-methyl-pyridazin-3-one (24d) A mixture of 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-indan-4-yl]isoindoline-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 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 1:1) to give 24d. MS mass calculated: [M+1] + (C 17 H 20 ClN3O2) m / z 334.1, LCMS observed: m / z 334.1.

[0392] N-(6-chloro-7-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-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 equiv) in THF (5 mL) was added TEA (9.09 mg, 89.87 umol, 12.51 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (6.67 mg, 44.94 umol). The mixture was stirred at 25°C for 0.5 h. The reaction mixture was quenched with MeOH (1 mL) at 25°C and then concentrated under reduced pressure to give a residue. The residue was checked by HPLC and then purified by preparative HPLC (column: Luna C18 100 x 30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 35%-60%, 12 min) to give Example 24. MS mass calculated: [M+1] + (C 20 H 20 ClN5O5) m / z 446.1, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0394] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazin-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) was degassed and then heated to 100 °C under N2 for 16 h. The solid was filtered off, and the filtrate was added with water (20 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layer 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 = 5:1) to give 25a. MS mass calculated: [M+1] + (C 13 H 10 Cl3N3O) m / z 330.0, LCMS observed: m / z 329.9 / 331.9;

[0395] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (25b) To a solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (11.80 mg, 90.75 umo) in THF (2 mL) was added one drop of DMF, followed by (COCl) (11.52 mg, 90.75 umol, 7.94 uL, 1.5 equiv) at 0°C, and the mixture was stirred at 25°C for 1 hour. 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 umol) and TEA (18.37 mg, 181.50 umol, 25.26 uL) in DCM (3 mL) at 25°C, and the resulting mixture was stirred at 25°C for 30 minutes. The mixture was concentrated and the residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give 25b. MS mass calculated: [M+1]+ (C 16 H 10 Cl3N5O4) m / z 442.0, LCMS observed: m / z 442.0.

[0396] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-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-cyclopropylpyridazin-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 to 110° C. for 16 hours. The mixture was concentrated. The residue was purified by preparative HPLC (neutral) C to give Example 25. MS mass calculated: [M+1] + (C 16 H 11 Cl2N5O5) m / z 424.2, LCMS observed: 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-dihydropyridazin-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-methylpyridazin-3(2H)-one (26a) To a suspension of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl-pyridazin-3-one (1e) (20 g, 60.94 mmol) in CHCN (200 mL) and THF (60 mL) was added NaHCO (15.36 g, 182.82 mmol) under a nitrogen atmosphere. To the resulting solution, Select F (21.59 g, 60.94 mmol) was added portionwise over 30 minutes. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was partitioned between 200 mL of H2O and 300 mL of EtOAc. The organic phase was separated, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 1 / 1; TLC) to give 26a. MS mass calculated: [M+1] + (C 14 H 14 Cl2FN3O2) m / z 346.0, LCMS observed: 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-dihydropyridazin-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-fluoro-phenoxy)-4-isopropyl-2-methyl-pyridazin-3-one (26a) (13 g, 37.55 mmol) in THF (130 mL) was added 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). The mixture was stirred at 20 °C for 0.5 h. LCMS showed a peak with the desired MS. The mixture was diluted with 1 M HCl to adjust the pH to 6-7 and extracted with 300 mL of EtOAc (100 mL × 3). The combined organic layers were washed with 150 mL of brine, dried over anhydrous sodium sulfate, and filtered to give a light yellow liquid. The light yellow liquid was concentrated under reduced pressure to remove the solvent until the solids dissolved. The mixture was stirred at 20° C. for 1 hour and filtered to give Example 26. Calculated MS mass: [M+1] + (C 17 H 14 Cl2FN5O5) m / z 458.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0401] 2-((3,5-Dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (27a) To a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (26a) (20 mg, 57.77 umol) in ACN (2 mL) was added 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). The mixture was stirred at 100 °C for 20 h. The suspension was filtered through a pad of Celite, and the pad was washed with EtOAc (5 mL × 3). The combined filtrate was concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 27a. MS mass calculated: [M+1] + (C 16 H 15 Cl2FN4O2) m / z 385.2, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (27a) (20 mg, 51.92 umol) in THF (3 mL) was added DMAP (6.34 mg, 51.92 umol) and BocO (33.99 mg, 155.76 umol, 35.78 uL) at 20 °C. The mixture was stirred at 20 °C for 20 minutes. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=2:1) ​​to give 27b. MS mass calculated: [M+1] + (C 21 H 23Cl2FN4O4) m / z 485.3, LCMS observed: 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-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)carbamate (27b) (20 mg, 41.21 umol) in DMF (2 mL) was added NHOH·HCl (22.91 mg, 329.67 umol) and NaOAc (27.04 mg, 329.67 umol) at 20 °C. The mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned twice between 10 mL of ethyl acetate and 5 mL of H2O. 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 preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give 27c. Calculated MS mass: [M+1] + (C 21 H 26 Cl2FN5O5) m / z 518.4, LCMS observed: m / z 518.0.

[0404] tert-Butyl (3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-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) was added DSC (12.85 mg, 50.16 umol) and TEA (7.81 mg, 77.17 umol, 10.74 uL). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO2, DCM:MeOH = 10:1, P1:R f =0.3) to give 27d. Calculated MS mass: [M+1] + (C 22 H 24 Cl2FN5O6) m / z 544.4, LCMS observed: m / z 544.0.

[0405] 3-(((3,5-Dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 27) A solution of tert-butyl (3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate (27d) (8 mg, 14.70 umol) in HCl / EtOAc (2 mL) was stirred at 20° C. for 1.5 hours. The mixture was concentrated under reduced pressure to give 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 give Example 27. MS mass calculated: [M+1] + (C 17 H 16 Cl2FN5O4) m / z 444.2, LCMS observed: 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-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0407] 4-((5-(tert-butyl)-6-chloropyridazin-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) were added 4-amino-2,6-dichlorophenol (173.61 mg, 0.975 mmol), KCO (404.34 mg, 2.93 mmol), and CuI (111.44 mg, 0.585 mmol), and the mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The solvent was diluted with EtOAc (10 mL) and HO (10 mL), extracted with EA (10 mL × 2), and the organic layer was washed with brine (20 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 28a. MS mass calculated: [M+1] + (C 14 H 14 Cl3N3O) m / z 346.6, LCMS observed: 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-chloropyridazin-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-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (28a) (100 mg, 288.48 mmol) in THF (2 mL), TEA (87.58 mg, 865.45 umol), 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (64.26 mg, 432.73 umol) in DCM (2 mL) was added under a nitrogen atmosphere. The mixture was stirred at 20 °C under N for 0.5 h. The mixture was poured into HO (10 mL), and the resulting mixture was extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give 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 observed: m / z 458.1.

[0409] N-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 28) To a mixture of N-(4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (140 mg, 305.2 ummol) in HOAc (10 mL) was added NaOAc (125.19 mg, 1.53 mmol). The mixture was then stirred at 120° C. for 16 hours. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (CHCN in HO, 40%) to give Example 28 (9.9 mg, 7.4% yield). MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.2, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0411] 1-(3,6-Dichloropyridazin-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) was added but-3-yn-2-ol (278.59 mg, 3.97 mmol). The mixture was stirred in a sealed tube at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1, TLC) to give 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 uL) in DCM (10 mL) was added TsOH (13.38 mg, 77.71 umol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 5:1, by TLC) to give 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 and purged with nitrogen three times, and then the mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed one peak with the desired MS. The reaction mixture was diluted with 5 mL of H2O and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 10 mL of brine and dried over anhydrous sodium sulfate. 、 Filtration and concentration under reduced pressure gave a residue, which was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1, TLC) to give 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) was added TEA (181.26 mg, 1.79 mmol, 249.32 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (133.00 mg, 895.63 umol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH = 10:1, by TLC) to give 29d. MS mass calculated: [M+1] + (C 20 H 18 Cl3N5O6) m / z 530.0, LCMS observed: m / z 529.9.

[0415] 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)acetic acid ethyl ester (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) was added NaOAc (37.09 mg, 452.19 umol). 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. MS mass calculated: [M+1] + (C 17 H 13 Cl2N5O7) m / z 470.0, LCMS observed: m / z 470.0.

[0416] 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) To a solution of ethyl 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)acetate (29e) (105 mg, 223.30 umol) in MeOH (3 mL) and HO (0.5 mL) was added LiOH.HO (18.74 mg, 446.60 umol). The mixture was stirred at 25 °C for 1 h. LCMS showed 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 EtOAc (5 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Luna C18 100x30 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 1%-40%, 12 min) to give Example 29. MS mass calculated: [M+1] + (C 15 H 11 Cl2N5O6) m / z 428.0, LCMS observed: 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-dihydropyridazin-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: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH × HO MeOH]; B%: 40%-40%, 10 min) to give Example 29-P1 and Example 29-P2.

[0418] Example 29-P1: MS mass calculated: [M+1] + (C 15 H 11 Cl2N5O6) m / z 428.0, LCMS observed: 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: MS mass calculated: [M+1]+(C15H11Cl2N5O6) m / z 428.0, LCMS observed: 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) was added PPh3 (1.83 g, 6.97 mmol). The mixture was then cooled to 0-5 °C. CBr4 (2.31 g, 6.97 mmol) was then added portionwise to the mixture. The mixture was then stirred under N2 at 15 °C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10:1, TLC) to give 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) was added NaCN (244.35 mg, 4.99 mmol) at 15 °C. The mixture was then stirred at 15 °C for 16 h. The mixture was partitioned twice between ethyl acetate (50 mL) and aqueous NH4Cl (20 mL). The combined organic phase was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 3:1, TLC) to give 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-isopropylpyridazin-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) was added t-BuOK (1 M, 7.14 mL, 2 equiv.) dropwise at 60 °C, and the resulting mixture was heated to 60 °C for 1 h. 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 × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 3:1, TLC) to give 30c. MS mass calculated: [M+1] + (C 17 H 17 BrClN3) m / z 378.0, LCMS observed: 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-isopropylpyridazin-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) in AcOH (10 mL), HO (10 mL), and HCl (40 mL) was heated at 120° C. for 48 h. LCMS indicated 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., and the solid was filtered and dried to give 30d. The product was used directly in the next step without further purification. Calculated MS mass: [M+1] + (C 16 H 19 BrNO) m / z 335.1, LCMS observed: 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-isopropylpyridazin-3(2H)-one (30e) To a solution of 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin-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) was added t-BuONa (43.00 mg, 447.44 umol), Pd(dba) (27.32 mg, 29.83 umol), and Xantphos (17.26 mg, 29.83 umol). The mixture was degassed and purged with nitrogen three times and stirred at 80 °C for 16 h. The mixture was partitioned between DCM (20 mL) and saturated aqueous NH4Cl (10 mL) and extracted a second time with DCM. The combined organic layers were washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 30e. MS mass calculated: [M+1] + (C 29 H 29 N3O) m / z 436.2, LCMS found: m / z 436.4. The residue was used directly in the next step without further purification.

[0426] 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30f) A solution of 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30e) (100 mg, 229.59 umol) in HCl / EtOAc (5 mL) was stirred at 15 °C for 16 h. LCMS showed the desired MS was detected. The mixture was diluted with 5 mL of water and adjusted to pH = 9-10 with saturated aqueous NaHCO3. The suspension was extracted with EtOAc (15 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 30f. Calculated MS mass: [M+1] + (C 16 H 21 NO) m / z 272.2, LCMS observed: 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-isopropylpyridazin-3(2H)-one (30f) (10 mg, 36.85 umol) in THF (1 mL) was added TEA (14.92 mg, 147.41 umol, 20.52 uL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (10.95 mg, 73.70 umol) at 15°C. The mixture was stirred at 15°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 x 30 mm 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 12 min) to give Example 30. Calculated MS mass: [M+1] + (C 19 H 21 N5O4) m / z 384.2, LCMS observed: 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-dihydropyridazin-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 HO (5 mL) was added AgNO (193.84 mg, 1.14 mmol), ammonium persulfate (286.44 mg, 1.26 mmol), and HSO (335.75 mg, 3.42 mmol, 182.48 μL) in HO (2.5 mL) in one portion at 60 °C under nitrogen. The mixture was stirred at 70 °C for 20 min. After cooling, the mixture was extracted with ethyl acetate (5 mL × 2), and the organic phase was washed with NaHCO (2 mL), brine (5 mL), and then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1) to give 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-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (31b) To a solution of 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) in DMSO (9 mL) was added KCO (385.55 mg, 2.79 mmol) and CuI (79.69 mg, 418.45 umol) in one portion under nitrogen at 25 °C. The mixture was stirred at 90 °C for 16 h. The residue was partitioned between ethyl acetate (20 mL) and HO (5 mL × 2). The combined organic phase was washed with brine (5 mL × 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 give 31b. Calculated MS mass: [M+1] + (C 15 H 12 Cl3N3O) m / z 356.0, LCMS observed: m / z 355.9.

[0431] N-(4-((5-(bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazin-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-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (31b) (30 mg, 84.12 umol) in DCM (5 mL) was added TEA (25.54 mg, 252.36 umol, 35.13 uL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (18.74 mg, 126.18 umol) in one portion under nitrogen at 0°C, and the reaction 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 give 31c.

[0432] N-(4-((5-(bicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 31) To a mixture of N-(4-((5-(bicyclo[1.1.1]pentan-1-yl)-6-chloropyridazin-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) was added NaOAc (15.75 mg, 192.03 umol) in one portion. The mixture was then stirred at 120° C. under nitrogen for 16 hours. The mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 45%-75%, 10 min) to give Example 31. Calculated MS mass: [M+1] + (C 18 H 13 Cl2N5O5) m / z 450.0, LCMS observed 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-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0434] 1-(3,6-Dichloropyridazin-4-yl)propan-1-ol (32a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1 g, 6.62 mmol) in Tol. (10 mL) was added pent-1-yn-3-ol (1.11 g, 13.25 mmol, 1.14 mL) at 20 °C. The mixture was stirred in a sealed tube at 110 °C for 16 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give 32a. Calculated MS mass: [M+1] + (C7H8Cl2N2O) m / z 207.1, LCMS observed: 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)oxy)propyl)pyridazine (32b) To a solution of 1-(3,6-dichloropyridazin-4-yl)propan-1-ol (32a) (140 mg, 676.14 umol) and DHP (284.37 mg, 3.38 mmol, 309.10 uL) in DCM (5 mL) was added TsOH (5.82 mg, 33.81 umol). The mixture was stirred at 20 °C for 1 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 2:1, TLC) to give 32b. Calculated MS mass: [M+1] + (C 12 H 16Cl2N2O2) m / z 291.2, LCMS observed: 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)pyridazin-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) was added K2CO3 (246.83 mg, 1.79 mmol) and CuI (51.02 mg, 267.88 umol), degassed, and purged with nitrogen three times. The mixture was then stirred at 90 °C under a nitrogen atmosphere for 16 h. LCMS showed the desired product. The mixture was diluted with EtOAc (5 mL), filtered, and the filtrate was partitioned between ethyl acetate (5 mL) and HO (3 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was 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 give 32c. MS mass calculated: [M+1] + (C 18 H 20 Cl3N3O3) m / z 432.7, LCMS observed: 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) was added 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). The mixture was stirred at 20° C. for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give 32d. Calculated MS mass: [M+1] + (C 21 H 20 Cl3N5O6) m / z 544.8, LCMS observed: 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-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-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 equiv) in HOAc (5 mL) was added NaOAc (97.88 mg, 1.19 mmol). The mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove AcOH to give 32e. MS mass calculated: [M+1] + (C 18 H 15 Cl2N5O7) m / z 484.2, LCMS found: 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-dihydropyridazin-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-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (32e) (115 mg, 237.48 umol) in MeOH (3 mL) and HO (0.5 mL) was added LiOH.HO (1 M, 474.97 uL). The mixture was stirred at 25 °C for 1 h. 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 EtOAc (30 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 x 30 mm x 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 10 min) to give Example 32. MS mass calculated: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.2, LCMS observed: 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] Example 32-P1 and P2: 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 [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 give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Luna C18 100×30 mm×5 um; Mobile phase: [water (0.2% FA)-ACN]; B%: 35%-65%, 10 min) to give 32f. MS mass calculated: [M+1] + (C 16 H 12 Cl3N5O5) m / z 460.0, LCMS observed: 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: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH × HO MeOH]; B%: 30%-30%, 5 min) to give 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 HO (0.1 mL) was stirred at 120° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Luna C18 200×40 mm×10 um; Mobile phase: [water (0.225% FA)-ACN]; B%: 20%-50%, 12 min) to give Example 32-P1. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.0, LCMS observed: 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 HO (0.1 mL) was stirred at 120° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Luna C18 100×30 mm×5 um; Mobile phase: [water (0.2% FA)-ACN]; B%: 20%-50%, 10 min) to give Example 32-P2. Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O6) m / z 442.0, LCMS observed: 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-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka]

[0446] 2-(3,6-Dichloropyridazin-4-yl)propan-2-ol (33a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (500 mg, 3.31 mmol) in Tol. (5 mL) was added 2-methylbut-3-yn-2-ol at 20 °C. The mixture was placed in a sealed tube and stirred at 115 °C for 16 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1 to 4:1, TLC) to give 33a. Calculated MS mass: [M+1] +(C7H8Cl2N2O) m / z 207.0, LCMS observed: 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-dichloropyridazin-4-yl)propan-2-ol (33a) (70 mg, 338.07 umol) in DCM (5 mL) was added DHP (142.19 mg, 1.69 mmol, 154.56 uL) and PPTS (16.99 mg, 67.61 umol). The mixture was stirred at 20 °C for 16 h. 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 give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 5:1, TLC) to give 33b. MS mass calculated: [M+1] + (C 12 H 16 Cl2N2O2) m / z 291.1, LCMS observed: 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)pyridazin-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) was added K2CO3 (75.94 mg, 549.50 umol) and CuI (15.70 mg, 82.43 umol), degassed, and purged with nitrogen three times. The mixture was then stirred at 90 °C under a nitrogen atmosphere for 16 h. LCMS showed the desired product. The mixture was diluted with EtOAc (5 mL) and filtered. The filtrate was partitioned between ethyl acetate (5 mL) and H2O (3 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was 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 give 33c. MS mass calculated: [M+1] + (C 18 H 20 Cl3N3O3) m / z 432.1, LCMS observed: m / z 432.1.

[0449] 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) 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) was added 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). The mixture was stirred at 20° C. for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate) to give 33d. Calculated MS mass: [M+1] + (C 21 H 20Cl3N5O6) m / z 544.0, LCMS observed: 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-dihydropyridazin-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 HO (0.1 mL) was stirred at 120° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Luna C18 200×40 mm×10 um; Mobile phase: [water (0.225% FA)-ACN]; B%: 20%-55%, 12 min) to give Example 33. MS mass calculated: [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-dihydropyridazin-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-isopropylpyridazin-3(2H)-one (34a) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (8b) (300 mg, 954.91 umol) in CHCN (10 mL) and THF (10 mL) was added NaHCO (240.66 mg, 2.86 mmol, 111.41 uL). Select F (372.11 mg, 1.05 mmol) was then added in one portion to the mixture at 20 °C. The mixture was then stirred at 20 °C for 2 h. The mixture was diluted with EtOAc (30 mL) and HO (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 give 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-dihydropyridazin-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-isopropylpyridazin-3(2H)-one (34a) (100 mg, 301.06 umol) in DCM (4 mL) was added 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). The mixture was stirred at 20° C. for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate) to give the desired material. The desired compound was repurified by preparative HPLC (column: Phenomenex Luna C18 200 x 40 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 12 min) to give Example 34. Calculated MS mass: [M+1] + (C16H12Cl2FN5O5) m / z 444.0, LCMS observed: 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-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (compound 35c) [ka]

[0455] 2-(3,6-Dichloropyridazin-4-yl)propan-1-ol (35a) To HO (25 mL) was added TFA (4.97 g, 43.63 mmol, 3.23 mL) at 50 °C, and then 2-methylpropane-1,3-diol (6.65 g, 73.8 mmol, 6.59 mL) was added to the mixture, followed by 3,6-dichloropyridazine (5 g, 33.6 mmol) and AgNO (7.70 g, 45.3 mmol). Next, a solution of ammonium hydrogen thiosulfate (15.3 g, 67.1 mmol, 14.6 mL) in HO (15 mL) was added portionwise to the mixture at 50 °C, and the resulting mixture was stirred at 50 °C for 0.5 h. The reaction mixture was partitioned between HO (45 mL) and EtOAc (50 mL). The organic phase was separated, washed with HO (50 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate) to give 35a. MS mass calculated: [M+1] + (C7H8Cl2N2O) m / z 207.0, LCMS observed: 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-chloro-dimethyl-silane (2.47 g, 16.4 mmol, 2.01 mL) in DMF (25 mL) was added imidazole (1.34 g, 19.7 mmol). The mixture was stirred at 25° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 35b. The product was used directly in the next step without further purification. MS mass calculated: [M+1] + (C 13 H 22 Cl2N2OSi) m / z 321.1, LCMS observed: 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-chloropyridazin-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) was added 4-amino-2,6-dichlorophenol (752.84 mg, 3.11 mmol), KCO (1.29 g, 9.34 mmol), and CuI (355.63 mg, 1.87 mmol). The mixture was stirred at 90 °C under a nitrogen atmosphere for 5 h. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOAc (50 mL). The reaction mixture was quenched by the addition of HO (30 mL) and then extracted with ethyl acetate (50 mL) and EtOAc (50 mL × 5). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate) to give 35c. MS mass calculated: [M+1] + (C 19 H 26 Cl3N3O2Si) m / z 462.1, LCMS observed: m / z 462.1.

[0458] Example 35: N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-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-dioxoisoindolin-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35d) To a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (510 mg, 1.10 mmol) in HOAc (8 mL) was added isobenzofuran-1,3-dione (244.8 mg, 1.65 mmol) and NaOAc (271.2 mg, 3.31 mmol). The mixture was stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate) to give 35d. MS mass calculated: [M+1] + (C 23 H 17 Cl2N3O6) m / z 502.0, LCMS observed: m / z 502.1.

[0460] 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindolin-2-yl)phenoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35e) To a solution of 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindolin-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35d) (230 mg, 457.9 umol) in DMF (3 mL) was added KCO 3( To the resulting mixture was added MeI (107.6 mg, 778.4 umol) and MeI (130.0 mg, 915.8 umol, 57.0 uL). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched at 25° C. by the addition of HO (15 mL) and then extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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 observed: m / z 516.1.

[0461] 6-(4-amino-2,6-dichlorophenoxy)-4-(1-hydroxypropan-2-yl)-2-methylpyridazin-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-dihydropyridazin-4-yl)propyl acetate (35e) (223 mg, 431.89 umol) in MeOH (5 mL) was added butan-1-amine (1.11 g, 15.2 mmol, 1.5 mL). The mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate) to give 35f. MS mass calculated: [M+1] + (C 14 H 15 Cl2N3O3) m / z 344.0, LCMS observed: m / z 344.0.

[0462] N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-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-methylpyridazin-3(2H)-one (35f) (50 mg, 145.3 umol) in THF (3 mL) was added 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). The mixture was stirred at 25 °C for 5 min. TLC and LCMS showed that 35f was completely consumed and the desired mass + Ac was detected. The reaction mixture was quenched at 25 °C by the addition of MeOH (5 mL). The pH was then adjusted to 100 with LiOH. . The pH was adjusted to 10-12 with HO, and the resulting mixture was stirred at 25°C for 1 hour. LCMS showed the desired MS was found in the major peak. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; Mobile Phase: [Water (10 mM NH4HCO3)-MeCN]) to give Example 35. Calculated MS mass: [M+1] + (C 17 H15 Cl2N5O6) m / z 456.0, LCMS observed: 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-dihydropyridazin-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-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (50 mg, 108.0 umol) in THF (2 mL) was added 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). 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 in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 36a. MS mass calculated: [M+1] + (C 16 H 12 Cl3N5O5) m / z 460.0, LCMS observed: m / z 460.0.

[0465] 2 -(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl formate (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 h. The reaction mixture was concentrated under reduced pressure to remove HCOOH. The residue was purified by preparative TLC (SiO, ethyl acetate:petroleum ether) to give 36b. MS mass calculated: [M+1] + (C 17 H 13 Cl2N5O7) m / z 470.0, LCMS observed: m / z 470.0.

[0466] N-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazin-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-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl formate (36b) (35 mg, 74.4 umol) in MeOH (4 mL) was added LiOH.HO (3.8 mg, 89.3 umol) and HO (1 mL). 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 um; Mobile phase: [water (10 mM NH4HCO3)-MeCN]) to give Example 36. Calculated MS mass: [M+1] + (C16H13Cl2N5O6) m / z 442.0, LCMS observed 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-dihydropyridazin-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-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (37a) To a mixture of 3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazin-3-yl)oxy)aniline (33c) (100 mg, 231.1 umol) and isobenzofuran-1,3-dione (37.7 mg, 254.2 umol) in HOAc (2 mL) was added NaOAc (94.8 mg, 1.16 mmol) under N. The mixture was stirred at 120 °C for 16 h. Water (5 mL) was poured into the residue. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate) to give 37a. Calculated MS mass: [M+1] + (C 21 H 15 Cl2N3O5) m / z 460.0, MS mass observed: m / z 460.0; 1 H NMR (400 MHz, CDCl3)δ 9.91 (br s, 2H), 8.11 - 7.93 (m, 2H), 7.92 - 7.74 (m, 3H), 7.61 (d, J=1.6 Hz, 3H), 7.30 - 7.28 (m, 1H), 2.16 - 2.00 (m, 3H), 1.90 - 1.84 (m, 2H), 1.68 (br d, J=6.0 Hz, 1H), 1.67 - 1.65 (m, 1H), 1.67 - 1.65 (m, 1H), 1.66 (s, 1H).

[0469] 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (37b) To a mixture of 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (37a) (50 mg, 108.6 umol) in DMF (3 mL) under N was added KCO (30.0 mg, 217.3 umol) and MeI (30.8 mg, 217.3 umol, 13.53 uL). The mixture was stirred at 20 °C for 1 h. The reaction was poured into water (5 mL). The aqueous phase was extracted with EtOAc (15 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate) to give 37b. Calculated MS mass: [M+1] + (C 22 H 17 Cl2N3O5) m / z 474.1, MS mass observed: m / z 474.1.

[0470] 6-(4-amino-2,6-dichlorophenoxy)-4-(2-hydroxypropan-2-yl)-2-methylpyridazin-3(2H)-one (37c) To a mixture of 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (37b) (30 mg, 63.3 umol) in MeOH (1.5 mL) was added n-butylamine (11.6 mg, 158.1 umol, 15.63 uL) under N. The mixture was stirred at 70 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate), and the resulting crude product was repurified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 um; mobile phase: [water (10 mM NHHCO)-MeCN]) to give 37c. 1H NMR (400 MHz, CDCl3)δ 7.20 - 7.08 (m, 1H), 6.75 - 6.62 (m, 2H), 5.68 - 5.51 (m, 1H), 3.85 - 3.71 (m, 2H), 3.63 - 3.50 (m, 3H), 1.62 (s, 6H).

[0471] N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 37) To a mixture of 6-(4-amino-2,6-dichlorophenoxy)-4-(2-hydroxypropan-2-yl)-2-methylpyridazin-3(2H)-one (37c) (10 mg, 29.05 umol) in THF (2 mL) was added TEA (8.82 mg, 87.12 umol, 12.1 uL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (12.9 mg, 87.2 umol) under N2. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150 × 30 mm × 5 um; mobile phase: [water (0.1% TFA)-MeCN]) to give Example 37. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O6) m / z 456.0, MS mass observed: m / z 456.0; 1 H NMR (400 MHz, CD3OD)δ 7.96 - 7.88(m, 2H), 7.60 - 7.52(m, 1H), 4.46 - 4.37(m, 1H), 3.68 - 3.59(m, 1H), 3.53 - 3.47(m, 1H), 3.50 - 3.47(m, 1H), 3.49(s, 1H), 1.94 - 1.84(m, 1H), 1.66 - 1.54(m, 6H).

[0472] Biological Example: Biological Screening Example B1: Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay for thyroid hormone receptor agonist screening The LanthaScreen™ TR-FRET Thyroid Receptor Alpha Coactivator Assay Kit (ThermoFisher) and the LanthaScreen™ TR-FRET Thyroid Receptor Beta Coactivator Assay Kit (ThermoFisher) were used for agonist compound screening. Compounds in DMSO were serially diluted 10-point, 3-fold, twice into a 384-well plate (5 μM final highest concentration) using an ECHO Liquid Handler (Labcyte Inc.). Buffer C (ThermoFisher) was added to each well before a 4-fold mix of fluorescein-SCR2-2 coactivator (final concentration 200 nM), terbium-labeled anti-GST antibody (final concentration 2 nM), and TR alpha-LBD (final concentration 0.4 nM) or TR beta-LBD (final concentration 1.0 nM). After 2 hours of incubation at room temperature in the dark, TR-FRET signals were measured on an EnVision plate reader (PerkinElmer) with excitation at 340 nm and dual emission readings at 495 and 520 nm with a 100-microsecond delay and 200-microsecond integration time. EC values ​​were calculated using GraphPad Prism (GraphPad Software) using the ratio of the emission signals at 520 and 495 nm. 50 was calculated. In all batches of compound screening, T3 (L-3,3',5-triiodothyronine sodium salt, >95%) (Calbiochem) was used as the reference compound. The measured EC 50 was within 3-fold of the reference value provided by the assay kit manufacturer (ThermoFisher Scientific). Z' factors measured for all batches of screening using T3 as the high percent effect (HPE) control and 0.5% DMSO as the zero percent effect (ZPE) control ranged from 0.5 to 0.8. THR-beta selectivity values ​​f...

Claims

1. Formula (I): 【Chemistry 1】 (I) [In the formula, Ring A having a carbonyl (keto) group in the ring forms a 5-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle contains 1 to 2 C 1 -C 3 Alkyl group or C 3 -C 4 a cycloalkyl group, optionally substituted, where a carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 is C optionally substituted with 1 to 5 halo or hydroxyl groups; 1 -C 4 Alkyl, C 3 -C 5 Cycloalkyl, CON(R 10 ) 2 , or N.R. 10 COR 10 is; R 2 is H or C 1 -C 3 is alkyl; L is O, CH 2 , S, SO, SO 2 , CO, CHF, CF 2 , C(R 11 )CN, CHR 11 , or C(R 11 )R 11 is; R 3 and R 4 is independently Cl, Br, methyl, or ethyl; R 5 H, halo, C 1 -C 4 Alkyl, or C 3 -C 4 is cycloalkyl; Or R 5 is R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; X is Absent, O, NR 12 , C(O)NR 12 , N.R. 12 C(O), CR 12 R 12 , OCR 12 R 12 , C.R. 12 R 12 O, N.R. 12 CR 12 R 12 , C.R. 12 R 12 NR 12 , S.O. 2 NR 12 , or N.R. 12 SO 2 is; Each R 10 is independent, C 1 -C 3 is alkyl or H; Each R 11 independently represents 1 to 5 halo, optionally substituted C 1 -C 2 is alkyl, or The Two R's 11 the groups, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl ring; and Each R 12 are independently H or methyl. or a pharma- ceutically acceptable salt thereof.

2. Formula (IIA) or (IIB): 【Chemistry 2】 [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, and L are as defined in claim 1. or a pharma- ceutically acceptable salt thereof.

3. Formula (VD): 【Chemistry 3】 (VD) [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 has the same meaning as in claim 1. or a pharma- ceutically acceptable salt thereof.

4. R 1 is optionally substituted with 1 to 2 halo or hydroxyl groups; 1 -C 4 Alkyl or C 3 -C 5 4. The compound of claim 1, wherein the compound is cycloalkyl, or a pharma- ceutically acceptable salt thereof.

5. R 1 However, isopropyl, t-butyl, HO-CH(CH 3 )-, HO-CH(CH 2 CH 3 )-, HO-C(CH 3 ) 2 -,HO-CH 2 CH(CH 3 )-, cyclopropyl, or 【Chemistry 4】 5. The compound of claim 4, which is: or a pharma- ceutically acceptable salt thereof.

6. R 2 is H or -CH 3 6. The compound according to any one of claims 1 to 5, which is: or a pharma- ceutically acceptable salt thereof.

7. R 3 But chloro or -CH 3 7. The compound according to any one of claims 1 to 6, which is: or a pharma- ceutically acceptable salt thereof.

8. R 4 But chloro or -CH 3 or R 5 But R 4 and together with the intervening atoms form a 5-6 membered cycloalkyl, or a pharma- ceutically acceptable salt thereof.

9. R 5 But R 4 and together with the intervening atoms form cyclopentyl, or a pharma- ceutically acceptable salt thereof.

10. R 5 The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein is H or fluoro.

11. 11. The compound according to any one of claims 1, 2 and 4 to 10, or a pharma- ceutically acceptable salt thereof, wherein X is a bond.

12. X is NR 12 C(O), OCR 12 R 12 , or N.R. 12 CR 12 R 12 and each R 12 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is independently H or methyl.

13. X is -OCH 2 -, -NHCH 2 -, -NHC(O)-, -N(CH 3 )CH 2 - or -N(H)CH(CH 3 13. The compound of claim 12, wherein:

14. L is O, CH 2 , S.O. 2 , C.O., C.H.R. 11 , or C(R 11 )R 11 and each R 11 is independently methyl or ethyl, or a pharma- ceutically acceptable salt thereof.

15. L is O, CH 2 , S.O. 2 15. The compound of claim 14, wherein:

16. Formula (Ia): 【Chemistry 5】 (Ia) [In the formula, Ring A having a carbonyl (keto) group in the ring forms a 5-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, where the heterocycle contains 1 to 2 C 1 -C 3 Alkyl group or C 3 -C 4 a cycloalkyl group, optionally substituted, where a carbonyl (keto) group is not adjacent to the atom bonded to X; R 1 is C optionally substituted with 1 to 5 halo, preferably fluoro; 1 -C 4 Alkyl; C 3 -C 5 Cycloalkyl, CON(R 10 ) 2 , or N.R. 10 COR 10 where each R 10 is independent, C 1 -C 3 is alkyl or H; R 2 is H or C 1 -C 3 is alkyl; L is O, CH 2 , S, SO, SO 2 , CO, CHF, CF 2 , C(R 11 )CN, CHR 11 , or C(R 11 )R 11 And each R 11 are independently 1 to 5 halo, preferably fluoro, optionally substituted C 1 -C 2 Alkyl or two R 11 the groups, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl ring; R 3 and R 4 each is independently Cl, Br, methyl, or ethyl; R 5 H, halo, C 1 -C 4 Alkyl, or C 3 -C 4 cycloalkyl or R 5 is R 4 and together with the intervening atoms form a 5- to 7-membered cycloalkyl or a 5- to 7-membered heterocycle containing 1 to 2 heteroatoms; X is absent (i.e., X is a bond), or is O, NR 12 , C(O)NR 12 , N.R. 12 C(O), CR 12 R 12 , OCR 12 R 12 , C.R. 12 R 12 O, N.R. 12 CR 12 R 12 , C.R. 12 R 12 NR 12 , S.O. 2 NR 12 , N.R. 12 SO 2 where each R 12 are independently H or methyl. or a tautomer or N-oxide thereof, or each isotopomer thereof, or each prodrug of the above, or a stereoisomer of the above, or each pharma- ceutically acceptable salt of the above, or each solvate of the above.

17. A compound selected from the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

19. A method of agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition according to claim 18.

20. A method of treating a disorder mediated by THR beta in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to claim 18.

21. 21. The method of claim 20, wherein the disorder is nonalcoholic steatohepatitis (NASH).

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