Thyroid hormone receptor beta agonist compounds

Abstract

To provide a selective agonist for thyroid hormone receptor beta.SOLUTION: The present invention provides a compound represented by the following formula, or a pharmaceutically acceptable salt thereof. (R1: C1-C6 alkyl, C3-C6 cycloalkyl or the like. R2: H, C1-C6 alkyl, C3-C6 cycloalkyl or the like. R3: H, halo. R4: H, CH3. L: O, S, S(O) or the like. M1, M2: halo, OH, CN or the like. M3: H, halo, OH or the like).SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 745,195, filed October 12, 2018, the entire disclosure of which is incorporated herein by reference for all purposes. Technical Field Provided herein are compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, methods for their preparation, and methods for agonizing THR beta, as well as methods for treating disorders that benefit from THR beta agonism. [Background technology]

[0002] Beneficial effects resulting from treating patients with hyperthyroidism or hypothyroidism with T3 / T4 endogenous ligands or early analogs of these endogenous ligands have been described in the literature (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 the side effects of both hyperthyroidism and hypothyroidism (Klein, I. et al., Circulation, 2007, 1725-1735). In particular, tachycardia, hypertrophy, atrial arrhythmias, and atrial fibrillation are serious problems. In addition, it has been noted that increased bone turnover leads to decreased bone mineral density. The negative effects at both cardiac and bone sites are associated with agonism of the THR alpha isoform, whereas the 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] THR beta-related diseases or disorders include non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.For example, there is a need to develop novel thyroid hormone analogs that are selective agonists of THR beta, particularly for treating patients with non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia, preferably avoiding the undesirable effects associated with the agonism of THR alpha and maintaining the beneficial effects of thyroid hormone for treatment. [Means for solving the problem]

[0004] SUMMARY OF THE PRESENT APPLICATION In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) [In the formula, R1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo; R2 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R3 is H or halo; R4 is H or a substituted or unsubstituted straight chain C1-C3 alkyl; L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halo, -CN, or substituted or unsubstituted C1-C6 alkyl, or R5 and R6 together with the carbon atom to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; R7 and R8 are independently H, or a substituted or unsubstituted C1-C6 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 7-membered heterocycloalkyl; R9 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 10 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8), or -O(R 11 ) is; R 11 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl; M1 and M2 are independently halo, or substituted or unsubstituted C1-C6 alkyl; and M3 is H, halo, or substituted or unsubstituted C1-C6 alkyl, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharma- ceutically acceptable salt thereof: During the ceremony, R1 is C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo; R2 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R3 is H or halo; R4 is H or a straight chain C1-C3 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl); L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halo, -CN, or C1-C6 alkyl, or R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, where each C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -OH, -CN, and halo; R7 and R8 are independently H or C1-C6 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl, where each C1-C6 alkyl or 3-7 membered heterocycloalkyl is optionally independently substituted with 1-5 substituents selected from the group consisting of -OH, -CN, and halo; R9 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 10 is C1-C6 alkyl, C3-C6 cycloalkyl, -N(R7)(R8), or -O(R 11 ), wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 11 is C1-C6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; M1 and M2 are independently halo, or C1-C6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; and M3 is H, halo, or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, -CN, and halo, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0006] In some embodiments, R1 is C1-C6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is cyclopropyl, isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0007] In some embodiments, R2 is H or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, R2 is H or methyl.

[0008] In some embodiments, R3 is H.

[0009] In some embodiments, R4 is H or a straight chain C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is H, methyl, ethyl, -CH2C(O)O(CH2CH3), -CH2CF3, -CH2CN, or -CH2CHF2.

[0010] In some embodiments, L is -O-, -C(O)-, or -CH2-.

[0011] In some embodiments, M1 and M2 are independently halo or C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, M1 and M2 are independently halo or methyl. In some embodiments, M1 and M2 are each chloro. In some embodiments, M1 and M2 are each methyl.

[0012] In some embodiments, M3 is H, halo, or C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, M3 is H, F, or methyl.

[0013] In some embodiments, the present disclosure provides compounds 1-3 and 5-35, or a pharma- ceutically acceptable salt thereof.

[0014] Further provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0015] In another aspect, the present disclosure provides a method of agonizing thyroid hormone beta (THR beta), comprising contacting THR beta with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a compound described herein.

[0016] In another aspect, there is provided a method for treating a disorder mediated by THR beta in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a compound described herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description of the Invention definition As used herein, the following definitions shall 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.

[0018] "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 will 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 components recited, and substantial method steps. Embodiments defined by any of these connecting phrases are within the scope of the present invention. Thus, aspects and embodiments described herein as "comprising" are understood to include "consisting of" and "consisting essentially of" embodiments.

[0019] An "effective amount" or dose of a compound or composition means that amount of the compound, or a pharma- ceutically acceptable salt thereof, 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 dose (lethal for 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).

[0020] The term "excipient" as used herein 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 present 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 flavorings, suspending / gelling agents, or wet granulation agents. Binders include, for example, carbopol, povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, and the like; 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, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, maltodextrin, enteric coatings, and the like. lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

[0021] "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.

[0022] By "pharmaceutically acceptable" is meant preferably safe and non-toxic in vivo, and more preferably for human administration.

[0023] "Pharmaceutically acceptable salt" means a salt that is pharma-ceutically acceptable. The compounds described herein can be administered as a pharma-ceutically acceptable salt.

[0024] "Prodrug" refers to a compound that, after administration, is metabolized or otherwise converted into a biologically active or more active compound (or drug) with respect to 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 generated by metabolism or other biological processes after the prodrug is administered. A prodrug may have altered metabolic stability or transport properties, reduced side effects or toxicity, improved flavor, compared to an active drug (see, for example, reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may 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.

[0025] "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 nitrogen bases and alkylated nitrogen bases. Exemplary and 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, phosphoric acid, and the like. Exemplary and 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.

[0026] A "therapeutically effective amount" or dose of a compound or composition means that amount of the compound or composition that results in the alleviation or inhibition of symptoms or prolongation of survival in a patient. The result may require multiple administrations of the compound or composition.

[0027] As used herein, "treating" or "treatment" is an approach to obtain 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 a disease or disorder, reducing the severity of a disease or disorder, stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder), delaying the onset or recurrence of a disease or disorder, delaying or slowing the progression of a disease or disorder, improving the condition of a disease or disorder, providing remission (partial or total) of a disease or disorder, reducing the dosage of one or more other drugs required to treat a disease or disorder, enhancing the effectiveness of another drug used to treat a disease or disorder, slowing the progression of a disease or disorder, improving the quality of life, and / or prolonging the survival of a patient. "Treatment" also includes reducing the pathological consequences of a disease or disorder. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0028] An "isotopomer" of a compound is a compound in which one or more atoms of the compound are replaced by isotopes 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) scanning. 14 N 15 Substituting N, 15This results in a compound that can be detected / monitored by NNMR spectroscopy. For example, an isotopomer of a compound that contains -CH2CH3 would be that compound but with -CD2CD3 instead of -CH2CH3.

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

[0030] "Tautomer" means alternative forms of a compound which differ in the location of a proton, such as enol-keto and imine-enamine tautomers, tautomeric forms of heteroaryl groups which contain ring atoms bonded 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. The 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 straight-chain or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, and preferably from 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. x Alkenyl means an alkenyl group having x carbon atoms.

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

[0034] "Substituted alkyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, 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, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0035] "Substituted alkenyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkylamino ...

[0036] In the present invention, the term "alkyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of alkyloxy, 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, SOH, 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" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl ... 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, SOH, 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, and the like.

[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 alkoxy, alkynyl, substituted 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 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 at least one of R is not hydrogen, and where 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 be referred to as 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 or R is hydrogen, but not both. 31 or R 32 This 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 -SONR 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-SONR 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)-one-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, substituted heterocyclylaminocarboxyl, carboxyl ester, (carboxyl ester)amino ...

[0046] In the present invention, the aryl group is substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of aryl, aryloxy, 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, SOH, 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" means 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" means 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 a divalent radical: -C(O)-, which is synonymous with -C(=O)-.

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

[0063]

[0043] "Carboxyl 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-heterocyclic, and -C(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0064] "(Carboxyl ester)amino" is -NR 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O-substituted alkenyl, -NR 30 -C(O)O-alkynyl, -NR 30 -C(O)O-substituted alkynyl, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O-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 -C(O)O-substituted heterocyclic group, where R 30 is 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] "(Carboxyl 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)O--substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0066] "Cyano" 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, ...

[0046] In the present invention, the cycloalkyl group has 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, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0068] "Cycloalkyloxy" means -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, where substituted cycloalkyl is as defined herein.

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

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

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

[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 are optionally taken together with the nitrogen to which they are attached to 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" means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

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

[0078] "Heteroalkylene" means that one or more carbons are -O-, -S-, SO2, -NR Q -, [ka] means an alkylene group replaced by a moiety, where R Q is H or C1-C6 alkyl. "Substituted heteroalkylene" means a heteroalkynylene group having from 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 1-10 carbon atoms in the ring and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. 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] "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" means -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 "heterocyclic" 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, 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, 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 that is substituted with 1 to 5 or preferably 1 to 3 substituents, the same substituents defined for substituted cycloalkyl.

[0089] "Substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" means a heterocyclyl group that is 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, where 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, naphthyloxydinyl, pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isothiazolyl, phenazinyl, isoxazyl, phenyl ... 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 radical --NO2.

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

[0099] "Spiro ring system" means a bicyclic ring system having a single ring carbon atom common to both rings.

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

[0101] "Sulfonyl" means a 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-heterocycle, -SO2-substituted heterocycle 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. 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 especially halogenated methyl groups such as trifluoromethyl, difluoromethyl, 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, and the like.

[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-heterocycle, -OSO2-substituted heterocycle group, 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.

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

[0106] "Thioacyl" means the 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)- 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.

[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" means 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.dbd.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 occur. 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 wherein 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 substituted group (e.g., an alkyl group in "substituted alkyl") can be substituted with one or more substituents, such as, for example, 1, 2, 3, 4 or 5 substituents, which can be the same or different. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituents are oxo, halo, -CN, NO2, -CO2R1 00 , -OR1 00 , -SR100 , -SOR1 00 , -SO2R1 00 , -NR1 01 R1 02 , -CONR1 01 R1 02 , -SO2NR1 01 R1 02 , C1-C6 alkyl, C1-C6 alkoxy, -CR1 00 =C(R1 00 )2, -CCR1 00 , C3-C 10 Cycloalkyl, C4-C 10 Heterocyclyl, C6-C 14 Aryl and C5-C 12 heteroaryl, where each R is independently selected from 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 1-3 halo, 1-3 C1-C6 alkyl, 1-3 C1-C6 haloalkyl, or 1-3 C1-C6 alkoxy groups. More preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, iso-propyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0116] R1 01 and R1 02 are independently hydrogen; C1-C8 alkyl, C1-C6 alkoxy, oxo, -CR1 optionally substituted with -CO2H or its ester. 03 =C(R1 03 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 14 Aryl, or C2-C 12 heteroarylC1-C8 alkyl, where each R1 03 are independently hydrogen or C1-C8 alkyl; C3-C12 Cycloalkyl;C4-C 10 Heterocyclyl;C6-C 14 Aryl; or C2-C 12 and heteroaryl; where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R1 01 and R1 02 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle.

[0117] Unless otherwise stated, the nomenclature of substituents not explicitly defined herein is derived 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] In all of the above defined substituents, it is understood that polymers arrived at by defining the substituents themselves with further substituents (such as substituted aryls having substituted aryl groups as substituents themselves substituted with substituted aryl groups) are not intended to be included herein. In such cases, the maximum number of such substituents is 3. That is, each of the above definitions is constrained by the restriction that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0119] In some embodiments of substituted moieties, the moiety is substituted with a group that may be substituted with an additional group, but the additional group cannot be further substituted. For example, in some embodiments of "substituted alkyl," the alkyl moiety is substituted with a group which may be further substituted (e.g., substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, substituted alkylthio), but a substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio on the alkyl moiety is not substituted with a moiety which is itself further substituted. "Substituted alkyl" is provided as an example, but such embodiment contemplates each of the substituted moieties described herein.

[0120] In some embodiments of substituted moieties, the moiety is substituted with a group that is not further substituted. Thus, in some embodiments, a "substituted alkyl" is an alkyl moiety substituted with one or more moieties, and in some embodiments 1 or 2 or 3 or 4 or 5 moieties independently selected from the group consisting of alkoxy, acyl, acylamino, acyloxy, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SOH, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio. "Substituted alkyl" is provided as an example, but such embodiment contemplates each of the substituted moieties described herein.

[0121] 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.

[0122] It is understood that certain features of the invention that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity 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.

[0123] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) [In the formula, R1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo; R2 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R3 is H or halo; R4 is H or a substituted or unsubstituted straight chain C1-C3 alkyl; L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halo, -CN, or substituted or unsubstituted C1-C6 alkyl, or R5 and R6 together with the carbon atom to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; R7 and R8 are independently H, or a substituted or unsubstituted C1-C6 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 7-membered heterocycloalkyl; R9 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 10 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8), or -O(R 11 ) is; R 11 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl; M1 and M2 are independently halo, or substituted or unsubstituted C1-C6 alkyl; and M3 is H, halo, or substituted or unsubstituted C1-C6 alkyl, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharma- ceutically acceptable salt thereof: During the ceremony, R1 is C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo; R2 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R3 is H or halo; R4 is H or a straight chain C1-C3 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl); L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halo, -CN, or C1-C6 alkyl, or R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, where each C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -OH, -CN, and halo; R7 and R8 are independently H or C1-C6 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl, where each C1-C6 alkyl or 3-7 membered heterocycloalkyl is optionally independently substituted with 1-5 substituents selected from the group consisting of -OH, -CN, and halo; R9 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 10 is C1-C6 alkyl, C3-C6 cycloalkyl, -N(R7)(R8), or -O(R 11 ), wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 11is C1-C6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; M1 and M2 are independently halo, or C1-C6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; and M3 is H, halo, or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, -CN, and halo, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0125] In some embodiments, R1 is C1-C6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is cyclopropyl, isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0126] In some embodiments, R1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with 1-4 halogen atoms. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with 1-4 chloro or fluoro atoms. In some embodiments, R1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. In some embodiments, R1 is a substituted or unsubstituted C3-C6 alkyl, such as an unsubstituted C3-C6 alkyl, which in one embodiment is a dC3-C6 alkyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is a substituted or unsubstituted C1-C3 alkyl, such as an unsubstituted C1-C3 alkyl, which in one embodiment is a straight chain C1-C3 alkyl. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with 1-2 -OH groups. In some embodiments, R1 is a C1-C6 alkyl optionally substituted with one -OH group, such as -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), or -CH(OH)(CH3). In some embodiments, R1 is a C1-C6 alkyl optionally substituted with one oxo group. In some embodiments, R1 is a C1-C6 alkyl substituted with one oxo group, such as -C(O)(CH3). In some embodiments, R1 is an unsubstituted C1-C6 alkyl, such as methyl, ethyl, isopropyl, -CH(CH2CH3)2, or -CH(CH3)(CH2CH3). In some embodiments, R1 is isopropyl, ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3).

[0127] In some embodiments, R1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1-4 halogen atoms and / or 1-4 C1-C6 alkyl groups. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1-4 chloro or fluoro atoms. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1-4 C1-C6 alkyl groups. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl, ethyl, or propyl groups. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is an unsubstituted C3-C6 cycloalkyl.

[0128] In some embodiments, R1 is halo. In some embodiments, R1 is fluoro, chloro, bromo, or iodo. In some embodiments, R1 is fluoro or chloro. In some embodiments, R1 is chloro.

[0129] In some embodiments, R1 is -C(O)N(R7)(R8). In some embodiments, R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 and R8 are each H. In some embodiments, R7 is H and R8 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 is H and R8 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 and R8 are independently substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 and R8 are independently methyl, ethyl, propyl, isopropyl, or butyl. In any of these variations where R7 and / or R8 are C1-C6 alkyl, the C1-C6 alkyl group is optionally substituted with 1-4 halogen atoms. In some embodiments, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl optionally substituted with 1-4 halogen atoms and / or 1-4 C1-C6 alkyl groups. 7 and R 8 together with the nitrogen atom to which they are attached form a 3-5 membered heterocycloalkyl optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0130] In some embodiments, R1 is -N(R9)C(O)(R 10 ). In some embodiments, R9 is H. In some embodiments, R9 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R9 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R9 is substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R9 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 10 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R10 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 10 is a substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 10 R and / or R are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 10 In any of these variations where R is C1-C6 alkyl, the C1-C6 alkyl group is optionally substituted with 1 to 4 halogen atoms. 10 In any of these variations where R is C3-C6 alkyl, the C3-C6 cycloalkyl group is optionally substituted with 1-4 halogen atoms and / or 1-4 C1-C6 alkyl groups. In some embodiments, R is H and R 10 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R9 is H and R 10 In some embodiments, R is substituted or unsubstituted C-C alkyl and R 10 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R9 and R 10 are each methyl.

[0131] R1 is -N(R9)C(O)(R 10 In some embodiments, R 10is -N(R7)(R8). In some embodiments, R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 and R8 are each H. In some embodiments, R7 is H and R8 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 is H and R8 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 and R8 are independently substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 and R8 are independently methyl, ethyl, propyl, isopropyl, or butyl. In any of these variations where R7 and / or R8 are C1-C6 alkyl, the C1-C6 alkyl group is optionally substituted with 1 to 4 halogen atoms. In some embodiments, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl optionally substituted with 1-4 halogen atoms and / or 1-4 C1-C6 alkyl groups. 7 and R 8 together with the nitrogen atom to which they are attached form a 3-5 membered heterocycloalkyl optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0132] R1 is -N(R9)C(O)(R 10 In some embodiments, R 10 is -O(R 11 In some embodiments, R 11 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 11 is C1-C6 alkyl optionally substituted with 1 to 4 halogen atoms. In some embodiments, R 11 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 11 is a substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 11is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 11 is a C3-C6 cycloalkyl optionally substituted with 1 to 4 halogen atoms and / or 1 to 4 C1-C6 alkyl groups.

[0133] In some embodiments, R2 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, where C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, R2 is H, or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, R2 is H or methyl.

[0134] In some embodiments, R2 is H. In some embodiments, R2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-4 halogen atoms. In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1 or 2 chloro or fluoro atoms. In some embodiments, R2 is methyl, ethyl, propyl, isopropyl, butyl, or pentyl. In some embodiments, R2 is methyl. In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, R2 is an unsubstituted C1-C6 alkyl.

[0135] In some embodiments, R3 is H. In some embodiments, R3 is halo. In some embodiments, R3 is fluoro, chloro, bromo, or iodo. In some embodiments, R3 is fluoro or chloro.

[0136] In some embodiments, R4 is H or a straight chain C1-C3 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is H or a straight chain C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is H, methyl, ethyl, -CH2C(O)OCH2CH3, -CH2CF3, -CH2CN, or -CH2CHF2.

[0137] In some embodiments, R4 is H.

[0138] In some embodiments, R4 is a substituted or unsubstituted linear C1-C3 alkyl. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-4 halogen atoms and / or 1-4 hydroxyl groups. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-2 halogen atoms and / or 1-2 hydroxyl groups. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1 or 2 chloro or fluoro atoms. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1 or 2 hydroxyl groups. In some embodiments, R4 is a substituted or unsubstituted linear C1-C2 alkyl. In some embodiments, R4 is a linear C1-C2 alkyl optionally substituted with 1-2 halogen atoms and / or 1-2 hydroxyl groups. In some embodiments, R4 is an unsubstituted linear C1-C3 alkyl. In some embodiments, R4 is an unsubstituted linear C1-C2 alkyl. In some embodiments, R4 is methyl, ethyl, or propyl. In some embodiments, R4 is methyl. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-3 halo groups, such as chloro or fluoro. In some embodiments, R4 is a linear C1-C3 alkyl optionally substituted with 1-3 fluoro groups. In some embodiments, R4 is -CF3, -CH2CF3, or -CH2CHF2. In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with one oxo group. In some embodiments, R4 is -CH2C(O)CH3, -C(O)CH2CH3, or -C(O)CH3.In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with one -O(C1-C2 alkyl). In some embodiments, R4 is -CH2OCH3, -CH2OCH2CH3, or -CH2CHOCH3. In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with one oxo group and one -O(C1-C2 alkyl) group. In some embodiments, R4 is -CH2C(O)OCH3, -C(O)OCH3, or -C(O)OCH2CH3. In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with one to two cyano groups. In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with one cyano group. In some embodiments, R4 is -CH2CN or -CH2CH2CN. It will be understood that when R4 is a straight chain C1-C3 alkyl optionally substituted with carbon-containing moieties such as -CN and -O(C1-C2 alkyl), the total number of carbon atoms in R4 is greater than 3. In some embodiments, R4 is -CH2CH2CH2CN. In some embodiments, R4 is -CH2C(O)OCH2CH3, -CH2CH2C(O)OCH2CH3, or -CH2CH2C(O)OCH3. In some embodiments, R4 is methyl, ethyl, -CH2C(O)OCH2CH3, -CH2CF3, -CH2CN, or -CH2CHF2.

[0139] In some embodiments, L is -O- or -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -C(O)-. In some embodiments, L is -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -C(R5)(R6)-. In some embodiments, R5 and R6 are independently H, halo, -CN, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R5 and R6 are each H. In some embodiments, R5 and R6 are independently C1-C6 alkyl optionally substituted with 1-4 halogen atoms. In some embodiments, R5 is H and R6 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R5 and R6, together with the carbon atom to which they are attached, form a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 1-4 halogen atoms and / or 1-4 C1-C6 alkyl groups. In some embodiments, L is -O-, -C(O)-, or -CH2-.

[0140] In some embodiments, M1 and M2 are independently halo or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, M1 and M2 are independently halo or methyl. In some embodiments, M1 and M2 are each chloro. In some embodiments, M1 and M2 are each methyl.

[0141] In some embodiments, M1 and M2 are independently halo or substituted or unsubstituted C1-C6 alkyl. In some embodiments, M1 and M2 are independently halo. In some embodiments, M1 and M2 are independently fluoro, chloro, bromo, or iodo. In some embodiments, M1 and M2 are independently fluoro or chloro. In some embodiments, M1 and M2 are each chloro. In some variations, at least one of M1 and M2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, at least one of M1 and M2 is a C1-C6 alkyl optionally substituted with 1-4 halogen atoms. In some embodiments, at least one of M1 and M2 is a C1-C6 alkyl optionally substituted with 1 or 2 halogen atoms. In some embodiments, at least one of M1 and M2 is a C1-C4 alkyl optionally substituted with 1 or 2 fluoro or chloro atoms. In some embodiments, M1 and M2 are independently C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, M1 and M2 are independently C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, M1 and M2 are independently unsubstituted C1-C6 alkyl. In some embodiments, M1 and M2 are independently unsubstituted C1-C3 alkyl. In some embodiments, M1 and M2 are each methyl. In some embodiments, M1 and M2 are the same. In other embodiments, M1 and M2 are different. In some embodiments, M1 is methyl and M2 is ethyl. In some embodiments, M1 is ethyl and M2 is methyl. In some embodiments, M1 is methyl and M2 is chloro. In some embodiments, M1 is chloro and M2 is methyl.

[0142] In some embodiments, M3 is H, halo, or C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, -CN, and halo, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3 is H, halo, or C1-C3 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, M3 is H, F, or methyl.

[0143] In some embodiments, M3 is H, halo, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, M3 is H. In some embodiments, M3 is halo. In some embodiments, M3 is fluoro, chloro, bromo, or iodo. In some embodiments, M3 is fluoro. In some embodiments, M3 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, M3 is C1-C6 optionally substituted with 1-4 halogen atoms. In some embodiments, M3 is C1-C6 optionally substituted with 1 or 2 fluoro or chloro atoms. In some embodiments, M3 is methyl, ethyl, propyl, isopropyl, butyl, or pentyl. In some embodiments, M3 is methyl. In some embodiments, M3 is C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, CN, and halo. In some embodiments, M3 is C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of -OH, -CN, and halo. In some embodiments, M3 is -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CF3, -CHF2, -CH2F, -CCl3, or -CHCl2. In some embodiments, M3 is unsubstituted C1-C6 alkyl.

[0144] In some embodiments, M3, together with M2 and the carbon atom to which they are attached, forms a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3, together with M2 and the carbon atom to which they are attached, forms a 5-7 membered ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3, together with M2 and the carbon atom to which they are attached, forms a 5-7 membered ring containing 1 or 2 heteroatoms selected from the group consisting of N and O. In some embodiments, M3, together with M2 and the carbon atom to which they are attached, forms a 5-7 membered ring containing 1 heteroatom selected from the group consisting of N and O. In some embodiments, M3, together with M2 and the carbon atom to which they are attached, forms a saturated 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3 together with M2 and the carbon atom to which they are attached form a partially saturated 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, M3 together with M2 and the carbon atom to which they are attached form an aromatic 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0145] When present, all variations of L described for formula (I) are intended to be combined with R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R 10 , R 11It is intended and understood that each variable described for formula (I) can be combined with all variations of M1, M2, and M3. Similarly, it is intended and understood that each variable described for formula (I) can be combined with all variables described for formulas (Ia), (Ib), (Ic), and (Id) below, as if every combination was specifically and individually described. Furthermore, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein as if each such subcombination of chemical groups was individually and explicitly disclosed herein.

[0146] In some embodiments, the compound of Formula (I) has the formula (Ia): [ka] (Ia) or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined for compounds of formula (I). In some embodiments, R1 is C1-C3 alkyl or C3-C5 cycloalkyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, and halo. In some embodiments, R1 is ethyl, -CH(CH2CH3)2, -CH(CH3)(CH2OH), -CH(OH)(CH2CH3), -CH(OH)(CH3), -CH(CH3)(CH2CH3), or -C(O)(CH3). In some embodiments, R2 is H or C1-C3 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or a straight chain C1-C3 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, R4 is a straight chain C1-C3 alkyl optionally substituted with 1-5 substituents selected from the group consisting of -OH, oxo, -CN, halo, and -O(C1-C2 alkyl). In some embodiments, R4 is ethyl, -CH2C(O)O(CH2CH3), -CH2CF3, -CH2CN, or -CH2CHF2. In some embodiments, M3 is H or a C1-C3 alkyl. In some embodiments, M3 is H. In some embodiments, M3 is methyl. In some embodiments, M3 is halo. In some embodiments, M3 is F.

[0147] In some embodiments, the compound of Formula (I) has the formula (Ib): [ka] (Ib) or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined for compounds of formula (I). In some embodiments, R1 is C1-C3 alkyl. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or C1-C3 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or straight chain C1-C3 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or C1-C3 alkyl. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0148] In some embodiments, the compound of Formula (I) has the formula (Ic): [ka] (I C) or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined for compounds of formula (I). In some embodiments, R1 is C1-C3 alkyl. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or C1-C3 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or straight chain C1-C3 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or C1-C3 alkyl. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0149] In some embodiments, the compound of Formula (I) has the formula (Id): [ka] (Id) or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R4, and M3 are as defined for compounds of formula (I). In some embodiments, R1 is C1-C3 alkyl. In some embodiments, R1 is isopropyl. In some embodiments, R2 is H or C1-C3 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is methyl. In some embodiments, R4 is H or straight chain C1-C3 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is methyl. In some embodiments, M3 is H or C1-C3 alkyl. In some embodiments, M3 is H. In some embodiments, M3 is methyl.

[0150] In some embodiments, the compounds of formula (I) are agonists of THR beta. In some embodiments, the compounds of formula (I) are agonists of THR beta and are more selective than THR alpha. In some embodiments, the compounds of formula (I) have at least 2-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 5-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 10-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 20-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 50-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 75-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have at least 100-fold selectivity for THR beta over THR alpha. In some embodiments, the compounds of formula (I) have 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 selectivity for THR beta over 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.

[0151] In one embodiment, the present disclosure provides a compound selected from the compounds summarized in Table 1 below, or a pharma- ceutically acceptable salt thereof: Table 1 [Table 1] [Table 2] [Table 3] [Table 4]

[0152] ×Compound 4 is not within the scope of Formula (I) and is provided for comparative purposes only. ××The biological data set forth in Table 2 for compounds to which stereochemistry has been arbitrarily assigned in Table 1 can be related to the appropriate compounds in Table 1 by reference to the details of the corresponding synthetic examples. Thus, compounds associated with a given chiral chromatographic elution pattern and biological data set may have the same or different absolute stereochemistry as compounds to which stereochemistry has been arbitrarily assigned in Table 1.

[0153] In some embodiments, the compound of formula (I) is selected from compounds 1-3 and 5-35, or a pharma- ceutically acceptable salt thereof.

[0154] In some embodiments, the present disclosure provides the following: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0155] The present invention also includes all salts, such as pharma- ceutically acceptable salts, of the compounds referred to herein. The present invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms, as well as any tautomeric or other forms, such as N-oxides, solvates, prodrugs, or isotopomers of the compounds described. 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 are also included in the present invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising the compounds of the present invention, such as compositions of substantially pure compounds comprising a specific stereochemical form thereof, are also contemplated. Compositions comprising 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 scalemic mixtures of the compounds, are also included in the present invention.

[0156] Synthesis: General scheme Schemes S1-S8 below show synthetic routes for preparing compounds of the present disclosure. Unless otherwise specified, in each of Schemes S1-S8, the variables R1, R2, R3, R4, M1, M2, and M3 are as defined for compounds of formula (I); the additional variables V, T, and W (where EWG is a suitable electron-withdrawing group) are as defined in the particular scheme; and the variable R is a suitable boronic ester protecting group, such as H or alkyl.

[0157] Scheme S1 shows a general synthesis of compounds of formula (I) where L is O or S.

[0158] Scheme S1: [ka] [ka]

[0159] Scheme S2 outlines a general synthesis of compounds of Formula (I) where L is -C(O)-.

[0160] Scheme S2: [ka] [ka]

[0161] Scheme S3 shows a general synthesis of compounds of Formula (I) where L is -CH2-.

[0162] Scheme S3: [ka]

[0163] Scheme S4 ​​shows a general synthesis of compounds of Formula (I) where L is -S(O)- or -S(O)2-.

[0164] Scheme S4: [ka]

[0165] Scheme S5 shows a general synthesis of compounds of Formula (I) where L is -CHF-.

[0166] Scheme S5: [ka]

[0167] Scheme S6 shows a general synthesis of compounds of Formula (I) where L is -CF2-.

[0168] Scheme S6: [ka]

[0169] Scheme S7 outlines a general synthesis of compounds of Formula (I) where L is -CH(CH3)-.

[0170] Scheme S7: [ka]

[0171] Scheme S8 shows a general synthesis of compounds of formula (I) where L is [ka] It is.

[0172] Scheme S8: [ka]

[0173] The synthesis of certain compounds provided herein is outlined above and provided in the Examples section below. The synthesis of other compounds provided herein will be apparent to one of skill in the art based on the guidance provided herein and on synthetic methods known to those of skill in the art.

[0174] If it is desired to obtain a particular 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, for example a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, for example, crystallization, and the desired enantiomer is recovered. In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described, if necessary.

[0175] 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.

[0176] Solvates and / or polymorphs of the compounds provided herein, and their pharma- ceutically acceptable salts, 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 crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in the dominance of a single crystal.

[0177] It is understood that the synthetic processes disclosed herein can be modified to arrive at various 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, for example, the formulae of the schemes provided herein contemplate and include compounds in which such reactive or incompatible groups are in appropriately protected form. For a general description of protecting groups and their use, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

[0178] Pharmaceutical Compositions and Formulations Any pharmaceutical composition of the compounds detailed herein is included in the present invention.Thus, the present invention includes pharmaceutical compositions comprising the compounds of the present invention or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or excipients.In one embodiment, the pharmaceutically acceptable salt is an acid addition salt, such as the salt formed with inorganic or 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.

[0179] In one aspect, the compounds detailed herein may be in purified form, and compositions comprising the compounds in purified form are detailed herein. Compositions comprising the compounds detailed herein or salts thereof are provided, such as compositions of substantially pure compounds. 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 having 10% or less impurities, where impurities refer to compounds other than the compound or salts thereof 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 having 10% or less impurities, where impurities refer to compounds other than the compound or salts thereof. In one variation, a composition of a substantially pure compound or salt thereof is provided, where the composition has 5% or less impurities. In another variation, a composition of a substantially pure compound or salt thereof is provided, where the composition has 2% or less impurities. In yet another variation, a composition of a substantially pure compound or salt thereof is provided, where the composition has 1% or less impurities. In a further variation, a composition of a substantially pure compound or salt thereof is provided, where the composition has 0.5% or less impurities. In yet other variations, a composition of a substantially pure compound means that the composition contains 10% or less, preferably 5% or less, more preferably 1% or less, even more preferably 0.5% or less, and most preferably 0.1% or less of an impurity, which may be a compound of a different stereochemical form. For example, and without limitation, a composition of a substantially pure (S) compound means that the composition contains 10% or less, or 5% or less, or 3% or less, or 1% or less, or 0.5% or less of an (R) form of the compound.

[0180] In one variation, the compounds herein are synthetic compounds prepared for administration to a patient, such as a human. In another variation, a pharmaceutical composition is provided that includes the compound in a substantially pure form. In another variation, the present invention encompasses a pharmaceutical composition that includes the compound detailed herein and a pharma- ceutically acceptable carrier or excipient. In another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition, and method of administering the compound are suitable for any compound or form detailed herein.

[0181] 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 suitable carriers to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, troches, 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.

[0182] One or more compounds described herein can be used to prepare formulations such as pharmaceutical preparations by combining a compound or compounds as active ingredients with a pharma- ceutically acceptable carrier as described above. Depending on the treatment form of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. In addition, pharmaceutical preparations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also include other substances with valuable therapeutic properties. Pharmaceutical preparations 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.

[0183] The compounds described herein can be administered to patients (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 are lactose, corn starch or derivatives thereof, talc, stearates or salts thereof, etc. Acceptable carriers for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical preparations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0184] Any of the compounds described herein can be formulated into tablets in any of the dosage forms described.

[0185] Also described herein is a pharmaceutical composition, such as a pharmaceutical composition comprising the compound provided herein or its pharmaceutically acceptable salt.In one variation, the composition comprises the compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.In another variation, a composition of substantially pure compound or its pharmaceutically acceptable salt is provided.

[0186] How to use / treat The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any of the formulas provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient, may be used in the administration and treatment methods provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods in which the compound, or a salt thereof, or composition is administered to a cell for screening purposes and / or to perform quality control assays.

[0187] In one embodiment, the present disclosure 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 a salt thereof, such as a pharma- ceutically acceptable salt, or an effective amount of any of the pharmaceutical compositions provided herein. In one embodiment, the present disclosure provides a method of 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 pharma-ceutically acceptable salt, 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.

[0188] 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 of formula (I), or a pharma- ceutically acceptable salt thereof, that selectively agonizes THR beta over THR alpha.

[0189] In one embodiment, 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 embodiment, 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 embodiment, 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 embodiment, 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 embodiment, 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, the present disclosure provides 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.

[0190] 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.

[0191] 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, in which case 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.

[0192] 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 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 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 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 composition provided herein. In one embodiment, the present disclosure provides a method for slowing 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 embodiment, the present disclosure provides a method for slowing 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.

[0193] In one aspect, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, for use in treatment. In some embodiments, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharma- ceutically acceptable salt thereof, for use in the treatment of non-alcoholic fatty liver disease. In some embodiments, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharma- ceutically acceptable salt thereof, for use in the treatment of non-alcoholic steatohepatitis (NASH). In some embodiments, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutical composition comprising such a compound or a pharma- ceutical acceptable salt thereof, for use in the treatment of metabolic syndrome. In some embodiments, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutical composition comprising such a compound or a pharma- ceutical acceptable salt thereof, for use in the treatment of dyslipidemia. In some embodiments, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharma- ceutically acceptable salt thereof, for use in the treatment of hypercholesterolemia.

[0194] In another embodiment, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease. In another embodiment, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of non-alcoholic steatohepatitis (NASH). In another embodiment, the present disclosure provides a compound of formula (I) or any variant thereof, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of 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.

[0195] 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 years old, or is about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.

[0196] 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.

[0197] The compounds provided herein, or salts thereof, can be administered to an individual via a variety of routes, such as, for example, intravenously, intramuscularly, subcutaneously, orally, or transdermally.

[0198] In one embodiment, an effective amount of a compound may be a dose between about 0.01 and about 100 mg / kg. Effective amounts or doses of compounds of the present disclosure may 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 drug, the severity and course of the disease being treated, the health, physical condition, and weight of the patient. Exemplary doses range from about 0.7 mg to 7 g, or about 7 mg to 350 mg, or about 350 mg to 1.75 g, or about 1.75 to 7 g daily.

[0199] 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 pharma- ceutically acceptable excipient.

[0200] 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 lifetime of the individual. In one variation, the compounds are administered on a daily or intermittent schedule. The compounds can be administered to an individual continuously (e.g., at least once a day) for a period of time. The dosing frequency can also be less than once a day, such as about once a week dosing. The dosing frequency can also be more than once a day, such as twice or three times a day. The dosing frequency can also be intermittent, including "drug holidays" (e.g., 7 days of daily dosing followed by 7 days of no 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 can be used with any of the compounds described herein, along with any of the dosages described herein.

[0201] Products and Kits The present disclosure further provides a product comprising a compound or salt thereof as described herein, a composition as described herein, or one or more unit doses as 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.

[0202] 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 pharma- ceutically acceptable salt thereof, or a composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof.The kit can use any of the compounds disclosed herein.In one variation, the kit uses a compound described herein, or a pharma- ceutically acceptable salt thereof.The kit can be used for any one or more applications described herein, and thus can include instructions for treating any disease, or disease described herein, such as, for example, non-alcoholic steatohepatitis (NASH).

[0203] The kit generally includes suitable packaging. The kit may include one or more containers that include any compound described herein or its pharma-ceutically acceptable salt. Each component (if there are multiple components) can be packaged in separate containers, or some components can be combined in one container, as long as cross-reactivity and shelf life permit.

[0204] The kits may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain a sufficient dose of a compound as disclosed herein, or a pharma- ceutically acceptable salt thereof, and / or additional pharma- ceutical active compounds useful for the diseases detailed herein, to provide effective treatment of an individual for an extended period of time, such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or more. The kits may include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in a pharmacy (such as a hospital pharmacy or a compounding pharmacy).

[0205] 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 in the kit will generally include information regarding the components and their administration to an individual.

[0206] 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.

[0207] Embodiment 1. Formula (I): [ka] (I) [In the formula, R1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo; R2 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R3 is H or halo; R4 is H or a substituted or unsubstituted straight chain C1-C3 alkyl; L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halo, -CN, or substituted or unsubstituted C1-C6 alkyl, or R5 and R6 together with the carbon atom to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; R7 and R8 are independently H, or a substituted or unsubstituted C1-C6 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 7-membered heterocycloalkyl; R9 is H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 10 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8), or -O(R 11 ) is; R 11 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl; M1 and M2 are independently halo, or substituted or unsubstituted C1-C6 alkyl; and M3 is H, halo, or substituted or unsubstituted C1-C6 alkyl, or M3 together with M2 and the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. or a pharma- ceutically acceptable salt thereof.

[0208] Embodiment 2. The compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0209] Embodiment 3. The compound of embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein R1 is isopropyl.

[0210] Embodiment 4. A compound of embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein R1 is cyclopropyl.

[0211] Embodiment 5. The compound of any one of embodiments 1-4, or a pharma- ceutically acceptable salt thereof, wherein R2 is substituted or unsubstituted C1-C6 alkyl.

[0212] Embodiment 6. A compound of embodiment 5, or a pharma- ceutically acceptable salt thereof, wherein R2 is methyl.

[0213] Embodiment 7. A compound of any one of embodiments 1-4, or a pharma- ceutically acceptable salt thereof, wherein R2 is H.

[0214] Embodiment 8. A compound of any one of embodiments 1-7, or a pharma- ceutically acceptable salt thereof, wherein R3 is H.

[0215] Embodiment 9. A compound of any one of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein R4 is H.

[0216] Embodiment 10. A compound of any one of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein R4 is a substituted or unsubstituted straight chain C1-C3 alkyl.

[0217] Embodiment 11. The compound 0 of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein R4 is methyl.

[0218] Embodiment 12. A compound of any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein L is -O-.

[0219] Embodiment 13. A compound of any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein L is -C(O)-.

[0220] Embodiment 14. A compound of any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein L is -CH2-.

[0221] Embodiment 15. The compound of any one of embodiments 1-14, or a pharma- ceutically acceptable salt thereof, wherein M1 and M2 are independently halo.

[0222] Embodiment 16. The compound of embodiment 15, or a pharma- ceutically acceptable salt thereof, wherein M1 and M2 are each chloro.

[0223] Embodiment 17. A compound according to any one of embodiments 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein M3 is H.

[0224] Embodiment 18. A compound according to any one of embodiments 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein M3 is substituted or unsubstituted C1-C6 alkyl.

[0225] Embodiment 19. The compound of embodiment 18, or a pharma- ceutically acceptable salt thereof, wherein M3 is methyl.

[0226] Embodiment 20. The following: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0227] Embodiment 21. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0228] Embodiment 22. A method of agonizing thyroid hormone receptor beta (THR beta), comprising contacting THR beta with an effective amount of a compound of any one of embodiments 1 to 20, or a pharma- ceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition of embodiment 21.

[0229] Embodiment 23. A method for treating a disorder mediated by THR beta in a patient, comprising administering to the patient a therapeutically effective amount of a compound of embodiments 1 to 20, or a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a composition of embodiment 21. EXAMPLES

[0230] The following abbreviations may be relevant to this application: Abbreviation Ac: Acetyl ACN: Acetonitrile Boc: tertiary butyloxycarbonyl BSA: Bis(trimethylsilyl)acetamide Bu: butyl CAN: Cerium ammonium nitrate DBA: Dibenzylideneacetone DCM: dichloromethane DMAP: Dimethylaminopyridine DMF: Dimethylformamide DMF-DMA: Dimethylformamide dimethyl acetal DMSO: Dimethyl sulfoxide DSC: Disuccinimidyl carbonate Et: Ethyl HPLC: High-performance liquid chromatography MeOH: Methanol OAc: Acetate 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 Si-TMT: Silica-bound 2,4,6-trimercaptotriazine Toluene Ts: Tosil t-Bu Xphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0231] Synthesis Example Example S1: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 1) Scheme 1 [ka]

[0232] 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 AgNO3 (5.70 g, 33.56 mmol, 5.64 mL) in H2O (200 mL) at 60 °C. Then, a solution of ammonium persulfate (45.95 g, 201.37 mmol) in H2O (100 mL) was added dropwise to the mixture at 75 °C and the resulting mixture was stirred at 75 °C for 30 min. TLC showed that the reaction was complete. After the mixture was cooled, it was adjusted to pH = 9-10 with NH3 / H2O. The mixture was extracted with ethyl acetate (200 mL×2) and the organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give 1a (11 g, 57.57 mmol, 85.77% yield) as a pale yellow oil. 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).

[0233] 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 under nitrogen atmosphere at 90 °C for 16 h. TLC and LCMS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1000 mL × 2) and H2O (500 mL). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 3:1, by TLC) to give 1b (3.5 g, 10.52 mmol, 62.44% yield) as a light brown oil. 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-d6) 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).

[0234] 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 that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCO3 solution (10 mL). Then the mixture was partitioned between ethyl acetate (30 mL x 2) and H2O (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid was diluted with ethyl acetate (10 mL) and then petroleum ether (50 mL) was added to the mixture. The mixture was filtered to collect the solid. The solid was dried to give 1c (2.48 g, 3.65 mmol, 46.71% yield) as a brown solid. MS mass calculated: [M+1] + (C 21 H 15 Cl2N3O4) m / z 444.0, LCMS observed: m / z 444.1; 1 H NMR (400MHz, DMSO-d6)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=6.85 Hz, 6H).

[0235] 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 the starting material was completely consumed and two new spots were formed. 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 to give 1d as a yellow solid. The product was used directly in the next step without purification.

[0236] 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 analyzed by preparative TLC (petroleum ether:ethyl acetate=1:1, P1:R f =0.6) to give 1e (285 mg, 868.39 umol, 56.85% yield) as a white solid. MS mass calculated: [M+1] + (C 14 H 15 Cl2N3O2) m / z 328.1, LCMS observed: m / z 328.2; 1 H NMR (400MHz, MeOH-d4)δ 7.22(s, 1H) 6.70(s, 1H) 3.52(s, 3H) 3.17(dt, J=13.81, 7.13 Hz, 1H) 1.43(s, 2H) 1.25(d, J=6.58 Hz, 6H).

[0237] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1f) To a solution of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl-pyrazin-3-one (1e) (50 mg, 152.35 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (116.06 mg, 457.05 umol) in CH3CN (3 mL) was added tert-butyl nitrite (23.57 mg, 228.52 umol, 27.18 uL) dropwise at 20°C. The mixture was then stirred at 20°C for 2 hours. LCMS and TLC (petroleum ether:ethyl acetate=5:1, R f =0.6) indicated the reaction was complete and the desired MS was detected. The mixture was extracted with EtOAc (10 mL) and the organic layer was washed with H2O (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f =0.6) to give 1f (40 mg, crude) as a pale yellow solid. MS mass calculated: [M+1] + (C 20 H 25 BCl2N2O4) m / z 439.1, LCMS observed: m / z 439.0 and 356.9 (MS of boric acid); 1 H NMR (400MHz, CDCl3)δ 7.79(s, 1H), 7.01 - 7.09(m, 1H), 3.46 - 3.55(m, 2H), 3.18 - 3.32(m, 1H,) 1.36(s, 5H), 1.21 - 1.29(m, 12H).

[0238] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (1) To a mixture of 6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-4-isopropyl-2-methyl-pyrazin-3-one (1f) (40 mg, 91.09 umol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (26.23 mg, 136.63 umol) in dioxane (3 mL) and H2O (1.5 mL) was added K2CO3 (25.18 mg, 182.17 umol). Pd(dppf)Cl2 (6.66 mg, 9.11 umol) was then added to the mixture under N2. The mixture was then stirred at 80 °C under N2 for 2 h. LCMS and TLC (petroleum ether:ethyl acetate = 0:1, R f =0.6) indicated the reaction was complete and the desired MS was detected. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (10 mL) and H2O (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 36-66%, 10 min) to give 1 (4.5 mg, 10.52 umol, 11.55% yield). Calculated MS mass: [M+1] + (C 20 H 25 BCl2N2O4) m / z 424.1, LCMS observed: m / z 424.0; 1 H NMR (400MHz, MeOH-d4)δ 8.18(s, 2H), 7.34(d, J=0.74 Hz, 1H), 3.50(s, 3H), 3.10 - 3.25(m, 1H), 1.28(d, J=6.8 Hz, 6H).

[0239] Example S2: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 2) Scheme 2 [ka]

[0240] 3 -Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazine (2a) To a solution of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyrazin-3-yl)oxy-aniline (1b) (500 mg, 1.50 mmol) in HCl (15.03 mmol, 5 M, 1.79 mL) was added NaNO2 (124.47 mg, 1.80 mmol) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. A solution of KI (499.08 mg, 3.01 mmol) in H2O (5 mL) was then added and the mixture was stirred at 20 °C for another 16 h. TLC (petroleum ether:ethyl acetate=3:1, R f =0.6) indicated that 1b was completely consumed. The reaction mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1 to 1:1) to give 2a (340 mg, 613.31 umol, 40.80% yield) as a pale yellow solid.

[0241] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) To a solution of 3-chloro-6-(2,6-dichloro-4-iodo-phenoxy)-4-isopropyl-pyridazine (2a) (340 mg, 766.64 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (584.04 mg, 2.30 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2 (28.05 mg, 38.33 umol) and KOAc (376.19 mg, 3.83 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 90° C. for 16 h. TLC (petroleum ether:ethyl acetate=5:1, R f=0.5) indicated that 2a was completely consumed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (10 mL×3). The combined filtrates were concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=5:1) to give 2b (380 mg, 685.37 umol, 89.40% yield) as a white gum. MS mass calculated: [M+1] + (C 19 H 22 BCl3N2O3) m / z 443.1, LCMS observed: m / z 443.1. 1 H NMR (400 MHz, CDCl3)δ 7.82 - 7.80(m, 2H), 7.22 - 7.20(m, 1H), 3.31 - 3.23(m, 1H), 1.36 - 1.36(m, 3H), 1.36 - 1.35(m, 12H), 1.35 - 1.34(m, 3H).

[0242] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (2c) To a solution of 3-chloro-6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-4-isopropyl-pyridazine (2b) (70 mg, 157.81 umol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (45.44 mg, 236.72 umol) in dioxane (4 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (11.55 mg, 15.78 umol) and K2CO3 (65.43 mg, 473.44 umol). The mixture was degassed and purged with N2 three times, then stirred at 80 °C under nitrogen atmosphere for 16 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.30) indicated the reaction was complete. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (5 mL×4). The combined filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1) to give 2c (10.5 mg, 22.05 umol, 13.97% yield) as a pale yellow solid. MS mass calculated: [M+1] + (C16 H 12 Cl3N5O3) m / z 428.0, LCMS observed: m / z 428.1 / 430.1.

[0243] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (2) To a solution of 6-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyrazin-3-yl)oxy-phenyl]-2H-1,2,4-triazine-3,5-dione (2c) (10 mg, 21.00 umol) in AcOH (2 mL) was added NaOAc (6.89 mg, 83.98 umol). The mixture was stirred at 120° C. for 2 h. LCMS showed that ∼10% of 2c remained and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.2% FA)-ACN]; B%: 25-50%, 12 min) to give 2 (2.56 mg, 6.24 umol, 29.72% yield). Calculated MS mass: [M+1] + (C 16 H 13 Cl2N5O4) m / z 410.0, LCMS observed: m / z 410.1 / 412.1. 1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 2H), 7.34 (s, 1H), 3.12 - 3.18 (m, 1H), 1.27 - 1.29 (d, J=8.0 Hz, 6H).

[0244] Example S3: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 3) Scheme 3a [ka]

[0245] 6-Bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) To a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (200 mg, 1.04 mmol) in MeCN (5 mL) was added BSA (529.85 mg, 2.60 mmol). The mixture was heated at 82° C. for 3 h. Then, MeI (221.81 mg, 1.56 mmol) was added to the mixture, and the resulting mixture was stirred at 90° C. for an additional 16 h. TLC (petroleum ether:ethyl acetate=1:1, product R f =0.5) indicated complete consumption of starting material. The reaction mixture was extracted with EtOAc (10 mL×3). The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1, by TLC) to give 3a (170 mg, 660.20 umol, 63.37% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.53 - 12.45 (m, 1H), 3.43 (s, 3H).

[0246] Scheme 3b [ka]

[0247] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3b) To a solution of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (50 mg, 112.72 umol) and 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (69.66 mg, 338.17 umol) in dioxane (4 mL) was added Pd(dppf)Cl2 (8.25 mg, 11.27 umol) and K2CO3 (46.74 mg, 338.17 umol) in HO (1 mL). The mixture was stirred at 80 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1, R f=0.4) indicated that 2b was completely consumed. The suspension was filtered through a pad of Celite and the filter 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 (SiO2, petroleum ether:ethyl acetate=5:1, by TLC) to give 3b (21 mg, 37.95 umol, 33.67% yield) as a white solid. MS mass calculated: [M+1] + (C 17 H 14 Cl3N5O3) m / z 442.0, LCMS observed: m / z 444.0.

[0248] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3b) (17 mg, 38.40 umol) in HOAc (5 mL) was added NaOAc (15.75 mg, 192.01 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 3b was completely consumed and one main peak with the desired MS was detected. The reaction mixture was concentrated in vacuo to give a crude residue. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 30-70%, 15 min) to give 3 (2.57 mg, 5.82 umol, 15.14% yield). MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O4) m / z 424.1, LCMS observed: m / z 424.0. 1 H NMR (400 MHz, CDCl3)δ 8.21 - 8.16 (m, 2H), 7.37 - 7.34 (m, 1H), 3.69 - 3.66 (m, 3H), 3.21 - 3.13 (m, 1H), 1.31 - 1.27 (m, 6H).

[0249] Example S4: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 4) Scheme 4a [ka]

[0250] 6-Bromo-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4a) To a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (150 mg, 781.37 umol) in ACN (6 mL) was added BSA (397.38 mg, 1.95 mmol). The mixture was heated at 82° C. for 3 hours, and then 2-iodopropane (199.24 mg, 1.17 mmol) was added to the mixture. The resulting mixture was stirred at 82° C. for an additional 16 hours. TLC (ethyl acetate:petroleum ether=2:1, R f =0.6) indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether=1:1, by TLC) to give 4a (155 mg, 629.14 umol, 80.52% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.50 - 12.28 (m, 1H), 4.76 - 4.67 (m, 1H), 1.23 - 1.20 (m, 6H).

[0251] Scheme 4b [ka]

[0252] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4b) To a solution of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (100 mg, 225.45 umol) and 6-bromo-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4a) (105.53 mg, 450.90 umol) in dioxane (4 mL) was added Pd(dppf)Cl2 (16.50 mg, 22.54 umol) and K2CO3 (93.48 mg, 676.35 umol) in HO (1 mL). The mixture was stirred at 80 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.3) and LCMS showed that 2b was completely consumed and the desired mass was detected. The suspension was filtered through a pad of Celite and the filter 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 (SiO2, petroleum ether:ethyl acetate=1:1, by TLC) to give 4b (50 mg, 84.97 umol, 37.69% yield) as a white solid. MS mass calculated: [M+1] + (C 19 H 18 Cl3N5O3) m / z 470.0, LCMS observed: m / z 470.1.

[0253] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (4b) (50 mg, 106.22 umol) in HOAc (5 mL) was added NaOAc (43.56 mg, 531.08 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 4b was completely consumed and one main peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 20-60%, 15 min) to give 4 (9.21 mg, 20.16 umol, 18.98% yield). MS mass calculated: [M+1] + (C 19 H 19 Cl2N5O4) m / z 452.1, LCMS observed: m / z 452.0. 1 H NMR (400 MHz, MeOH-d4)δ 8.19 - 8.16(m, 2H), 7.37 - 7.34(m, 1H), 5.01 - 4.95(m, 1H), 3.21 - 3.13(m, 1H), 1.43 - 1.40(m, 6H), 1.30 - 1.28(m, 6H).

[0254] Example S5: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-2-methylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 5) Scheme 5 [ka]

[0255] 3,5-Dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)-2-methylaniline (15a) To a mixture of 4-amino-2,6-dichloro-3-methyl-phenol (1a) (0.1 g, 520.72 umol), 3,6-dichloro-4-isopropyl-pyridazine (99.49 mg, 520.72 umol) in DMSO (1 mL) was added K2CO3 (287.87 mg, 2.08 mmol) and CuI (59.50 mg, 312.43 umol) at 25 °C. The mixture was stirred at 90 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.43) indicated the reaction was complete. H2O (5 mL) was added to the mixture and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5a (0.1 g, 288.48 umol, 55.40% yield) as a yellow solid. MS mass calculated: [M+1] + (C 14 H 14 Cl3N3O) m / z 346.0, LCMS observed: m / z 346.0; 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 6.78 - 6.80 (m, 1H), 5.50 (s, 2H,) 3.13 - 3.19 (m, 1H), 2.13 (s, 3H), 1.28 (d, J=6.8 Hz, 6H).

[0256] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-2-methylphenyl)isoindoline-1,3-dione (5b) To a mixture of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyrazin-3-yl)oxy-2-methyl-aniline (5a) (0.1 g, 288.48 umol) and isobenzofuran-1,3-dione (42.73 mg, 288.48 umol) in AcOH (3 mL) was added NaOAc (94.66 mg, 1.15 mmol) at 25° C. The mixture was stirred at 120° C. for 6 h. LCMS showed the reaction was complete. The mixture was concentrated to give a residue. To the residue was added H2O (10 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was diluted with MTBE (5 mL) and filtered. The filter cake was dried under vacuum to give 5b (0.05 g, 109.10 umol, 37.82% yield) as a yellow solid. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O4) m / z 458.1, LCMS observed: m / z 458.0; 1 H NMR (400 MHz, CDCl3)δ 9.91(br s, 1 H), 8.00(dd, J=5.5, 3.0 Hz, 2 H), 7.85(dd, J=5.5, 3.0 Hz, 2H), 7.30(s, 1H), 7.16(s, 1H), 3.23 - 3.29(m, 1H), 3.22(s, 1H), 2.25(s, 3H), 1.30(d, J=6.85 Hz, 6H).

[0257] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-2-methylphenyl)isoin-doline-1,3-dione (5c) A mixture of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyrazin-3-yl)oxy]-2-methyl-phenyl]isoindoline-1,3-dione (5b) (0.37 g, 807.34 umol) in DMF-DMA (5 mL) was stirred at 105° C. for 4 h. LCMS showed the reaction was complete. H2O (20 mL) was added to the mixture and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5c as a yellow solid. The crude material was used directly in the next step. MS mass calculated: [M+1] + (C 23 H 19 Cl2N3O4) m / z 472.1, LCMS observed: m / z 472.1.

[0258] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (5d) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyrazin-3-yl)oxy-2-methyl-phenyl]isoin-doline-1,3-dione (5c) (440 mg, 931.57 umol) in MeOH (1 mL) was added butyl-1-amine (2 M, 1.40 mL) at 70° C. The mixture was stirred at 70° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:1, R f =0.6) and LCMS showed the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give 5d as a white solid. MS mass calculated: [M+1] + (C 15 H 17 Cl2N3O2) m / z 341.1, LCMS observed: m / z 342.1; 1 H NMR (400MHz, MeOH-d4)δ 7.22(s, 1H), 6.77(s, 1H), 3.50(s, 3H), 3.17(td, J=6.8, 13.8 Hz, 1H), 2.20(s, 3H), 1.26(d, J=6.6 Hz, 6H).

[0259] 6-(2,6-dichloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (5e) To a mixture of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (5d) (20 mg, 58.44 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (742.03 mg, 2.92 mmol) in CH3CN (8 mL) was added t-BuONO (12.05 mg, 116.88 umol, 13.90 uL) at 20°C. The mixture was then stirred at 20°C for 16 hours. TLC (petroleum ether:ethyl acetate=5:1, R f =0.4) and LCMS showed that the starting material was completely consumed and the desired MS was found. The mixture was concentrated under reduced pressure. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate=5:1, P1:R f =0.4) to give 5e (25 mg, crude) as a white solid. MS mass calculated: [M+1] + (C 21 H 27 BCl2N2O4) m / z 453.2, LCMS observed: m / z 453.0; 1 H NMR (400MHz, CDCl3)δ 7.76(s, 1H), 7.04(s, 1H), 3.58 - 3.63(m, 3H), 3.49 - 3.51(m, 5H), 3.24(s, 1H), 2.62(s, 3H), 1.21 - 1.30(m, 6H).

[0260] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-2-methylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (5) To a mixture of 6-(2,6-dichloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (5e) (25 mg, 55.17 umol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (10.59 mg, 55.17 umol) in dioxane (2 mL) and H2O (0.5 mL) was added K2CO3 (22.87 mg, 165.50 umol) and Pd(dppf)Cl2 (4.04 mg, 5.52 umol). The mixture was degassed and purged with N2 three times, then stirred at 90 °C under nitrogen atmosphere for 16 h. HPLC and LCMS showed that the starting material was completely consumed 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: Luna C18 100×30 5u; Mobile phase: [water (0.1% TFA)-ACN]; B%: 25-60%, 12 min) to give the desired compound (20 mg, 40.77 umol, 73.89% yield, 89.33% purity). The product was then re-purified by Prep-HPLC (Column: HUAPU C8 Extreme BDS 150×30 5u; Mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to give 5 (0.26 mg, 2.60% yield). Calculated MS mass: [M+1] + (C18H 17 Cl2N5O4) m / z 438.3, LCMS observed: m / z 438.0; 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.46 (s, 1H), 3.39 (br s, 3H), 3.08 (s, 1H), 2.25 (s, 3H), 1.19 (d, J=7.0 Hz, 6H).

[0261] Example S6: 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 6) Scheme 6 [ka]

[0262] 3,6-Dichloro-4-cyclopropylpyridazine (6a) H2SO4 (1.98 g, 20.14 mmol, 1.07 mL) was added to a solution of 3,6-dichloropyridazine (1 g, 6.71 mmol), cyclopropanecarboxylic acid (577.86 mg, 6.71 mmol, 530.15 uL) and AgNO3 (1.14 g, 6.71 mmol) in H2O (20 mL) at 60 °C, then ammonium persulfate (4.60 g, 20.14 mmol, 4.38 mL) H2O (10 mL) was added at 70 °C, and the resulting mixture was stirred at 70 °C for 30 min. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) indicated the completion of the reaction, the mixture was extracted with ethyl acetate (20 mL×2), and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by MPLC (SiO2, petroleum ether:ethyl acetate=5:1) to give 6a (0.64 g, 3.39 mmol, 50.44% yield) as a colorless oil. MS mass calculated: [M+1] + (C7H6Cl2N2) m / z 189.0, LCMS observed: m / z 189.1; 1 H NMR (400MHz, CDCl3) δ 6.94 (s, 1H), 2.22 (tt, J=5.0, 8.4 Hz, 1H), 1.37 - 1.28 (m, 2H), 0.93 - 0.83 (m, 2H).

[0263] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)aniline (6b) 3,6-Dichloro-4-cyclopropylpyridazine (6a) (0.3 g, 1.59 mmol), 4-amino-2,6-dichlorophenol (282.50 mg, 1.59 mmol), K2CO3 (328.99 mg, 2.38 mmol) and CuI (60.45 mg, 317.39 umol) in DMA (5 mL) was degassed and then heated to 100 °C under N2 for 16 h. LCMS showed the desired product and TLC (petroleum ether:ethyl acetate = 3:1, R f=0.33) showed one new spot. The mixture was filtered; the filtrate was extracted with water (20 mL) and ethyl acetate (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (petroleum ether:ethyl acetate=5:1) to give 6b (0.3 g, 907.45 umol, 57.18% yield) as a yellow solid. MS mass calculated: [M+1] + (C 13 H 10 Cl3N3O) m / z 330.0, LCMS observed: m / z 330.1; 1 H NMR (400MHz, DMSO-d6) δ 7.34(s, 1H), 6.70(s, 2H), 5.67(s, 2H), 2.17 - 2.11(m, 1H), 1.23 - 1.19(m, 2H), 1.07 - 1.01(m, 2H).

[0264] 3-Chloro-4-cyclopropyl-6-(2,6-dichloro-4-iodophenoxy)pyridazine (6c) To a solution of 3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)aniline (6b) (0.1 g, 302.48 umol) in concentrated HCl (2 mL) and HO (2 mL) was added NaNO (31.30 mg, 453.72 umol) portionwise at 0° C. and stirred for 30 min, then KI (100.43 mg, 604.97 umol) and HO (1 mL) were added dropwise to the mixture and the resulting mixture was stirred at 25° C. for 1.5 h to give a brown suspension. LCMS showed the desired MS was detected, TLC (petroleum ether:ethyl acetate=5:1, R 2 O) was added dropwise to give a brown suspension. f =0.59) indicated the completion of the reaction, the mixture was filtered, the filter cake was washed with water (2 mL×2), dried, and the solid was purified by prep-TLC (petroleum ether:ethyl acetate=5:1) to give 6c (0.11 g, 249.16 umol, 82.37% yield) as a yellow solid. MS mass calculated: [M+1] + (C 13 H8Cl3IN2O) m / z 440.9, LCMS observed: m / z 440.9; 1H NMR (400MHz, CDCl3)δ 7.77 - 7.69 (m, 2H), 6.78 (s, 1H), 2.25 - 2.18 (m, 1H), 1.31 - 1.26 (m, 2H), 0.94 - 0.89 (m, 2H).

[0265] (3,5-Dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)boronic acid (6d) A mixture of 3-chloro-4-cyclopropyl-6-(2,6-dichloro-4-iodophenoxy)pyridazine (6c) (0.11 g, 249.16 umol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (189.82 mg, 747.49 umol, 3 equiv.), KOAc (146.72 mg, 1.49 mmol) and Pd(dppf)Cl2 (18.23 mg, 24.92 umol) in dioxane (5 mL) was degassed and then heated to 90 °C under N2 for 16 h. LCMS showed the desired product was detected, TLC (petroleum ether:ethyl acetate=3:1, R 2 : 1) was eluted and the resulting mixture was eluted at 90 °C for 16 h. LCMS showed the desired product was detected, TLC (petroleum ether:ethyl acetate=3:1, R 2 : 1) was eluted and the resulting mixture was eluted at 90 °C for 16 h. f =0.35) showed a new spot. The mixture was filtered, the filter cake was washed with ethyl acetate (10 mL×2), and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=3:1) to give 6d (85 mg, 236.51 umol, 94.92% yield) as a white solid. MS mass calculated: [M+1] + (C 13 H 10 BCl3N2O3) m / z 359.0, LCMS observed: m / z 359.0;

[0266] 6-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (6e) A mixture of (3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)boronic acid (6d) (85 mg, 236.51 umol), 6-bromo-2H-1,2,4-triazine-3,5-dione (59.02 mg, 307.46 umol), Pd(dppf)Cl2 (17.31 mg, 23.65 umol) and K2CO3 (65.37 mg, 473.01 umol) in dioxane (5 mL) and HO (0.5 mL) was degassed and then heated to 90 °C under N2 for 16 h. LCMS showed the desired product was found, TLC (DCM:MeOH=10:1, R20) showed no significant difference from the original MS / MS reaction. f =0.42) found a new spot. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give 6e (30 mg, 70.32 umol, 29.73% yield) as a yellow solid. MS mass calculated: [M+1] + (C 16 H 10 Cl3N5O3) m / z 426.0, LCMS observed: m / z 426.0; 1 H NMR (400MHz, MeOH-d4) δ 8.23(s, 2H), 7.26(s, 1H), 2.33 - 2.26(m, 1H), 1.33 - 1.30(m, 2H), 1.08 - 1.02(m, 2H).

[0267] 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (6) A mixture of 6-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (6e) (30 mg, 70.32 umol) and NaOAc (28.84 mg, 351.58 umol) in HOAc (3 mL) was heated to 110° C. for 16 h, LCMS showed the reaction was complete and the desired MS was found. The mixture was concentrated. The residue was purified by preparative HPLC (FA) to give 6 (10.19 mg, 24.96 umol, 35.50% yield). Calculated MS mass: [M+1] + (C 16 H 10Cl3N5O3) m / z 408.0, LCMS observed: m / z 408.0; 1 H NMR (400MHz, DMSO-d6) δ 12.60(s, 1H), 12.18(br s, 1H), 8.01(s, 2H), 7.15(s, 1H), 2.12(br s, 1H), 1.06(br d, J=6.8 Hz, 2H), 0.99(br s, 2H).

[0268] Example S7: 6-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 7) Scheme 7 [ka]

[0269] 2-Cyano-2-(2,6-dichloro-4-nitro-phenyl)ethyl acetate (7a) To a suspension of NaH (3.53 g, 88.32 mmol, 60% purity) in DMSO (100 mL) was added dropwise 2-cyanoethyl acetate (9.99 g, 88.32 mmol, 9.42 mL) at 0° C., and the mixture was then stirred at 25° C. for 30 min. Then, 1,2,3-trichloro-5-nitro-benzene (10 g, 44.16 mmol) was added to the mixture, and the resulting mixture was stirred at 25° C. for 16 h. TLC (petroleum ether:ethyl acetate=5:1, R f =0.49) indicated the reaction was complete. The reaction mixture was quenched by adding water (100 mL) at 25 °C. Then, the pH was adjusted to 1 with HCl (4 M) and the yellow precipitate was collected by suction filtration and dried in vacuum to give 7a (12.5 g, 41.24 mmol, 93.39% yield) as a yellow solid. The product was used directly in the next step without purification.

[0270] 2-(2,6-Dichloro-4-nitro-phenyl)acetonitrile (7b) A mixture of ethyl 2-cyano-2-(2,6-dichloro-4-nitro-phenyl)acetate (7a) (12.5 g, 41.24 mmol) and LiCl (2.62 g, 61.86 mmol) in DMSO (16 mL) and HO (6 mL) was heated to 165 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, R f=0.8) indicated the reaction was complete with the formation of one new spot. The reaction was clear by TLC. After cooling, the mixture was quenched with water (100 mL×4) and extracted with ethyl acetate (50 mL×4). The combined organic phase was washed with brine (20 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7b (9.2 g, 39.82 mmol, 96.56% yield) as a brown solid. The product was used directly in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ 8.33 - 8.21 (m, 2H), 4.11 - 4.07 (m, 3H).

[0271] 2-(4-amino-2,6-dichloro-phenyl)acetonitrile (7c) To a solution of 2-(2,6-dichloro-4-nitro-phenyl)acetonitrile (7b) (5 g, 21.64 mmol) in HOAc (30 mL) was added iron powder (6.04 g, 108.21 mmol). The mixture was stirred at 25° C. for 1 h. TLC (petroleum ether:ethyl acetate=3:1, R f =0.4) indicated the completion of the reaction and one new spot was formed. The mixture was filtered and the filtrate was extracted with water (100 mL×4) and ethyl acetate (50 mL×4). The combined organic layers were neutralized with saturated NaHCO3 (30 ml×5), washed with brine (30 mL×2), dried over sodium sulfate, filtered and concentrated to give 7c (4.2 g, 20.89 mmol, 96.53% yield) as a brown solid. The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.67(s, 2H), 3.88(s, 2H).

[0272] 2-(4-amino-2,6-dichloro-phenyl)-2-(6-chloro-5-isopropyl-pyrazin-3-yl)acetonitrile (7d) To a solution of 2-(4-amino-2,6-dichloro-phenyl)acetonitrile (7c) (4.2 g, 20.89 mmol) and 3,6-dichloro-4-isopropyl-pyridazine (3.99 g, 20.89 mmol) in THF (20 mL) was added t-BuOK (1M in THF, 41.78 mL) dropwise at 60° C. The resulting mixture was stirred at this temperature for 2 h. TLC (petroleum ether:ethyl acetate=2:1, R f =0.49) showed that one major spot with less polarity was detected. After cooling the mixture, it was extracted with ethyl acetate (100 mL×3), and the organic layer was washed with brine (50 mL×2). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1 to 1:1) to give 7d (4 g, 11.25 mmol, 53.84% yield) as an orange solid. 1 H NMR (400 MHz, CDCl3)δ 7.62 - 7.56 (m, 1H), 6.68 (s, 2H), 6.32 (s, 1H), 3.35 - 3.27 (m, 1H), 1.33 - 1.28 (m, 6H).

[0273] (4-Amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyrazin-3-yl)methanone (7e) To a solution of 2-(4-amino-2,6-dichloro-phenyl)-2-(6-chloro-5-isopropyl-pyrazin-3-yl)acetonitrile (7d) (2.2 g, 6.19 mmol) in MeCN (15 mL) was added t-BuOK (1M THF solution, 6.19 mL) at 25° C. The mixture was stirred at this temperature for 0.5 h, then cooled to 0° C., and H2O2 (1.40 g, 12.37 mmol, 1.19 mL, 30% purity) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at 25° C. for 2 h. TLC (petroleum ether:ethyl acetate=2:1, R f=0.69) showed that one new spot was formed. LCMS showed that the desired mass was found. The reaction mixture was quenched by adding Na2SO3 (5 mL) and then stirred at 20 °C for 1 h. The mixture was then concentrated under reduced pressure. The residue was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, 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 7e (885 mg, 2.57 mmol, 41.51% yield) as a pale yellow solid. MS mass calculated: [M+1] + (C 14 H 12 Cl3N3O) m / z 344.0, LCMS observed: m / z 344.1. 1 H NMR (400 MHz, MeOH-d4) δ 8.23 ​​- 8.21 (m, 1H), 6.69 - 6.66 (m, 2H), 3.44 - 3.36 (m, 1H), 1.40 - 1.36 (m, 6H).

[0274] 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1H-pyridazine-3-carbonyl)phenyl]isoindoline-1,3-dione (7f) To a solution of (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyrazin-3-yl)methanone (7e) (250 mg, 725.43 umol) in HOAc (10 mL) was added NaOAc (297.55 mg, 3.63 mmol) and isobenzofuran-1,3-dione (107.45 mg, 725.43 umol). The mixture was stirred at 120° C. for 16 hours. TLC (petroleum ether:ethyl acetate=2:1, R f =0.31) showed one new spot formed. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure and the residue was diluted with H2O (50 mL) and aqueous NaHCO3 (50 mL). The mixture was then extracted with ethyl acetate (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give 7f (200 mg, 438.33 umol, 60.42% yield) as a white solid. The crude product was used in the next step without further purification. MS mass calculated: [M+1] + (C 22 H15 Cl2N3O4) m / z 456.0, LCMS observed: m / z 456.1.

[0275] 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazine-3-carbonyl)phenyl]isoindoline-1,3-dione (7g) A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1H-pyridazine-3-carbonyl)phenyl]isoindoline-1,3-dione (7f) (350 mg, 767.08 umol) in DMF-DMA (10 mL) was stirred at 110° C. for 3 h. LCMS showed the reaction was complete and the desired mass was found. The reaction mixture was partitioned between H2O (50 mL×2) and ethyl acetate (50 mL×2). The organic phase was concentrated under reduced pressure to give 7g (300 mg, 637.89 umol, 83.16% yield) as a white solid. The 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.

[0276] 6-(4-amino-2,6-dichloro-benzoyl)-4-isopropyl-2-methyl-pyrazin-3-one (7h) To a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazine-3-carbonyl)phenyl]isoindoline-1,3-dione (7g) (300 mg, 637.89 umol) in MeOH (2 mL) was added N-butylamine (285.58 mg, 1.91 mmol, 307.08 uL). The mixture was stirred at 70° C. for 0.5 h. TLC (petroleum ether:ethyl acetate=2:1) ​​showed two new spots (R f =0.41, 0.31) was formed. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=2:1) ​​to give 7h (122 mg, 358.61 umol, 56.22% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3)δ 7.84(d, J=1.0 Hz, 1H), 6.65 - 6.61(m, 2H), 3.77 - 3.74(m, 3H), 3.27 - 3.18(m, 1H), 1.27(d, J=6.8 Hz, 6H).

[0277] 6-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-4-isopropyl-2-methyl-pyrazin-3-one (7i) To a solution of 6-(4-amino-2,6-dichloro-benzoyl)-4-isopropyl-2-methyl-pyrazin-3-one (7h) (40 mg, 117.58 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (89.57 mg, 352.73 umol) in MeCN (2 mL) was added t-BuONO (24.25 mg, 235.15 umol, 27.97 uL). The mixture was stirred at 25° C. for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=4:1) to give 7i (31 mg, 68.71 umol, 58.44% yield) as a pale yellow solid. MS mass calculated: [M+1] + (C 21 H 24 BCl2N2O4) m / z 451.1, LCMS observed: m / z 451.2. 1 H NMR (400MHz, CDCl3)δ 7.86(d, J=0.6 Hz, 1H), 7.75(s, 2H), 3.71(s, 3H), 3.27 - 3.19(m, 1H), 1.37(s, 12H), 1.29 - 1.27(m, 6H).

[0278] 6-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazine-3-carbonyl)phenyl]-2H-1,2,4-triazine-3,5-dione (7) A mixture of 7i (30 mg, 66.50 umol, 6-bromo-2H-1,2,4-triazine-3,5-dione (12.77 mg, 66.50 umol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N three times, then cooled to 100° C. for 2 h. The mixture was ... 2(4.87 mg, 6.65 umol) and K2CO3 (27.57 mg, 199.49 umol) were added. The mixture was then stirred at 90° C. for 1 h under nitrogen atmosphere. LCMS showed that the desired mass was found. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (NH4CO3) to give 7 (7.65 mg, 17.44 umol, 26.23% yield). MS mass calculated: [M+1] + (C18H 15 Cl2N5O4) m / z 436.2, LCMS observed: m / z 436.0. 1 H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 2H), 7.93 - 7.91 (m, 1H), 3.72 - 3.68 (m, 3H), 3.24 - 3.16 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).

[0279] Example S8: 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 8) Scheme 8 [ka]

[0280] (6-Chloro-5-isopropylpyrazin-3-yl)(2,6-dichloro-4-iodophenyl)methanone (8a) To a solution of (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyrazin-3-yl)methanone (7e) (120 mg, 348.21 umol) in HCl (5 M, 2 mL) was added NaNO2 (28.83 mg, 417.85 umol) at 0 °C and the mixture was stirred for 0.5 h. Then, to the mixture was added a solution of KI (115.60 mg, 696.41 umol) in H2O (5 mL) and the resulting mixture was stirred at 20 °C for an additional 16 h. TLC (petroleum ether:ethyl acetate=5:1, R f=0.6) indicated that 7e was completely consumed. The reaction mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=5:1, by TLC) to give 8a (75 mg, 131.72 umol, 37.83% yield) as a white solid. MS mass calculated: [M+1] + (C 14 H 10 Cl3IN2O) m / z 454.9, LCMS observed: m / z 454.9.

[0281] (6-Chloro-5-isopropylpyrazin-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (8b) To a solution of (6-chloro-5-isopropylpyrazin-3-yl)(2,6-dichloro-4-iodophenyl)methanone (8a) (100 mg, 219.54 umol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (167.25 mg, 658.61 umol) in dioxane (3 mL) was added Pd(dppf)Cl2 (8.03 mg, 10.98 umol) and KOAc (107.73 mg, 1.10 mmol). The mixture was degassed and purged with N2 three times and stirred at 90 °C for 16 h. TLC (petroleum ether:ethyl acetate=5:1, R f =0.5) and LCMS showed that 8a was completely consumed and the desired mass was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (10 mL×3). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=5:1, by TLC) to give 8b (150 mg, crude) as a white solid. MS mass calculated: [M+1] + (C 20 H 22 BCl3N2O3) m / z 455.1, LCMS observed: m / z 455.0. 1H NMR (400 MHz, CDCl3)δ 8.20 - 8.18 (m, 1H), 7.79 - 7.74 (m, 2H), 3.40 - 3.32 (m, 1H), 1.38 - 1.34 (m, 18H).

[0282] 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8c) To a solution of (6-chloro-5-isopropylpyrazin-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (8b) (50 mg, 109.75 umol) and 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (63.21 mg, 329.26 umol) in dioxane (4 mL) was added Pd(dppf)Cl2 (8.03 mg, 10.98 umol) and K2CO3 (45.51 mg, 329.26 umol) in HO (1 mL). The mixture was stirred at 80 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1) and LCMS showed that 18b was completely consumed and the desired mass was detected. The suspension was filtered through a pad of Celite 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 (SiO2, DCM:MeOH=20:1, by TLC) to give 8c (25 mg, 28.37 umol, 25.85% yield) as a white solid. MS mass calculated: [M+1] + (C 17 H 12 Cl3N5O3) m / z 440.0, LCMS observed: m / z 442.0.

[0283] 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8) To a solution of 6-(3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-carbonyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (8c) (25 mg, 56.73 umol) in HOAc (3 mL) was added NaOAc (23.27 mg, 283.66 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 8c was completely consumed and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Nano-Micro UniSil 5-100 C18 ULTRA 100×250 mm 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 25-65%, 10 min) to give 8 (1.86 mg, 4.19 umol, 7.38% yield). MS mass calculated: [M+1] + (C 17 H 13 Cl2N5O4) m / z 422.0, LCMS observed: m / z 422.1. 1 H NMR (400 MHz, MeOH-d4) δ 8.16 - 8.12 (m, 2H), 7.92 - 7.90 (m, 1H), 3.21 - 3.12 (m, 1H), 1.29 (d, J=7.0 Hz, 6H).

[0284] Example S9: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 9) Scheme 9 [ka]

[0285] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (9) To a solution of 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (1f) (30 mg, 68.32 umol) and 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (42.22 mg, 204.95 umol) in dioxane (2 mL) was added a solution of Pd(dppf)Cl2 (5.00 mg, 6.83 umol) and K2CO3 (28.33 mg, 204.95 umol) in H2O (0.5 mL). The mixture was stirred at 80 °C for 3 h. LCMS showed that 1f was completely consumed and the desired mass was detected. To the mixture was added palladium scavenger Si-TMT (1 g) and stirred at 20° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 9. Calculated MS mass: [M+1] + (C18H 17 Cl2N5O4) m / z 438.1, LCMS observed: m / z 438.0. 1 H NMR (400MHz, MeOH-d4)δ 8.14 - 8.24(m, 2H), 7.32 - 7.35(m, 1H), 3.64 - 3.72(m, 3H), 3.49(s, 3H), 3.20(td, J=7.0, 13.6 Hz, 1H), 1.28(d, J=6.8 Hz, 6H).

[0286] Example S10: 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 10) Scheme 10 [ka]

[0287] 6-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (10a) A mixture of 3-chloro-4-cyclopropyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridazine (6d) (75 mg, 169.86 umol), 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (45.49 mg, 220.82 umol), Pd(dppf)Cl2 (12.43 mg, 16.99 umol) and K2CO3 (46.95 mg, 339.72 umol, 2 equiv) in dioxane (5 mL), HO (0.5 mL) was heated under N2 at 90 °C for 16 h. LCMS showed 6d was completely consumed and the desired MS was detected. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (ethyl acetate:MeOH) to give 10a. MS mass calculated: [M+1] + (C 17 H 12 Cl3N5O3) m / z 440.0, LCMS observed: m / z 440.1. 1 H NMR (400 MHz, DMSO-d6)δ 8.16 - 8.10(m, 2H), 7.51(s, 1H), 3.58(s, 4H), 1.22 - 1.20(m, 1H), 1.23 - 1.20(m, 1H), 1.19 - 1.14(m, 1H), 1.19 - 1.14(m, 1H), 1.11 - 1.05(m, 1H), 1.10 - 1.05(m, 1H).

[0288] 6-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (10) A mixture of 6-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (10a) (28 mg, 63.54 umol) and NaOAc (26.06 mg, 317.70 umol) in HOAc (1 mL) was heated to 110° C. for 16 h. LCMS showed that 10a was completely consumed and the desired MS was detected. The mixture was concentrated. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase: [water (0.1% TFA)-ACN]) to give 10. Calculated MS mass: [M+1] + (C 17 H 13 C l2 N5O4) m / z 422.0, LCMS observed: m / z 422.0. 1 H NMR (400 MHz, DMSO-d6)δ 12.43(s, 1H), 12.17(s, 1H), 8.07(s, 2H), 7.16(s, 1H), 3.57(s, 3H), 2.19 - 2.10(m, 1H), 1.11 - 1.05 (m, 2H), 1.01 (td, J=2.8, 5.2 Hz, 2H).

[0289] Example S11: 6-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 11) Scheme 11 [ka]

[0290] Compound 11 can be prepared using intermediate 6b by following the procedure described in Example S5, replacing 5a with 6b and following the rest of the synthetic sequence.

[0291] Example S12: 6-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 12) Scheme 12 [ka]

[0292] Compound 12 can be prepared by reacting 3A with boronic ester derivative d, the synthesis of which is outlined in Example S11, following the reaction conditions used for the preparation of compound 7.

[0293] Example S13: 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 13) Scheme 13 [ka]

[0294] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-4-isopropylpyrazin-3(2H)-one (13a) To a solution of (6-chloro-5-isopropylpyrazin-3-yl)(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (8b) (200 mg, 439.01 umol) in HOAc (10 mL) was added NaOAc (180.07 mg, 2.20 mmol). The mixture was stirred at 120° C. for 16 h. LCMS showed that one major peak of the desired mass was found. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL×3) and H2O (10 mL). The combined organic layers were washed with NaHCO3 (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 13a. MS mass calculated: [M+1] + (C 20 H 23 BCl2N2O4) m / z 437.1, LCMS observed: m / z 437.1. 1 H NMR (400 MHz, CD3OD) δ 7.90(s, 1H), 7.68 - 7.70(m, 1H), 7.43 - 7.46(m, 1H), 3.13 - 3.20(m, 1H), 1.29 - 1.30(m, 6H), 1.20(s, 12H).

[0295] 6-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 13) A mixture of 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-4-isopropylpyrazin-3(2H)-one (13a) (60 mg, 137.26 umol), 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (28.28 mg, 137.26 umol), Pd(dppf)Cl2 (10.04 mg, 13.73 umol), and K2CO3 (56.91 mg, 411.78 umol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. LCMS showed one major peak of the desired mass formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150 x 30 mm x 5 um; mobile phase: [water (0.225% FA)-ACN]) to give 13. Calculated MS mass: [M+1] + (C18H 15 Cl2N5O4) m / z 436.1, LCMS observed: m / z 436.0. 1 H NMR (400 MHz, CD3OD) δ 8.14- 8.17 (m, 2H), 7.90 - 7.93 (m, 1H), 3.67 - 3.70 (m, 3H), 3.35 (s, 3H), 3.13 - 3.21 (m, 1H), 1.30 (d, J=6.8 Hz, 6H).

[0296] Example 14: 6-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 14) Scheme 14 [ka]

[0297] Compound 14 can be prepared by reaction of 7i with 3A following the conditions used for the preparation of compound 7.

[0298] Example S15: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 15) Scheme 15 [ka]

[0299] 6-(4-Amino-2,6-dichlorobenzyl)-4-isopropylpyrazin-3(2H)-one (15a) A solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyrazin-3-yl)acetonitrile (7d) (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 reaction was complete and the desired MS was detected. After cooling, the mixture was adjusted to pH-7 with 4M NaOH at 0° C. and the solid was filtered and dried to give 15a (0.12 g, crude). Calculated MS mass: [M+1] + (C 14 H 15 Cl2N3O) m / z 312.1, LCMS observed: m / z 312.1.

[0300] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyrazin-3(2H)-one (15b) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyrazin-3(2H)-one (15a) (200 mg, 640.63 umol) in DMF (5 mL) was added PMB-Cl (120.39 mg, 768.75 umol, 104.69 uL) and K2CO3 (106.25 mg, 768.75 umol). The mixture was stirred at 20°C for 16 h. TLC showed ~10% 15a remained and one new spot formed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (5 mL x 3). The combined filtrates were concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 15b. 1 H NMR (400MHz, DMSO-d6)δ 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=7.0 Hz, 6H).

[0301] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyrazin-3(2H)-one (15c) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyrazin-3(2H)-one (15b) (70 mg, 161.91 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (822.29 mg, 3.24 mmol) in CH3CN (2 mL) was added t-BuONO (33.39 mg, 323.82 umol, 38.51 uL) at 0°C, and the mixture was then stirred at 0°C for 4 hours. The mixture was then stirred at 25°C for another 12 hours. TLC showed that reactant 15b was completely consumed and many new spots were formed. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic phase was separated, washed with brine (5 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum teeth: ethyl acetate) to give 15c (100 mg, crude). MS mass calculated: [M+1] + (C 28 H 33 BCl2N2O4) m / z 543.2, LCMS observed: m / z 543.1.

[0302] 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (15d) To a solution of 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyrazin-3(2H)-one (15c) (20 mg, 36.81 umol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (10.60 mg, 55.22 umol) in dioxane (2 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (2.69 mg, 3.68 umol) and K2CO3 (15.26 mg, 110.44 umol). The mixture was stirred at 90 °C for 12 h. LCMS showed 15c was consumed and the desired MS was detected. The reaction mixture was partitioned between ethyl acetate (5 mL) and H2O (5 mL). The organic phase was separated, washed with brine (3 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2) to give 15d. MS mass calculated: [M+1] + (C 25 H 23 Cl2N5O4) m / z 528.1, LCMS observed: m / z 528.0.

[0303] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (15) To a solution of 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (15d) (15 mg, 28.39 umol) in CH3CN (2 mL) and HO (0.5 mL) was added CAN (77.82 mg, 141.94 umol, 70.74 uL). The mixture was stirred at 25°C for 16 hours. LC-MS showed complete consumption of 15d with one major peak of the desired m / z. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 15. Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O3) m / z 408.1, LCMS observed: m / z 408.0. 1H NMR (400 MHz, MeOH-d4) δ 8.10 - 8.13 (m, 2H), 7.24 - 7.27 (m, 1H), 4.36 (s, 2H), 3.07 - 3.15 (m, 1H), 1.19 - 1.23 (m, 6H).

[0304] Example S16: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 16) Scheme 16 [ka]

[0305] 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (16a) A mixture of 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropyl-2-(4-methoxybenzyl)pyrazin-3(2H)-one (15c) (130 mg, 239.28 umol), 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (73.94 mg, 358.93 umol), Pd(dppf)Cl2 (17.51 ​​mg, 23.93 umol), and K2CO3 (99.21 mg, 717.85 umol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. LCMS showed one peak of the desired mass. The reaction mixture was extracted with ethyl acetate (10 mL×3) and H2O (10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol) to give 16a. MS mass calculated: [M+1] + (C 26 H 25 Cl2N5O4) m / z 542.1, LCMS observed: m / z 542.1.

[0306] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (16) To a solution of 6-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (16a) (20 mg, 36.87 umol) in CH3CN (2 mL) and HO (0.5 mL) was added CAN (80.86 mg, 147.49 umol, 73.51 uL) at 20°C. The mixture was then stirred at 20°C for 16 hours. TLC and LCMS showed that one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN) to give 16. Calculated MS mass: [M+1] + (C18H 17 Cl2N5O3) m / z 422.1, LCMS observed: m / z 422.0. 1 H NMR (400 MHz, CD3OD)δ 8.12 - 8.14(m, 2H), 7.24 - 7.26(m, 1H), 4.35 - 4.37(m, 2H), 3.66 - 3.68(m, 3H), 3.12 - 3.15(m, 1H), 1.21(d, J=6.8 Hz, 6H).

[0307] Example S17: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 17) Scheme 17 [ka]

[0308] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17a) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyrazin-3(2H)-one (15a) (450 mg, 1.44 mmol) in HOAc (5 mL) was added isobenzofuran-1,3-dione (213.50 mg, 1.44 mmol). The mixture was stirred at 130° C. for 4 h. LCMS showed that one peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove HOAc. 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 17a. MS mass calculated: [M+1] + (C 22 H 17 Cl2N3O3) m / z 442.1, LCMS observed: m / z 442.1.

[0309] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17b) A mixture of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17a) (600 mg, 1.36 mmol) and DMF-DMA (5 mL) was heated to 105° C. for 3 h. LCMS showed one peak of the desired mass. The reaction mixture was concentrated in vacuo to give 17b. MS mass calculated: [M+1] + (C 23 H 19 Cl2N3O3) m / z 456.1, LCMS observed: m / z 456.1.

[0310] 6-(4-Amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyrazin-3(2H)-one (17c) A solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (17b) (600 mg, 1.31 mmol) N-butylaniline (981.11 mg, 6.57 mmol, 1.05 mL) and MeOH (3 mL) was heated to 70 °C for 3 h. LCMS showed one peak of the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 17c. MS mass calculated: [M+1] + (C 15 H 17 Cl2N3O) m / z 326.1, LCMS observed: m / z 326.1. 1 H NMR (400 MHz, CD3OD) δ 7.04 - 7.08 (m, 1H), 6.69 - 6.72 (m, 2H), 4.13 (s, 2H), 3.70 (s, 3H), 3.06 - 3.14 (m, 1H), 1.15 (d, J=6.8 Hz, 6H).

[0311] 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropyl-2-methylpyrazin-3(2H)-one (17d) To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyrazin-3(2H)-one (17c) (33 mg, 101.16 umol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (77.06 mg, 303.48 umol) in MeCN (1 mL) was added t-BuONO (20.86 mg, 202.32 umol, 24.06 uL). The mixture was stirred at 20° C. for 16 hours. LCMS showed one peak of the desired mass. The reaction mixture was extracted with ethyl acetate (20 mL×3) and H2O (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 17d. MS mass calculated: [M+1] + (C 21 H 27BCl2N2O3) m / z 437.1, LCMS observed: m / z 437.1. 1 H NMR (400 MHz, CDCl3)δ 7.75(s, 2H), 6.88(s, 1H), 4.27(s, 2H), 3.71(s, 3H), 3.16(td, J=7.0, 13.8 Hz, 1H), 1.36(s, 12H), 1.15(d, J=6.8 Hz, 6H).

[0312] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (17) A mixture of 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropyl-2-methylpyrazin-3(2H)-one (17d) (24.7 mg, 56.50 umol), 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (10.85 mg, 56.50 umol), Pd(dppf)Cl2 (4.13 mg, 5.65 umol) and K2CO3 (23.43 mg, 169.50 umol, 3 equiv) in dioxane (1 mL) and HO (0.5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. LCMS showed one peak of the desired mass. The mixture was added with palladium scavenger Si-TMT (3 g) and stirred at 20° C. for 1 h, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5 u; mobile phase: [water (0.225% FA)-ACN]) to give 17. MS mass calculated: [M+1] + (C18H 17 Cl2N5O3) m / z 422.1, LCMS observed: m / z 422.1. 1 H NMR (400 MHz, MeOH-d4)δ 8.10 - 8.14(m, 2H), 7.21 - 7.23(m, 1H), 4.35 - 4.37(m, 2H), 3.64(s, 3H), 3.13(quin, J=6.9 Hz, 1H), 1.19(d, J=6.8 Hz, 6H).

[0313] Example S18: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 18) Scheme 18 [ka]

[0314] Compound 18 can be prepared by reaction of 17d with 3A according to the procedure described in Example S17.

[0315] Example S19: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 19) Scheme 19 [ka]

[0316] 6-Bromo-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19a) To a solution of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (50 mg, 260.46 umol) in CH3CN (2 mL) was added BSA (132.46 mg, 651.15 umol, 160.95 uL). The mixture was then stirred at 82°C for 3 hours. Iodoethane (60.93 mg, 390.69 umol, 31.25 uL) was then added to the mixture. The resulting mixture was stirred at 82°C for an additional 16 hours. LCMS and TLC showed that the starting material was consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane:methanol) to give 19a. Calculated MS mass: [M+1] + (C5H6BrN3O2) m / z 220.0, LCMS observed: m / z 219.9. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H), 3.79 - 3.89 (m, 2H), 1.19 (t, J=7.2 Hz, 3H).

[0317] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19b) To a solution of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (40 mg, 90.18 umol) and 6-bromo-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19a) (19.84 mg, 90.18 umol) in dioxane (4 mL) and H2O (1 mL) was added K2CO3 (37.39 mg, 270.54 umol) and Pd(dppf)Cl2 (659.85 ug). The mixture was then stirred at 80 °C under N2 for 2 h. LCMS showed 19a was complete. The mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (10 mL×2) and H2O (5 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol) to give 19b (20 mg, crude). The product was used directly in the next step. MS mass calculated: [M+1] + (C18H 16 Cl3N5O3) m / z 456.0, LCMS observed: m / z 456.1.

[0318] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-ethyl-1,2,4-triazine-3,5(2H,4H)-dione (19b) (20 mg, 43.79 umol) in AcOH (3 mL) was added NaOAc (17.96 mg, 218.96 umol). The mixture was then stirred at 120° C. for 16 hours. LCMS and HPLC showed that 19b was complete and the desired was found in the major peak. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Nano-Micro UniSil 5-100 C18 ULTRA 100×250 mm 5 um; Mobile phase: [Water (0.1% TFA)-ACN]) to give 19. Calculated MS mass: [M+1] + (C18H17Cl2N5O4) m / z 438.1, LCMS observed: m / z 438.0. 1H NMR (400 MHz, MeOH-d4)δ 8.18(s, 2H), 7.36(s, 1H), 4.10(q, J=7.2 Hz, 2H), 3.15(d, J=13.2 Hz, 1H), 1.39(t, J=7.0 Hz, 3H), 1.29(d, J=7.0 Hz, 6H).

[0319] Example S20: 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (compound 20) Scheme 20 [ka]

[0320] 2-(6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20a) BSA (1.32 g, 6.51 mmol, 1.61 mL) was added to a mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (500 mg, 2.60 mmol) in CH3CN (5 mL) at 82 °C for 3 h, then 2-bromoethyl acetate (652.45 mg, 3.91 mmol, 432.08 uL) was added and the resulting mixture was stirred at 82 °C for 16 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 mL x 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:MeOH) to give 20a. MS mass calculated: [M+1] + (C7H8BrN3O4) m / z 278.0, LCMS observed: m / z 278.0. 1 H NMR (400 MHz, MeOH-d4) δ 4.70 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

[0321] 2-(6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20b) To a solution of ethyl 2-(6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetate (20a) (80 mg, 287.71 umol) and 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (128.20 mg, 287.71 umol) in THF (2 mL) was added Pd(dppf)Cl2 (18.75 mg, 28.77 umol) and K3PO4 (122.14 mg, 575.42 umol) in HO (0.5 mL). The mixture was stirred at 80 °C under N2 for 16 h. LCMS showed that 20a was completely consumed 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 preparative TLC (petroleum ether:ethyl acetate) to give 20b. MS mass calculated: [M+1] + (C 20 H 18 Cl3N5O5) m / z 514.0, LCMS observed: m / z 514.0.

[0322] 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethyl acetate (20) A mixture of ethyl 2-(6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetate (20b) (48 mg, 93.25 umol) and NaOAc (38.25 mg, 466.25 umol) in HOAc (3 mL) was heated to 110° C. and stirred for 16 h. LCMS showed that 20b was completely consumed and the desired MS was detected. The mixture was concentrated. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to give 20. Calculated MS mass: [M+1] + (C 20 H 19Cl2N5O6) m / z 496.1, LCMS observed: m / z 496.1. 1 H NMR (400 MHz, DMSO-d6)δ 12.67(s, 1H), 12.21(s, 1H), 8.09(s, 2H), 7.43(s, 1H), 4.83(s, 2H), 4.19(q, J=7.2 Hz, 2H), 3.05(td, J=6.8, 13.5 Hz, 1H), 1.25 - 1.18(m, 9H).

[0323] Example S21: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 21) Scheme 21 [ka]

[0324] 4-Allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a) To a solution of 6-bromo-2H-1,2,4-triazine-3,5-dione (1) (200 mg, 1.04 mmol) and 3-bromoprop-1-ene (126.04 mg, 1.04 mmol) in DMSO (2.5 mL) was added NaH (41.67 mg, 1.04 mmol, 60% purity) in portions at 25° C. The reaction mixture was stirred for 1 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 21a. 1 H NMR (400MHz, MeOH-d4) δ 5.85 - 5.90 (m, 1H), 5.19 - 5.28 (m, 2H), 4.49 - 4.50 (d, 2H).

[0325] 4-Allyl-6-bromo-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21b) To a solution of 4-allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a) (55 mg, 237.03 umol) in DMF (2 mL) was added Cs2CO3 (154.46 mg, 474.07 umol). Then, 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.02 mg, 284.44 umol, 25.00 uL) was added to the mixture. The resulting mixture was then stirred at 20° C. for 1 h. TLC showed the reaction was complete and one new spot was formed. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 21b. 1 H NMR (400MHz, CDCl3)δ 7.28 - 7.98 (m, 1H), 5.86 (ddt, J=17.0, 10.4, 6.2, 6.2 Hz, 1H), 5.24 - 5.47 (m, 2H), 4.53 - 4.66 (m, 4H).

[0326] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21c) To a solution of 4-allyl-6-bromo-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21b) (20 mg, 63.68 umol) and 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (33.90 mg, 76.42 umol) in dioxane (3 mL) and HO (1 mL) was added KCO (17.60 mg, 127.36 umol) and Pd(dppf)Cl (4.66 mg, 6.37 umol) under N. The mixture was then stirred at 90 °C under N for 16 h. LCMS and TLC showed the reaction was complete and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane:methanol) to give 21c (20 mg, crude). MS mass calculated: [M+1] + (C18H 13Cl3F3N5O3) m / z 510.0, LCMS observed: m / z 510.1.

[0327] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (21c) (20 mg, 39.16 umol) in HOAc (3 mL) was added NaOAc (16.06 mg, 195.82 umol). The mixture was then stirred at 120° C. for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL×2) and H2O (5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Kromasil 150×25 mm×10 um; mobile phase: [water (0.04% NH3H2O+10 mM NH4HCO3)-ACN]) to give 21. MS mass calculated: [M+1] + (C18H 14 Cl2F3N5O4) m / z 492.0, LCMS observed: m / z 492.0. 1 H NMR (400MHz, MeOH-d4)δ 8.17(s, 2H), 7.38(d, J=1 Hz, 1H), 4.80(q, J=8.6 Hz, 2H), 3.10 - 3.25(m, 1H), 1.31(d, J=7.0 Hz, 6H).

[0328] Example S22: 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetonitrile (compound 22) Scheme 22 [ka]

[0329] 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetamide (22a) A mixture of ethyl 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetate (27 mg, 54.40 umol) in NH3.H2O (3 mL) was stirred at 20° C. for 1 h under N2. LCMS showed complete consumption of 20 and the desired MS was detected. The mixture was concentrated to give 22a. The product was used directly in the next step. Calculated MS mass: [M+1] + (C18H 16 Cl2N6O5) m / z 467.1, LCMS observed: m / z 467.1.

[0330] 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetonitrile (22) A solution of SOCl2 (31.83 mg, 267.52 umol, 19.41 uL) in anhydrous DMF (2 mL) was added dropwise to a solution of 2-(6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)acetamide (22a) (25 mg, 53.50 umol) in anhydrous DMF (1 mL) with stirring at 25 °C. The mixture was heated to 120 °C for 3 h. LCMS showed that 22a was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 mL x 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 preparative HPLC (Conditions; Column: Xtimate C18 150×25 mm×5 um; Mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 22. MS mass calculated: [M+1] + (C18H 14 Cl2N6O4) m / z 449.0, LCMS observed: m / z 449.0. 1H NMR (400 MHz, CDCl3) δ 9.93 (br s, 1H), 8.08 (s, 2H), 7.18 (br s, 1H), 5.00 (s, 2H), 3.27 (br s, 1H), 1.33 (br d, J=6.4 Hz, 6H).

[0331] Example S23: 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 23) Scheme 23 [ka]

[0332] 4-Allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23a) To a solution of 4-allyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (21a) (10 mg, 43.10 umol) in DMF (1 mL) was added Cs2CO3 (28.08 mg, 86.19 umol). Then, 2,2-difluoroethyl trifluoromethanesulfonate (11.07 mg, 51.72 umol, 25.00 uL) was added to the mixture. The resulting mixture was then stirred at 20° C. for 1 hour. TLC showed the reaction was complete and one new spot was formed. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 23a. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H), 3.79 - 3.89 (m, 2H), 1.19 (t, J=7.2 Hz, 3H).

[0333] 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23b) To a solution of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazine (2b) (50 mg, 112.72 umol) and 4-allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23a) (36.71 mg, 124.00 umol) in dioxane (3 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (8.25 mg, 11.27 umol) and K2CO3 (31.16 mg, 225.45 umol). The mixture was then stirred at 90 °C under N2 for 16 h. LCMS and TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol) to give 23b (20 mg, crude). MS mass calculated: [M+1] + (C18H 14 C l3 F2N5O3) m / z 492.0, LCMS observed: m / z 492.1.

[0334] 6-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-isopropylpyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23b) (20 mg, 40.59 umol) in HOAc (2 mL) was added NaOAc (16.65 mg, 202.97 umol). The mixture was then stirred at 120° C. for 16 hours. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (5 mL×2) and H2O (5 mL). The organic layer was dried under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.1% TFA)-ACN]) to give 23. MS mass calculated: [M+1] + (C18H 15Cl2F2N5O4) m / z 474.0, LCMS observed: m / z 474.0. 1 H NMR (400 MHz, MeOH-d4)δ 8.17(s, 2H), 7.36(s, 1H), 6.05 - 6.46(m, 1H), 4.87(s, 13H), 4.43(td, J=13.6, 4.0 Hz, 2H), 3.17(dt, J=13.6, 7.0 Hz, 1H), 1.29(d, J=6.8 Hz, 6H).

[0335] Example S24: 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 24) Scheme 24 [ka]

[0336] 6-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (24) To a solution of 4-allyl-6-bromo-2-(2,2-difluoroethyl)-1,2,4-triazine-3,5(2H,4H)-dione (23a) (40 mg, 135.10 umol) and 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (1f) (59.33 mg, 135.10 umol) in dioxane (3 mL) and H2O (1 mL) was added K2CO3 (37.34 mg, 270.21 umol) and Pd(dppf)Cl2 (9.89 mg, 13.51 umol) under N2. The mixture was then stirred at 90 °C under N2 for 16 h. LCMS and TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane:methanol) to give 24. MS mass calculated: [M+1] + (C 19 H 17 Cl2F2N5O4) m / z 488.0, LCMS observed: m / z 488.0. 1H NMR (400MHz, DMSO-d6)δ 12.62(br s, 1H), 8.13(s, 2H), 7.46(s, 1H), 6.24 - 6.60(m, 1H), 4.34 - 4.49(m, 2H), 3.39(s, 3H), 3.08 - 3.12 (m, 1H), 1.21 (d, J=7.0 Hz, 6H).

[0337] Example S25: 6-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 25) Scheme 25 [ka]

[0338] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (25a) To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (1e) (500 mg, 1.52 mmol) in MeCN (10 mL) was added Select F (593.68 mg, 1.68 mmol). The mixture was stirred at 15° C. for 3 h. TLC and LCMS showed that 1e was completely consumed and the desired MS was detected. The reaction mixture was quenched by adding 10 mL of H2O. The reaction mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 25a. Calculated MS mass: [M+1] + (C 14 H 14 C l2 FN3O2) m / z 346.0, LCMS observed: m / z 346.2. 1 H NMR(400 MHz, CDCl3)δ 7.02(d, J=0.6 Hz, 1H), 6.78 - 6.85(m, 1H), 3.88(s, 1H), 3.52 - 3.57(m, 3H), 3.24(dt, J=14.2, 7.0 Hz, 1H), 1.26(d, J=6.8 Hz, 6H).

[0339] (3,5-Dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phen-yl)boronic acid (25b) To a mixture of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyrazin-3(2H)-one (25a) (150 mg, 433.30 umol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.20 g, 8.67 mmol) in CH3CN (8 mL) was added t-BuONO (89.36 mg, 866.59 umol, 103.07 uL) at 15°C. The mixture was then stirred at 15°C for 16 hours. TLC, LCMS and HPLC showed that 25a was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase: [water (0.1% TFA)-ACN]) to give 25b. MS mass calculated: [M+1] + (C 14 H 14 BCl2FN2O4) m / z 375.0, LCMS observed: m / z 375.1. 1 H NMR (400 MHz, CDCl3)δ 7.87(s, 1H), 7.07(s, 1H), 3.51(s, 3H), 3.23 - 3.29(m, 1H), 1.38(s, 3H), 1.27 - 1.29(m, 6H).

[0340] 6-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (25) To a mixture of (3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phen-yl)boronic acid (25b) (10 mg, 26.67 umol) and 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (7.68 mg, 40.00 umol) in THF (2 mL) and HO (0.5 mL) was added di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (1.74 mg, 2.67 umol) and KPO (11.32 mg, 53.34 umol). The mixture was then degassed and purged with N three times, and the mixture was then stirred at 90° C. under a nitrogen atmosphere for 16 hours. LCMS and HPLC showed that 25b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.1% TFA)-ACN]) to give 25. Calculated MS mass: [M+1] + (C 17 H 14 Cl2FN5O4) m / z 442.0, LCMS observed: m / z 442.0. 1 H NMR (400 MHz, MeOH-d4) δ 7.72 (d, J=6.8 Hz, 1H), 7.38 (s, 1H), 3.51 (s, 3H), 3.20 (dt, J=13.6, 6.8 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H).

[0341] Example S26: 6-(4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)-3,5-dimethylphenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 26) Scheme 26 [ka]

[0342] 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene (26a) To a solution of (4-bromo-2,6-dimethylphenyl)methanol (1 g, 4.65 mmol) in DCM (30 mL) was added PPh3 (1.83 g, 6.97 mmol) under N2. The mixture was then cooled to 0-5 °C, and CBr4 (2.31 g, 6.97 mmol) was added portionwise to the mixture. The mixture was then stirred at 15 °C under N2 for 0.5 h. TLC showed that the starting material was completely consumed and one new spot was formed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 26a. 1 H NMR (400 MHz, CDCl3) δ 7.21(s, 2H), 4.50(s, 2H), 2.39(s, 6H).

[0343] 2-(4-Bromo-2,6-dimethylphenyl)acetonitrile (26b) To a solution of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene (26a) (1.26 g, 4.53 mmol) in DMF (30 mL) was added NaCN (244.35 mg, 4.99 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 16 h. TLC showed that 26a was completely consumed and one new spot was formed. To the mixture was added aqueous NH4Cl (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 26b. 1 H NMR (400MHz, MeOH-d4) δ 7.28(s, 2H), 3.79(s, 2H), 2.38(s, 6H).

[0344] 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyrazin-3-yl)acetonitrile (26c) To a solution of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (26b) (800 mg, 3.57 mmol) and 3,6-dichloro-4-isopropylpyridazine (682.05 mg, 3.57 mmol) in THF (10 mL) was added dropwise t-BuOK (1 M, 7.14 mL) at 60° C. The resulting mixture was heated to 60° C. for 1 h. TLC and LCMS showed that 26b was completely consumed and the desired MS was detected. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 26c. Calculated MS mass: [M+1] + (C 17 H 17 BrClN3) m / z 378.0, LCMS observed: m / z 378.2. 1 H NMR (400MHz, MeOH-d4)δ 7.34(s, 3H), 7.21(s, 1H), 6.28(s, 1H), 3.01(dt, J=13.4, 6.8 Hz, 1H), 2.89(dt, J=13.8, 6.8 Hz, 1H), 2.27(s, 6H), 1.30 - 1.27(m, 6H).

[0345] 6-(4-Bromo-2,6-dimethylbenzyl)-4-isopropylpyrazin-3(2H)-one (26d) A solution of 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyrazin-3-yl)acetonitrile (26c) (1 g, 2.78 mmol) in AcOH (10 mL), HO (10 mL) and HCl (40 mL) was heated to 120° C. for 48 h. LCMS showed that 26c was completely consumed and the desired MS was detected. At 15° C., the mixture was adjusted to pH ∼7 with 3M NaOH and the solid was collected by filtration and dried to give 26d. Calculated MS mass: [M+1] + (C 16 H 19 BrNO) m / z 335.1, LCMS observed: m / z 335.2. 1H NMR (400MHz, DMSO-d6) δ 12.56(s, 1H), 7.24(s, 2H), 7.11(s, 1H), 3.90(s, 2H), 2.97(quin, J=6.8 Hz, 1H), 2.21(s, 6H), 1.11(d, J=6.8 Hz, 6H).

[0346] 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropylpyrazin-3(2H)-one (26e) To a solution of 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyrazin-3(2H)-one (26d) (50 mg, 149.15 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (113.62 mg, 447.44 umol) in dioxane (3 mL) was added KOAc (73.19 mg, 745.74 umol) and Pd(dppf)Cl2 (10.91 mg, 14.91 umol). The mixture was degassed and purged with nitrogen three times and stirred at 90° C. for 16 hours. TLC and LCMS showed that 26d was completely consumed and the desired MS was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL×2). The combined organic 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 (petroleum ether:ethyl acetate) to give 26e. MS mass calculated: [M+1] + (C 22 H 31 BN2O3) m / z 383.2, LCMS observed: m / z 383.4. 1 H NMR (400MHz, MeOH-d4)δ 7.42(s, 2H), 6.98(s, 1H), 4.05(s, 2H), 3.06(dt, J=13.6, 6.8 Hz, 1H), 2.29(s, 6H), 1.34(s, 12H), 1.14(d, J=6.8 Hz, 6H).

[0347] 6-(4-((5-isopropyl-6-oxo-1,6-dihydropyrazin-3-yl)methyl)-3,5-dimethylphenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (26) To a mixture of 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropylpyrazin-3(2H)-one (26e) (32 mg, 83.70 umol) and 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (25.86 mg, 125.55 umol) in THF (4 mL) and HO (1 mL) was added Pd(dppf)Cl2 (5.46 mg, 8.37 umol) and K3PO4 (35.53 mg, 167.41 umol). The mixture was then degassed and purged with N2 three times. The mixture was then stirred at 90 °C under nitrogen atmosphere for 16 h. HPLC and LCMS showed that 26e was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 26. Calculated MS mass: [M+1] + (C 20 H 23 N5O3) m / z 382.2, LCMS observed: m / z 382.2. 1 H NMR (400MHz, MeOH-d4)δ 7.68(s, 2H), 7.04(s, 1H), 4.07(s, 2H), 3.65(s, 3H), 3.07(dt, J=13.8, 6.6 Hz, 1H), 2.33(s, 6H), 1.15(d, J=6.8 Hz, 6H).

[0348] Example S27: 6-(3,5-dichloro-4-((6-oxo-5-(pentan-3-yl)-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 27) Scheme 27 [ka]

[0349] 3,6-Dichloro-4-(pentan-3-yl)pyridazine (27a) To a mixture of 3,6-dichloropyridazine (1 g, 6.71 mmol) and 2-ethylbutanoic acid (779.70 mg, 6.71 mmol, 845.66 uL) in H2O (20 mL) was added AgNO3 (1.14 g, 6.71 mmol) and TFA (2.30 g, 20.14 mmol, 1.49 mL) in one portion at 50 °C, then a solution of (NH4)2S2O8 (4.60 g, 20.14 mmol, 4.38 mL) in H2O (10 mL) was added to the mixture, then the mixture was stirred at 70 °C for 30 min. LCMS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 27a. 1 H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 2.89 - 2.98 (m, 1H), 1.67 - 1.80 (m, 2H), 1.55 - 1.64 (m, 2H), 0.82 (t, J=7.4 Hz, 6H).

[0350] 3,5-Dichloro-4-((6-chloro-5-(pentan-3-yl)pyrazin-3-yl)oxy)aniline (27b) To a solution of 3,6-dichloro-4-(pentan-3-yl)pyridazine (27a) (530 mg, 2.42 mmol) and 4-amino-2,6-dichlorophenol (516.72 mg, 2.90 mmol) in DMSO (20 mL) was added K2CO3 (1.34 g, 9.68 mmol) and CuI (276.40 mg, 1.45 mmol). The reaction mixture was degassed and purged with N2 three times, then stirred at 90 °C under nitrogen atmosphere for 16 h. TLC and LCMS showed that 27a was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (50 mL x 2) and H2O (20 mL). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 27b. MS mass calculated: [M+1]+ (C 15 H 16 Cl3N3O) m / z 360.0, LCMS observed: m / z 360.1. 1 H NMR (400 MHz, MeOH-d4) δ 7.40(s, 1H), 6.74(s, 2H), 4.86(s, 4H), 2.96 - 3.05(m, 1H), 1.65 - 1.88(m, 4H), 0.87(t, J=7.4 Hz, 6H).

[0351] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(pentan-3-yl)pyridazine (27c) To a solution of 3,5-dichloro-4-((6-chloro-5-(pentan-3-yl)pyrazin-3-yl)oxy)aniline (27b) (575 mg, 1.59 mmol) in HCl (5 mL) was added NaNO2 (132.00 mg, 1.91 mmol) at 0 °C, and the mixture was then stirred at 0 °C for 0.5 h. To the reaction mixture was then added a solution of KI (529.31 mg, 3.19 mmol) in H2O (5 mL), and the mixture was then stirred at 15 °C for 1.5 h. TLC and LCMS showed that 27b was completely consumed and the desired mass was detected. The mixture was extracted with ethyl acetate (100 mL × 2) and H2O (50 mL). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 27c. MS mass calculated: [M+1] + (C 15 H 14 Cl3IN2O) m / z 470.9, LCMS observed: m / z 470.8. 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 2H), 7.13 (s, 1H), 2.96 - 3.05 (m, 1H), 1.61 - 1.87 (m, 4H), 0.89 (t, J=7.46 Hz, 6H).

[0352] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(pentan-3-yl)pyridazine (27d) To a solution of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(pentan-3-yl)pyridazine (27c) (500 mg, 1.06 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (807.78 mg, 3.18 mmol) in dioxane (15 mL) was added KOAc (520.32 mg, 5.30 mmol) and Pd(dppf)Cl2 (77.59 mg, 106.03 umol). The mixture was degassed and purged with nitrogen three times and stirred at 90° C. for 16 h. TLC and LCMS showed that 27d was completely consumed and the desired mass was detected. The mixture was extracted with ethyl acetate (50 mL×2) and H2O (20 mL). The combined organic phase was washed with brine (20 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) to give 27d. MS mass calculated: [M+1] + (C 21 H 26 BCl3N2O3) m / z 471.1, LCMS observed: m / z 471.1. 1 H NMR (400 MHz, CDCl3)δ 7.81(s, 2H), 7.13(s, 1H), 2.94 - 3.04(m, 1H), 1.62 - 1.86(m, 4H), 1.35(s, 11H), 0.89(t, J=7.4 Hz, 6H).

[0353] 6-(3,5-dichloro-4-((6-chloro-5-(pentan-3-yl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (27e) To a mixture of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(pentan-3-yl)pyridazine (27d) (150 mg, 318.06 umol) and 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (98.28 mg, 477.09 umol) in THF (4 mL) and HO (1 mL) was added Pd(dppf)Cl (20.73 mg, 31.81 umol) and KPO (135.03 mg, 636.12 umol), degassed and purged with N three times, then the mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. TLC and LCMS showed that 27d was completely consumed and the desired MS was detected. The reaction mixture was dissolved in water and the pH was adjusted to 4 with HCl (1M, 1 mL). The mixture was then partitioned into ethyl acetate (20 mL×2). 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 preparative TLC (petroleum ether:ethyl acetate) to give 27e. MS mass calculated: [M+1] + (C 19 H 18 Cl3N5O3) m / z 470.0, LCMS observed: m / z 470.1. 1 H NMR (400 MHz, MeOH-d4)δ 8.25(s, 2H), 7.61(s, 1H), 4.10(q, J=7.2 Hz, 1H), 3.69(s, 3H), 1.71 - 1.90(m, 5H), 0.90(t, J=7.4 Hz, 7H).

[0354] 6-(3,5-dichloro-4-((6-oxo-5-(pentan-3-yl)-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (27) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-(pentan-3-yl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (27e) (80 mg, 169.95 umol) in AcOH (5 mL) was added NaOAc (69.71 mg, 849.73 umol) at 15° C. The mixture was then stirred at 120° C. for 16 h. LCMS and HPLC showed that 27e was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to give 27. Calculated MS mass: [M+1] + (C 19 H 19 Cl2N5O4) m / z 452.1, LCMS observed: m / z 452.1. 1 H NMR (400 MHz, DMSO-d6)δ 12.44(br s, 1H), 12.19(s, 1H), 8.09(s, 2H), 7.43(s, 1H), 3.57(s, 3H), 2.78(quin, J=7.0 Hz, 1H), 1.59 - 1.68 (m, 4H), 0.79 (t, J=7.4 Hz, 6H).

[0355] Example S28: 6-(3,5-dichloro-4-((5-ethyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 28) Scheme 28 [ka]

[0356] 3,6-Dichloro-4-ethylpyridazine (28a) To a mixture of 3,6-dichloropyridazine (1 g, 6.71 mmol) and propionic acid (497.24 mg, 6.71 mmol, 500.75 uL) in H2O (30 mL) was added TFA (2.30 g, 20.14 mmol, 1.49 mL) and AgNO3 (1.14 g, 6.71 mmol) and (NH4)2S2O8 (4.60 g, 20.14 mmol, 4.38 mL) in one portion at 50 °C. The mixture was stirred at 70 °C for 30 min. LCMS showed completion of 3,6-dichloropyridazine. To the residue was poured NaHCO3 (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 28a. MS mass calculated: [M+1] + (C6H6Cl2N2) m / z 177.0, LCMS observed: m / z 177.0. 1 H NMR (400 MHz, CDCl3)δ 8.12 - 8.16 (m, 2H), 7.90 - 7.92 (m, 1H), 3.12 - 3.21 (m, 1H), 1.29 (d, J=7.0 Hz, 6H).

[0357] 6-(4-Bromo-2,6-dichlorophenoxy)-3-chloro-4-ethylpyridazine (28b) A solution of 3,6-dichloro-4-ethylpyridazine (28a) (340 mg, 1.92 mmol) and 4-bromo-2,6-dichlorophenol (511.04 mg, 2.11 mmol) in Py (5 mL) was stirred at 130 °C for 16 h in a microwave tube. LCMS and TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.5) showed that 28a was completely consumed and the desired MS was detected. Water (5 mL) was poured into the residue. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (5 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) to give 28b (200 mg, crude). MS mass calculated: [M+1] + (C 12H8BrCl3N2O) m / z 380.9, LCMS observed: m / z 380.9. 1 H NMR (400 MHz, CDCl3)δ 7.44(s, 4H), 7.15(s, 1H), 7.10(s, 1H), 2.72 - 2.80(m, 3H), 2.66 - 2.71(m, 2H), 1.22 - 1.31(m, 7H), 1.17(br t, J=7.58 Hz, 3H).

[0358] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-ethylpyridazine (28c) To a solution of 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-ethylpyridazine (28b) (150 mg, 392.19 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (298.78 mg, 1.18 mmol) in dioxane (6 mL) was added Pd(dppf)Cl2 (28.70 mg, 39.22 umol) and KOAc (192.45 mg, 1.96 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 16 h. TLC (petroleum ether:ethyl acetate) showed that 28b was completely consumed. The suspension was filtered through a Celite pad and the pad cake was washed with ethyl acetate (15 mL×3). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 28c. MS mass calculated: [M+1] + (C18H 20 BCl3N2O3) m / z 429.1, LCMS observed: m / z 429.1.

[0359] 6-(3,5-dichloro-4-((6-chloro-5-ethylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (28d) To a solution of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-ethylpyridazine (28c) (160 mg, 372.50 umol) and 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (115.10 mg, 558.75 umol) in THF (4 mL) was added Pd(dppf)Cl2 (24.28 mg, 37.25 umol) and K3PO4 (158.14 mg, 745.00 umol) in HO (1 mL). The mixture was stirred at 80 °C for 16 h. LCMS showed that 28c was completely consumed and the desired MS was detected. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.2% FA)-ACN]) to give 28d. MS mass calculated: [M+1] + (C 16 H 12 Cl3N5O3) m / z 428.0, LCMS observed: m / z 428.0. 1 H NMR (400 MHz, MeOH-d4) δ 8.25(s, 2H), 7.59(s, 1H), 3.69(s, 3H), 2.83 - 2.90(m, 2H), 1.36(t, J=7.6 Hz, 3H).

[0360] 6-(3,5-dichloro-4-((5-ethyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (28) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-ethylpyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (28d) (78 mg, 181.96 umol) in HOAc (3 mL) was added NaOAc (74.64 mg, 909.82 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 28d was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to give 28. MS mass calculated: [M+1]+ (C 16 H 13 Cl2N5O4) m / z 410.0, LCMS observed: m / z 410.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (br s, 1H), 8.14 (s, 2H), 7.46 (s, 1H), 3.54 (s, 3H), 1.17 (t, J=7.4 Hz, 3H).

[0361] Example S29: 6-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (29) Scheme 29a [ka]

[0362] 2-Methyl-6-(trimethylstannyl)-1,2,4-triazine-3,5(2H,4H)-dione (29a) To a solution of 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (900 mg, 4.37 mmol) in toluene (15 mL), trimethyl(trimethylstannyl)stannane (1.72 g, 5.24 mmol, 1.09 mL), Pd(PPh3)4 (504.86 mg, 436.90 umol) were added and the mixture was stirred at 110°C under nitrogen atmosphere for 16 h. TLC showed traces of starting material remaining and one new spot formed. The reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate (15 mL), washed with aqueous KF solution (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 29a. MS mass calculated: [M+1] + (C7H 13 N3O2Sn) m / z 292.0, LCMS observed: m / z 292.2. Scheme 29b [ka]

[0363] 2-(3,6-Dichloropyrazin-4-yl)propan-1-ol (29b) To a mixture of 3,6-dichloropyridazine (2 g, 13.42 mmol) and 2-methylpropane-1,3-diol (2.65 g, 29.40 mmol, 2.62 mL) in H2O (10 mL) was added TFA (1.88 g, 16.48 mmol, 1.22 mL) and AgNO3 (3.07 g, 18.07 mmol) at 80 °C. Then, to the mixture was added (NH4)2S2O8 (6.72 g, 10.93 mmol) in one portion at 80 °C. The mixture was stirred at 80 °C for 30 min. TLC showed that the starting material was completely consumed. Water (10 mL) was poured into the residue. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 29b. 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 3.84 - 3.91 (m, 2H), 3.33 - 3.42 (m, 1H), 1.35 (d, J=7.0 Hz, 3H).

[0364] 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,6-dichloropyridazine (29c) To a solution of 2-(3,6-dichloropyrazin-4-yl)propan-1-ol (29b) (700 mg, 3.38 mmol) and tert-butyl-chloro-dimethyl-silane (509.55 mg, 3.38 mmol, 414.26 uL) in DMF (15 mL) was added imidazole (276.18 mg, 4.06 mmol). The mixture was stirred at 25° C. under nitrogen atmosphere for 1 h. TLC showed that 29b was completely consumed. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 29c. 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 321.2. 1H NMR (400 MHz, CDCl3)δ 7.48(s, 1H), 3.73 - 3.81(m, 2H), 3.29 - 3.39(m, 1H), 1.32(d, J=7.2 Hz, 3H), 0.84(s, 9H), 0.01(s, 3H), -0.04(s, 3H).

[0365] 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyrazin-3-yl)oxy)-3,5-dichloroaniline (29d) To a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,6-dichloropyridazine (29c) (300 mg, 933.66 umol) in DMSO (10 mL) was added 4-amino-2,6-dichlorophenol (225.85 mg, 933.66 umol), K2CO3 (387.12 mg, 2.80 mmol) and CuI (106.69 mg, 560.19 umol). The mixture was stirred at 90 °C under nitrogen atmosphere for 6 h. LCMS showed that 29c was completely consumed and the desired mass was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (50 mL). The reaction mixture was quenched at 20 °C with H2O (30 mL) then diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL x 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 preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give 29d. MS mass calculated: [M+1] + (C 19 H 26 Cl3N3O2Si) m / z 462.1, LCMS observed: m / z 462.1. 1 H NMR (400 MHz, MeOH-d4)δ 7.44(s, 1H), 6.73(s, 2H), 3.83 - 3.92(m, 2H), 3.37 - 3.45(m, 1H), 1.34(d, J=7.0 Hz, 3H), 0.83(s, 9H), -0.01(d, J=7.2) Hz, 6H).

[0366] 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (29e) To a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyrazin-3-yl)oxy)-3,5-dichloroaniline (29d) (50 mg, 108.02 umol) in ACN (1 mL) was added tert-butyl nitrite (22.28 mg, 216.04 umol) and KI (35.86 mg, 216.04 umol). The reaction mixture was then degassed and purged with N2 three times. The mixture was stirred at 20 °C for 2 h. TLC showed that 29d was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (5 mL) and ethyl acetate (10 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layer (10 mL) was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 29e. MS mass calculated: [M+1] + (C 19 H 24 Cl3IN2O2Si) m / z 573.0, LCMS observed: m / z 573.0.

[0367] 6-(4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (29f) To a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (29e) (27 mg, 47.06 umol) in dioxane (1 mL) was added 2-methyl-6-(tributylstannyl)-1,2,4-triazine-3,5(2H,4H)-dione (29a) (13.92 mg, 48.00 umol) and Pd(dppf)Cl2.CH2Cl2 (3.84 mg, 4.71 umol). The mixture was then degassed and purged with N2 three times, then the mixture was stirred at 110 °C under nitrogen atmosphere for 16 h. LCMS showed 40% 29e remaining and the desired mass was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (5 mL×3). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 29f. MS mass calculated: [M+1] + (C 23 H 28 Cl3N5O4Si) m / z 572.1, LCMS observed: m / z 572.1.

[0368] 2-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyrazin-4-yl)propyl acetate (29g) To a solution of 6-(4-((5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (29f) (19 mg, 33.16 umol) in HOAc (1 mL) was added NaOAc (13.60 mg, 165.81 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 29f was completely consumed and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH to give 29g (30 mg, crude). The product was used in the next step without further purification. Calculated MS mass: [M+1] + (C 19 H 17 Cl2N5O6) m / z 482.1, LCMS observed: m / z 482.1.

[0369] 6-(3,5-dichloro-4-((5-(1-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (29) To a solution of 2-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyrazin-4-yl)propyl acetate (29g) (30 mg, 62.21 umol) in THF (1 mL), LiOH . H2O (1 M, 3 mL) was added. The mixture was stirred at 20°C for 16 hours. LCMS showed that 29g was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100x30mm 5um; mobile phase: [water (0.225% FA)-ACN]) to give 29. MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.0, LCMS observed: m / z 440.0. 1 H NMR (400 MHz, MeOH-d4)δ 8.18(s, 2H), 7.39(s, 1H), 3.78 - 3.86(m, 1H), 3.64 - 3.74(m, 4H), 3.21 - 3.27(m, 1H), 1.30(d, J=7.0 Hz, 3H).

[0370] Example S30: 6-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 30) Scheme 30 [ka]

[0371] 1-(3,6-Dichloropyrazin-4-yl)propan-1-ol (30a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (300 mg, 1.99 mmol) in toluene (5 mL) was added pent-1-yn-3-ol (334.34 mg, 3.97 mmol, 342.91 uL). The mixture was stirred in a sealed tube at 110° C. for 16 h. TLC showed that the starting material was completely consumed and many new spots were formed. LCMS showed that the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 30a. MS mass calculated: [M+1] + (C7H8Cl2N2O) m / z 207.0, LCMS observed: m / z 207.1. 1 H NMR(400 MHz, CDCl3)δ ppm 7.77(s, 1H), 4.91 - 4.96(m, 1H), 2.31(d, J=4.0 Hz, 1H), 1.95(dqd, J=14.4, 7.4, 7.4, 7.4, 3.4 Hz, 1H), 1.67(dquin, J=14.6, 7.4, 7.4, 7.4, 7.4 Hz, 1H), 1.06(t, J=7.4 Hz, 3H).

[0372] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (30b) To a solution of 1-(3,6-dichloropyrazin-4-yl)propan-1-ol (30a) (370 mg, 1.79 mmol) and DHP (751.56 mg, 8.93 mmol, 816.91 uL) in DCM (8 mL) was added TsOH (15.39 mg, 89.35 umol). The mixture was stirred at 20° C. for 1 h. LCMS and TLC showed that 30a was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 30b. MS mass calculated: [M+1] + (C 12 H 16 Cl2N2O2) m / z 291.1, LCMS observed: m / z 291.1. 1H NMR (400 MHz, CDCl3)δ ppm 7.71(s, 1H), 7.56(s, 1H), 4.97(dt, J=7.8, 4.0 Hz, 3H), 4.78(dd, J=7.0, 4.0 Hz, 1H), 4.68 - 4.71(m, 1H), 4.58(br s, 6H), 4.40(t, J=3.4 Hz, 1H), 1.02 - 1.09(m, 4H), 0.95(t, J=7.4 Hz, 3H).

[0373] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrazin-3-yl)oxy)aniline (30c) To a solution of 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (30b) (500 mg, 1.72 mmol) and 4-amino-2,6-dichlorophenol (305.69 mg, 1.72 mmol) in DMSO (15 mL) was added K2CO3 (949.33 mg, 6.87 mmol) and CuI (196.22 mg, 1.03 mmol), degassed and purged with N2 three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. TLC showed that 30b was completely consumed and one new spot was formed. LCMS showed that the desired MS was detected. The mixture was diluted with ethyl acetate (5 mL) and the filtrate was extracted with ethyl acetate (10 mL × 3) and H2O (5 mL). The combined organic phase was washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 30c. MS mass calculated: [M+1] + (C18H 20 Cl3N3O3) m / z 432.1, LCMS observed: m / z 432.0. 1H NMR (400 MHz, CDCl3)δ ppm 7.48(s, 1H), 7.29(s, 1H), 6.69(s, 2H), 4.97(dd, J=7.2, 3.8 Hz, 1H), 4.76 - 4.83(m, 1H), 4.58(br s, 1H), 4.46(br s, 1H), 3.98(br d, J=7.6 Hz, 1H), 3.79(br d, J=3.6 Hz, 2H), 3.33 - 3.63(m, 3H), 1.06(br t, J=7.2 Hz, 2H), 0.96(br t, J=7.2 Hz, 2H).

[0374] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (30d) A solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrazin-3-yl)oxy)aniline (30c) (170 mg, 392.86 umol) in ACN (3 mL) was added to KI (130.43 mg, 785.71 umol) and t-BuONO (202.56 mg, 1.96 mmol, 233.63 uL). The mixture was stirred at 20° C. for 2 hours. TLC showed that 30c was completely consumed and one new spot was formed. LCMS showed the desired MS. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 30d. Calculated MS mass: [M+1] + (C18H 18 Cl3IN2O3) m / z 542.9, LCMS observed: m / z 542.9. 1 H NMR (400 MHz, CDCl3)δ 7.73(s, 2H), 7.57(s, 1H), 4.94(dt, J=7.6, 3.8 Hz, 1H), 2.19(d, J=4.0 Hz, 1H), 2.03 - 1.94(m, 1H), 1.85(dt, J=14.6, 7.2 Hz, 1H), 1.70(dquin, J=14.6, 7.34, 7.4, 7.4, 7.4 Hz, 1H), 1.27(t, J=7.2 Hz, 1H), 1.12 - 1.05(m, 3H).

[0375] 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (30e) To a solution of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (30d) (70 mg, 128.77 umol) and 2-methyl-6-(trimethylstannyl)-1,2,4-triazine-3,5(2H,4H)-dione (29a) (41.06 mg, 141.65 umol) in dioxane (4 mL) was added Pd(dppf)Cl2.CH2Cl2 (10.52 mg, 12.88 umol). The mixture was degassed and purged with nitrogen three times and stirred at 110 °C for 16 h. TLC and LCMS showed that ∼2 / 3 of 30d remained and the desired MS was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 30e. MS mass calculated: [M+1] + (C 22 H 22 Cl3N5O5) m / z 542.1, LCMS observed: m / z 452.1. 1 H NMR(400 MHz, CDCl3)δ 8.20(s, 1H), 7.58(s, 1H), 7.40(s, 1H), 7.40 - 7.41(m, 1H), 5.00(dd, J=7.4, 3.6 Hz, 1H), 4.77 - 4.85(m, 1H), 4.48 - 4.52 (m, 1H), 3.94 - 4.02 (m, 1H), 3.76 (s, 2H), 3.56 - 3.67 (m, 1H), 3.36 - 3.43 (m, 1H), 1.51 - 2.01 (m, 6H), 1.19 - 1.32 (m, 1H), 1.19 - 1.32(m, 1H), 1.08(t, J=7.4 Hz, 1H), 0.98(t, J=7.4 Hz, 1H).

[0376] 1-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyrazin-4-yl)propyl acetate (30f) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (30e) (15 mg, 27.63 umol) in HOAc (2 mL) was added NaOAc (11.33 mg, 138.17 umol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 30e was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo to give 30f (20 mg, crude). Calculated MS mass: [M+1] + (C 19 H 17 Cl2N5O6) m / z 482.1, LCMS observed: m / z 482.0.

[0377] 6-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (30) To a solution of 1-(6-(2,6-dichloro-4-(2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenoxy)-3-oxo-2,3-dihydropyrazin-4-yl)propyl acetate (30f) (20 mg, 41.47 umol) in MeOH (3 mL) and H2O (0.5 mL) was added LiOH.H2O (1 M, 82.94 uL). The mixture was stirred at 25 °C for 1 h. HPLC and LCMS showed that 30f was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×5 um; mobile phase: [water (0.2% FA)-ACN]) to give 30. MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O5) m / z 440.0, LCMS observed: m / z 440.1. 1H NMR (400 MHz, MeOH-d4)δ 8.19(s, 2H), 7.50(d, J=1.0 Hz, 1H), 4.74(dd, J=7.6, 2.8 Hz, 1H), 3.68(s, 3H), 1.89 - 2.00 (m, 1H), 1.59 (dquin, J=14.2, 7.2, 7.2, 7.2, 7.2Hz, 1H), 1.03 (t, J=7.4 Hz, 3H).

[0378] Example S31: 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 31) Scheme 31 [ka]

[0379] 3,6-Dichloro-4-(2-methyl-1,3-dioxolan-2-yl)pyridazine (31a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1000 mg, 6.62 mmol) in toluene (15 mL) was added 2-ethynyl-2-methyl-1,3-dioxolane (1.49 g, 13.25 mmol, 311.62 uL). The mixture was stirred in a sealed tube at 110° C. for 16 h. TLC showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 31a. 1 H NMR (400MHz, CDCl3) δ 7.74 (s, 1H), 4.19 - 4.08 (m, 2H), 3.89 - 3.77 (m, 2H), 1.80 (s, 3H).

[0380] 3,5-Dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3-yl)oxy)aniline (31b) To a solution of 4-amino-2,6-dichlorophenol (591.45 mg, 3.32 mmol) and 3,6-dichloro-4-(2-methyl-1,3-dioxolan-2-yl)pyridazine (31a) (710 mg, 3.02 mmol) in DMSO (25 mL) was added K2CO3 (1.25 g, 9.06 mmol) and CuI (345.14 mg, 1.81 mmol), degassed and purged with N2 three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. TLC showed the reactants were completely consumed. The reaction mixture was diluted with H2O (50 mL), and then the pH was adjusted to 4-6 with HCl (1M). The mixture was extracted with 150 mL of ethyl acetate (50 mL × 3). The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 31b. 1 H NMR (400MHz, CDCl3) δ 7.50 (s, 1H), 6.69 (s, 2H), 4.20 - 4.11 (m, 2H), 3.93 - 3.85 (m, 2H), 3.79 (br s, 2H), 1.83 (s, 3H).

[0381] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyridazine (31c) To a solution of 3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3-yl)oxy)aniline (31b) (600 mg, 1.59 mmol) in ACN (30 mL) was added t-BuONO (821.41 mg, 7.97 mmol, 947.41 uL) and KI (528.91 mg, 3.19 mmol) at 0° C. The mixture was then stirred at 20° C. for 1 h. TLC showed that 31b was completely consumed and one major spot was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 31c. 1 H NMR (400MHz, CDCl3) δ 7.74 (s, 2H), 7.57 (s, 1H), 4.21 - 4.11 (m, 2H), 3.95 - 3.84 (m, 2H), 1.84 (s, 3H).

[0382] 6-(3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31d) A mixture of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyridazine (31c) (200 mg, 410.25 umol), 2-methyl-6-(trimethylstannyl)-1,2,4-triazine-3,5(2H,4H)-dione (30a) (237.87 mg, 820.51 umol), Pd(dppf)Cl2.CH2Cl2 (33.50 mg, 41.03 umol) in dioxane (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110 °C under nitrogen atmosphere for 16 h. TLC and LCMS showed that 31c was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and then filtered to give 31d (162 mg, crude). MS mass calculated: [M+1] + (C18H 14 Cl3N5O5) m / z 486.0, LCMS observed: m / z 486.0. 1 Obtained H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 8.19 - 8.13 (m, 2H), 7.83 - 7.80 (m, 1H), 4.08 (br t, J=7.0 Hz, 2H), 3.87 - 3.82 (m, 2H), 3.61 - 3.55(m, 3H), 1.77 - 1.74(m, 3H).

[0383] 6-(4-((5-acetyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31e) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31d) (160 mg, 328.75 umol) in dioxane (4 mL) was added HCl (4 M, 4.11 mL). The mixture was stirred at 80° C. for 1 h. LCMS showed one major peak of the desired MS was formed. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (5 mL×3). The combined filtrate was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 31e (80 mg, crude). Calculated MS mass: [M+1] + (C 16 H 11 Cl2N5O5) m / z 424.0, LCMS observed: m / z 424.0.

[0384] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31) To a solution of 6-(4-((5-acetyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31e) (80 mg, 141.44 umol) in MeOH (5 mL) was added NaBH4 (26.75 mg, 707.22 umol) at 0°C. The mixture was stirred at 0-20°C for 0.5 h. LCMS showed that 31e was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (15 mL) and extracted with ethyl acetate (30 mL x 10 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (0.225% FA)-ACN]) to give 31. MS mass calculated: [M+1] + (C 16 H 13Cl2N5O5) m / z 426.0, LCMS observed: m / z 426.0. 1 H NMR (400MHz, DMSO-d6)δ 12.44(br s, 1H), 12.29(br s, 1H), 8.10(s, 2H), 7.43(d, J=1.0 Hz, 1H), 4.75 - 4.68(m, 1H), 3.58(s, 3H), 3.57(br s, 1H), 1.34(d, J=6.8 Hz, 3H).

[0385] Example S31 P1 and P2: (S)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione and (R)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compounds 31 P1 and 31 P2) Scheme 31a [ka]

[0386] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31) Dichloro(p-cymene)ruthenium(II) dimer (1.08 mg, 1.77 umol) was suspended in degassed HO (2 mL) and the mixture was degassed with nitrogen for 10 min. A solution of 6-(4-((5-acetyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31f) (20 mg, 35.36 umol) in degassed THF (1 mL) and sodium fumarate (4.81 mg, 70.72 umol, 3.82 uL) was added to the mixture. The reaction mixture was degassed with nitrogen for 5 min and stirred at 20° C. for 30 min. TLC and LCMS showed that 31f was completely consumed. The mixture was diluted with water (5 mL) and extracted with ethyl acetate 30 mL (10 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase: [water (0.1% TFA)-ACN]) to give 31. MS mass calculated: [M+1] + (C 16 H 13 Cl2N5O5) m / z 426.0, LCMS observed: m / z 426.0.1 H NMR (400MHz, MeOH-d4) δ 8.21(s, 2H), 7.54(d, J=1.0 Hz, 1H), 4.96 - 4.92(m, 1H), 3.70(s, 3H), 1.48(d, J=6.4 Hz, 3H).

[0387] (S)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31 P1) and (R)-6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31 P2) 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (31) (4.8 mg, 9.20 umol) was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 um); mobile phase: [Neu-EtOH]; B%: 30%-30%, 8 min) to give 31 P1 (1.05 mg, 2.43 umol): MS mass calculated: [M+1] + (C 16 H 13 Cl2N5O5) m / z 426.0, LCMS observed: m / z 426.0; 1 H NMR (400MHz, MeOH-d4)δ 8.20(s, 2H), 7.53(d, J=1.1 Hz, 1H), 4.94 - 4.92(m, 1H), 3.69(s, 3H), 1.47(d, J=6.4 Hz, 3H); and 31 P2(1.57 mg, 3.68 umol): Calculated value of MS mass: [M+1] + (C 16 H 13 Cl2N5O5) m / z 426.0, LCMS observed: m / z 426.0; 1 H NMR (400 MHz, MeOH-d4) δ 8.19 (s, 2H), 7.52 (s, 1H), 4.94 - 4.90 (m, 1H), 3.68 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H) was obtained. In this example, isomers 31 P1 and 31 P2 were separated by chiral chromatography, but the absolute chirality of each isomer was not determined. The elution order was used to track the individual isomers.

[0388] Example S32: 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (compound 32) Scheme 32 [ka]

[0389] 4-(sec-Butyl)-3,6-dichloropyridazine (32a) To a mixture of 3,6-dichloropyridazine (200 mg, 1.34 mmol) and (2S)-2-methylbutanoic acid (137.11 mg, 1.34 mmol, 146.17 uL) in H2O (2 mL) was added AgNO3 (228.05 mg, 1.34 mmol) and TFA (459.22 mg, 4.03 mmol, 298.20 uL) in one portion at 50 °C. Then, (NH4)2S2O8 (919.07 mg, 4.03 mmol, 875.30 uL) in H2O (2 mL) was added at 70 °C. The mixture was stirred at 70 °C for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 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 (petroleum ether:ethyl acetate) to give 32a. 1 H NMR(400 MHz, CDCl3)δ 7.34(s, 1H), 3.08(sxt, J=7.0 Hz, 1H), 1.59 - 1.76(m, 1H), 1.58 - 1.61(m, 1H), 1.28(d, J=6.8 Hz, 2H), 1.26 - 1.31 (m, 1H), 0.95 (t, J=7.4 Hz, 3H).

[0390] 4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichloroaniline (32b) To a solution of 4-(sec-butyl)-3,6-dichloropyridazine (32a) (100 mg, 487.61 umol) and 4-amino-2,6-dichlorophenol (104.16 mg, 585.13 umol) in DMSO (5 mL) was added K2CO3 (269.57 mg, 1.95 mmol) and CuI (55.72 mg, 292.56 umol). The reaction mixture was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. TLC and LCMS showed that 32a was completely consumed and the desired MS was detected. The mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (30 mL x 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 32b. MS mass calculated: [M+1] + (C 14 H 14 Cl3N3O) m / z 346.0, LCMS observed: m / z 346.1. 1 H NMR (400 MHz, MeOH-d4)δ 7.42(s, 1H), 6.72 - 6.76(m, 2H), 3.06 - 3.15(m, 1H), 1.62 - 1.84(m, 2H), 1.32(d, J=7.0 Hz, 3H), 0.93 - 0.98(m, 3H).

[0391] 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (32c) To a solution of 4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichloroaniline (32b) (80 mg, 230.79 umol) in HCl (3 mL) was added NaNO2 (19.11 mg, 276.95 umol) at 0 °C and the mixture was stirred for 0.5 h. Then, a solution of KI (76.62 mg, 461.58 umol) in H2O (3 mL) was added to the mixture and the mixture was stirred at 15 °C for another 1.5 h. TLC and LCMS showed that 32b was completely consumed and the desired mass was detected. The mixture was extracted with ethyl acetate (20 mL x 2) and H2O 10 mL. The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 32c. Calculated MS mass: [M+1] + (C 14 H 12 Cl3IN2O) m / z 456.9, LCMS observed: m / z 457.0. 1 H NMR (400 MHz, CDCl3)δ 7.73(s, 2H), 7.18(s, 1H), 3.05 - 3.12(m, 1H), 1.59 - 1.83(m, 2H), 1.32(d, J=6.6 Hz, 3H), 0.97(t, J=7.4 Hz, 3H).

[0392] 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridazine (32d) To a solution of 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-iodophenoxy)pyridazine (32c) (60 mg, 131.14 umol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (99.91 mg, 393.43 umol) in dioxane (4 mL) was added KOAc (64.35 mg, 655.71 umol) and Pd(dppf)Cl2 (9.60 mg, 13.11 umol). The mixture was degassed and purged with nitrogen three times and stirred at 90 °C for 16 h. TLC and LCMS showed that 32c was completely consumed and the desired mass was detected. The mixture was extracted with ethyl acetate (20 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 preparative TLC (petroleum ether:ethyl acetate) to give 32d. MS mass calculated: [M+1] + (C 20 H 24 BCl3N2O3) m / z 457.1, LCMS observed: m / z 457.2. 1 H NMR (400 MHz, CDCl3)δ 7.81(s, 2H), 7.17(s, 1H), 3.04 - 3.12(m, 1H), 1.59 - 1.81(m, 3H), 1.27(s, 102H), 0.94 - 1.00(m, 1H), 0.97(t, J=7.4 Hz, 3H).

[0393] 6-(4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (32e) To a mixture of 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridazine (32d) (60 mg, 131.12 umol) and 6-bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (3a) (40.52 mg, 196.68 umol) in THF (4 mL) and HO (1 mL) was added di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (8.55 mg, 13.11 umol) and KPO (55.67 mg, 262.25 umol), degassed and purged with N three times, then the mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. TLC and LCMS showed that 32d was completely consumed and the desired MS was detected. The reaction mixture was dissolved in water and the pH was adjusted to 4 with HCl (1M, 1 mL). The mixture was then extracted with ethyl acetate (15 mL×2). 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 preparative TLC (petroleum ether:ethyl acetate) to give 32e. MS mass calculated: [M+1] + (C18H 16 Cl3N5O3) m / z 456.0, LCMS observed: m / z 455.8. 1 H NMR (400 MHz, MeOH-d4)δ 8.23 ​​- 8.27(m, 2H), 7.60(s, 1H), 3.68(s, 3H), 3.09 - 3.18(m, 1H), 1.65 - 1.88(m, 2H), 1.35(d, J=6.8 Hz, 3H), 0.97(t, J=7.4 Hz, 3H).

[0394] 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (32) To a solution of 6-(4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (32e) (40 mg, 87.58 umol) in AcOH (3 mL) was added NaOAc (35.92 mg, 437.91 umol) at 15° C. The mixture was then stirred at 120° C. for 16 h. LCMS and HPLC showed that 32e was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5u; mobile phase: [water (0.225% FA)-ACN]) to give 32. Calculated MS mass: [M+1] + (C18H 17 Cl2N5O4) m / z 438.1, LCMS observed: m / z 438.0. 1 H NMR (400 MHz, DMSO-d6)δ 12.45(br s, 1H), 12.20(s, 1H), 8.10(s, 2H), 7.43(s, 1H), 3.58(s, 3H), 2.85 - 2.94(m, 1H), 1.46 - 1.76(m, 2H), 1.18(d, J=7.0 Hz, 3H), 0.86(t, J=7.4 Hz, 3H).

[0395] Example S33 P1 and P2: (R)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione and (S)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compounds 33 P1 and 33 P2) Scheme 33 [ka]

[0396] 6-(4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (33a) To a mixture of 4-(sec-butyl)-3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridazine (32d) (280 mg, 611.91 umol) and 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (3a) (176.20 mg, 917.86 umol) in THF (4 mL) and HO (1 mL) was added Pd(dppf)Cl2 (39.88 mg, 61.19 umol) and K3PO4 (259.78 mg, 1.22 mmol). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. TLC and LCMS showed that 32d was completely consumed and the desired MS was detected. The mixture was extracted with ethyl acetate (50 mL×2) and H2O (15 mL). The combined organic phase was washed with brine (15 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 33a. MS mass calculated: [M+1] + (C 20 H 24 BCl3N2O3) m / z 457.1, LCMS observed: m / z 457.2. 1 H NMR (400 MHz, MeOH-d4)δ 8.21 - 8.24(m, 1H), 7.60(s, 1H), 3.10 - 3.16(m, 1H), 1.66 - 1.86(m, 2H), 1.35(d, J=6.84 Hz, 3H), 0.97(t, J=7.39 Hz, 3H).

[0397] 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (33b) To a solution of 6-(4-((5-(sec-butyl)-6-chloropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (33a) (175 mg, 395.32 umol) in AcOH (8 mL) was added NaOAc (162.14 mg, 1.98 mmol) at 15° C. The mixture was then stirred at 120° C. for 16 h. HPLC and LCMS showed that 33a was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (5 mL). The suspension was extracted with ethyl acetate (30 mL×3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 100×30 5 u; mobile phase: [water (0.2% FA)-ACN]) to give 33b. MS mass calculated: [M+1] + (C 17 H 15 Cl2N5O4) m / z 424.1, LCMS observed: m / z 424.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.34 (s, 1H), 2.97 - 3.04 (m, 1H), 1.55 - 1.82 (m, 2H), 1.26 (d, J=7.0 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H).

[0398] (R)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione and (S)-6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compounds 33 P1 and 33 P2) 6-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (33b) (28 mg, 66.00 umol) was separated by SFC separation (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 45%-45%) to give 33 P1 (11.36 mg, 26.78 umol, 40.57% yield): MS mass calculated: [M+1] + (C 17 H 15Cl2N5O4) m / z 424.1, LCMS observed: m / z 424.0; 1 H NMR (400 MHz, MeOH-d4)δ 8.15(s, 2H), 7.33(s, 1H), 3.35(s, 1H), 2.97 - 3.04(m, 1H), 1.54 - 1.82(m, 2H), 1.26(d, J=7.0 Hz, 3H), 0.95(t, J=7.4 Hz, 3 H); and 33 P2 (11.17 mg, 26.33 umol, 39.89% yield): Calculated MS mass: [M+1] + (C 17 H 15 Cl2N5O4) m / z 424.1, LCMS observed: m / z 424.0; 1 H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 2H), 7.33 (s, 1H), 2.97 - 3.04 (m, 1H), 1.54 - 1.83 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) were obtained. In this example, isomers 33 P1 and 33 P2 were separated by chiral chromatography, but the absolute chirality of each isomer was not determined. The elution order was used to track the individual isomers.

[0399] Example S34: (6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 34) Scheme 34 [ka]

[0400] 1-(3,6-Dichloropyrazin-4-yl)ethanol (34a) To a solution of 3,6-dichloro-1,2,4,5-tetrazine (500 mg, 3.31 mmol) in toluene (3 mL) was added but-3-yn-2-ol (278.59 mg, 3.97 mmol, 311.62 uL). The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. TLC showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 34a. 1H NMR (400MHz, 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).

[0401] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34b) To a solution of 1-(3,6-dichloropyrazin-4-yl)ethanol (34a) (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. TLC showed the reactants were completely consumed and many new spots had formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 34b. 1 H NMR(400MHz, CDCl3)δ 7.77(s, 1H), 7.63(s, 1H), 5.10(q, J=6.4 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).

[0402] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrazin-3-yl)oxy)aniline (34c) To a solution of 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34b) (167.00 mg, 938.13 umol) and 4-amino-2,6-dichlorophenol (200 mg, 721.64 umol) in DMSO (5 mL) was added K2CO3 (299.21 mg, 2.16 mmol) and CuI (82.46 mg, 432.98 umol). The reaction mixture was then degassed and purged with N2 three times. The mixture was stirred at 90 °C under nitrogen atmosphere for 2 h. TLC and LCMS showed that 34b was completely consumed. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate) to give 34c. 1 H NMR (400MHz, 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=6.4 Hz, 3H), 1.49(d, J=6.4 Hz, 3H).

[0403] 3-Chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34d) To a solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrazin-3-yl)oxy)aniline (34c) (165 mg, 394.08 umol) in ACN (5 mL) was added t-BuONO (609.56 mg, 5.91 mmol, 703.06 uL) and KI (130.83 mg, 788.15 umol) at 0° C. The mixture was then stirred at 20° C. for 1 h. TLC and LCMS showed that 34d was completely consumed and many new spots were formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 34d. MS mass calculated: [M+1] + (C 17 H 16 Cl3IN2O3) m / z 528.9, LCMS observed: m / z 528.9.

[0404] 3-Chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34e) A mixture of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34d) (53 mg, 100.08 umol), BPD (76.24 mg, 300.24 umol), AcOK (49.11 mg, 500.39 umol) and Pd(dppf)Cl2 (7.32 mg, 10.01 umol) in dioxane (3 mL). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. TLC and LCMS showed that 34d was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 34e (75 mg, crude). The crude material was used directly in the next step. MS mass calculated: [M+1] + (C23 H 28 BCl3N2O5) m / z 529.1, LCMS observed: m / z 447.0.

[0405] 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (34f) To a solution of 3-chloro-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (34e) (75 mg, 141.60 umol), 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (32.62 mg, 169.92 umol) in THF (2.4 mL) and HO (0.6 mL) was added KPO (60.12 mg, 283.21 umol) and Pd(dppf)Cl (9.23 mg, 14.16 umol). The mixture was degassed and purged with N2 three times, then the mixture was stirred under nitrogen atmosphere at 80°C for 16 h. TLC and LCMS showed that reactant 34e was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:MeOH) to give 34f. MS mass calculated: [M+1] + (C 20 H 18 Cl3N5O5) m / z 514.0, LCMS observed: m / z 514.0.

[0406] 6-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (34) To a solution of 6-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (34f) (43 mg, 66.83 umol) in dioxane (1 mL) was added HCl (4 M, 835.36 uL). The mixture was stirred at 80° C. for 16 hours. LCMS showed the reaction was complete and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase: [water (0.1% TFA)-ACN]) to give 34. MS mass calculated: [M+1] + (C 15 H 11 Cl2N5O5) m / z 412.0, LCMS observed: m / z 412.0. 1 H NMR (400MHz, MeOH-d4)δ 8.19 - 8.13 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 4.93 - 4.88 (m, 1H), 1.46 (d, J=6.6 Hz, 3H).

[0407] Example S35: 6-(4-((5-acetyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (compound 35) Scheme 35 [ka]

[0408] 6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3(2H)-one (35a) To a solution of 3-chloro-6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyridazine (31c) (150 mg, 307.69 umol) in AcOH (3 mL) was added NaOAc (126.20 mg, 1.54 mmol). The mixture was stirred at 120° C. for 16 h. LCMS showed that 31c was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The crude material was triturated with H2O (5 mL) at 20° C. for 15 min, then the crude product was triturated with petroleum ether:ethyl acetate=20:1 (5 mL) at 20° C. for 30 min to give 35a as a white solid. MS mass calculated: [M+1] + (C 14 H 11 Cl2IN2O4) m / z 468.9, LCMS observed: m / z 468.9.

[0409] 6-(2,6-dichloro-4-iodophenoxy)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3(2H)-one (35b) A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3(2H)-one (35a) (80 mg, 170.55 umol), K2CO3 (47.14 mg, 341.11 umol), CHI (29.05 mg, 204.67 umol, 12.74 uL) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 25 °C under nitrogen atmosphere for 1 h. LCMS showed that 35a was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was triturated with H2O (5 mL) and stirred at 20 °C for 1 h. The mixture was then filtered to collect the solid. The solid was triturated with a solution of petroleum ether:ethyl acetate = 5:1 (5 mL) and filtered to give 35b. MS mass calculated: [M+1] + (C 15 H 13 Cl2IN2O4) m / z 482.9, LCMS observed: m / z 483.0.

[0410] 4-Acetyl-6-(2,6-dichloro-4-iodophenoxy)-2-methylpyrazin-3(2H)-one (35c) To a solution of 6-(2,6-dichloro-4-iodophenoxy)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)pyrazin-3(2H)-one (35b) (70 mg, 144.90 umol) in dioxane (2 mL) was added HCl (4 M, 2 mL). The mixture was stirred at 80° C. for 16 h. LCMS showed that 35b was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was triturated with a solution of petroleum ether:ethyl acetate and stirred at 20° C. for 1 h. The mixture was filtered to give 35c. MS mass calculated: [M+1] + (C 13 H9Cl2IN2O3) m / z 438.9, LCMS observed: m / z 438.9; 1 H NMR (400 MHz, MeOH-d4) δ 7.89(s, 2H), 7.78(s, 1H), 3.54(s, 3H), 2.66(s, 3H).

[0411] 4-Acetyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methylpyrazin-3(2H)-one (35d) To a solution of 4-acetyl-6-(2,6-dichloro-4-iodophenoxy)-2-methylpyrazin-3(2H)-one (35c) (60 mg, 136.66 umol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (104.11 mg, 409.99 umol) in dioxane (3 mL) under N2 was added Pd(dppf)Cl2 (10.00 mg, 13.67 umol) and KOAc (67.06 mg, 683.32 umol). The mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. LCMS showed ~40% 35c remaining with the desired mass detected. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (10 mL×3). The combined organic layers were washed with H2O (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate) to give 35d. MS mass calculated: [M+1] + (C 19 H 21BCl2N2O5) m / z 439.1, LCMS observed: m / z 439.1. 1 H NMR (400 MHz, CDCl3)δ 7.80(s, 2H), 7.71(s, 1H), 3.56 - 3.60(m, 3H), 2.75 - 2.77(m, 3H), 1.34 - 1.39(m, 12H).

[0412] 6-(4-((5-acetyl-1-methyl-6-oxo-1,6-dihydropyrazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (35) To a solution of 4-acetyl-6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methylpyrazin-3(2H)-one (35d) (40 mg, 91.10 umol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (34.98 mg, 182.19 umol) in THF (2 mL) and HO (0.5 mL) under N was added Pd(dppf)Cl2 (5.94 mg, 9.11 umol) and K3PO4 (38.67 mg, 182.19 umol). The mixture was stirred at 80 °C under a nitrogen atmosphere for 5 h. LCMS showed that 35d was completely consumed and the desired mass was detected. The suspension was filtered through a Celite pad and the pad cake was washed with ethyl acetate (10 mL x 3). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xtimate C18 100 x 30 mm x 3 um; mobile phase: [water (0.225% FA)-ACN]) to give 35. MS mass calculated: [M+1] + (C 16 H 11 Cl2N5O5) m / z 424.0, LCMS observed: m / z 424.0; 1 H NMR (400 MHz, MeOH-d4) δ 8.18 - 8.21 (m, 2H), 7.79 (s, 1H), 3.54 (s, 3H), 3.50 - 3.51 (m, 1H), 2.67 (s, 3H).

[0413] Biological Example: Biological Screening Example B1: Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for thyroid hormone receptor agonist screening LanthaScreen™ TR-FRET Thyroid Receptor Alpha Coactivator Assay Kit (ThermoFisher) and LanthaScreen™ TR-FRET Thyroid Receptor Beta Coactivator Assay Kit (ThermoFisher) were used for agonist compound screening. Compounds in DMSO were diluted twice (5 microM final top concentration) in a 10-point 3-fold serial manner into a 384-plate 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 THR alpha-LBD (final concentration 0.4 nM) or THR beta-LBD (final concentration 1.0 nM). After 2 h of incubation at room temperature in the dark, the TR-FRET signal was measured on an EnVision plate reader (PerkinElmer) with excitation at 340 nm and dual emission readings at 495 and 520 nm with a delay time of 100 μs and an integration time of 200 μs. The ratio of the emission signals at 520 and 495 was used to calculate the EC 50 was calculated. In all batches of compound screening, T3 (L-3,3',5-triiodothyronine sodium salt, >95%) (Calbiochem) was used as a reference compound. The measured EC 50 were within 3-fold of the reference values ​​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 ​​for compounds are calculated from the T3 selectivity normalized data. Data obtained using the TR-FRET assay for certain compounds disclosed herein are listed in Table 2.

[0414] Table 2 [Table 5] [Table 6] *Compound 4 is not within the scope of formula (I) and is provided for comparative purposes only. a All compounds are run in duplicate and the average data is recorded.

[0415] All publications, including patents, patent applications, and scientific articles mentioned in this specification are incorporated by reference in their entirety for all purposes as if each individual publication, including a patent, patent application, or scientific article, was specifically and individually indicated to be incorporated by reference.

[0416] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced in light of the above teachings. Therefore, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

1. Formula (I): 【Chemistry 1】 (I) [In the formula, R 1 is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, -C(O)N(R 7 )(R 8 ), -N(R 9 )C(O)(R 10 ), or halo; R 2 is H, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl; R 3 is H or halo; R 4 is H or a substituted or unsubstituted linear C 1 -C 3 is alkyl; L is -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, or -C(R 5 )(R 6 )-is; R 5 and R 6 are independently H, halo, -CN, or substituted or unsubstituted C 1 -C 6 alkyl or R 5 and R 6 together with the carbon atom to which they are attached, substituted or unsubstituted C 3 -C 6 forming a cycloalkyl; R 7 and R 8 are independently H or substituted or unsubstituted C 1 -C 6 alkyl or R 7 and R 8 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 7-membered heterocycloalkyl; R 9 is H, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl; R 10 is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, -N(R 7 )(R 8 ), or -O(R 11 ) is; R 11 is a substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl; M 1 and M. 2 are independently halo, or substituted or unsubstituted C 1 -C 6 is alkyl; and M 3 is H, halo, or substituted or unsubstituted C 1 -C 6 Alkyl or M 3 is M 2 and together with the carbon atom to which they are attached form a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. or a pharma- ceutically acceptable salt thereof.

2. R 1 But, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C(O)N(R 7 )(R 8 ), -N(R 9 )C(O)(R 10 ), or halo, where C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo; R 2 But, H, C 1 -C 6 Alkyl, or C 3 -C 6 cycloalkyl, where C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 3 is H or halo; R 4 is H, or -OH, oxo, -CN, halo, and -O(C 1 -C 2 A straight chain C optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl 1 -C 3 is alkyl; L is -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, or -C(R 5 )(R 6 )-is; R 5 and R 6 are independently H, halo, -CN, or C 1 -C 6 alkyl or R 5 and R 6 together with the carbon atoms to which they are attached, C 3 -C 6 Form a cycloalkyl, where each C 1 -C 6 Alkyl or C 3 -C 6 The cycloalkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -OH, -CN, and halo; R 7 and R 8 are independently H or C 1 -C 6 alkyl or R 7 and R 8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl, where each C 1 -C 6 The alkyl or 3- to 7-membered heterocycloalkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -OH, -CN, and halo; R 9 But, H, C 1 -C 6 Alkyl, or C 3 -C 6 cycloalkyl, where C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 10 But, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -N(R 7 )(R 8 ), or -O(R 11 ), where C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; R 11 But, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; M 1 and M. 2 is independently halo, or C optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, -CN, and halo; 1 -C 6 is alkyl; and M 3 is optionally substituted with 1 to 5 substituents selected from the group consisting of H, halo, or -OH, -CN, and halo; 1 -C 6 Alkyl or M 3 But, M 2 and together with the carbon atom to which they are attached form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S, or a pharma- ceutically acceptable salt thereof.

3. R 1 But, C 1 -C 6 Alkyl or C 3 -C 6 3. The compound of claim 1 or 2, wherein each of said alkyl groups is cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of -OH, oxo, -CN, and halo, or a pharma- ceutically acceptable salt thereof.

4. R 1 Cyclopropyl, isopropyl, ethyl, -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )(CH 2 -OH), -CH(OH)(CH 2 CH 3 ), -CH(OH)(CH 3 ), -CH(CH 3 )(CH 2 CH 3 ), or -C(O)(CH 3 4. The compound of claim 3, wherein:

5. R 2 is optionally substituted with 1 to 5 substituents selected from the group consisting of H, —OH, —CN, and halo; 1 -C 6 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

6. R 2 The compound of claim 5, or a pharma- ceutically acceptable salt thereof, wherein is H or methyl.

7. R 3 The compound according to any one of claims 1 to 6, wherein is H, or a pharma- ceutically acceptable salt thereof.

8. R 4 is H, or -OH, oxo, -CN, halo, and -O(C 1 -C 2 A straight chain C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl 1 -C 3 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

9. R 4 H, methyl, ethyl, -CH 2 C(O)OCH 2 CH 3 , -CH 2 CF 3 , -CH 2 CN, or -CH 2 CHF 2 9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt thereof.

10. L is -O-, -C(O)-, or -CH 2 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

11. M 1 and M. 2 is independently halo, or C optionally substituted with 1 to 3 substituents selected from the group consisting of -OH, -CN, and halo; 1 -C 3 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

12. M 1 and M. 2 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein is independently halo or methyl.

13. M 1 and M. 2 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein each is chloro.

14. M 1 and M. 2 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein each is methyl.

15. M 3 is optionally substituted with 1 to 3 substituents selected from the group consisting of H, halo, or -OH, -CN, and halo; 1 -C 3 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

16. M 3 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof, wherein is H, F, or methyl.

17. A compound selected from compounds 1-3 and 5-35, 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 a 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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