Thyroid hormone receptor beta-agonist compounds

Abstract

To provide thyroid hormone receptor beta agonist compounds, and compositions thereof.SOLUTION: The present invention provides a compound represented by the formula below, a tautomer thereof, or a pharmaceutically acceptable salt thereof. [In the formula, A is as defined below, and ring B is a 5-membered heterocyclyl or a 5- to 6-membered heteroaryl].SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 891,078, filed on 23 August 2019, and U.S. Provisional Application No. 62 / 967,943, filed on 30 January 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] Field of the present invention The present invention relates to compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, methods for producing the same, methods for agonizing THR beta, and methods for treating THR beta-mediated disorders. [Background technology]

[0003] Beneficial effects resulting from treating patients with hyperthyroidism or hypothyroidism with T3 / T4 endogenous ligands or early analogues of these endogenous ligands have been documented in the literature (Richardson Hill Jr., S. et al. J. Clin. Invest. 1960, 39, 523-533). These early studies, and similar follow-up studies, have shown the heart to be the primary organ where side effects of both hyperthyroidism and hypothyroidism manifest (Klein, I. et al. Circulation, 2007, 1725-1735). In particular, tachycardia, hypertrophy, atrial arrhythmias, and atrial fibrillation are serious concerns. Furthermore, increased bone metabolism leading to decreased bone mineral density has also been noted. Negative effects in both the heart and bone are associated with agonism of the THR alpha isoform, while beneficial effects of THR agonism in the liver are primarily associated with the THR beta isoform (Sinha, RA et al. Nat. Rev. Endocrinology 2018, 14, 259-269).

[0004] Diseases or disorders associated with THR beta include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. There is a need for thyroid hormone analogs, such as THR beta agonists, that avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones, for example, for the treatment of patients with non-alcoholic steatohepatitis (NASH). In particular, there is a need to develop novel thyroid hormone analogs that are selective agonists of THR beta, preferably that avoid the undesirable effects associated with THR alpha agonism while maintaining the beneficial effects of thyroid hormones, for example, for the treatment of patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia. [Overview of the project]

[0005] In one embodiment, in this specification, formula (I): [ka] (I) [In the formula, A, B, Y, Z 1 , Z 2 , and, Z 3 This is as described in this specification. A compound represented by, or its tautomer, or a pharmaceutically acceptable salt thereof is provided.

[0006] In one embodiment, a pharmaceutical composition is provided herein, comprising a compound provided herein and at least one pharmaceutically acceptable excipient.

[0007] In one embodiment, a method for agonizing thyroid hormone receptor beta (THR beta) is provided herein, comprising contacting THR beta with an effective amount of either a compound provided herein or a pharmaceutical composition provided herein.

[0008] In one embodiment, the Specified Publicly Provided Method for treating a THR beta-mediated disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH). [Modes for carrying out the invention]

[0009] definition In this specification, unless otherwise specified, the following definitions shall apply. Furthermore, unless otherwise defined below, terms or symbols used herein shall have their ordinary meanings in the art.

[0010] "Contains" is intended to mean that a composition or method contains the elements described but does not exclude others. "Essentially consists of," when used to define a composition or method, means excluding other elements that are essentially important to the combination. For example, a composition essentially consisting of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel characteristics of the claimed invention. "Consists of" means, for example, excluding amounts exceeding trace amounts of other components and amounts exceeding the steps of the substantial method described. Embodiments defined by each of these transitional terms are within the scope of the invention.

[0011] The “effective amount” or dose of a compound or composition means the amount of the compound or composition that produces the desired intended result based on the disclosure herein. The effective amount is determined by standard pharmaceutical methods in cell culture or experimental animals, for example, but not limited to, LD 50 (A lethal dose in 50% of the population), and ED 50 This can be determined by finding the dose that is therapeutically effective in 50% of the population.

[0012] In this specification, the term “excipient” means an inert or non-active substance that may be used in the manufacture of drugs or pharmaceuticals, such as tablets, containing the compounds of the present invention as an active ingredient. A variety of substances may be included in the term “excipient,” but are not limited to those used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavorings, suspensions / gelling agents, or wet granulation agents. Examples of binders include carbomer, povidone, and xanthan gum; examples of coating agents include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coating agents; examples of compression / encapsulation aids include calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; sometimes combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, and sucrose; examples of disintegrants include croscarmellose sodium, gellan gum, and sodium starch glycolate; as a cream or lotion... Examples of lubricants include maltodextrin and carrageenan; examples of lubricants include magnesium stearate, stearic acid, and sodium stearyl fumarate; examples of chewable tablet materials include dextrose, fructose dc, and lactose (monohydrate, sometimes combined with aspartame or cellulose); examples of suspending / gelling agents include carrageenan, sodium starch glycolate, and xanthan gum; examples of sweeteners include aspartame, dextrose, fructose dc, sorbitol, and sucrose dc; and examples of wet granulating agents include calcium carbonate, maltodextrin, and microcrystalline cellulose.

[0013] "Patient" means a mammal, including humans and non-human mammals. Examples of patients, though not limited to, include mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, "patient" means human.

[0014] "Pharmacologically acceptable" means safe and non-toxic, preferably safe and non-toxic in vivo, and more preferably in human administration.

[0015] "Pharmacologically acceptable salt" means that the salt is pharmaceutically acceptable. The compounds described herein may be administered as pharmaceutically acceptable salts.

[0016] "Salt" refers to an ionic compound formed between an acid and a base. When a compound provided herein contains an acidic functional group, such salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, and ammonium salts. In this specification, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Useful cations in pharmaceutically acceptable salts include, but are not limited to, ammonium cations based on Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and naturally occurring amino acids. When a compound used herein contains a basic functional group, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, as well as salts of inorganic acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Useful anions in pharmaceutically acceptable salts include, but are not limited to, oxalates, maleates, acetates, propions, succinates, tartrates, chlorides, sulfates, bisulfates, monobasic phosphates, dibasic phosphates, and tribasic phosphates, mesylates, and tosylates.

[0017] A "therapeutically effective amount" or dose of a compound or composition refers to an amount of the compound or composition that results in alleviation or inhibition of symptoms, or prolongation of survival, in a patient. As a result, multiple administrations of the compound or composition may be required.

[0018] "Treatment" or "treating" of a disease in a patient means: 1) preventing the occurrence of the disease in a patient who is predisposed to the disease or does not yet exhibit symptoms of the disease; 2) inhibiting the disease or arresting its onset; or 3) causing amelioration or regression of the disease. As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of the present invention, beneficial or desired results include, but are not limited to, one or more of the following: reduction of one or more symptoms caused by a disease or disorder, reduction in the extent of the disease or disorder, stabilization of the disease or disorder (e.g., prevention or delay of worsening of the disease or disorder), delay of onset or recurrence of the disease or disorder, delay or slowing of progression of the disease or disorder, improvement of the condition of the disease or disorder, provision of remission (partial or complete) of the disease or disorder, reduction in the dose of one or more other medicaments required to treat the disease or disorder, enhancement of the effect of another medicament used to treat the disease or disorder, slowing the progression of the disease or disorder, improving quality of life, and / or prolonging survival of the patient. In addition, "treatment" also encompasses alleviation of the pathological consequences of the disease or disorder. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0019] An "isotopic isomer" of a compound is a compound in which one or more atoms of the compound are replaced with isotopes of the same atoms. For example, when H is replaced with D or T, 12 C is 11 replaced with C, or 14 N is 15In some cases, N may be substituted. For example, but not limited to this, substituting with D may, in some cases, result in a decrease in metabolic rate and a longer half-life. Substituting H with T may provide a radioligand that could be useful for binding studies. 12 C is a short-lived isotope 11 Replacing it with C can provide a ligand useful for positron emission tomography (PET) scans. 14 N 15 If we replace it with N, 15 Compounds that can be detected / monitored by N-NMR spectroscopy are provided. For example, an isotopic isomer of a compound containing -CH2CH3 is a compound containing -CD2CD3 instead of -CH2CH3.

[0020] Unless a specific isotope of an element is shown in the formula, this disclosure refers to, for example, deuterated derivatives of a compound (where H is 2 This includes all isotopic substitutions of the compounds disclosed herein, such as H (which can become D). The isotopic substitutions can be performed at any or all sites in the structure, or at any or all sites in the structure, with atoms present at their natural abundance.

[0021] "Stereoisomers" or "multiple stereoisomers" refers to compounds that differ in the stereoforming properties of their constituent atoms, such as the chirality of one or more stereocenters, or compounds related to the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds, but are not limited to these. Stereoiomers include enantiomers and diastereomers.

[0022] "Tautomer" refers to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomer forms of heteroaryl groups containing ring atoms bonded to both the ring-NH- and ring=NH- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0023] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. This term includes, by example, linear or branched hydrocarbyl groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x carbon atoms.

[0024] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a monocycle (e.g., phenyl (Ph)) or a fused polycycle (e.g., naphthyl or anthryl), where the bonded portion is on an aromatic carbon atom, and the fused ring may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl). Preferred aryl groups include phenyl and naphthyl.

[0025] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group having a monocyclic or polycyclic ring including condensation, crosslinking, and spirocyclic systems, comprising 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. x A cycloalkyl group refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings can be aryl, heteroaryl, or heterocyclic rings, provided the bonding site is via a saturated carbocyclic ring of a non-aromatic, non-heterocyclic ring.

[0026] "Halo" or "halogen" means fluoro, chloro, bromo, and iodine, preferably fluoro or chloro.

[0027] "Hydroxy" or "hydroxyl" refers to the group represented by -OH.

[0028] "Heteroaryl" means an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in its ring. Such heteroaryl groups can be monocyclic (e.g., pyridinyl or furyl) or fused polycyclic (e.g., indolidinyl or benzothienyl), where the fused ring may or may not be aromatic, provided that the bonding portion is via an atom of the aromatic heteroaryl group, and / or may not contain heteroatoms. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group may optionally be oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5-membered or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include nine- or ten-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0029] "Heterocyclic" or "heterocyclic formula" or "heterocycloalkyl" or "heterocyclyl" means a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms, more preferably 1 to 2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. xA heterocycloalkyl group means a heterocycloalkyl group having x ring atoms, each containing a ring heteroatom. A heterocycle includes monocycles or condensed polycycles, including condensation, bridging, and spirocycle systems. In a condensed ring system, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the bonding portion is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group may optionally be oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0030] Examples of heterocyclyls and heteroaryls include, but are not limited to, azetidinyl, pyrrolyl, imidazolyl, pyrazol, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carborinyl, phenanthridine, acridinyl, phenanthrolinyl, isothiazolyl, phenadinyl Examples include phenazinyl, isoxazolyl, 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 known as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0031] "Oxo" refers to an atom represented by (=O) or (O).

[0032] As used throughout this specification, the terms “optional” or “occasionally” mean that the events or situations described thereafter may or may not occur, and the descriptions include both cases in which the events or situations occur and cases in which they do not. For example, “the nitrogen atom may, optionally, be oxidized to provide an N-oxide (N→O) moiety” means that the nitrogen atom can be oxidized, but does not have to be oxidized, and this description includes both the situation in which the nitrogen atom is not oxidized and the situation in which the nitrogen atom is oxidized.

[0033] "Optionally substituted" means, unless otherwise specified, that the group may be unsubstituted, or may be substituted by one or more substituents (e.g., 1, 2, 3, 4, or 5) listed for the group, which may be identical or different, as long as they do not exceed the normal valency of the group. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In yet another embodiment, the optionally substituted group has three substituents. In yet another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1-2, 2-5, 3-5, 2-3, 2-4, 3-4, 1-3, 1-4, or 1-5 substituents.

[0034] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is done by naming the terminal portion of the functional group, followed by the functional groups adjacent to the bond site. For example, the substituent "alkoxycarbonylalkyl" means a group represented by (alkoxy)-C(O)-(alkyl)-.

[0035] It is understood that polymers formed by defining substituents that have further substituents on themselves in all the substituted groups defined above (e.g., substituted aryls having substituted aryl groups as substituents that themselves are substituted with substituted aryl groups) are not intended to be included here. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is constrained, for example, by the restriction that the substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0036] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with four fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0037] It is understood that certain features of the Invention described in the context of a different embodiment for clarification may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the Invention described in the context of a single embodiment may also be provided in another or any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variable groups are specifically covered by the Invention and are disclosed herein in the same way that all such combinations are individually and expressly 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 listed in embodiments describing such variable groups are also specifically covered by the Invention and are disclosed herein in the same way that all such subcombinations of chemical groups are individually and expressly disclosed herein.

[0038] compound In one embodiment, in this specification, formula (I): [ka] (I) [In the formula, A is [ka] and; [ka] is a 5-membered heterocyclyl or a 5-6 membered heteroaryl, where each may optionally contain 1-2 additional ring heteroatoms selected from the group consisting of N and O. Here, each heteroatom of the heterocyclyl or heteroaryl is given one R if necessary to satisfy the valence of the heteroatom. 1 Bonds with the group, and Here, each carbon atom of the heterocyclyl or heteroaryl is one R if necessary to satisfy the valence of the carbon atom. 2 It bonds with the group, provided that the R required to satisfy the valence of each carbon atom 2 There is only one base; Z 1 , Z 2 , and, Z 3 These are independently N or CH; Y is either N or C; Each R 1 These are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl, Here, each C1-C6 alkyl or C3-C6 cycloalkyl group may have 1 to 5 R 3 It may also be substituted with the base; Each R 2 These are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxyl, or oxo. Here, each C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), or -O(C3-C6 cycloalkyl) group may have 1 to 5 R groups. 3 It may also be substituted with the base; Or, R 1and R 2 They combine to form a 5-6 member heteroaryl or a 5-7 member heterocycline; Or, two R's 2 The groups combine to form 5-6 membered heteroaryls, 5-7 membered heterocyclyls, C5-C7 cycloalkyls, or C6 aryls; Each R 3 These are independently halogens, C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 haloalkyls, C1-C6 alkyl-OH, -NH2, -CN, or hydroxyls. A compound represented by, or its tautomers, N-oxides, isotopic isomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, is provided.

[0039] In some embodiments, compounds of formula (I), tautomers thereof, or pharmaceutically acceptable salts thereof are provided. In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, A is [ka] That is the case. In some embodiments, A is [ka] That is the case. In some embodiments, A is [ka] That is the case.

[0041] In some embodiments, the compound of formula (I) is of formula (II): [ka] (II) [In the formula, B, Y, Z 1, Z 2 , and Z 3 This is as defined in equation (I). It is the compound shown by [the symbol].

[0042] In some embodiments, the compound of formula (I) is formula (III): [ka] (III) [In the formula, B, Y, Z 1 , Z 2 , and Z 3 This is as defined in equation (I). It is a compound represented by [the formula shown].

[0043] In some embodiments, the compound of formula (I) is of formula (IV): [ka] (IV) [In the formula, B, Y, Z 1 , Z 2 , and Z 3 This is as defined in equation (I). It is a compound represented by [the formula shown].

[0044] In some embodiments of the compound of formula (I) or its variations, Z 1 In some embodiments, Z 1 It is N.

[0045] In some embodiments of the compound of formula (I) or its variations, Z 2 In some embodiments, Z 2 It is N.

[0046] In some embodiments of the compound of formula (I) or its variations, Z 3 In some embodiments, Z 3 It is N.

[0047] In some embodiments of the compound of formula (I) or its variations, Z 1 CH is, and Z 2 In some embodiments, Z 1 CH is, and Z 2 In some embodiments, Z 1 N is N, and Z 2 In some embodiments, Z 1 N is N, and Z 2 In some embodiments, Z 1 CH is, and Z 3 In some embodiments, Z 1 CH is, and Z 3 In some embodiments, Z 1 N is N, and Z 3 In some embodiments, Z 1 N is N, and Z 3 In some embodiments, Z 2 CH is, and Z 3 In some embodiments, Z 2 CH is, and Z 3 In some embodiments, Z 2 is N, and Z 3 In some embodiments, Z 2 N is N, and Z 3 In some embodiments, Z 1 CH is; Z 2 CH is; and Z 3 In some embodiments, Z 1 CH is; Z 2 CH is; and Z 3 In some embodiments, Z 1 CH is; Z 2is N; and Z 3 is N. In some embodiments, Z 1 is CH; Z 2 is N; and Z 3 is CH. In some embodiments, Z 1 is N; Z 2 is CH; and Z 3 is CH. In some embodiments, Z 1 is N; Z 2 is CH; and Z 3 is N. In some embodiments, Z 1 is N; Z 2 is N; and Z 3 is CH. In some embodiments, Z 1 , Z 2 , and Z 3 one of is N. In some embodiments, Z 1 , Z 2 , and Z 3 two of are N.

[0048] In some embodiments, the compound of formula (I) is selected from formulae (I-1) to (I-3), (II-1) to (II-3), (III-1) to (III-3), and (IV-1) to (IV-3):

Chemical Formula

[0049] In some embodiments of the compound of formula (I), the compound is represented by formula (I-1). In some embodiments, the compound is represented by formula (I-2). In some embodiments, the compound is represented by formula (I-3). In some embodiments, the compound is represented by formula (II-1). In some embodiments, the compound is represented by formula (II-2). In some embodiments, the compound is represented by formula (II-3). In some embodiments, the compound is represented by formula (III-1). In some embodiments, the compound is represented by formula (III-2). In some embodiments, the compound is represented by formula (III-3). In some embodiments, the compound is represented by formula (IV-1). In some embodiments, the compound is represented by formula (IV-2). In some embodiments, the compound is represented by formula (IV-3).

[0050] In some embodiments of the compound of formula (I) or its variations, [ka] This is a 5-6 member heteroaryl, which may optionally include 1-2 additional ring heteroatoms selected from the group consisting of N and O, where each heteroatom of the heteroaryl is one R if necessary to satisfy the valence of the heteroatom. 1 Bonded to the group, and here, each carbon atom of the heteroaryl is one R if necessary to satisfy the valence of the carbon atom. 2 It bonds with the group, provided that the R required to satisfy the valence of each carbon atom 2 There is only one base. In some embodiments, [ka] It is a 5- to 6-membered heteroaryl that does not contain additional ring heteroatoms. In some embodiments, [ka] It is a 5-6 membered heteroaryl compound, which may optionally contain 1-2 additional ring heteroatoms that are N. In some embodiments, [ka] It is a 5- to 6-membered heteroaryl, which may optionally contain one additional ring heteroatom, which is nitrogen. In some embodiments, [ka] It is a 5- to 6-membered heteroaryl compound, which may optionally contain one additional ring heteroatom that is oxygen. In some embodiments, [ka] It is a 5-6 member heteroaryl compound, which may optionally contain two additional ring heteroatoms that are N. In some embodiments, [ka] It is a six-membered heteroaryl compound, which may optionally contain one or two additional ring heteroatoms selected from the group consisting of N and O. In some embodiments, [ka] It is a six-membered heteroaryl compound, which may optionally contain one or two additional ring heteroatoms that are N. In some embodiments, [ka] It is a six-membered heteroaryl compound, which may optionally contain one additional ring heteroatom, which is nitrogen. In some embodiments, [ka] It is a six-membered heteroaryl compound, which may optionally contain two additional ring heteroatoms that are N. In some embodiments, [ka] It is a five-membered heteroaryl compound, which may optionally contain one or two additional ring heteroatoms that are N. In some embodiments, [ka] It is a five-membered heteroaryl compound, which may optionally contain one additional ring heteroatom, which is nitrogen. In some embodiments, [ka] It is a five-membered heteroaryl compound, which may optionally contain one additional ring heteroatom that is oxygen. In some embodiments, [ka] It is a five-membered heteroaryl compound, which may optionally contain two additional ring heteroatoms that are N.

[0051] In some embodiments of the compound of formula (I) or its variations, [ka] This is a five-membered heterocycline, which may optionally contain one or two additional ring heteroatoms selected from the group consisting of N and O, where each heteroatom of the above heterocycline has one R if necessary to satisfy the valence of the heteroatom. 1Bonded to a group, and here, each carbon atom of the heterocycline has one R if necessary to satisfy the valence of the carbon atom. 2 It bonds with the group, provided that the R required to satisfy the valence of each carbon atom 2 There is only one base. In some embodiments of the compound of formula (I) or its variations, [ka] It is a five-membered heterocycline that does not contain any additional ring heteroatoms. In some embodiments, [ka] It is a five-membered heterocycline, which may optionally contain one or two additional ring heteroatoms that are nitrogen. In some embodiments, [ka] It is a five-membered heterocycline, which may optionally contain one additional ring heteroatom, which is nitrogen. In some embodiments, [ka] It is a five-membered heterocycline, which may optionally contain one additional ring heteroatom that is oxygen. In some embodiments, [ka] It is a five-membered heterocycline, which may optionally contain two additional ring heteroatoms that are N.

[0052] In some embodiments of the compound of formula (I) or its variations, Y is N. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, Y is C. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case. In some embodiments, [ka] teeth, [ka] That is the case.

[0053] In some embodiments, compounds of formula (I) are (I-4) to (I-9), (II-4) to (II-9), (III-4) to (III-9), and (IV-4) to (IV-9): [ka] [ka] [In the formula, A, Z 1 , Z 2 , Z 3 , R 1 , and R 2 This is as defined in equation (I). It is one of the compounds shown.

[0054] In some embodiments of the compound of formula (I), the compound is represented by formula (I-4). In some embodiments, the compound is represented by formula (I-5). In some embodiments, the compound is represented by formula (I-6). In some embodiments, the compound is represented by formula (I-7). In some embodiments, the compound is represented by formula (I-8). In some embodiments, the compound is represented by formula (I-9). In some embodiments, the compound is represented by formula (II-4). In some embodiments, the compound is represented by formula (II-5). In some embodiments, the compound is represented by formula (II-6). In some embodiments, the compound is represented by formula (II-7). In some embodiments, the compound is represented by formula (II-8). In some embodiments, the compound is represented by formula (II-9). In some embodiments, the compound is represented by formula (III-4). In some embodiments, the compound is represented by formula (III-5). In some embodiments, the compound is represented by formula (III-6). In some embodiments, the compound is represented by formula (III-7). In some embodiments, the compound is represented by formula (III-8). In some embodiments, the compound is represented by formula (III-9). In some embodiments, the compound is represented by formula (IV-4). In some embodiments, the compound is represented by formula (IV-5). In some embodiments, the compound is represented by formula (IV-6). In some embodiments, the compound is represented by formula (IV-7). In some embodiments, the compound is represented by formula (IV-8). In some embodiments, the compound is represented by formula (IV-9).

[0055] In some embodiments of the compound of formula (I) or its variations, each R 1These are independently H, C1-C3 alkyl, or C3-C5 cycloalkyl, where each C1-C3 alkyl or C3-C5 cycloalkyl may have 1 to 3 R 3 It may be substituted with a base. In some embodiments, each R 1 R is independently H, -CH3, or -CH2CH3. In some embodiments, each R 1 R is independently H, cyclopropyl, -CH3, -CH(CH3)2, t-butyl, or -CH2CH3. In some embodiments, R 1 If such a thing exists, then at least one R 1 H is H. In some embodiments, R 1 If such a thing exists, then at least one R 1 Depending on the case, 1 to 5 R 3 It is a C1-C6 alkyl group, which may be substituted with a group. In some embodiments, R 1 If such a thing exists, then at least one R 1 R is an unsubstituted C1-C6 alkyl group. In some embodiments, R 1 If such a thing exists, then at least one R 1 Depending on the case, 1 to 3 R 3 It is a C1-C3 alkyl group, which may be substituted with a group. In some embodiments, R 1 If such a thing exists, then at least one R 1 R is an unsubstituted C1-C3 alkyl group. In some embodiments, R 1 If such a thing exists, then at least one R 1 is -CH3 or -CH2CH3. In some embodiments, R 1 If such a thing exists, then at least one R 1 is -CH3, -CH(CH3)2, t-butyl, or -CH2CH3. In some embodiments, R 1 If such a thing exists, then at least one R 1 is -CH3. In some embodiments, R 1 If such a thing exists, then at least one R 1is -CH2CH3. In some embodiments, R 1 If such a thing exists, then at least one R 1 is -CH(CH3)2. In some embodiments, R 1 If such a thing exists, then at least one R 1 is t-butyl. In some embodiments, R 1 If such a thing exists, then at least one R 1 Depending on the case, 1 to 5 R 3 It is a C3-C6 cycloalkyl group, which may be substituted with a group. In some embodiments, R 1 If such a thing exists, then at least one R 1 R is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 1 If such a thing exists, then at least one R 1 Depending on the case, 1 to 3 R 3 It is a C3-C5 cycloalkyl group, which may be substituted with a group. In some embodiments, R 1 If such a thing exists, then at least one R 1 R is an unsubstituted C3-C5 cycloalkyl group. In some embodiments, R 1 If such a thing exists, then at least one R 1 R is cyclopropyl. In some embodiments, 1 If such a thing exists, then at least one R 1 is one R 3 It is a cyclopropyl substituted with a group. In some embodiments, R 1 If such a thing exists, then at least one R 1 is one R 3 It is a cyclopropyl substituted with a group, where R 3 The group is a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments, R 1 If such a thing exists, then at least one R 1 teeth, [ka] In some embodiments, R1 If such a thing exists, then at least one R 1 teeth, [ka] In some embodiments, R 1 If such a thing exists, then at least one R 1 teeth, [ka] In some embodiments, R 1 If such a thing exists, then at least one R 1 teeth, [ka] That is the case.

[0056] In some embodiments of the compound of formula (I) or its variations, each R 2 These are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, -O(C1-C3 alkyl), -O(C3-C5 cycloalkyl), hydroxyl, or oxo, where each C1-C3 alkyl, C3-C5 cycloalkyl, -O(C1-C3 alkyl), or -O(C3-C5 cycloalkyl) group may have 1 to 3 R groups. 3 It may be substituted with a base. In some embodiments, each R 2 These are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, -O(C1-C3 alkyl), or oxo, where each C1-C3 alkyl, C3-C5 cycloalkyl, or -O(C1-C3 alkyl) group may have 1 to 3 R 3 It may be substituted with a base. In some embodiments, each R 2 R is independently H, -CH3, -CH2CH3, -OCH3, or oxo. In some embodiments, each R 2 R is independently H, -CH3, -CH2CH3, -OCH3, cyclopropyl, or oxo. In some embodiments, R 2If such a thing exists, then at least one R 2 H is H. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 5 R 3 It is a C1-C6 alkyl group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 3 R 3 It is a C1-C3 alkyl group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted C1-C3 alkyl group. In some embodiments, R 2 If such a thing exists, then at least one R 2 is -CH3 or -CH2CH3. In some embodiments, R 2 If such a thing exists, then at least one R 2 is -CH3. In some embodiments, R 2 If such a thing exists, then at least one R 2 is -CH2CH3. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 5 R 3 It is a C3-C6 cycloalkyl group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 3 R 3 It is a C3-C5 cycloalkyl group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2R is an unsubstituted C3-C5 cycloalkyl group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is cyclopropyl. In some embodiments, 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 5 R 3 It is -O(C1-C6 alkyl), which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted -O(C1-C6 alkyl) group. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 3 R 3 It is -O(C1-C3 alkyl), which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted -O(C1-C3 alkyl) group. In some embodiments, R 2 If such a thing exists, then at least one R 2 is -OCH3. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 5 R 3 It is a -O(C3-C6 cycloalkyl) group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted -O(C3-C6 cycloalkyl) group. In some embodiments, R 2 If such a thing exists, then at least one R 2 Depending on the case, 1 to 3 R 3 It is a -O(C3-C5 cycloalkyl) group, which may be substituted with a group. In some embodiments, R 2 If such a thing exists, then at least one R 2 R is an unsubstituted -O(C3-C5 cycloalkyl) group. In some embodiments, R 2If such a thing exists, then at least one R 2 R is a hydroxyl group. In some embodiments, R 2 If such a thing exists, then at least one R 2 It is oxo.

[0057] In some embodiments of the compound of formula (I) or its variations, R 1 and R 2 These together form a 5-6 member heteroaryl or a 5-7 member heterocycline. In some embodiments, R 1 and R 2 These together form a 5-6 member heteroaryl, such as pyridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, or furanyl. In some embodiments, R 1 and R 2 These combine to form a 5-membered heteroaryl. In some embodiments, R 1 and R 2 These combine to form a 6-membered heteroaryl. In some embodiments, R 1 and R 2 These combine to form 5-7 member heterocyclines, such as tetrahydrofuranil, pyrrolidinil, piperidinil, piperazinil, morpholinil, azepanil, oxazinanyl, or thiomorpholinil. In some embodiments, R 1 and R 2 These combine to form a 5-6 member heterocycline. In some embodiments, R 1 and R 2 These combine to form a 5-membered heterocycline. In some embodiments, R 1 and R 2 These combine to form a 6-membered heterocycline. In some embodiments, R 1 and R 2These together form a 7-membered heterocycline. In some embodiments, R 1 and R 2 Together, [ka] It forms a structure.

[0058] In some embodiments of the compound of formula (I) or its variations, two R 2 The groups combine to form a 5-6 member heteroaryl, a 5-7 member heterocyclyl, a C5-C7 cycloalkyl, or a C6 aryl. In some embodiments, two R 2 The groups together form a 5-6 member heteroaryl, such as pyridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, or furanyl. In some embodiments, two R groups 2 The groups combine to form a 5-membered heteroaryl. In some embodiments, two R 2 The groups combine to form a 6-membered heteroaryl. In some embodiments, two R 2 The groups together form 5-7 membered heterocyclines, such as tetrahydrofuranil, pyrrolidinil, piperidinil, piperazinil, morpholinil, azepanil, or thiomorpholinil. In some embodiments, two R 2 The groups combine to form a 5-6 member heterocycline. In some embodiments, two R 2 The groups combine to form a 5-membered heterocycline. In some embodiments, two R 2 The groups combine to form a 6-membered heterocycline. In some embodiments, two R 2 The groups combine to form a 7-membered heterocycline. In some embodiments, two R 2These combine to form a C5-C7 cycloalkyl group. In some embodiments, two R 2 These combine to form a C5-C6 cycloalkyl group. In some embodiments, two R 2 These together form a C5 cycloalkyl group. In some embodiments, two R 2 These together form a C6 cycloalkyl group. In some embodiments, two R 2 These together form a C7 cycloalkyl group. In some embodiments, two R 2 These combine to form a C6 aryl group.

[0059] In some embodiments of the compound of formula (I), each R 3 If present, R is independently a halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-OH, -NH2, -CN, or hydroxyl. In some embodiments, each R 3 If present, R is independently Cl, F, -CH3, -CF3, -CHF2, -CH2OH, -NH2, -CN, or hydroxyl. In some embodiments, R 3 If such a thing exists, then at least one R 3 is a halogen, for example, Cl or F. In some embodiments, R 3 If such a thing exists, then at least one R 3 is Cl. In some embodiments, R 3 If such a thing exists, then at least one R 3 In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 alkyl group, for example, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -CH3. In some embodiments, R 3 If such a thing exists, then at least one R3 is a C3-C6 cycloalkyl group. In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 haloalkyl. In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 haloalkyl having 1 to 3 halogen atoms. In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 haloalkyl having one halogen atom. In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 haloalkyl having two halogen atoms. In some embodiments, R 3 If such a thing exists, then at least one R 3 R is a C1-C3 haloalkyl having three halogen atoms. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -CF3. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -CHF2. In some embodiments, R 3 If such a thing exists, then at least one R 3 is a C1-C3 alkyl-OH group. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -CH2OH. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -NH2. In some embodiments, R 3 If such a thing exists, then at least one R 3 is -CN. In some embodiments, R 3 If such a thing exists, then at least one R 3 It is a hydroxyl molecule.

[0060] In some embodiments of the compound of formula (I), [ka] teeth, [ka] That is the case. In other embodiments of the compound of formula (I), [ka] teeth, [ka] That is the case.

[0061] Several embodiments are provided of a compound of formula (I) or a variation thereof, wherein the compound has one or more of the following characteristics: (I) A is, [ka] is; (II) Z 1 , Z 2 , Z 3 The combination is, (iv) Z 1 , Z 2 , Z 3 However, each of them is CH, (v) Z 1 However, N is, and Z 2 and Z 3 However, each of them is either CH or, (vi) Z 2 However, N is, and Z 1 and Z 3 However, each of them is CH; (III) [ka] teeth, (vii) A 5-6 member heteroaryl, which may optionally include 1-2 additional ring heteroatoms selected from the group consisting of N and O, for example, [ka] is it, or, (viii) A five-membered heterocycline, which may optionally contain one or two additional ring heteroatoms selected from the group consisting of N and O, for example, [ka] is; (IV) Each R 1 These are independently H, C1-C3 alkyl, or C3-C5 cycloalkyl, where each C1-C3 alkyl or C3-C5 cycloalkyl may have 1 to 3 R 3 It may be substituted with the base; (V) Each R 2 These are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, -O(C1-C3 alkyl), or oxo, where each C1-C3 alkyl, C3-C5 cycloalkyl, or -O(C1-C3 alkyl) group may have 1 to 3 R 3 It may be substituted with the base.

[0062] In some embodiments, (II) applies. In some embodiments, (IV) applies. In some embodiments, (V) applies. In some embodiments, (i) applies. In some embodiments, (ii) applies. In some embodiments, (iii) applies. In some embodiments, (iv) applies. In some embodiments, (v) applies. In some embodiments, (vi) applies. In some embodiments, (vii) applies. In some embodiments, (viii) applies. In some embodiments, (i) and (II) apply. In some embodiments, (ii) and (II) apply. In some embodiments, (iii) and (II) apply. In some embodiments, (vii) and (II) apply. In some embodiments, (viii) and (II) apply. In some embodiments, (iv) and (vii) apply. In some embodiments, (iv) and (viii) apply. In some embodiments, (v) and (vii) apply. In some embodiments, (v) and (viii) apply. In some embodiments, (vi) and (vii) apply. In some embodiments, (vi) and (viii) apply. In some embodiments, (I), (II), (III), (IV), and (V) apply. In some embodiments, (i), (II), (III), (IV), and (V) apply. In some embodiments, (ii), (II), (III), (IV), and (V) apply. In some embodiments, (iii), (II), (III), (IV), and (V) apply. In some embodiments, (I), (iv), (III), (IV), and (V) apply. In some embodiments, (I), (v), (III), (IV), and (V) apply. In some embodiments, (I), (vi), (III), (IV), and (V) apply.In some embodiments, (I), (II), (vii), (IV), and (V) apply. In some embodiments, (I), (II), (viii), (IV), and (V) apply.

[0063] In some embodiments, the compound of formula (I) is an agonist of THR beta. In some embodiments, the compound of formula (I) is an agonist of THR beta that is more selective than THR alpha. In some embodiments, the compound of formula (I) has at least twice the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least five times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least ten times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least twenty times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least fifty times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least seventy times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) has at least one hundred times the selectivity for THR beta compared to THR alpha. In some embodiments, the compound of formula (I) exhibits 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 selectivity over THR-beta compared to THR-alpha. In such embodiments, in one aspect, the selectivity is evaluated via a biochemical assay such as the TR-FRET assay described in Example B1. In some embodiments, in another aspect, the selectivity is evaluated via a biochemical assay such as the RXR heterodimer assay described in Example B2.

[0064] In this specification, all descriptions, variations, embodiments, or aspects of a part can be combined with all descriptions, variations, embodiments, or aspects of the other parts, just as each and every combination of descriptions is described individually and specifically. For example, with respect to A of formula (I), all descriptions, variations, embodiments, or aspects provided herein are Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 All descriptions, variations, embodiments, or aspects of B, and Y, and all combinations thereof, can be combined in the same way as if they were described individually and specifically. It is also understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally to other formulas described herein, where applicable, and that all descriptions, variations, embodiments, or aspects are described equally in the same way as they are described individually and specifically for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to any of the formulas detailed herein, e.g., formulas (I-1) to (I-9), (II), (II-1) to (II-9), (III), (III-1) to (III-9), (IV), (IV-1) to (IV-9), where applicable, and that all descriptions, variations, embodiments, or aspects are described equally in the same way as they are described individually and specifically for all formulas.

[0065] In some embodiments, compounds selected from the compounds in Table 1, or pharmaceutically acceptable salts thereof, are provided. While specific compounds described in this disclosure, including Table 1, are presented as specific stereoisomers and / or non-stereochemical forms, any or all stereochemical forms, including any enantiomer or diastereomer forms, and any tautomers, or any other form of any compound of this disclosure, including Table 1, are understood to be described herein.

[0066] In one embodiment, the following compounds are provided herein, selected from those shown in Table 1 (Tables 1-1 to 1-5), or their tautomers, N-oxides, isotopic isomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0067] In some embodiments, compounds selected from those listed in Table 1 or pharmaceutically acceptable salts thereof are provided herein. In some embodiments, compounds selected from Examples 1 to 59 or pharmaceutically acceptable salts thereof are provided herein.

[0068] The present invention also includes all salts of the compounds referenced herein, including pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms, including any enantiomer or diastereomer, as well as any tautomers or other forms of the described compounds, such as N-oxides, solvates, or isotopic isomers. Unless the stereochemistry is expressly indicated by the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the indicated compound. Furthermore, if a particular stereochemical form is indicated, it is understood that other stereochemical forms are also included in the present invention. All forms of the compound, such as crystalline or amorphous forms of the compound, are also included in the present invention. Compositions containing the compounds of the present invention, for example, substantially pure compositions of the compound containing a particular stereochemical form thereof, are also intended. Furthermore, compositions containing mixtures of the compounds of the present invention in any ratio are also included in the present invention, and include mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, thereby including racemic, non-racemic, enantiorich, and scalemic mixtures of the compounds.

[0069] Synthesis method Scheme 1a: [ka] Scheme 1a shows the synthesis of a compound of general formula (A), where variable groups B and Z 1 , Z 2 , and Z 3 This is as defined for the compound of formula (I). The amine derivative of formula (A-1) can react with 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride in the presence of a base to form the compound of formula (A).

[0070] Scheme 1b: [ka] Scheme 1b outlines the general synthesis of the compound of formula (B), where variable groups B and Z are used. 1, Z 2 , and Z 3 This is as defined for the compound of formula (I). By treating the compound of formula (A-1) with dioxaborolane 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane, the compound of formula (B-1) can be obtained, which can then be formed by Suzuki coupling with 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione to form the compound of general formula (B).

[0071] Scheme 1c: [ka] Scheme 1c shows the synthesis of a compound of general formula (C), where variable groups B and Z 1 , Z 2 , and Z 3 This is as defined for the compound of formula (I). By reacting the compound of formula (A-1) with ethyl (2-cyanoacetyl)carbamate, the intermediate compound of formula (C-1) is obtained, which is then treated with a base to obtain the compound of formula (C).

[0072] Scheme 2: [ka] Scheme 2 shows the synthesis of the compound of general formula (A-1), where variable groups B and Z 1 , Z 2 , and Z 3This is as defined for the compound of formula (I), which is used in the synthetic methods described herein, as outlined in schemes 1a-1c. The bromide derivative (A-1a) can be reacted with hypodiboric acid to form a boronic acid derivative (A-1b), which can then be oxidized to form a hydroxide (A-1c). Subsequently, the compound of formula (A-1c) can be treated with 1,3-dichloro-2-fluoro-5-nitrobenzene and a base to obtain a nitro derivative (A-1d), which can then be reduced to form the compound of formula (A-1).

[0073] Scheme 3: [ka] Scheme 3 outlines the synthesis of the compound of general formula (D), where the variable group R 1 This is defined for the compound of formula (I), which is used in the synthetic methods described herein to introduce a fused ring system containing ring B. 4-bromo-2-fluoro-1-nitrobenzene and R 1 -A derivative of formula (D-1) can be obtained by reaction with a substituted amine, and this can be reduced to form the amine derivative of formula (D-2). Subsequently, the compound of formula (D-2) is reacted with trimethoxymethane to obtain the compound of formula (D).

[0074] Scheme 4: [ka] Scheme 4 outlines the synthesis of the compound of general formula (E), where the variable group R 1 This is defined for the compound of formula (I), which is used in the synthetic methods described herein to introduce a fused ring system containing ring B. The compound of formula (E) can be obtained by the reaction of an amine derivative (D-2) with a carbonyl source.

[0075] Scheme 4a: [ka] Scheme 4a outlines a method for producing alkoxy derivatives of general formula (E-1), where the variable group R 1 The compound of formula (I) is as defined, where R is an alkyl group, which is used in the synthetic methods described herein to introduce a fused ring system containing ring B. The compound of formula (E-1) is obtained by the reaction of an amine derivative (D-2) with C(OR)4 as a carbonyl source. In some variations, R is methyl. In some embodiments, the compound of formula (E-1) is an intermediate in the preparation of the compound of formula (E), as provided in Scheme 4. In some embodiments, the compound of formula (E-1) can be further reacted with an agent that cleaves CO bonds in an ether (e.g., BCl3) to obtain the compound of formula (E), as provided in Scheme 4. In some embodiments, the compound of formula (E-1) is the compound of formula (A-1a), as provided in Scheme 2, and can be reacted according to the general method outlined in Scheme 2, where the intermediate and product compounds retain the -OR present in the compound of formula (E-1).

[0076] Scheme 5: [ka] Scheme 5 outlines the general synthesis of the compound of formula (F), and the variable group R 2 This is defined for the compound of formula (I), which is used in the synthetic methods described herein to introduce a fused ring system containing ring B. The compound of formula (F) can be obtained by the reaction of a fluoro derivative (F-1) with hydrazine.

[0077] The synthesis of the specific compounds provided herein is outlined above and provided in the following section of Examples. The variable groups described in the above scheme are defined for the compound of formula (I) or any variation, embodiment, or aspect thereof. The synthesis of other compounds provided herein will be apparent to those skilled in the art based on the guidance provided herein and on synthesis methods well known to those skilled in the art.

[0078] If it is desirable to obtain a specific enantiomer of a compound, it can be obtained from a corresponding mixture of enantiomers using any suitable conventional method for separating or decomposing the enantiomer. For example, a diastereomer derivative can be produced by the reaction of a mixture of enantiomers, e.g., a racemate, with a suitable chiral compound. The diastereomer can then be separated by any convenient means, e.g., crystallization, and the desired enantiomer can be recovered. In another separation process, the racemate can be separated using chiral high-performance liquid chromatography. Alternatively, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes, if necessary.

[0079] Chromatography, recrystallization, and other conventional separation techniques can also be used on intermediates or final products when it is desired to obtain specific isomers of a compound, or at least to purify the reaction products.

[0080] Solvates of the compounds or pharmaceutically acceptable salts thereof provided herein are also intended. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. If the solvent is water, a hydrate is formed; if the solvent is an alcohol, an alcoholate is formed.

[0081] It is understood that the synthesis processes disclosed herein can be modified by selecting appropriate reagents and starting materials to obtain various compounds of the present invention. It is also understood that, if protection of certain active or unsuitable groups (e.g., amines or carboxylic acids) is required, the formulas, for example, in the schemes provided herein, are intended to include compounds in which such active or unsuitable groups are appropriately protected. For a general description of protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4. th See edition, Wiley-Interscience, New York, 2006.

[0082] Pharmaceutical compositions and formulations Pharmaceutical compositions of any compound detailed herein are included in the present invention. Accordingly, the present invention includes pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the present invention can be in a form suitable for oral, intraoral, parenteral, intranasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0083] The compounds detailed herein may, in one embodiment, be in a purified form, and compositions comprising the purified form of the compounds are detailed herein. Compositions comprising the compounds detailed herein or salts thereof, such as substantially pure compositions of the compounds, are provided. In some embodiments, compositions comprising the compounds detailed herein or salts thereof are in a substantially pure form. In one modification, “substantially pure” means a composition with an impurity content of 35% or less, where impurities mean compounds other than the compound or salts thereof that constitute the main part of the composition. For example, a composition of a substantially pure compound selected from the compounds of Table 1 is intended to have an impurity content of 35% or less, where impurities mean compounds other than the compound or salts thereof. In one modification, a substantially pure composition of the compound or salt thereof is provided, in which the impurity content of the composition is 25% or less. In another modification, a substantially pure composition of the compound or salt thereof is provided, in which the impurity content of the composition is 20% or less. In yet another modification, a substantially pure composition of the compound or salt thereof is provided, in which the impurity content of the composition is 10% or less. In further modifications, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 5% or less of impurities. In another modification, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 3% or less of impurities. In yet another modification, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 1% or less of impurities. In yet another modification, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 0.5% or less of impurities. In yet another modification, a substantially pure compound composition is provided, wherein the composition contains 15% or less, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and even more preferably 1% or less of impurities, wherein the impurities may be compounds of different stereochemical forms. For example, but not limited to, a substantially pure (S) compound composition means that the content of the (R) isomer of that compound in the composition is 15% or less, or 10% or less, or 5% or less, or 3% or less, or 1% or less.

[0084] In one variation, the compounds described herein are synthetic compounds prepared for administration to an organism such as a human. In another variation, a composition comprising a substantially pure form of the compound is provided. In yet another variation, the present invention encompasses a pharmaceutical composition comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In yet another variation, a method for administering the compound is provided. The purified forms, pharmaceutical compositions, and methods for administering the compound are suitable for any of the compounds or forms detailed herein.

[0085] Compounds can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, cheek, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. Compounds can be formulated with a suitable carrier to provide a delivery form, but are not limited to tablets, caplets, capsules (e.g., hard gelatin capsules or elastic soft gelatin capsules), cachets, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0086] One or more of the compounds described herein may be used in the manufacture of pharmaceutical formulations, etc., by combining the compound or more compounds as active ingredients with a pharmaceutically acceptable carrier as described above. Depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet), the carrier may take various forms. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants to adjust osmotic pressure. Formulations containing the compounds may also contain other substances having valuable therapeutic properties. Pharmaceutical formulations can be manufactured by known pharmaceutical methods. Suitable formulations are, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st See ed. (2005), which is incorporated herein by reference.

[0087] The compounds described herein may be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and hard or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used in the manufacture of such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants to adjust osmotic pressure.

[0088] Any of the compounds described herein can be formulated into tablets in any of the described dosage forms.

[0089] Compositions comprising the compound or pharmaceutically acceptable salts thereof provided herein are also described. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, a substantially pure composition of the compound is provided.

[0090] Usage / Treatment Compounds and compositions detailed herein, such as compounds of any of the formulas provided herein or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising pharmaceutically acceptable carriers or excipients, can be used in the administration methods and treatments provided herein. Compounds and compositions can also be used in in vitro methods, for example, in in vitro methods in which the compound or composition is administered to cells for screening purposes and / or quality control assays.

[0091] In one embodiment, a method for agonizing thyroid hormone receptor beta (THR beta) is provided herein, comprising contacting THR beta with an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition provided herein.

[0092] In one embodiment, a method is provided herein for treating a THR beta-mediated disorder in a patient, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein, to a patient in need thereof.

[0093] Methods for treating THR beta-mediated disorders, including but not limited to non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and their respective symptoms and signs, are well known to those skilled in the art and may be applied to treat the disorders by compounds or pharmaceutically acceptable salts or compositions provided herein.

[0094] In one embodiment, a method for agonizing thyroid hormone receptor beta (THRbeta) is provided, comprising contacting THRbeta with an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein. In one embodiment, a method for selectively agonizing THRbeta more than THRalpha is provided, comprising contacting THRbeta with an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein. In such an embodiment, the method selectively agonizes THRbeta more than THRalpha by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times. In any such embodiment, in one aspect, selectivity is evaluated via a biochemical assay such as the TR-FRET assay described in Example B1. In any such embodiment, in another aspect, selectivity is evaluated via a biochemical assay such as the RXR heterodimer assay described in Example B2.

[0095] In one embodiment, a method is provided herein for treating a THR beta-mediated disease or disorder in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a composition provided herein. In one embodiment, the disease or disorder is a disease or disorder of the liver. In one embodiment, a method is provided herein for treating a liver disease or disorder associated with sub-optimal THR beta agonism in a patient in need, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes THR beta rather than THR alpha.

[0096] In one embodiment, a method for treating non-alcoholic fatty liver disease in a patient in need is provided, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method for treating non-alcoholic steatohepatitis (NASH) in a patient in need is provided, comprising administering to the patient an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method for treating metabolic syndrome in a patient in need is provided, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method for treating dyslipidemia in a patient in need is provided, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method for treating hypertriglyceridemia in a patient in need is provided, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein. In one embodiment, a method for treating hypercholesterolemia in a patient in need is provided, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein.

[0097] In any of the embodiments described herein, patients having a disease or disorder related to THR betaagonism may include, but are not limited to, patients with underlying hypothyroidism.

[0098] In another embodiment, a method is provided for delaying the onset and / or progression of a THRbeta-mediated disease or disorder in a patient (e.g., a human) at risk of developing the disease or disorder. It is understood that delaying onset may include prevention in cases where the individual does not develop the disease or disorder. In one embodiment, an individual at risk of developing a THRbeta-mediated disease or disorder has one or more risk factors for developing the disease or disorder, such as age, increased waist circumference, increased body mass index, or associated comorbidities.

[0099] In one embodiment, a method is provided herein for delaying the onset and / or progression of non-alcoholic fatty liver disease in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method is provided herein for delaying the onset and / or progression of non-alcoholic steatohepatitis (NASH) in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method is provided herein for delaying the onset and / or progression of metabolic syndrome in a patient who needs it, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method is provided herein for delaying the onset and / or progression of dyslipidemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method is provided herein for delaying the onset and / or progression of hypertriglyceridemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein. In one embodiment, a method is provided herein for delaying the onset and / or progression of hypercholesterolemia in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition provided herein.

[0100] In one embodiment, a compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, is provided herein for therapeutic use. In some embodiments, a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided herein for use in the treatment of non-alcoholic fatty liver disease. In some embodiments, a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided herein for use in the treatment of non-alcoholic steatohepatitis (NASH). In some embodiments, a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of metabolic syndrome. In some embodiments, a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of dyslipidemia. In some embodiments, pharmaceutical compositions are provided for use in the treatment of hypertriglyceridemia, comprising a compound of formula (I) or a variant thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a variant thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of hypercholesterolemia.

[0101] In another embodiment, the compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, is provided herein for use in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease. In another embodiment, the compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, is provided herein for use in the manufacture of a medicament for the treatment of non-alcoholic steatohepatitis (NASH). In another embodiment, the compound of formula (I) or a variant thereof, or a pharmaceutically acceptable salt thereof, is provided 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.

[0102] 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 about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old, or any of these ages or older. In some embodiments, the human is a child. In some embodiments, the human is about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old, or any of these ages or younger.

[0103] Dosage and method of administration The dosage of the compounds described herein, or their stereoisomers, tautomers, solvates, or salts, administered to an individual (such as a human) may vary depending on the specific compound or salt thereof, the method of administration, and the specific disease or disorder being treated, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia. In some embodiments, the amount of the compound, or its stereoisomers, tautomers, solvates, or salts, is a therapeutically effective amount.

[0104] The compounds or salts thereof provided herein can be administered to an individual via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0105] The effective dose of the compound may, in one embodiment, be a dose of about 0.01 to about 100 mg / kg. The effective dose or dosage of the compound of this disclosure can be determined by predetermined methods such as modeling, dose escalation, or clinical trials, taking into account predetermined 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 status, symptoms, and body weight of the subject. The dosage may be in the range of, for example, about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0106] Any method provided herein may, in one embodiment, involve administering to an individual a pharmaceutical composition comprising an effective amount of the compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.

[0107] The compounds or compositions provided herein can be administered to an individual for a desired time or period, e.g., 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 longer, according to an effective dosage regimen, which in some variations may extend to the lifetime of the individual. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered to an individual continuously over a period of time (e.g., at least once a day). The dosage frequency may also be less than once a day, e.g., about once a week. The dosage frequency may also be more than once a day, e.g., twice or three times a day. The dosage frequency may also be intermittent, including “drug-free periods” (e.g., 14 days of once-daily administration followed by 7 days of no administration, repeated for e.g., about 2 months, about 4 months, about 6 months or longer). Any dosage frequency can be used with any compound or pharmaceutically acceptable salt described herein, in any dosage described herein.

[0108] Products and kits This disclosure further provides products comprising the compounds or salts thereof described herein, the compositions described herein, or one or more unit doses described herein in appropriate packaging. In particular embodiments, the products are intended for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The products can be further sterilized and / or sealed.

[0109] This disclosure further provides a kit for carrying out the method of this disclosure, comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, or a composition comprising the compounds described herein. The kit may use the compounds disclosed herein or pharmaceutically acceptable salts thereof. In one variation, the kit may use the compounds described herein or pharmaceutically acceptable salts thereof. The kit may be used for one or more of the uses described herein and therefore may include instructions for the treatment of any of the diseases described herein, for example, for the treatment of non-alcoholic steatohepatitis (NASH).

[0110] The kit generally includes appropriate packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if there are multiple components) may be packaged in a separate container, or several components may be combined in one container, if cross-reactivity and shelf life permit.

[0111] The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. For example, a kit can be provided containing a sufficient dose of the compounds disclosed herein or pharmaceutically acceptable salts thereof, and / or additional pharmaceutically active compounds useful for the diseases detailed herein, which can provide effective treatment of an individual for an extended period, for example, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. The kit may contain multiple unit doses of the compounds and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (such as a hospital pharmacy or a compounding pharmacy).

[0112] The kit may include, depending on the circumstances, a set of instructions, general instructions, but an electronic storage medium (e.g., a magnetic diskette or optical disc) containing the instructions is also acceptable and relates to the use of the components of the method of this disclosure. The instructions included in the kit typically contain information about the components and their administration to individuals. [Examples]

[0113] This disclosure is made merely as an example, and it will be understood that numerous changes in the combination and arrangement of parts can be made by those skilled in the art, as long as they do not deviate from the spirit and scope of this disclosure.

[0114] The chemical reactions described in the examples can be readily adapted to produce many other compounds disclosed herein, and alternative methods for producing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, the synthesis of compounds not illustrated in this disclosure can be adequately carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known to those skilled in the art other than those described, or by making predetermined changes to the reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as applicable to producing other compounds of this disclosure.

[0115] The following abbreviations may be relevant to this application. Abbreviation Ac: Acetyl ACN, or MeCN: Acetonitrile BAST: Bis(2-methoxyethyl)aminosulfur trifluoride BINAP: 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl BPD: Bispinacolatodiborone Boc: Tertiary butyloxycarbonyl Bu: Butyl cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) DBA: Dibenzylideneacetone DCM: Dichloromethane DIEA, or DIPEA: N,N-diisopropylethylamine DMA: Dimethylacetamide DMAP: Dimethylaminopyridine DMF: Dimethylformamide DMF-DMA: Dimethylformamide Dimethylacetal DMSO: Dimethyl sulfoxide DPPA: Diphenylphosphoryl azide DSC: Disucine Imidyl Carbonate Et: Ethyl FA: Formic acid MBTE: Methyl tert-butyl ether Me: Methyl NIS: N-iodosuccinimide Pd(dba)2: Bis(dibenzylideneacetone)palladium(0) Pr: Propyl Py, or Pyr: Pyridine rt: room temperature sat: saturation SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride SFC: Supercritical Fluid Chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Tol: Toluene XPhos: 2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl t-Bu Xphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0116] Example of synthesis Scheme A Synthesis of 3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (compound 1e) [ka] Synthesis of 5-bromo-3-ethyl-1H-indazole (1a) A solution of 1-(5-bromo-2-fluorophenyl)propan-1-one (770 mg, 3.33 mmol) in N2H4.H2O (6.72 mL) was stirred under a sealed tube at 115°C for 32 hours. LC-MS indicated that the starting material had been completely consumed, and the desired MS was detected. The mixture was poured into a mixture of ice and water. The precipitate was collected by filtration and thoroughly washed with water to obtain 1a. MSmas calculation value: [M+1] + (C9H9BrN2), m / z 225.0, LCMS measured value m / z 225.1; 1 H NMR (400 MHz, CDCl3) δ 9.81 (br s, 1H), 7.87 (d, J = 1.0 Hz, 1H), 7.46 (dd, J = 8.8, 1.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 2.99 (q, J = 7.8 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H).

[0117] Synthesis of 5-bromo-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1b) A solution of 5-bromo-3-ethyl-1H-indazole (1a) (610 mg, 2.71 mmol) in DCM (8 mL) was added dropwise to SEM-Cl (451.83 mg, 2.71 mmol, 479.65 μL) and DIEA (420.30 mg, 3.25 mmol, 566.45 μL) at 0°C. The mixture was then stirred at 20°C for 4 hours. TLC showed that 1a had been completely consumed and two new spots had formed. LC-MS showed the desired MS. The mixture was extracted with DCM (30 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate) to obtain 1b. MSmas calculation value: [M+1] + (C 15 H23 BrN2OSi), m / z 355.1, LCMS measured value m / z 355.1; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.2, 1.8 Hz, 1H), 5.72 (s, 2H), 3.57 - 3.64 (m, 2H), 3.11 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H), 0.87 - 0.95 (m, 2H), -0.04 (s, 9H).

[0118] Synthesis of 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol(1c) A mixture of 5-bromo-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1b) (190 mg, 534.69 μmol), 2-[(5-bromo-3-ethyl-indazole-2-yl)methoxy]ethyl-trimethyl-silane (200 mg, 562.83 μmol), KOH (39.00 mg, 695.10 μmol), Pd2(dba)3 (48.96 mg, 53.47 μmol), and t-Bu Xphos (34.06 mg, 80.20 μmol) in dioxane (5 mL) and H2O (5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 3.5 hours under an N2 atmosphere. TLC showed that 1b was completely consumed and many new spots were formed. LC-MS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (5 ml x 3). The combined filtrate 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 Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to obtain 1c. MSmas calculation value: [M+1] + (C 15 H24 N2O2Si), m / z 293.2, LCMS measured value m / z 293.2; 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.61 (m, 1H), 6.93 - 7.00 (m, 1H), 6.90 (d, J = 1.8 Hz, 1H), 5.69 (s, 2H), 4.96 (br s, 2H), 3.55 - 3.64 (m, 2H), 3.07 (q, J = 7.6 Hz, 2H), 1.23 - 1.29 (m, 3H), 0.87 - 0.94 (m, 4H), -0.04 (s, 9H).

[0119] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole(1d) 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol (1c) (115 mg, 393.23 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (90.83 mg, 432.56 μmol) were dissolved in DMF (5 mL) and K2CO3 (81.52 mg, 589.85 μmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. TLC showed that 1c had been completely consumed and a new spot had formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified using Prep-TLC (petroleum ether: ethyl acetate) to obtain 1d. MSmas calculation value: [M+1] + (C 21 H 25 Cl2N3O4Si), m / z 482.1, LCMS measured value m / z 482.2; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.12 (dd, J = 9.4, 2.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 5.69 (s, 2H), 3.59 - 3.64 (m, 2H), 3.53 - 3.58 (m, 1H), 3.02 (q, J = 7.6 Hz, 2H), 1.26 - 1.31 (m, 4H), -0.03 (s, 9H)

[0120] Synthesis of 3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (1e) To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1d) (100 mg, 207.28 μmol) in EtOH (4 mL), iron powder (57.88 mg, 1.04 mmol) and NH4Cl (55.44 mg, 1.04 mmol) were added. The mixture was stirred at 80°C for 2 hours. TLC showed that 1d had been completely consumed and a new spot had formed. LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (5 mL x 3). The combined filtrate was extracted with ethyl acetate (20 mL x 2) and washed with H2O (10 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to obtain 1e. MSmas calculation value: [M+1] + (C 21 H 27 Cl2N3O2Si), m / z 452.1, LCMS measured value m / z 452.1

[0121] Example 1 2-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (1g) 3,5-Dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (1e) (20 mg, 44.20 μmol) was added to a solution of HCl (0.5 mL) and H2O (1 mL) at 0°C with NaNO2 (3.96 mg, 57.47 μmol), and the mixture was stirred at 0°C for 0.5 hours. The solution was then added to a solution of ethyl (2-cyanoacetyl)carbamate (7.59 mg, 48.62 μmol) in H2O (1 mL) and Py (0.5 mL) at 0°C, and the reaction mixture was stirred for a further 0.5 hours at 0°C. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered, and the filtered cake was dried under reduced pressure to obtain 1 g.

[0122] Synthesis of 2-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 1) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (1 g) (18 mg, 36.79 μmol) in HOAc (1 mL) was mixed with NaOAc (15.09 mg, 183.93 μmol) under N2. The mixture was stirred at 120°C for 3 hours. LC-MS showed that the starting material had been completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)-MeCN]) to obtain Example 1. MSmas calculation value: [M+1] + (C 19 H 12 Cl2N6O3), m / z 443.0, LCMS measured value m / z 443.0; 1 H NMR (400 MHz, CD3OD) δ 7.80 (s, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.94 - 6.91 (m, 1H), 2.94 - 2.85 (m, 2H), 1.33 - 1.27 (m, 3H).

[0123] Example 2 6-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [ka] Synthesis of 5-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2a) 3,5-Dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (1e) (10 mg, 22.10 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (16.84 mg, 66.31 μmol) were added to a mixture of CH3CN (2 mL) at 20°C with t-BuONO (4.56 mg, 44.20 μmol, 5.26 μL). The mixture was then stirred at 20°C for 16 hours. TLC and LCMS showed that the starting materials were completely consumed, and the desired MS was detected. The mixture was concentrated under vacuum to obtain the residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate) to obtain 2a. MSmas calculation value: [M+1] + (C 21 H 27 Cl2N3O2Si), m / z 563.2, LCMS measured value m / z 563.2.

[0124] Synthesis of 6-(3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H),-dione(2b) To a mixture of 5-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2a) (10 mg, 17.75 μmol) and 6-bromo-2H-1,2,4-triazine-3,5-dione (3.41 mg, 17.75 μmol) in H2O (0.5 mL) and THF (2 mL), K3PO4 (7.54 mg, 35.50 μmol) and ditert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (1.16 mg, 1.77 μmol) were added, the mixture was degassed, purged three times with N2, and then stirred at 90°C for 3 hours under an N2 atmosphere. TLC and LCMS indicated that 2a was completely consumed, and the desired MS was detected. The mixture was extracted with ethyl acetate (30 mL x 2) and H2O (15 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The mixture was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 2b. 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(s, 2H), 7.60 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.19 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 5.70 (s, 2H), 3.80 (s, 2H), 3.61 (t, J = 8.2 Hz, 2H), 3.49 (s, 3H), 3.14 (s, 3H), 3.04 (d, J = 7.6 Hz, 2H), 1.95 (s, 1H), 1.22 - 1.31 (m, 23H), 1.20 (s, 9H), -0.04 (s, 7H).

[0125] Synthesis of 6-(3,5-dichloro-4-((3-ethyl-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H),-dione (Example 2) A solution of 6-(3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H),-dione(2b) (20 mg, 36.46 μmol) in HCl / dioxane (7 mL) was stirred at 20°C for 1 hour. HPLC and LC-MS showed that 2b was completely consumed, and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (FA), column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)-MeCN] to obtain Example 2. MSmas calculation value: [M+1] + (C 18 H 13 Cl2N5O3), m / z 418.0, LCMS measured value m / z 418.0; 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(s, 2H), 7.52 (d, J = 9.2 Hz, 1H), 7.22 (dd, J = 9.2, 2.4 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 4.82 - 4.95 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 1.29 - 1.33 (m, 3H).

[0126] Scheme B Synthesis of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (compound 3f) [ka] Synthesis of 5-bromo-3-methyl-1H-indazole (3a) A mixture of 1-(5-bromo-2-fluorophenyl)-ethanone (3 g, 13.82 mmol) and N₂H₄H₂O (41.20 g, 806.55 mmol, 40.00 mL, 98% purity) was stirred under N₂ at 120°C for 16 hours. TLC showed that the starting material had been completely consumed and a new spot had formed. The residue was poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 3a. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 1.4 Hz, 1H), 7.46 (s, 1H), 7.47 - 7.42 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 3.97 (br s, 1H), 2.57 (s, 3H).

[0127] Synthesis of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3b) To a mixture of 5-bromo-3-methyl-1H-indazole (3a) (1.7 g, 8.05 mmol) in DMF (25 mL), NaH (386.59 mg, 9.67 mmol, 990.33 μL, 60% purity) was added under N2 at 0°C, followed by the addition of SEM-Cl (1.34 g, 8.05 mmol, 1.43 mL) to the mixture. The mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into NH4Cl (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate) to obtain 3b. 1H NMR (400 MHz, CDCl3) δ 7.90 - 7.73 (m, 1H), 7.48 (dd, J = 1.8, 8.8 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.36 - 7.19 (m, 1H), 5.64 (s, 2H), 3.63 - 3.44 (m, 2H), 2.54 (s, 3H), 0.99 - 0.77 (m, 2H), -0.06 (s, 9H).

[0128] Synthesis of (3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)boronic acid (3c) To a mixture of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3b) (1.7 g, 4.98 mmol) in MeOH (15 mL), diboronic acid (hypodiboric acid) (1.34 g, 14.94 mmol), DIPEA (1.93 g, 14.94 mmol, 2.60 mL), and [2-(2-aminophenyl)phenyl]-chloropalladium;bis(1-adamantyl)-butylphosphane (33.30 mg, 49.81 μmol) were added under N2. The mixture was stirred at 50°C for 1.5 hours. LC-MS showed that 3b was completely consumed and the desired MS was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 3c. MSmas calculation value: [M+1] + (C 14 H 23 BN2O3Si), m / z 307.1, LCMS measured value m / z 307.1.

[0129] Synthesis of 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol (3d) (3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)boronic acid (3c) (1.53 g, 5.00 mmol) was added to a mixture of H2O (5 mL) and CH3CN (10 mL) under N2, with ammonium bicarbonate (394.97 mg, 5.00 mmol) and H2O2 (1.13 g, 9.99 mmol, 30% purity). The mixture was stirred at 20°C for 2 hours. LC-MS showed that 3c was completely consumed and the desired MS was detected. TLC showed that the starting material was completely consumed and new spots were formed. The residue was poured into NaHS2O3 (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate) to obtain 3d. MSmas calculation value: [M+1] + (C 14 H 22 N2O2Si), m / z 279.1, LCMS measured value m / z 279.1.

[0130] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole(3e) A mixture of 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol (3d) (1.06 g, 3.81 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (879.42 mg, 4.19 mmol) in DMF (10 mL) was mixed with K2CO3 (789.26 mg, 5.71 mmol) under N2. The mixture was stirred at 20°C for 1 hour. TLC showed that the starting materials were completely consumed, and two spots were formed. The residue was poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate) to obtain 3e. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 2.4, 9.0 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 5.65 (s, 2H), 3.66 - 3.45 (m, 2H), 2.48 (s, 3H), 1.01 - 0.78 (m, 2H), -0.02 - -0.08 (m, 9H).

[0131] Synthesis of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (3f) 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3e) (200 mg, 426.98 μmol) was added to a mixture of EtOH (5 mL) and H2O (1 mL) with NH4Cl (114.20 mg, 2.13 mmol) and Fe (119.22 mg, 2.13 mmol). The mixture was stirred at 80°C for 2 hours. TLC and LCMS showed that 3e was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3f. MSmas calculation value: [M+1] + (C 20 H 25 Cl2N3O2Si), m / z 438.0, LCMS measured value m / z 438.0; 1H NMR (400 MHz, CDCl3) δ 7.50 - 7.43 (m, 1H), 7.19 - 7.10 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.82 - 6.65 (m, 2H), 5.63 (s, 2H), 3.79 (br s, 2H), 3.64 - 3.45 (m, 2H), 2.47 (s, 3H), 1.57 (s, 2H), 0.99 - 0.79 (m, 2H), 0.03 -0.14 (m, 9H).

[0132] Example 3 2-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxyaniline (3g) A solution of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (3f) (50 mg, 114.05 μmol) in MeCN (1 mL) and HCl (1 mL) was stirred at 20°C for 1 hour. LC-MS showed that 3f was completely consumed, and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain 3 g. MSmas calculation value: [M+1] + (C 14 H 11 Cl2N3O), m / z 308.0, LCMS measured value m / z 308.0.

[0133] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (3h) To a solution of 3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)aniline (3 g) (35 mg, 113.58 μmol) in HCl (1 mL) and H2O (2 mL), NaNO2 (10.19 mg, 147.65 μmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then the mixture was quickly filtered to obtain the solution. The solution was added to a solution of ethyl N-(2-cyanoacetyl)carbamate (19.51 mg, 124.93 μmol) in H2O (2 mL) and Pyr (1 mL) at 0°C, and the reaction mixture was stirred at 0°C for a further 0.5 hours. LC-MS showed that 3 g had been completely consumed, and the desired MS was detected. The suspension was filtered and then washed with H2O (5 mL × 3). The filtered cake was dried under reduced pressure to obtain 3 h. MSmas calculation value: [M+1] + (C 20 H 16 Cl2N6O4), m / z 475.0, LCMS measured value m / z 475.1.

[0134] Synthesis of 2-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 3) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (3h) (50 mg, 105.20 μmol) was dissolved in HOAc (3 mL) and NaOAc (43.15 mg, 526.00 μmol) was added. The mixture was stirred at 120 °C for 16 hours. LC-MS and HPLC showed that 3h had been completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (FA), column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-MeCN] to obtain Example 3. MSmas calculation value: [M+1] + (C 18 H10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0. 1 H NMR (400 MHz, CD3OD) δ 7.80 (s, 2H), 7.48 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 2.44 (s, 3H).

[0135] Example 4 N-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (4a) To a mixture of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (3f) (30 mg, 68.43 μmol) and THF (2 mL), TEA (20.77 mg, 205.28 μmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (30.49 mg, 205.28 μmol) were added under N2. The mixture was stirred at 25°C for 16 hours. TLC and LCMS showed that 3f was completely consumed, and the desired MS was detected. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO2, petroleum ether / ethyl acetate) to obtain 4a. MSmas calculation value: [M+1] + (C 23 H 25Cl2N5O5Si), m / z 550.1, LCMS measured value m / z 550.1.

[0136] Synthesis of N-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 4) N-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (4a) (20 mg, 36.33 μmol) was mixed with DCM (1.5 mL) and TFA (0.5 mL) under N2. The mixture was stirred at 25°C for 16 hours. LC-MS showed that 4a was completely consumed and the desired MS was detected. The residue was poured into NaHCO3 (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40mm×10μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 4. MSmas calculation value: [M+1] + (C 17 H 11 Cl2N5O4), m / z 420.0, LCMS measured value m / z 420.0; 1 H NMR (400 MHz, CD3OD) δ 7.97 (s, 2H), 7.49 - 7.42 (m, 1H), 7.14 (dd, J = 2.4, 9.0 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 2.47 - 2.40 (m, 3H).

[0137] Example 5 6-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [ka] Synthesis of 5-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5a) To a mixture of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (3f) (50 mg, 114.05 μmol) and BPD (86.88 mg, 342.14 μmol) in CH3CN (2 mL), 4A MS (100 mg, 1.00 mmol, 8.77 eq) was added, and t-BuONO (23.52 mg, 228.09 μmol, 27.13 μL, 2 eq) was added under N2 at 0°C. The mixture was stirred at 20°C for 16 hours. TLC and LCMS showed that 3f was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-TLC (SiO2, petroleum ether / ethyl acetate) to obtain 5a. MSmas calculation value: [M+1] + (C 26 H 35 BCl2N2O4Si), m / z 549.2, LCMS measured value m / z 549.2.

[0138] Synthesis of 6-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (5b) A mixture of 5-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5a) (40 mg, 72.81 μmol) and 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (15.38 mg, 80.09 μmol) in THF (2 mL) was added under N2, along with H2O (0.5 mL) of K3PO4 (30.91 mg, 145.62 μmol, 2 eq) and a mixture of ditert-butyl(cyclopentyl)phosphan; dichloropalladium (4.75 mg, 7.28 μmol). The mixture was stirred at 90°C for 2 hours. LC-MS indicated that 5a was completely consumed, and the desired MS was detected. The mixture was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO2, petroleum ether / ethyl acetate) to obtain 5b. MSmas calculation value: [M+1] + (C 23 H 25 Cl2N5O4Si), m / z 534.1, LCMS measured value m / z 534.1.

[0139] Synthesis of 6-(3,5-dichloro-4-((3-methyl-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (Example 5) 6-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (5b) (20 mg, 37.42 μmol) was mixed with TFA (0.5 mL) and DCM (1.5 mL) under N2. The mixture was stirred at 25°C for 16 hours. LC-MS showed that 5b was completely consumed and the desired MS was detected. The residue was poured into NaHCO3 (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100×30mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 5. MSmas calculation value: [M+1] + (C 17 H 11 Cl2N5O3), m / z 404.0, LCMS measured value m / z 404.0; 1 H NMR (400 MHz, CD3OD) δ 8.22 (s, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.18 - 7.09 (m, 1H), 6.85 - 6.78 (m, 1H), 2.45 - 2.40 (m, 3H).

[0140] Scheme C Synthesis of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)aniline (compound 6e) [ka] Synthesis of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (6a) To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.41 mmol) in DMF (2 mL), NaH (84.88 mg, 2.12 mmol, 60% purity) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then, SEM-Cl (283.05 mg, 1.70 mmol, 300.48 μL) was added at 0°C. The mixture was stirred at 20°C for 1.5 hours. TLC indicated that the reaction was complete and a new spot had formed. The reaction mixture was quenched by the addition of H2O (2 mL), then diluted with Depositphotos (10 mL) and H2O (10 mL), and extracted with Depositphotos (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 6a. MSmas calculation value: [M+1] + (C 13 H 20 BrN3OSi), m / z 342.0, MS measured value m / z 342.1; 1 H NMR (400 MHz, CDCl3) δ 8.56 (t, J = 2.4 Hz, 1H), 8.13 (t, J = 2.4 Hz, 1H), 5.77 (d, J = 3.0 Hz, 2H), 3.57 - 3.68 (m, 2H), 2.56 (d, J = 3.0 Hz, 3H), 0.87 - 0.99 (m, 2H), -0.05 (d, J = 3.0 Hz, 9H).

[0141] Synthesis of (3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)boronic acid (6b) A mixture of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (6a) (340 mg, 993.26 μmol), hypodiboric acid (267.14 mg, 2.98 mmol, 3 eq), DIEA (385.11 mg, 2.98 mmol, 519.01 μL), and cataCXium A-Pd-G2 (6.64 mg, 9.93 μmol) in MeOH (4 mL) was degassed, purged three times with N2, and then stirred at 50°C for 1 hour under an N2 atmosphere. LCMS showed that 6a was completely consumed and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure, the solvent was removed to obtain 6b, which was used directly in the next step without purification. MSmas calculation value: [M+1] + (C 13 H 22 BN3O3Si), m / z 308.1, MS measured value m / z 308.1.

[0142] Synthesis of 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-ol(6c) (3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)boronic acid (6b) (300 mg, 976.47 μmol) was added to a solution of ACN (2 mL) with H2O2 (221.43 mg, 1.95 mmol, 187.65 μL, 30% purity) and a solution of NH4HCO3 (77.20 mg, 976.47 μmol, 80.41 μL) in H2O (1 mL). The mixture was stirred at 20°C for 1 hour. TLC and LCMS showed that 6b was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was diluted with HCl (20 mL) and Na2SO3 (10 mL) and extracted with HCl (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 6c. MSmas calculation value: [M+1] + (C 13 H 21 N3O2Si), m / z 280.1, MS measured value m / z 280.1; 1 H NMR (400 MHz, CDCl3) δ 8.26 - 8.33 (m, 1H), 7.40 (d, J = 2.6 Hz, 1H), 5.76 (s, 2H), 3.57 - 3.66 (m, 2H), 2.53 (s, 3H), 0.85 - 1.03 (m, 2H), -0.10 - -0.04 (m, 9H).

[0143] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine(6d) 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-ol (6c) (175 mg, 626.32 μmol, 1 eq) was dissolved in DMF (2 mL), to which K2CO3 (129.84 mg, 939.48 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (144.67 mg, 688.95 μmol) were added. The mixture was stirred at 20°C for 1 hour. TLC and LCMS showed that 6c was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was diluted with HCl (10 mL) and H2O (10 mL) and extracted with HCl (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 6d. MSmas calculation value: [M+1] + (C 19 H 22 Cl2N4O4Si), m / z 469.0, MS measured value m / z 469.1; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.6 Hz, 1H), 8.36 (s, 2H), 7.18 (d, J = 2.6 Hz, 1H), 5.79 (s, 2H), 3.59 - 3.73 (m, 2H), 2.51 (s, 3H), 0.84 - 1.04 (m, 2H), -0.04 (s, 9H).

[0144] Synthesis of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)aniline(6e) To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (6d) (180 mg, 383.47 μmol) in EtOH (3 mL), solutions of Fe (107.08 mg, 1.92 mmol) and NH4Cl (102.56 mg, 1.92 mmol) in H2O (0.1 mL) were added. The mixture was stirred at 80°C for 1 hour. TLC and LCMS showed that 6d was completely consumed, and one major peak of the desired mass was detected. The suspension was filtered through a Celite gel pad, and the pad was washed with EtOH (20 mL). The filtrate was concentrated and dried to obtain the residue. The residue was diluted with HCl (10 mL) and H2O (10 mL) and extracted with HCl (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 6e. MSmas calculation value: [M+1] + (C 19 H 24 Cl2N4O2Si), m / z 439.1, MS measured value m / z 439.1; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.6 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 6.74 (s, 2H), 5.77 (s, 2H), 3.82 (br s, 2H), 3.60 - 3.67 (m, 2H), 2.49 (s, 3H), 0.84 - 0.99 (m, 2H), -0.05 (s, 9H).

[0145] Example 6 N-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (6f) 3,5-Dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)aniline (6e) (50 mg, 113.79 μmol) was dissolved in THF (3 mL) and TEA (34.54 mg, 341.37 μmol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (25.35 mg, 170.68 μmol) were added. The mixture was stirred at 20 °C for 0.5 hours. TLC and LC-MS showed that 6e had been consumed and the desired mass was detected. The reaction mixture was quenched by the addition of H₂O (0.5 mL). The reaction mixture was diluted with ethyl acetate (10 mL) and H₂O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium ₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO₂, petroleum ether: ethyl acetate * 0.2% HOAc) to obtain 6f. MSmas calculation value: [M+1] + (C 22 H 24 Cl2N6O5Si), m / z 551.1, LCMS measured value m / z 551.1.

[0146] Synthesis of N-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 6) A mixture of N-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (6f) (58 mg, 105.18 μmol) in a mixture of TFA (1 mL) and DCM (2 mL) was stirred at 20°C for 1 hour under an N2 atmosphere. LC-MS showed that 6f had been consumed and the desired mass was detected. The reaction mixture was quenched by the addition of H2O (0.5 mL). The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-MeCN]) and prep-HPLC (column: Phenomenex Luna C18 100×30mm×5μm; mobile phase: [water (0.2%FA)-MeCN]) to obtain Example 6. MSmas calculation value: [M+1] + (C 16 H 10 Cl2N6O4), m / z 421.0, LCMS measured value m / z 421.0; 1 H NMR (400 MHz, CD3OD) δ 8.38 (d, J = 2.6 Hz, 1H) 8.00 (s, 2H) 7.38 (d, J = 2.6 Hz, 1H) 2.46 (s, 3H).

[0147] Example 7 2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (7a) 3,5-Dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)aniline (6e) (30 mg, 97.04 μmol) was added to a solution of HCl (1 mL) and H2O (2 mL) with NaNO2 (8.70 mg, 126.15 μmol). The mixture was stirred at 0°C for 0.5 hours. The solution was then added to a solution of ethyl (2-cyanoacetyl)carbamate (16.67 mg, 106.74 μmol) in Pyr (1 mL) and H2O (2 mL) at 0°C. The mixture was stirred for a further 0.5 hours at 0°C. LC-MS showed that 6e had been completely consumed, and one major peak indicating the desired mass was detected. The reaction mixture was filtered. The filtered cake was washed with H2O (10 mL) and dried under vacuum to obtain 7a. MSmas calculation value: [M+1] + (C 19 H 15 Cl2N7O4), m / z 476.0, LCMS measured value m / z 476.1.

[0148] Synthesis of 2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 7) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (7a) (40 mg, 83.99 μmol) was dissolved in HOAc (2 mL) and NaOAc (34.45 mg, 419.93 μmol) was added. The mixture was stirred at 120 °C for 3 hours. LC-MS showed that 7a was completely consumed and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 7. MSmas calculation value: [M+1] + (C 17 H9Cl2N7O3), m / z 430.0, MS measured value m / z 429.9; 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 2H) 8.45 (d, J = 2.6 Hz, 1H) 7.83 (s, 2H) 7.58 (br d, J = 2.6 Hz, 1H) 2.42 (s, 3H).

[0149] Scheme D Synthesis of 3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (compound 8d) [ka] Synthesis of 5-bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (8a) To a solution of 5-bromo-3-methoxy-1H-indazole (500 mg, 2.20 mmol) in DMF (10 mL), NaH (105.69 mg, 2.64 mmol, 60% purity) was added gradually over 5 minutes at 0°C. After the addition, the mixture was stirred at 0°C for 0.5 hours, and then SEM-Cl (550.70 mg, 3.30 mmol, 584.61 μL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. TLC showed that the starting material had been consumed and one major new spot was detected. The reaction mixture was poured into an aqueous solution of NH4Cl (40 mL) and then extracted with siRNA (30 mL x 2). The combined organic layers were washed with brine (20 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 obtain 8a.

[0150] Synthesis of 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol (8b) 5-Bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (8a) (250 mg, 699.66 μmol), KOH (51.04 mg, 909.56 μmol), Pd2 (dba )3 A mixture of dioxane (5 mL) and H2O (5 mL) containing (64.07 mg, 69.97 μmol) and t-Bu Xphos (44.57 mg, 104.95 μmol) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. TLC showed that 8a was completely consumed and many new spots were formed. LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (5 ml × 3). The combined filtrate was extracted twice with 15 mL of ethyl acetate and 5 mL of H2O. The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to obtain 8b. MS mass calculation value: [M-1] - (C 14 H 22 N2O3Si), m / z 293.0, LCMS measured value m / z 293.0.

[0151] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole(8c) 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-ol (8b) (30 mg, 101.90 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (23.54 mg, 112.08 μmol) were dissolved in DMF (2 mL) and K2CO3 (21.12 mg, 152.84 μmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. TLC showed that 8c had been completely consumed and one new spot had formed. The mixture was extracted with ethyl acetate (15 mL) and H2O (5 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate) to obtain 8c.

[0152] Synthesis of 3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (8d) To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (8c) (20 mg, 41.29 μmol) in EtOH (2 mL) and H2O (0.5 mL), iron powder (11.53 mg, 206.44 μmol) and NH4Cl (11.04 mg, 206.44 μmol) were added. The mixture was stirred at 80°C for 2 hours. TLC showed that 8d had been completely consumed and a new spot had formed. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was extracted with DCM (15 mL x 2) and H2O (5 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and dried by blowing nitrogen gas to obtain 8d. MSmas calculation value: [M+1] + (C 20 H 25 Cl2N3O3Si), m / z 454.1, LCMS measured value m / z 454.1; 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.37 (m, 1H), 7.22 (dd, J = 9.0, 2.4 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.71 (s, 2H), 5.51 (s, 2H), 4.05 (s, 3H), 3.73 (q, J = 7.0 Hz, 2H), 3.53 - 3.59 (m, 2H), 1.25 - 1.28 (m, 4H), 0.87 - 0.93 (m, 2H), -0.06 - -0.03 (m, 9H).

[0153] Example 8 Synthesis of N-(3,5-dichloro-4-((3-methoxy-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (8e) To a solution of 3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)aniline (8d) (7 mg, 15.40 μmol) in DCM (0.5 mL), TEA (4.68 mg, 46.21 μmol, 6.43 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (3.43 mg, 23.11 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. TLC showed that 8d had been completely consumed and one new spot had formed. LCMS showed the desired MS. The mixture was quenched with H2O (5 mL) and then extracted with DCM (10 mL × 2) and H2O (5 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 8e. MSmas calculation value: [M+1] + (C 23 H 25 Cl2N5O6Si), m / z 566.1, LCMS measured value m / z 566.1; 1 H NMR (400 MHz, CD3OD) δ 7.97 (s, 2H), 7.50 (br d, J = 9.05 Hz, 1H), 7.19 (br dd, J = 8.8, 2.2 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.54 (s, 2H), 4.28 - 4.40 (m, 7H), 4.02 (s, 4H), 3.88 (s, 1H), 3.52 - 3.67 (m, 11H), 3.42 - 3.50 (m, 10H), 1.76 - 1.87 (m, 12H), 1.62 - 1.76 (m, 12H), 0.77 - 0.90 (m, 3H), -0.08 (s, 9H).

[0154] Synthesis of N-(3,5-dichloro-4-((3-methoxy-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 8) A solution of N-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (8e) (5 mg, 8.83 μmol) in TFA (0.5 mL) and DCM (1 mL) was stirred at 25°C for 24 hours. LC-MS and HPLC showed that 8e was completely consumed, and the desired MS was detected. The mixture was concentrated under vacuum, and the residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 8. MSmas calculation value: [M+1] + (C 17 H 11 Cl2N5O5), m / z 435.9, LCMS measured value m / z 435.9; 1 H NMR (400 MHz, CD3OD) δ 7.96 (s, 2H), 7.34 (d, J = 9.0 Hz, 1H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 4.00 (s, 3H).

[0155] Example 9 2-(3,5-dichloro-4-((3-methoxy-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (9a) 3,5-Dichloro-4-((3-Methoxy-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazole-5-yl)oxy)aniline (8d) (20 mg, 44.01 μmol) and ethyl (2-cyanoacetyl)carbamate (7.56 mg, 48.41 μmol) were mixed in CH3CN (2.5 mL) at 0°C with t-BuONO (9.08 mg, 88.02 μmol, 10.47 μL). The mixture was then stirred at 0°C for 1 hour. LC-MS showed that 8d had been completely consumed and the desired MS was detected. The suspension was filtered. The pad cake was diluted in MeOH (15 mL) and concentrated under reduced pressure to obtain 9a. MSmas calculation value: [M+1] + (C 26 H 30 Cl2N6O6Si), m / z 621.1, LCMS measured value m / z 621.2.

[0156] Synthesis of 2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (9b) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (9a) (25 mg, 40.22 μmol) was dissolved in DMA (3 mL) and KOAc (7.89 mg, 80.44 μmol) was added. The mixture was stirred at 115 °C for 2 hours. LC-MS and HPLC showed that 9a was completely consumed and the desired MS was detected. The reaction mixture was extracted with ethyl acetate (15 mL x 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (FA) using a Phenomenex Synergi C18 column (150 × 25 × 10 μm) and a mobile phase [water (0.2% FA)-MeCN] to obtain 9b. 1 HNMR (400 MHz, CD3OD) δ 7.80 (s, 2H), 7.53 (d, J = 9.2 Hz, 1H), 7.23 (dd, J = 9.2, 2.4 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.55 (s, 2H), 4.03 (s, 4H), 3.56 (t, J = 8.0 Hz, 2H), 0.84 (t, J = 8.0 Hz, 2H), -0.08 (s, 9H).

[0157] Synthesis of 2-(3,5-dichloro-4-((3-methoxy-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 9) A solution of 2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (9b) (4 mg, 6.95 μmol) in TFA (0.5 mL) and DCM (1 mL) was stirred at 25°C for 16 hours. LC-MS and HPLC showed that 9b was completely consumed, and the desired MS was detected. The mixture was concentrated under vacuum to obtain the residue. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 9. MSmas calculation value: [M+1] + (C 18 H 10 Cl2N6O4), m / z 445.0, LCMS measured value m / z 444.9; 1 H NMR (400 MHz, CD3OD) δ 7.79 (s, 2H), 7.35 (d, J = 9.0 Hz, 1H), 7.18 (dd, J = 9.0, 2.45 Hz, 1H), 6.72 - 6.74 (m, 1H), 4.01 (s, 3H).

[0158] Example 10 N-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 1-methyl-1H-benzo[d]imidazole-6-ol (10a) A mixture of 6-bromo-1-methyl-1H-benzo[d]imidazole (620 mg, 2.94 mmol), KOH (214.28 mg, 3.82 mmol), Pd2(dba)3 (269.00 mg, 293.76 μmol), and t-Bu Xphos (187.11 mg, 440.64 μmol) in dioxane (5 mL) and H2O (5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 3.5 hours under an N2 atmosphere. TLC showed that the starting material was completely consumed and many new spots were formed. LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with SiO2 (10 ml x 3). The combined filtrate was extracted twice with ethyl acetate (30 mL) and H2O (10 mL). The combined organic phases were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, ethyl acetate / MeOH) to obtain 10a. MSmas calculation value: [M+1] + (C8H8N2O), m / z 149.1, LCMS measured value m / z 149.2; 1 H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 8.6, 2.2 Hz, 1H), 3.79 (s, 3H).

[0159] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (10b) 1-methyl-1H-benzo[d]imidazole-6-ol (10a) (200 mg, 1.35 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (311.81 mg, 1.48 mmol) were dissolved in DMF (10 mL) and K2CO3 (279.85 mg, 2.02 mmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. TLC showed that 10a had been completely consumed and a new spot had formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate: MeOH) to obtain 10b. MSmas calculation value: [M+1] + (C 14 H9Cl2N3O3), m / z 338.0, LCMS measured value m / z 338.0; 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 2H), 8.14 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.6, 2.4 Hz, 1H), 3.33 (s, 3H), 3.31 (s, 1H).

[0160] Synthesis of 3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxyaniline (10c) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (10b) (180 mg, 532.32 μmol) in EtOH (8 mL), Fe (148.65 mg, 2.66 mmol) and NH4Cl (142.37 mg, 2.66 mmol) were added. The mixture was stirred at 80°C for 2 hours. TLC showed that 10b had been completely consumed and a new spot had formed. LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with SiO2 (5 mL × 3). The combined filtrate was extracted with ethyl acetate (30 mL) and H2O (10 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 10c. MSmas calculation value: [M+1] + (C 14 H 11 Cl2N3O), m / z 308.0, LCMS measured value m / z 308.0; 1 H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.72 - 6.74 (m, 3H), 6.71 (d, J = 2.4 Hz, 1H), 5.61 - 5.66 (m, 2H), 3.74 (s, 3H).

[0161] Synthesis of N-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 10) A solution of 3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (10c) (50 mg, 162.25 μmol) and NaH (6.49 mg, 162.25 μmol, 60% purity) in DMSO (5 mL) was stirred at 20°C for 10 minutes, and then 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (36.14 mg, 243.38 μmol) was added to the mixture. The mixture was stirred at 20°C for 0.5 hours. TLC (ethyl acetate: MeOH) showed the formation of one new spot. LC-MS showed the desired MS. The mixture was extracted with ethyl acetate (15 mL) and saturated NH4Cl aqueous solution (5 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 10. MSmas calculation value: [M+1] + (C 17 H 11 Cl2N5O4), m / z 420.0, LCMS measured value m / z 420.0; 1 H NMR (400 MHz, DMSO) δ 10.94 (br s, 1H), 8.13 (br s, 1H), 8.11 (s, 1H), 8.10 - 8.14 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.8, 2.51 Hz, 1H), 6.72 (s, 1H), 3.73 - 3.75 (m, 3H).

[0162] Example 11 Synthesis of N-(3,5-dichloro-4-((1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 2-chloro-N-methyl-5-nitropyridine-4-amine (11a) To a solution of 2,4-dichloro-5-nitropyridine in THF (50 mL), a mixture of methylamine hydrochloride (629.74 mg, 9.33 mmol) and DIEA (1.34 g, 10.36 mmol, 1.81 mL) in THF (50 mL) was added gradually at 0°C. The mixture was then stirred at 0°C for 0.5 hours and at 20°C for 16 hours. TLC indicated that the reaction was complete, and a new spot was formed. The mixture was extracted with Depositphotos (20 mL) and H₂O (20 mL). The combined organic layers were concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 11a. 1 H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.17 (br s, 1H), 6.76 (s, 1H), 3.07 (dt, J = 3.4, 1.6 Hz, 3H).

[0163] Synthesis of 2-(4-amino-2,6-dichlorophenoxy)-N-methyl-5-nitropyridine-4-amine (11b) 2-chloro-N-methyl-5-nitropyridine-4-amine (11a) (580 mg, 3.09 mmol) and 4-amino-2,6-dichlorophenol (605.46 mg, 3.40 mmol) were dissolved in DMF (10 mL) and K2CO3 (1.71 g, 12.37 mmol) and CuI (353.32 mg, 1.86 mmol) were added at 20 °C. The mixture was then stirred at 90 °C for 16 hours. TLC indicated that the reaction was complete. The mixture was adjusted to pH 4-5 with HCl (1 M) and extracted with HCl (30 mL) and H2O (15 mL). The organic layer was dried under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 11b. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.10 (br s, 1H), 6.70 (s, 2H), 6.30 (s, 1H), 3.80 (m, 2H), 3.07 (d, J = 5.2 Hz, 3H).

[0164] Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-N4-methylpyridine-3,4-diamine(11c) To a solution of 2-(4-amino-2,6-dichlorophenoxy)-N-methyl-5-nitropyridine-4-amine (11b) (440 mg, 1.34 mmol) in EtOH (8 mL), iron powder (373.31 mg, 6.68 mmol) and NH4Cl (357.53 mg, 6.68 mmol) were added. The mixture was stirred at 80°C for 16 hours. LC-MS showed that 11b was completely consumed. The suspension was filtered through a Celite pad, and the pad cake was washed with siRNA (5 mL x 3). The combined filtrate 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 Na2SO4, filtered, and concentrated under reduced pressure to obtain 11c. MSmas calculation value: [M+1] + (C 12 H 12 Cl2N4O), m / z 299.0, LCMS measured value m / z 299.1.

[0165] Synthesis of 3,5-dichloro-4-((1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)oxyaniline (11d) A solution of 6-(4-amino-2,6-dichlorophenoxy)-N4-methylpyridine-3,4-diamine (11c) (150 mg, 501.41 μmol) in CH(OEt)3 (5 mL) and HCOOH (0.5 mL) was stirred at 100°C for 2 hours. TLC showed that 11c was completely consumed and a new spot was formed. LCMS showed the desired MS. The mixture was concentrated under vacuum to obtain the residue. The residue was purified by prep-TLC (SiO2, ethyl acetate:methanol) to obtain 11d. MSmas calculation value: [M+1] + (C 13 H 10 Cl2N4O), m / z 309.0, LCMS measured value m / z 309.1; 1 H NMR (400 MHz, CD3OD) δ 8.43 (d, J = 0.8 Hz, 1H), 8.18 (s, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.75 (s, 2H), 3.85 (s, 3H).

[0166] Synthesis of N-(3,5-dichloro-4-((1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 11) A solution of 3,5-dichloro-4-((1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)oxy)aniline (11d) (20 mg, 64.69 μmol) and NaH (2.59 mg, 64.69 μmol, 60% purity) in DMSO (3 mL) was stirred at 20°C for 10 minutes, and then 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (14.41 mg, 97.04 μmol) was added to the mixture. The mixture was stirred at 20°C for 0.5 hours. TLC showed the formation of one new spot. The mixture was extracted with ethyl acetate (20 mL x 2) and saturated NH4Cl aqueous solution (10 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 11. MSmas calculation value: [M+1] + (C 16 H 10 Cl2N6O4), m / z 421.0, LCMS measured value m / z 421.0; 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 8.43 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 7.98 (s, 2H), 7.39 (d, J = 0.8 Hz, 1H), 3.85 (s, 3H).

[0167] Example 12 Synthesis of N-(3,5-dichloro-4-((1-ethyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-ethyl-2-nitroaniline (12a) 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) and ethanamine (1.65 g, 36.53 mmol, 2.39 mL, HCl) were dissolved in CH3CN (50 mL), to which DIEA (5.87 g, 45.45 mmol) was added. The mixture was then stirred at 60 °C for 16 hours. TLC indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with siRNA (50 mL + 20 mL) and H2O (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 12a.

[0168] Synthesis of 5-bromo-N1-ethylbenzene-1,2-diamine (12b) 5-bromo-N-ethyl-2-nitroaniline (12a) (2 g, 8.16 mmol) was added to a mixture of EtOH (30 mL) and H2O (10 mL), to which NH4Cl (1.75 g, 32.64 mmol) and iron powder (1.82 g, 32.64 mmol) were added. The mixture was stirred at 80°C for 2 hours. TLC indicated that the reaction was complete. The mixture was filtered and concentrated under vacuum to obtain 12b.

[0169] Synthesis of 6-bromo-1-ethyl-1H-benzo[d]imidazole (12c) A mixture of 5-bromo-N1-ethylbenzene-1,2-diamine (12b) (500 mg, 2.32 mmol) and trimethoxymethane (2 mL) was degassed, purged three times with N2, and then stirred at 100°C for 2 hours under an N2 atmosphere. TLC showed that 12c was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 12c. MSmas calculation value: [M+1] + (C9H9BrN2), m / z 224.9, LCMS measured value m / z 224.9; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.6, 1.8 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H) ,1.43 - 1.68 (m, 3H).

[0170] Synthesis of (1-ethyl-1H-benzo[d]imidazole-6-yl)boronic acid (12d) A mixture of 6-bromo-1-ethyl-1H-benzo[d]imidazole (12c) (690 mg, 3.07 mmol), hypodiboric acid (824.47 mg, 9.20 mmol), DIEA (1.19 g, 9.20 mmol, 1.60 mL), and cataCXium A-Pd-G2 (20.50 mg, 30.66 μmol) in MeOH (3 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 50°C for 1 hour. TLC and LCMS showed that 12c was completely consumed and one major peak of the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain 12d. MSmas calculation value: [M+1] + (C9H 11 BN2O2), m / z 191.0, LCMS measured value m / z 191.1.

[0171] Synthesis of 1-ethyl-1H-benzo[d]imidazole-6-ol (12e) To a solution of (1-ethyl-1H-benzo[d]imidazole-6-yl)boronic acid (12d) (580 mg, 3.05 mmol) in ACN (6 mL), a solution of H2O2 (692.20 mg, 6.11 mmol, 586.61 μL, 30% purity) and NH4HCO3 (241.32 mg, 3.05 mmol, 251.37 μL) in H2O (3 mL) was added. The mixture was stirred at 20°C for 2 hours. TLC and LCMS showed that 12d was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was diluted with HCl (10 mL) and Na2S2O3 (10 mL) and extracted with HCl (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 12e. MSmas calculation value: [M+1] + (C9H 10 N2O), m / z 163.0, LCMS measured value m / z 163.1.

[0172] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-ethyl-1H-benzo[d]imidazole (12f) A mixture of 1-ethyl-1H-benzo[d]imidazole-6-ol (12e) (50 mg, 308.28 μmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (71.21 mg, 339.11 μmol), and K2CO3 (63.91 mg, 462.43 μmol) in DMF (2 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 20°C for 1 hour. TLC and LCMS showed that 12e was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was diluted with HCl (10 mL) and H2O (10 mL) and extracted with HCl (10 mL × 2). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, DCM / MeOH) to obtain 12f. MSmas calculation value: [M+1] + (C 15 H 11Cl2N3O3), m / z 352.0, LCMS measured value m / z 352.0; 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.79 - 6.86 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.53 (t, J = 7.4Hz, 3H).

[0173] Synthesis of 3,5-dichloro-4-((1-ethyl-1H-benzo[d]imidazole-6-yl)oxyaniline (12g) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-1-ethyl-1H-benzo[d]imidazole (12f) (94 mg, 266.92 μmol) in EtOH (3 mL), iron powder (74.53 mg, 1.33 mmol) and a solution of NH4Cl (71.39 mg, 1.33 mmol) in H2O (0.1 mL) were added. The mixture was stirred at 80°C for 1 hour. TLC and LCMS showed that 12f was completely consumed, and one major peak of the desired mass was detected. The suspension was filtered through a Celite gel pad, and the pad was washed with EtOH (20 mL). The filtrate was concentrated and dried to obtain a residue. The residue was diluted with HCl (10 mL) and H2O (10 mL) and extracted with HCl (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 12 g. MSmas calculation value: [M+1] + (C 15 H 13 Cl2N3O), m / z 322.0, LCMS measured value m / z 322.0; 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.73 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.71 - 3.85 (m, 2H), 1.48 - 1.58 (m, 3H).

[0174] Synthesis of N-(3,5-dichloro-4-((1-ethyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 12) To a solution of 3,5-dichloro-4-((1-ethyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (12 g) (60 mg, 186.23 μmol) in THF (2 mL), TEA (56.53 mg, 558.68 μmol, 77.76 μL) and a solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (41.48 mg, 279.34 μmol) in THF (2 mL) were added. The mixture was stirred at 20°C for 0.5 hours. TLC and LCMS showed that 12 g was completely consumed, and one major peak indicating the desired mass was detected. The reaction mixture was quenched by the addition of H2O (0.5 mL). The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100×30mm×5μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 12. MSmas calculation value: [M+1] + (C 18 H 13 Cl2N5O4), m / z 434.0, LCMS measured value m / z 434.0; 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.31 (s, 1H), 8.08 (s, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.8, 2.45 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

[0175] Example 13 2-(3,5-dichloro-4-(quinoline-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)quinoline (13a) To a solution of quinoline-6-ol (100 mg, 688.90 μmol) in DMF (3 mL), K2CO3 (190.42 mg, 1.38 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (144.66 mg, 688.90 μmol) were added. The mixture was then stirred at 20°C for 1 hour. TLC indicated that the reaction was complete. The mixture was extracted with siRNA (6 mL × 2) and H2O (10 mL). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 13a. The product was used directly in the next step.

[0176] Synthesis of 3,5-dichloro-4-(quinoline-6-yloxy)aniline (13b) 6-(2,6-dichloro-4-nitrophenoxy)quinoline (13a) (180 mg, 537.09 μmol) was dissolved in EtOH (5 mL) and H2O (2 mL), to which NH4Cl (143.65 mg, 2.69 mmol) and iron powder (149.97 mg, 2.69 mmol) were added. The mixture was then stirred at 80°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was extracted with siRNA (10 mL) and H2O (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 13b. MSmas calculation value: [M+1] + (C 15 H 10 Cl2N2O), m / z 305.0, LCMS measured value m / z 304.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (br s, 1H), 8.26 (br d, J = 8.0 Hz, 1H), 8.02 (br d, J = 9.0 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.04 (br s, 1H), 6.76 (s, 2H), 5.72 (br s, 2H).

[0177] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-(quinoline-6-yloxy)phenyl)hydrazono)acetyl)carbamate (13c) 3,5-Dichloro-4-(quinoline-6-yloxy)aniline (13b) (30 mg, 98.31 μmol) was added to a mixture of HCl (1 mL) and H2O (0.5 mL) at 0°C with NaNO2 (13.57 mg, 196.62 μmol). The mixture was then stirred at 0°C for 20 minutes. Next, the mixture was added to a solution of ethyl N-(2-cyanoacetyl)carbamate (16.88 mg, 108.14 μmol) in Pyr (1 mL) at 0°C. The mixture was then stirred at 0°C for a further 20 minutes. LC-MS indicated that the reaction was complete and the desired MS was detected. The mixture was extracted with HCl (5 mL × 2) and H2O (5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 13c. The product was used directly in the next step. MSmas calculation value: [M+1] + (C 21 H 15 Cl2N5O4), m / z 472.0, LCMS measured value m / z 471.9.

[0178] Synthesis of 2-(3,5-dichloro-4-(quinoline-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 13) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-(quinoline-6-yloxy)phenyl)hydrazono)acetyl)carbamate (13c) (40 mg, 84.70 μmol) was dissolved in HOAc (2 mL) and NaOAc (27.79 mg, 338.78 μmol) was added. The mixture was then stirred at 120 °C for 2 hours. LC-MS indicated that the reaction was complete, and the desired MS was observed in the major peak. The mixture was concentrated under vacuum. The residue was extracted with RINKAN (5 mL × 2) and H2O (5 mL). The combined organic layers were concentrated under vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 13. MSmas calculation value: [M+1] + (C19 H9Cl2N5O3), m / z 426.0, LCMS measured value m / z 426.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (br d, J = 2.8 Hz, 1H), 8.32 (br d, J = 7.8 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H),7.87 (s, 2H), 7.63 (dd, J = 8.8, 2.6 Hz, 1H), 7.50 (dd, J = 8.4, 3.8 Hz, 1H, 7.20 (d, J = 2.6 Hz, 1H).

[0179] Example 14 2-(3,5-dichloro-4-((2-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methylquinoline (14a) To a solution of 2-methylquinoline-6-ol (55 mg, 345.51 μmol) in DMF (2 mL), K2CO3 (95.51 mg, 691.02 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (72.55 mg, 345.51 μmol) were added. The mixture was then stirred at 20°C for 1 hour. TLC indicated that the reaction was complete. The mixture was diluted with H2O (10 mL), filtered, and the solid was collected. The solid was washed with H2O (2 mL x 2) and dried under vacuum to obtain 14a. The product was used directly in the next step.

[0180] Synthesis of 3,5-dichloro-4-((2-methylquinoline-6-yl)oxy)aniline (14b) 6-(2,6-dichloro-4-nitrophenoxy)-2-methylquinoline (14a) (100 mg, 286.40 μmol) was dissolved in EtOH (5 mL) and H2O (2 mL), to which NH4Cl (76.60 mg, 1.43 mmol) and iron powder (79.98 mg, 1.43 mmol) were added. The mixture was stirred at 90°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with H2O (10 mL), filtered, and the solid was collected. The solid was washed with H2O (2 mL x 2), dried under vacuum, and 14b was obtained. MSmas calculation value: [M+1] + (C 16 H 12 Cl2N2O), m / z 319.0, LCMS measured value m / z 318.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (br d, J = 8.4 Hz, 1H), 7.89 (br d, J = 8.8 Hz, 1H), 7.42 (br d, J = 7.0 Hz, 1H), 7.33 (br d, J = 8.4 Hz, 1H), 6.97 (br s, 1H), 6.73 (s, 2H), 5.68 (br s, 2H), 2.59 (s, 3H).

[0181] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (14c) 3,5-Dichloro-4-((2-methylquinoline-6-yl)oxy)aniline (14b) (50 mg, 156.65 μmol) was added to a mixture of HCl (1 mL) and H2O (0.5 mL) at 0°C with NaNO2 (21.62 mg, 313.30 μmol). The mixture was stirred at 0°C for 20 minutes. The mixture was then added to a solution of ethyl N-(2-cyanoacetyl)carbamate (26.90 mg, 172.31 μmol) in Pyr (1 mL) at 0°C. The mixture was then stirred at 0°C for a further 20 minutes. LC-MS indicated that the reaction was complete and the desired MS was detected. The mixture was filtered and the solid was collected. The solid was dried under vacuum to obtain 14c. The residue was used directly in the next step. MSmas calculation value: [M+1] + (C 22 H 17 Cl2N5O4), m / z 486.1, LCMS measured value m / z 486.1.

[0182] Synthesis of 2-(3,5-dichloro-4-((2-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 14) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (14c) (35 mg, 71.97 μmol) was dissolved in HOAc (2 mL) and NaOAc (23.62 mg, 287.88 μmol) was added. The mixture was then stirred at 120 °C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with RINKAN (5 mL × 2) and H₂O (5 mL). The combined organic layers were concentrated under vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 14. MSmas calculation value: [M+1] + (C 20 H 11Cl2N5O3), m / z 440.0, LCMS measured value m / z 440.0; 1 H NMR (400MHz, DMSO-d6) δ 8.26 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.93 (s, 2H), 7.62 (dd, J = 9.2, 2.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 2.69 (s, 3H).

[0183] Example 15 2-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4-methylquinoline (15a) To a mixture of 4-methylquinoline-6-ol (40 mg, 251.28 μmol) and DMF (3 mL), K2CO3 (52.09 mg, 376.92 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (58.04 mg, 276.41 μmol) were added under N2. The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material had been completely consumed, and the desired MS was detected. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 15a. MSmas calculation value: [M+1] + (C 16 H 10 Cl2N2O3), m / z 349.0, LCMS measured value m / z 349.0; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.2 Hz, 1H), 8.38 (s, 1H), 8.12 (d, J = 9.4 Hz, 1H), 7.37 (dd, J = 2.8, 9.2 Hz, 1H), 7.27 (s, 1H), 7.22 (dd, J = 3.4, 20.0 Hz, 2H), 2.58 (s, 3H).

[0184] Synthesis of 3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)aniline (15b) To a mixture of 6-(2,6-dichloro-4-nitrophenoxy)-4-methylquinoline (15a) (70 mg, 200.48 μmol) and EtOH (3 mL), NH4Cl (53.62 mg, 1.00 mmol) in H2O (0.5 mL) and Fe (55.98 mg, 1.00 mmol) were added under N2. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 15b was completely consumed, and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 15b. MS massmas calculation value: [M+1] + (C 16 H 12 Cl2N2O), m / z 319.0, LCMS measured value m / z 319.0;

[0185] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (15c) 3,5-Dichloro-4-((4-methylquinoline-6-yl)oxy)aniline (15b) (30 mg, 93.99 μmol) was added to a mixture of HCl (0.5 mL) and H2O (1 mL) under N2 at 0°C with NaNO2 (8.43 mg, 122.19 μmol). The mixture was stirred at 0°C for 0.5 hours, and then the resulting mixture was added to a solution of ethyl (2-cyanoacetyl)carbamate (16.14 mg, 103.39 μmol) in Py (0.5 mL) and H2O (1 mL) under N2 at 0°C, and the mixture was stirred for a further 0.5 hours at 0°C. TLC and LCMS showed that 15b was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was filtered, and the filtered cake was dried under vacuum to obtain 15c. MSmas calculation value: [M+1] + (C 22 H 17 Cl2N5O4), m / z 486.1, LCMS measured value m / z 486.1.

[0186] Synthesis of 2-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 15) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (15c) (45.71 mg, 93.99 μmol) was mixed with HOAc (2 mL) and NaOAc (38.55 mg, 469.97 μmol) under N2. The mixture was stirred at 120°C for 2.5 hours. LC-MS showed that the 15c had been completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 15. MSmas calculation value: [M+1] + (C 20 H 11 C l2N5O3), m / z 440.0, LCMS measured value m / z 439.9. 1 HNMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.86 (s, 2H), 7.32 - 7.43 (m, 3H), 2.55 (s, 3H).

[0187] Example 16 2-(3,5-dichloro-4-((3-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 2-amino-5-bromobenzaldehyde (16a) To a solution of (2-amino-5-bromophenyl)methanol (200 mg, 989.86 μmol) in DCM (10 mL), MnO2 (516.33 mg, 5.94 mmol) was added. The mixture was then stirred at 20°C for 16 hours. TLC indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain 16a.

[0188] Synthesis of 6-bromo-3-methylquinoline (16b) To a solution of 2-amino-5-bromobenzaldehyde (16a) (50 mg, 249.96 μmol) in EtOH (2 mL), Pyr (43.50 mg, 549.91 μmol, 44.39 μL) was added dropwise at 55 °C and stirred for 0.5 hours. Then, propanal (21.78 mg, 374.94 μmol, 27.29 μL) was added to the mixture. The mixture was heated to 90 °C and stirred for 16 hours. TLC showed that 16a had been completely consumed and many new spots had formed. LC-MS showed that the desired MS was detected. The mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (10 mL × 2) and H₂O (5 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified using Prep-TLC (petroleum ether: ethyl acetate) to obtain 16b. 1 HNMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.0 Hz, 1H), 7.91 - 7.96 (m, 2H), 7.84 (s, 1H), 7.72 (dd, J = 9.0, 2.2 Hz, 1H), 2.54 (s, 3H).

[0189] Synthesis of (3-methylquinoline-6-yl)boronic acid (16c) To a mixture of 6-bromo-3-methylquinoline (16b) (25 mg, 112.57 μmol) and MeOH (2 mL), diboronic acid (hypodiboric acid) (30.28 mg, 337.71 μmol), DIPEA (43.65 mg, 337.71 μmol, 58.82 μL), and [2-(2-aminophenyl)phenyl]-chloropalladium;bis(1-adamantyl)-butylphosphan (752.69 μg, 1.13 μmol) were added under N2. The mixture was stirred at 50°C for 1.5 hours. LC-MS showed that 16b was completely consumed and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with MeOH (5 mL x 3). The combined filtrate was concentrated under reduced pressure to obtain 16c. MSmas calculation value: [M+1] + (C10 H 10 BNO2), m / z 188.0, LCMS measured value m / z 188.1.

[0190] Synthesis of 3-methylquinoline-6-ol (16d) (3-methylquinoline-6-yl)boronic acid (16c) (20 mg, 106.95 μmol) was added to a mixture of H2O (1 mL) and CH3CN (2 mL) under N2, with ammonia; carbonate (8.45 mg, 106.95 μmol, 8.81 μL) and H2O2 (24.25 mg, 213.90 μmol, 20.55 μL, 30% purity). The mixture was stirred at 20°C for 1 hour. TLC showed that the 16c was completely consumed and many new spots were formed. LCMS showed the desired MS. The mixture was poured into NaHSO3 (10 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to obtain 16d. MSmas calculation value: [M+1] + (C 10 H9NO), m / z 160.0, LCMS measured value m / z 160.1.

[0191] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-3-methylquinoline (16e) 3-methylquinoline-6-ol (16d) (10 mg, 62.82 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (14.51 mg, 69.10 μmol) were dissolved in DMF (2 mL) and K2CO3 (13.02 mg, 94.23 μmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. TLC showed that 16d had been completely consumed and a new spot had formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (15 mL) and H2O (5 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 16e. MSmas calculation value: [M+1] + (C 16 H 10 Cl2N2O3), m / z 349.0, LCMS measured value m / z 349.0.

[0192] Synthesis of 3,5-dichloro-4-((3-methylquinoline-6-yl)oxy)aniline(16f) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3-methylquinoline (16e) (10 mg, 28.64 μmol) in EtOH (2 mL) and H2O (1 mL), Fe (8.00 mg, 143.20 μmol) and NH4Cl (7.66 mg, 143.20 μmol) were added. The mixture was stirred at 80°C for 1 hour. TLC showed that the 16e had been completely consumed and a new spot had formed. LCMS showed the desired MS. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 ml × 3). The combined filtrate was concentrated under reduced pressure to obtain the residue. The residue was extracted with ethyl acetate (10 mL × 2) and H2O (3 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 16f. MSmas calculation value: [M+1] + (C 16 H 12Cl2N2O), m / z 319.0, LCMS measured value m / z 319.1; 1 HNMR (400 MHz, CDCl3) δ 8.63 - 8.86 (m, 1H), 8.11 (br d, J = 17.4 Hz, 1H), 7.77 - 7.92 (m, 1H), 7.38 - 7.46 (m, 1H), 6.86 - 6.89 (m, 1H), 6.72 - 6.75 (m, 2H), 2.49 (s, 3H).

[0193] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (16g) 3,5-Dichloro-4-((3-methylquinoline-6-yl)oxy)aniline (16f) (5 mg, 15.66 μmol) was dissolved in HCl (0.5 mL) and H2O (1 mL) and NaNO2 (1.41 mg, 20.36 μmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The mixture was then added at 0°C to a solution of ethyl N-(2-cyanoacetyl)carbamate (2.69 mg, 17.23 μmol) in H2O (1 mL) and Pyr (0.5 mL). The reaction mixture was then stirred at 0°C for a further 0.5 hours. LC-MS showed that 16f had been completely consumed and the desired MS was detected. The suspension was filtered and then washed with H2O (5 mL × 3). The filtered cake was concentrated under reduced pressure to obtain 16 g. MSmas calculation value: [M+1] + (C 22 H 17 Cl2N5O4), m / z 486.0, LCMS measured value m / z 486.1.

[0194] Synthesis of 2-(3,5-dichloro-4-((3-methylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 16) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (16 g) (5 mg, 10.28 μmol) was dissolved in HOAc (1.5 mL) and NaOAc (4.22 mg, 51.41 μmol) was added. The mixture was stirred at 120 °C for 2.5 hours. LC-MS showed that 16 g had been completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 16. MSmas calculation value: [M+1] + (C 16 H 12 Cl2N2O), m / z 440.0, LCMS measured value m / z 439.9; 1 HNMR (400 MHz, CD3OD) δ 8.64 (d, J = 2.0 Hz, 1H), 7.99 - 8.04 (m, 2H), 7.84 (s, 2H), 7.50 - 7.55 (m, 1H), 7.01 (d, J = 2.8 Hz, 1H), 2.50 (s, 3H).

[0195] Example 17 2-(3,5-dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (2-methyl-2H-indazole-5-yl)boronic acid (17a) A mixture of 5-bromo-2-methyl-2H-indazole (150 mg, 710.70 μmol), hypodiboric acid (191.14 mg, 2.13 mmol), DIEA (275.55 mg, 2.13 mmol, 371.37 μL), and cataCXium A-Pd-G2 (4.75 mg, 7.11 μmol) in MeOH (4 mL) was degassed, purged three times with N2, and then the mixture was stirred at 50°C for 1 hour under an N2 atmosphere. LC-MS indicated that the reaction was complete, and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure, the solvent was removed, and 17a was obtained. MSmas calculation value: [M+1] + (C8H9BN2O2), m / z 177.0, LCMS measured value m / z 177.1.

[0196] Synthesis of 2-methyl-2H-indazole-5-ol (17b) To a solution of (2-methyl-2H-indazole-5-yl)boronic acid (17a) (120 mg, 681.90 μmol) in ACN (2 mL), a solution of NH4HCO3 (53.91 mg, 681.90 μmol, 56.15 μL) in H2O (1 mL) and H2O2 (154.63 mg, 1.36 mmol, 131.04 μL, 30% purity) were added. The mixture was stirred at 20°C for 1 hour. TLC and LCMS showed that 17a was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was diluted with HCl (20 mL) and Na2SO3 (10 mL) and extracted with HCl (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH) to obtain 17b. MSmas calculation value: [M+1] + (C8H8N2O), m / z 149.0, LCMS measured value m / z 149.1; 1H NMR (400 MHz, methanol-d4) δ 7.90 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 6.93 (dd, J = 9.2, 2.4 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 4.13 (s, 3H).

[0197] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-2-methyl-2H-indazole (17c) A mixture of 2-methyl-2H-indazole-5-ol (17b) (50 mg, 337.47 μmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (77.95 mg, 371.22 μmol), and K2CO3 (69.96 mg, 506.20 μmol) in DMF (2 mL) was stirred at 20°C for 1 hour under an N2 atmosphere. TLC showed that 17c had been completely consumed and a new spot had formed. H2O (2 mL) was added to the reaction mixture. The mixture was filtered, the filtered cake was washed with 5 mL of H2O, and dried under vacuum to obtain 17c. MSmas calculation value: [M+1] + (C 14 H9Cl2N3O3), m / z 338.0, LCMS measured value m / z 338.0; 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 2H) 7.75 (s, 1H) 7.73 (d, J = 9.2 Hz, 1H) 7.16 (dd, J = 9.2, 2.4 Hz, 1H) 6.67 (d, J = 2.2 Hz, 1H) 4.20 (s, 3H).

[0198] Synthesis of 3,5-dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)aniline (17d) A mixture of 5-(2,6-dichloro-4-nitrophenoxy)-2-methyl-2H-indazole (17c) (100 mg, 295.73 μmol), Fe (82.58 mg, 1.48 mmol), NH4Cl (79.09 mg, 1.48 mmol), and EtOH (2 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. LC-MS showed that 17c was completely consumed, and one major peak was detected indicating the desired mass. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was washed with 5 mL of H2O and dried under vacuum to obtain 17d. MSmas calculation value: [M+1] + (C 14 H 11 Cl2N3O), m / z 308.0, LCMS measured value m / z 308.0.

[0199] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (17e) 3,5-Dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)aniline (17d) (40 mg, 129.80 μmol) was added to a solution of HCl (0.5 mL) and H2O (1 mL) at 0°C with NaNO2 (11.64 mg, 168.74 μmol). The mixture was stirred at 0°C for 10 minutes. The mixture was then added to a solution of ethyl N-(2-cyanoacetyl)carbamate (22.29 mg, 142.78 μmol) in H2O (1 mL) and Pyr (0.5 mL) at 0°C. The reaction mixture was stirred for a further 10 minutes at 0°C. LCMS showed that 17d was completely consumed and detected one major peak indicating the desired mass. The reaction mixture was filtered, and the filter cake was washed with 10 mL of H2O and dried under vacuum to obtain 17e. MSmas calculation value: [M+1] + (C 20 H 16 Cl2N6O4), m / z 475.0, MS measured value m / z 475.1.

[0200] Synthesis of 2-(3,5-dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 17) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-2H-indazole-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (17e) (60 mg, 126.24 μmol) was dissolved in HOAc (2 mL) and NaOAc (51.78 mg, 631.20 μmol) was added. The mixture was stirred at 120 °C for 2 hours. LC-MS showed that 17e was completely consumed and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 17. MSmas calculation value: [M+1] + (C 18 H 10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.80 (s, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.12 (dd, J = 9.2, 2.4 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 4.10 (s, 3H).

[0201] Example 18 N-(3,5-dichloro-4-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-methyl-2-nitroaniline (18a) 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) and methylamine (2.47 g, 36.53 mmol, HCl) were dissolved in CH3CN (50 mL), to which DIEA (5.87 g, 45.46 mmol, 7.92 mL) was added. The mixture was then stirred at 60 °C for 12 hours. TLC indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with siRNA (50 mL + 20 mL) and H2O (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 18a.

[0202] Synthesis of 5-bromo-N1-methylbenzene-1,2-diamine (18b) 5-bromo-N-methyl-2-nitroaniline (18a) (1.8 g, 7.79 mmol) was dissolved in EtOH (30 mL) and H2O (10 mL), to which NH4Cl (2.08 g, 38.95 mmol) and iron powder (2.18 g, 38.95 mmol) were added. The mixture was then stirred at 80°C for 16 hours. LC-MS indicated that the reaction was complete, and the desired MS was detected. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain 18b. MSmas calculation value: [M+1] + (C7H9BrN2), m / z 201.0, LCMS measured value m / z 201.0.

[0203] Synthesis of 6-bromo-1-methyl-1H-benzo[d]imidazole-2(3H)-one (18c) To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (18b) (1.2 g, 5.97 mmol) in CH3CN (30 mL), TEA (1.81 g, 17.90 mmol, 2.49 mL) and DSC (1.68 g, 6.57 mmol) were added. The mixture was then stirred at 20 °C for 16 hours. TLC indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was diluted with H2O (15 mL) and toluene (15 mL). The mixture was filtered and the solid was collected. The solid was extracted with toluene (5 mL × 5) and dried under vacuum to obtain 18c.

[0204] Synthesis of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18d) To a mixture of 6-bromo-1-methyl-1H-benzo[d]imidazole-2(3H)-one (18c) (1.1 g, 4.84 mmol) in DMF (15 mL), NaH (213.14 mg, 5.33 mmol, 60% purity) was added at 20°C. The mixture was then stirred at 20°C for 10 minutes. Next, SEM-Cl (888.46 mg, 5.33 mmol) was added dropwise to the mixture. The mixture was then stirred at 20°C for 10 minutes. TLC showed that the starting material had been consumed and a new spot had formed. The mixture was added to H2O (45 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 18d. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 7.27 (s, 1 H), 7.23 (dd, J = 8.4, 1.8 Hz, 1 H), 7.13 (d, J = 1.8 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 5.30 (s, 2 H), 3.55 - 3.64 (m, 2 H), 3.41 (s, 3 H), 0.95 - 0.97 (m, 1 H), 0.88 - 0.94 (m, 2 H), -0.05 - 0.00 (m, 8 H).

[0205] Synthesis of (3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-yl)boronic acid (18e) 5-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18d) (200 mg, 559.73 μmol) and hypodiboric acid (150.54 mg, 1.68 mmol) were mixed in MeOH (5 mL) and, under N2 conditions, DIEA (217.02 mg, 1.68 mmol, 292.48 μL) and cataCXium A-Pd-G2 (3.74 mg, 5.60 μmol) were added. The mixture was stirred at 50°C for 1.5 hours. LC-MS showed that 18d was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue, which gave rise to 18e. MSmas calculation value: [M+1] + (C 14 H 23 BN2O4Si), m / z 323.2, LCMS measured value m / z 323.1

[0206] Synthesis of 5-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18f) (3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-yl)boronic acid (18e) (130 mg, 403.43 μmol) was mixed with CH3CN (2 mL) and, under N2 conditions, NH4HCO3 (31.89 mg, 403.43 μmol, 33.22 μL) in H2O (1 mL) solution and H2O2 (91.48 mg, 806.85 μmol, 77.53 μL, 30% purity) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into NaHSO3 (10 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 18f. MSmas calculation value: [M+1] + (C 14 H 22 N2O3Si), m / z 295.1, LCMS measured value m / z 295.2;1 HNMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 6.99 (s, 1H), 6.68 - 6.50 (m, 2H), 5.31 - 5.27 (m, 2H), 3.63 - 3.56 (m, 2H), 3.40 - 3.36 (m, 3H), 2.99 - 2.96 (m, 2H), 2.90 (s, 2H), 2.10 (s, 1H), 1.02 - 0.82 (m, 3H), -0.02 - -0.05 (m, 9H).

[0207] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18g) To a mixture of 5-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18f) (130 mg, 441.55 μmol) and DMF (3 mL), K2CO3 (91.54 mg, 662.32 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (101.99 mg, 485.70 μmol) were added under N2. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 18f was completely consumed, and the desired MS was detected. TLC showed that the starting material was completely consumed, and many new spots were formed. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate) to obtain 18 g. MSmas calculation value: [M+1] + (C 20 H 23 Cl2N3O5Si), m / z 484.1, LCMS measured value m / z 484.1; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 2H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.67 - 6.58 (m, 1H), 6.48 - 6.39 (m, 1H), 5.29 (s, 2H), 3.65 - 3.57 (m, 2H), 3.40 (s, 3H), 1.57 (s, 2H), 1.02 - 0.82 (m, 2H), -0.03 (s, 9H).

[0208] Synthesis of 5-(4-amino-2,6-dichlorophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18h) A mixture of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18 g) (100 mg, 206.44 μmol) and EtOH (4 mL) was mixed with a solution of Fe (57.64 mg, 1.03 mmol) and NH4Cl (55.21 mg, 1.03 mmol) in H2O (1 mL) under N2. The mixture was stirred at 80°C for 2 hours. LC-MS showed that the starting material was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 18H. MSmas calculation value: [M+1] + (C 20 H 25 Cl2N3O3Si), m / z 454.1, LCMS measured value m / z 454.1; 1HNMR (400 MHz, CDCl3) δ 7.04 - 6.98 (m, 1H), 6.72 (s, 2H), 6.60 - 6.58 (m, 1H), 6.54 - 6.50 (m, 1H), 5.28 (s, 2H), 3.71 - 3.50 (m, 2H), 3.38 (s, 3H), 1.02 - 0.82 (m, 2H), -0.02 (s, 9H).

[0209] Synthesis of N-(3,5-dichloro-4-((3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (18i) To a mixture of 5-(4-amino-2,6-dichlorophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2(3H)-one (18h) (20 mg, 44.01 μmol) and THF (1.5 mL), TEA (13.36 mg, 132.04 μmol, 18.38 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (6.54 mg, 44.01 μmol) were added under N2. The mixture was stirred at 20°C for 20 minutes. LC-MS showed that 18h was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-MeCN]) to obtain 18i. MSmas calculation value: [M+1] + (C 23 H 25 Cl2N5O6Si), m / z 566.1, LCMS measured value m / z 566.2; 1H NMR (400 MHz, methanol-d4) δ 8.00 - 7.92 (m, 2H), 7.19 - 7.08 (m, 1H), 6.81 - 6.72 (m, 1H), 6.57 - 6.50 (m, 1H), 5.33 - 5.28 (m, 2H), 3.66 - 3.57 (m, 2H), 3.39 - 3.38 (m, 3H), 0.96 - 0.82 (m, 2H), -0.01 - -0.07 (m, 9H).

[0210] Synthesis of N-(3,5-dichloro-4-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 18) N-(3,5-dichloro-4-((3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (18i) (8.5 mg, 15.01 μmol) was added to dioxane (0.5 mL) with HCl (2 mL) under N2. The mixture was stirred at 65°C for 6 hours. LC-MS showed that 18i had been consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-MeCN]) to obtain Example 18. MSmas calculation value: [M+1] + (C 17 H 11 Cl2N5O5), m / z 436.0, LCMS measured value m / z 435.9; 1H NMR (400 MHz, MeOH-d4) δ 8.02 - 7.94 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.6 Hz, 1H), 4.77 (s, 1H), 3.35 (s, 3H).

[0211] Example 19 2-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (19a) To a mixture of 3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (10c) (20 mg, 64.9 μmol) and HCl (0.5 mL), a solution of NaNO2 (5.82 mg, 84.4 μmol) in H2O (1 mL) was added under N2 at 0°C. The mixture was stirred at 0-5°C for 30 minutes, and then added to a solution of ethyl (2-cyanoacetyl)carbamate (20.3 mg, 130 μmol) in Pyr (0.5 mL) and H2O (1 mL) under N2 at 0°C. The resulting mixture was stirred for a further 30 minutes at 0-5°C. LC-MS indicated that the reaction was complete, and the desired MS was detected. The reaction mixture was filtered, and the filtered cake was dried under reduced pressure to obtain 19a. MSmas calculation value: [M+1] + (C 20 H 16 Cl2N6O4), m / z 475.1, LCMS measured value m / z 475.1.

[0212] Synthesis of 2-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 19) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (19a) (20 mg, 42.1 μmol) was mixed with HOAc (2 mL) and NaOAc (17.3 mg, 210 μmol) under N2. The mixture was stirred at 120 °C for 3 hours. LC-MS showed that 19a had been completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]; 20%-60%, 10 min) to obtain Example 19. MSmas calculation value: [M+1] + (C 18 H 10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0; 1 H NMR (400 MHz, CD3OD) δ 8.09 - 8.16 (m, 1H), 7.76 - 7.88 (m, 2H), 7.58 - 7.67 (m, 1H), 6.86 - 7.07 (m, 2H), 3.77 - 3.84 (m, 3H).

[0213] Example 20 N-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-isopropyl-2-nitroaniline (20a) A mixture of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) and propan-2-amine (1.07 g, 18.2 mmol, 1.56 mL) in CH3CN (20 mL) was mixed with DIEA (2.94 g, 22.7 mmol, 3.96 mL) under N2. The mixture was stirred at 50°C for 2 hours. TLC showed that the starting material had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain 20a. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 9.0 Hz, 2H), 6.97 - 7.11 (m, 1H), 6.68 - 6.76 (m, 1H), 3.74 - 3.87 (m, 1H), 1.32 - 1.36 (m, 6H).

[0214] Synthesis of 5-bromo-N1-isopropylbenzene-1,2-diamine (20b) To a mixture of 5-bromo-N-isopropyl-2-nitroaniline (20a) (1.3 g, 5.02 mmol) and EtOH (10 mL), a solution of NH4Cl (1.34 g, 25.1 mmol) in H2O (3 mL) and Fe (1.40 g, 25.1 mmol) were added under N2. The mixture was stirred at 80°C for 2 hours. TLC showed that 20a was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 20b. 1 H NMR (400 MHz, CDCl3) δ 6.68 - 6.85 (m, 2H), 6.48 - 6.68 (m, 1H), 3.49 - 3.63 (m, 1H), 2.99 - 3.41 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H).

[0215] Synthesis of 6-bromo-1-isopropyl-1H-benzo[d]imidazole (20c) A mixture of 5-bromo-N1-isopropylbenzene-1,2-diamine (20b) (1.1 g, 4.80 mmol) and HC(OMe)3 (12 mL) was stirred under N2 at 100°C for 2 hours. TLC (petroleum ether:ethyl acetate) showed that 20b had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to obtain 20c. 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.64 - 7.71 (m, 1H), 7.57 - 7.61 (m, 1H), 7.34 - 7.41 (m, 1H), 4.54 - 4.63 (m, 1H), 1.57 - 1.65 (d, 6H).

[0216] Synthesis of isopropyl-1H-benzo[d]imidazole-6-yl)boronic acid (20d) To a mixture of 6-bromo-1-isopropyl-1H-benzo[d]imidazole (20c) (1 g, 4.18 mmol) and MeOH (6 mL), diboronic acid (hypodiboric acid) (1.12 g, 12.6 mmol), DIEA (1.62 g, 12.6 mmol, 2.19 mL), and cataCXium A-Pd-G2 (28.0 mg, 41.8 μmol) were added under N2. The mixture was stirred at 50°C for 0.5 hours. TLC showed that 20c had been completely consumed and a new spot had formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain 20d.

[0217] Synthesis of isopropyl-1H-benzo[d]imidazole-6-ol (20e) To a mixture of isopropyl-1H-benzo[d]imidazole-6-yl)boronic acid (20d) (853 mg, 4.18 mmol) and CH3CN (10 mL), a solution of NH4HCO3 (330 mg, 4.18 mmol, 344 μL) in H2O (3 mL) and H2O2 (948 mg, 8.36 mmol, 803 μL, 30% purity) were added under N2. The mixture was stirred at 25°C for 1 hour. LC-MS showed that 20d was completely consumed and the desired MS was detected. The residue was poured into NaHSO3 (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 20e. MSmas calculation value: [M+1] + (C 10 H 12 N2O), m / z 177.1, LCMS measured value m / z 177.1.

[0218] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-1H-benzo[d]imidazole (20f) A mixture of 1-isopropyl-1H-benzo[d]imidazole-6-ol (20e) (640 mg, 3.63 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (839 mg, 4.00 mmol) in DMF (10 mL) was mixed with K2CO3 (753 mg, 5.45 mmol) under N2. The mixture was stirred at 25°C for 1 hour. TLC showed that 20e had been completely consumed and many new spots had formed. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 20f. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 2H), 8.25 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 2.6, 9.0 Hz, 1H), 4.85 (s, 8H), 4.62 - 4.72 (m, 1H), 1.56 (d, J = 6.8 Hz, 6H).

[0219] Synthesis of 3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxyaniline (20g) To a mixture of 6-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-1H-benzo[d]imidazole (20f) (500 mg, 1.37 mmol) and EtOH (8 mL), a solution of NH4Cl (365 mg, 6.83 mmol) in H2O (2 mL) and Fe (381 mg, 6.83 mmol) were added under N2. The mixture was stirred at 80°C for 2 hours. TLC showed that the 20f had been completely consumed and a new spot had formed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was washed with water to obtain 20 g. 1 H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 6.82 - 6.94 (m, 2H), 6.69 - 6.82 (m, 2H), 4.51 - 4.67 (m, 1H), 4.60 (br d, J = 7.0 Hz, 2H), 1.56 (d, J = 6.6 Hz, 6H).

[0220] Synthesis of N-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 20) To a mixture of 3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (20 g) (50 mg, 149 μmol) and THF (3 mL), TEA (45.2 mg, 446 μmol, 62.1 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (22.1 mg, 149 μmol) were added under N2. The mixture was stirred at 25°C for 1 hour. LC-MS showed that 20 g was completely consumed, and the desired MS was detected. The residue was poured into NaHCO3 (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was washed with water (2 mL x 2) and ethyl acetate (2 mL x 4) to obtain Example 20. MSmas calculation value: [M+1] + (C 19 H 15 Cl2N5O4), m / z 448.1, LCMS measured value m / z 448.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.36 (m, 1H), 7.61 - 7.80 (m, 2H), 7.51 - 7.60 (m, 1H), 7.00 - 7.13 (m, 1H), 6.61 - 6.73 (m, 1H), 4.57 - 4.70 (m, 1H), 3.33 (br s, 94H), 1.39 - 1.54 (m, 6H).

[0221] Example 21 2-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (21a) 3,5-Dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxyaniline (20 g) (100 mg, 297 μmol) was mixed with HCl (1 mL) and NaNO2 (26.7 mg, 387 μmol) in H2O (2 mL). The resulting mixture was stirred at 0-5°C for 0.5 hours. The reaction mixture was then added to a mixture of ethyl (2-cyanoacetyl)carbamate (92.9 mg, 595 μmol) in Py (1 mL) and H2O (2 mL) under N2. The final mixture was stirred for a further 0.5 hours at 0-5°C. LCMS showed that 20 g was completely consumed and the desired MS was detected. The reaction mixture was filtered, and the filtered cake was dried under vacuum to obtain 21a. MSmas calculation value: [M+1] + (C 22 H 20 Cl2N6O4), m / z 503.1, LCMS measured value m / z 503.1.

[0222] Synthesis of 2-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 21) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (21a) (100 mg, 199 μmol) was mixed with HOAc (4 mL) and NaOAc (81.5 mg, 993 μmol) under N2. The mixture was stirred at 120 °C for 3 hours. LC-MS showed that 21a was completely consumed and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 21. MSmas calculation value: [M+1] + (C 20 H 14 Cl2N6O3), m / z 457.1, LCMS measured value m / z 456.9; 1 H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.81 (s, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.83 - 7.00 (m, 1H), 4.63 - 4.72 (m, 1H), 4.68 (s, 1H), 2.59 - 2.67 (m, 1H), 1.90 - 2.01 (m, 1H), 1.63 - 1.65 (m, 1H), 1.57 (d, J = 6.6 Hz, 5H).

[0223] Example 22 N-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-cyclopropyl-2-nitroaniline (22a) A mixture of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) and cyclopropanamine (2.08 g, 36.36 mmol, 2.52 mL) in CH3CN (10 mL) was mixed with DIEA (5.87 g, 45.45 mmol, 7.92 mL) under N2. The mixture was stirred at 50°C for 1 hour. TLC showed that the starting materials were completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 22a. 1 H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 9.0, 2.0 Hz, 1H), 6.56 (dd, J = 9.0, 2.0 Hz, 1H), 4.57 (s, 7H), 3.01 (br s, 2H), 2.27 - 2.36 (m, 1H), 0.57 - 0.70 (m, 2H), 0.28 - 0.38 (m, 2H).

[0224] Synthesis of 5-bromo-N1-cyclopropylbenzene-1,2-diamine (22b) To a solution of 5-bromo-N-cyclopropyl-2-nitroaniline (22a) (1 g, 3.89 mmol) in EtOH (10 mL) and H2O (2 mL), Fe (1.09 g, 19.45 mmol) and NH4Cl (1.04 g, 19.45 mmol) were added. The mixture was stirred at 80°C for 5 hours. LC-MS showed that 22a had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was concentrated under reduced pressure. The residue 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 Na2SO4, filtered, and concentrated under reduced pressure to obtain 22b. MSmas calculation value: [M+1] + (C9H 11BrN2), m / z 227.0, LCMS measured value m / z 227.1; 1 H NMR (400 MHz, CD3OD) δ 6.64 - 7.36 (m, 1H), 5.85 - 6.51 (m, 2H), 2.40 - 2.87 (m, 2H), 1.28 - 2.21 (m, 1H), 0.34 - 0.85 (m, 2H), -0.33 - 0.28 (m, 1H).

[0225] Synthesis of 6-bromo-1-cyclopropyl-1H-benzo[d]imidazole (22c) A solution of 5-bromo-N1-cyclopropylbenzene-1,2-diamine (22b) (800 mg, 3.52 mmol) in HC(OMe)3 (5 mL) was stirred at 100°C for 2 hours. LC-MS showed that 22b was completely consumed, and the desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 22c. MSmas calculation value: [M+1] + (C 10 H9BrN2), m / z 237.0, LCMS measured value m / z 237.1; 1 H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.85 (s, 1H), 7.68 - 7.76 (m, 1H), 7.29 - 7.60 (m, 5H), 1.16 - 1.33 (m, 4H), 1.04 - 1.14 (m, 4H).

[0226] Synthesis of (1-cyclopropyl-1H-benzo[d]imidazole-6-yl)boronic acid (22d) To a mixture of 6-bromo-1-cyclopropyl-1H-benzo[d]imidazole (22c) (420 mg, 1.77 mmol) and MeOH (10 mL), diboronic acid (hypodiboric acid) (476.43 mg, 5.31 mmol), DIPEA (686.82 mg, 5.31 mmol, 925.63 μL), and [2-(2-aminophenyl)phenyl]-chloropalladium;bis(1-adamantyl)-butylphosphane (11.84 mg, 17.71 μmol) were added under N2. The mixture was stirred at 50°C for 1 hour. LCMS showed that 22c was completely consumed and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with MeOH (5 mL x 3). The combined filtrate was concentrated under reduced pressure to obtain 22d. MSmas calculation value: [M+1] + (C 10 H 11 BN2O2), m / z 203.1, LCMS measured value m / z 203.2.

[0227] Synthesis of 1-cyclopropyl-1H-benzo[d]imidazole-6-ol (22e) (1-cyclopropyl-1H-benzo[d]imidazole-6-yl)boronic acid (22d) (350 mg, 1.73 mmol) was added to a mixture of H2O (2 mL) and CH3CN (4 mL) under N2, with ammonium carbonate (136.97 mg, 1.73 mmol, 142.67 μL) and H2O2 (392.82 mg, 3.47 mmol, 332.90 μL, 30% purity). The mixture was stirred at 20°C for 1 hour. LC-MS showed that 22d was completely consumed, and the desired MS was detected. The residue was poured into NaHSO3 (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 22e. MSmas calculation value: [M+1] + (C 10 H 10 N2O), m / z 175.1, LCMS measured value m / z 175.2;1 H NMR (400 MHz, CD3OD) δ 7.93 - 8.01 (m, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.95 - 7.03 (m, 2H), 6.76 - 6.83 (m, 2H), 3.95 - 4.08 (m, 1H), 1.99 - 2.04 (m, 2H), 1.24 (t, J = 7.2 Hz, 4H), 1.11 - 1.17 (m, 2H).

[0228] Synthesis of 1-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (22f) 1-Cyclopropyl-1H-benzo[d]imidazole-6-ol (22e) (300 mg, 1.72 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (397.80 mg, 1.89 mmol) were dissolved in DMF (10 mL) and K2CO3 (357.03 mg, 2.58 mmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. LCMS and TLC showed that 22e was completely consumed and the desired MS was detected. The mixture was extracted with ethyl acetate (20 mL × 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 22f. MSmas calculation value: [M+1] + (C 16 H 11 Cl2N3O3), m / z 364.0, LCMS measured value m / z 364.0; 1H NMR (400 MHz, CD3OD) δ 8.46 - 8.48 (m, 2H), 8.14 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 4.03 - 4.07 (m, 1H), 3.42 (tt, J = 7.0, 3.6 Hz, 1H), 3.21 (s, 3H), 1.20 - 1.26 (m, 1H), 1.10 - 1.16 (m, 2H), 0.99 - 1.08 (m, 3H).

[0229] Synthesis of 3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxyaniline (22g) 1-Cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (22f) (410 mg, 1.13 mmol) was dissolved in EtOH (10 mL) and H2O (3 mL), to which Fe (314.38 mg, 5.63 mmol) and NH4Cl (301.10 mg, 5.63 mmol) were added. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 22f was completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was extracted with ethyl acetate (15 mL x 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 22 g. MSmas calculation value: [M+1] + (C 16 H 13 Cl2N3O), m / z 334.0, LCMS measured value m / z 334.1; 1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 6.75 - 6.80 (m, 2H), 3.36 - 3.42 (m, 1H), 1.07 - 1.14 (m, 2H), 0.95 - 1.03 (m, 2H).

[0230] Synthesis of N-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 22) 3,5-Dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (22 g) (25 mg, 74.81 μmol) was dissolved in THF (3 mL) and TEA (22.71 mg, 224.42 μmol, 31.24 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (16.66 mg, 112.21 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that 22 g was completely consumed and the desired MS was detected. The mixture was quenched with H2O (1 mL) and MeOH (5 mL) and stirred at 25°C for 10 minutes. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((NH4HCO3), column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-MeCN)] to obtain Example 22. MSmas calculation value: [M+1] + (C 16 H 13 Cl2N3O), m / z 446.0, LCMS measured value m / z 445.9; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (br s, 1H), 8.12 (s, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.94 (s, 1H), 6.75 (dd, J = 8.8, 2.6 Hz, 1H), 3.44 (td, J = 7.0, 3.6 Hz, 1H), 0.99 - 1.06 (m, 2H), 0.93 - 0.98 (m, 2H).

[0231] Example 23 2-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (23a) 3,5-Dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (22 g) (30 mg, 89.77 μmol) and ethyl N-(2-cyanoacetyl)carbamate (15.42 mg, 98.74 μmol) were mixed in CH3CN (2.5 mL) and t-BuONO (18.51 mg, 179.53 μmol, 21.35 μL) at 0°C. The mixture was then stirred at 0°C for 1 hour. LC-MS showed that 22 g had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with MeOH (5 mL x 3). The combined filtrate was concentrated under reduced pressure to obtain 23a. MSmas calculation value: [M+1] + (C 22 H 18Cl2N6O4), m / z 501.0, LCMS measured value m / z 501.1; 1 H NMR (400 MHz, CD3OD) δ 9.42 (br s, 1H), 7.91 (s, 1H), 7.77 - 7.86 (m, 2H), 7.70 (br s, 1H), 7.59 (br d, J = 7.8 Hz, 1H), 7.22 - 7.40 (m, 4H), 4.05 (br s, 4H), 1.19 - 1.38 (m, 36H), 0.89 (br d, J = 9.6 Hz, 4H).

[0232] Synthesis of 2-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 23) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (23a) (40 mg, 79.79 μmol) was dissolved in DMA (3 mL) and KOAc (15.66 mg, 159.58 μmol) was added. The mixture was stirred at 115 °C for 3 hours. LC-MS showed that 23a had been completely consumed and the desired MS was detected. The mixture was added dropwise to H2O (4 mL) over 10 minutes with stirring. The mixture was filtered, and the filter cake was washed with H2O (1 mL x 3) and dried under vacuum. The residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain Example 23. MSmas calculation value: [M+1] + (C 20 H 12 Cl2N6O3), m / z 455.0, LCMS measured value m / z 454.9; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.84 (s, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 6.75 (dd, J = 8.8, 2.6 Hz, 1H), 3.44 - 3.50 (m, 1H), 1.00 - 1.06 (m, 2H), 0.95 - 1.00 (m, 2H).

[0233] Example 24 N-(3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 2-chloro-6-(2,6-dichloro-4-nitro-phenoxy)quinoline (24a) A mixture of 2-chloroquinoline-6-ol (400 mg, 2.23 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (561.21 mg, 2.67 mmol), and K2CO3 (461.71 mg, 3.34 mmol) in DMF (10 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 1 hour. TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1~10:1) to obtain 24a. 1H NMR (400 MHz, CDCl3) 8.38 (s, 2H), 8.07 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H).

[0234] Synthesis of 2-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)quinoline (24b) A mixture of 2-chloro-6-(2,6-dichloro-4-nitrophenoxy)quinoline (24a) (200 mg, 541.15 μmol), cyclopropylboronic acid (92.97 mg, 1.08 mmol), K2CO3 (224.37 mg, 1.62 mmol), and Pd(PPh3)4 (62.53 mg, 54.11 μmol) in dioxane (10 mL) and H2O (1 mL) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 24b. MS mass calculation value: [M+H] + (C 18 H 12 Cl2N2O3), m / z, 375.0, LCMS measured value m / z 375.0.

[0235] Synthesis of 3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)aniline(24c) A mixture of 2-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)quinoline (24b) (200 mg, 533.04 μmol), Fe (148.84 mg, 2.67 mmol), and NH4Cl (142.57 mg, 2.67 mmol) in EtOH (20 mL) and H2O (4 mL) was degassed, purged three times with N2, and then stirred at 90°C for 3 hours under an N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was filtered, concentrated, diluted with H2O (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain 24c. MS mass calculation value: [M+H] + (C 18 H 14 Cl2N2O), m / z, 345.0, LCMS measured value m / z 345.0. 1 H NMR (400 MHz, CDCl3) 7.93 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.74 (s, 2H), 3.80 (s, 2H), 2.16 - 2.26 (m, 1H), 1.04 - 1.12 (m, 4H).

[0236] Synthesis of N-(3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 24) 3,5-Dichloro-4-[(2-cyclopropyl-6-quinolyl)oxy]aniline (24c) (20 mg, 57.93 μmol) and TEA (11.72 mg, 115.87 μmol, 16.13 μL) were mixed in THF (2 mL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (17.21 mg, 115.87 μmol) was added. The mixture was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 0.5 hours. LC-MS indicated that the reaction was complete and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (FA conditions: column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 24. MS mass calculation value: [M+H] + (C 21 H 14 Cl2N4O4), m / z, 457.0, LCMS measured value m / z 457.0. 1 H NMR (400 MHz, CD3OD) 8.04 (d, J = 8.6 Hz, 1H), 8.00 (s, 2H), 7.95 (d, J = 9.0 Hz, 1H), 7.47 - 7.50 (m, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 2.24 - 2.28 (m, 1H), 1.08 - 1.16 (m, 4H).

[0237] Example 25 N-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 25) To a mixture of 3,5-dichloro-4-((4-methylquinoline-6-yl)oxy)aniline (15b) (25 mg, 78.3 μmol) and THF (2 mL), TEA (15.9 mg, 157 μmol, 21.8 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (11.6 mg, 78.3 μmol) were added under N2. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 15b was completely consumed, and the desired MS was detected. The residue was poured into NaHCO3 (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was washed with DCM (2 mL × 1) and ethyl acetate (2 mL × 3) to obtain Example 25. MSmas calculation value: [M+1] + (C 19 H 12 Cl2N4O4), m / z 431.0, LCMS measured value m / z 430.9; 1 H NMR (400 MHz, DMSO-d6) δ 11.16 - 11.29 (m, 1H), 8.57 - 8.74 (m, 1H), 8.07 - 8.20 (m, 2H), 7.98 - 8.09 (m, 1H), 7.36 - 7.43 (m, 2H), 7.26 - 7.29 (m, 1H), 6.18 - 6.23 (m, 1H), 5.74 - 5.77 (m, 1H), 3.35 (br s, 1H), 2.55 - 2.72 (m, 2H), 2.55 (m, 1H), 2.54 (s, 3H).

[0238] Example 26 2-(3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (26b) To a solution of 3,5-dichloro-4-[(2-cyclopropyl-6-quinolyl)oxy]aniline (24c) (40 mg, 115.87 μmol) and ethyl N-(2-cyanoacetyl)carbamate (90.46 mg, 579.34 μmol) in CH3CN (3 mL), tert-butyl nitrite (23.90 mg, 231.73 μmol, 27.56 μL) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C for 1 hour. LC-MS indicated that the reaction was complete, and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain 26b. MS mass calculation value: [M+H] + (C 24 H 19 Cl2N5O4), m / z, 512.1, LCMS measured value m / z 512.1.

[0239] Synthesis of 2-(3,5-dichloro-4-((2-cyclopropylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 26) A mixture of ethyl N-[(2E)-2-cyano-2-[[3,5-dichloro-4-[(2-cyclopropyl-6-quinolyl)oxy]phenyl]hydrazono]acetyl]carbamate (26b) (60 mg, 117.11 μmol) and KOAc (22.99 mg, 234.22 μmol) in DMA (4 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 115°C for 3 hours. LC-MS indicated that the reaction was complete and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA conditions: column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 26. MS mass calculation value: [M+H] + (C 22 H13 Cl2N5O3), m / z, 466.0, LCMS measured value m / z 466.0; 1 H NMR (400 MHz, CD3OD) 8.03 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.83 (s, 2H), 7.50 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 2.22 - 2.30 (m, 1H), 1.04 - 1.17 (m, 4H).

[0240] Example 27 N-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 6-bromo-1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole (27a) To a solution of 5-bromo-N1-cyclopropylbenzene-1,2-diamine (22b) (1 g, 4.40 mmol) in AcOH (10 mL), tetramethoxymethane (1.20 g, 8.81 mmol) was added. The mixture was stirred at 50°C for 1 hour. LC-MS showed that 22b had been completely consumed, and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the AcOH. The residue was diluted with H2O (15 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, and filtered. 、 The solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 27a. MSmas calculation value: [M+1] + (C 11 H 11 BrN2O), m / z 267.0, LCMS measured value m / z 267.1;1 H NMR (400 MHz, CD3OD) δ 7.55 (d, J = 1.4 Hz, 1H), 7.22 - 7.34 (m, 2H), 4.16 (s, 3H), 3.08 (tt, J = 7.0, 3.6 Hz, 1H), 1.09 - 1.20 (m, 2H), 0.94 - 1.02 (m, 2H).

[0241] Synthesis of 1-cyclopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (27b) To a solution of 6-bromo-1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole (27a) (100 mg, 374.36 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (114.08 mg, 449.23 μmol) in dioxane (3 mL), KOAc (183.70 mg, 1.87 mmol) and Pd(PPh3)2Cl2 (26.28 mg, 37.44 μmol) were added under N2 at 20 °C. The mixture was stirred at 90 °C for 4 hours. LC-MS showed that 27a was completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (5 mL x 3). The combined filtrate was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 27b. MSmas calculation value: [M+1] + (C 17 H 23 BN2O3), m / z 315.2, LCMS measured value m / z 315.1; 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.57 (br d, J = 8.0 Hz, 2H), 7.36 - 7.44 (m, 1H), 4.17 (s, 3H), 3.11 (td, J = 7.0, 3.55 Hz, 1H), 1.32 - 1.41 (m, 13H).

[0242] Synthesis of 1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-ol (27c) 1-Cyclopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (27b) (110 mg, 350.11 μmol) in a mixture of H2O (1.5 mL) and CH3CN (3 mL) under N2, with ammonium carbonate (27.68 mg, 350.11 μmol, 28.83 μL) and H2O 2( 79.38 mg (700.22 μmol, 67.27 μL, 30% purity) was added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 27b was completely consumed and the desired MS was detected. The residue was poured into NaHSO3 (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 27c. MSmas calculation value: [M+1] + (C 11 H 12 N2O2), m / z 205.1, LCMS measured value m / z 205.1.

[0243] Synthesis of 1-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1H-benzo[d]imidazole (27d) 1-Cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-ol (27c) (70 mg, 342.76 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (79.17 mg, 377.04 μmol) were dissolved in DMF (3 mL) and K2CO3 (71.06 mg, 514.14 μmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 1 hour. LCMS and TLC showed that 27c was completely consumed and the desired MS was detected. The mixture was extracted with ethyl acetate (20 mL × 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 27d. MSmas calculation value: [M+1] + (C 17 H 13 Cl2N3O4), m / z 394.0, LCMS measured value m / z 394.1; 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 2H), 7.32 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 8.6, 2.4 Hz, 1H), 4.15 (s, 3H), 3.01 - 3.10 (m, 1H), 1.04 - 1.14 (m, 2H), 0.90 - 0.97 (m, 2H).

[0244] Synthesis of 3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxyaniline (27e) 1-Cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1H-benzo[d]imidazole (27d) (120 mg, 304.41 μmol) was dissolved in EtOH (3 mL) and H2O (1 mL), to which Fe (85.01 mg, 1.52 mmol) and NH4Cl (81.41 mg, 1.52 mmol) were added. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 27d had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL × 3). The combined filtrate was extracted with ethyl acetate (15 mL × 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using Prep-TLC (petroleum ether: ethyl acetate) to obtain 27e. MSmas calculation value: [M+1] + (C 17 H 15 Cl2N3O2), m / z 364.1, LCMS measured value m / z 364.1; 1 H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.53 - 7.70 (m, 1H), 7.28 (d, J = 8.6 Hz, 1H), 6.73 - 6.81 (m, 3H), 6.64 (br d, J = 8.6 Hz, 1H), 4.12 (s, 3H), 2.97 - 3.05 (m, 3H), 2.86 (s, 2H), 1.07 (br d, J = 5.8 Hz, 2H), 0.91 (br s, 2H).

[0245] Synthesis of N-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 27) To a solution of 3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (27e) (50 mg, 137.28 μmol) in DCM (2 mL), TEA (41.67 mg, 411.83 μmol, 57.32 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (30.58 mg, 205.92 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that 27e was completely consumed and the desired MS was detected. The mixture was quenched with H2O (1 mL) and MeOH (5 mL). The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((NH4HCO3), column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-MeCN]) to obtain Example 27. MSmas calculation value: [M+1] + (C 17 H 15 Cl2N3O2), m / z 462.0, LCMS measured value m / z 461.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (br s, 1H), 10.65 (s, 1H), 8.10 (s, 2H), 6.91 - 7.26 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.30 (dd, J = 8.4, 2.4 Hz, 1H), 2.81 (br s, 1H), 0.97 (br d, J = 5.4 Hz, 2H), 0.81 (br s, 2H).

[0246] Example 28 2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (28a) 3,5-Dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (27e) (180 mg, 494.20 μmol) and ethyl (2-cyanoacetyl)carbamate (84.88 mg, 543.62 μmol) were mixed in CH3CN (6 mL) and t-BuONO (101.92 mg, 988.40 μmol, 117.56 μL) was added at 0°C. The mixture was then stirred at 0°C for 1 hour. LC-MS showed that 27e had been completely consumed and the desired MS was detected. The mixture was concentrated under vacuum to obtain 28a. MSmas calculation value: [M+1] + (C 23 H 20 Cl2N6O5), m / z 531.1, LCMS measured value m / z 531.1.

[0247] Synthesis of 2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 28) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (28a) (260 mg, 489.32 μmol) was dissolved in DMA (3 mL) and KOAc (96.04 mg, 978.64 μmol) was added. The mixture was stirred at 115 °C for 3 hours. LC-MS was performed to detect the desired MS after the complete consumption of 28a. The suspension was filtered through a Celite pad, and the pad cake was washed with MeOH (5 mL x 3). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC ((FA), column: Welch Ultimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 28. MSmas calculation value: [M+1] + (C 21 H 14 Cl2N6O4), m / z 485.0, LCMS measured value m / z 484.9; 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 2H), 7.31 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.55 (dd, J = 8.6, 2.6 Hz, 1H), 4.07 (s, 3H), 3.10 (tt, J = 7.0, 3.6 Hz, 1H), 1.01 - 1.07 (m, 2H), 0.85 - 0.90 (m, 2H).

[0248] Example 29 N-(3,5-dichloro-4-((2-methoxy-1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-methyl-2-nitroaniline (29a) To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) in CH3CN (25 mL), DIEA (2.94 g, 22.7 mmol, 3.96 mL) and methanamine (1.23 g, 18.3 mmol, HCl) were added. The mixture was stirred at 50°C for 1 hour. TLC showed that the starting material had been completely consumed and a new spot had formed. The reaction mixture was separated with ethyl acetate (25 mL) and H2O (25 mL). The organic phase was separated, washed with saturated NaCl (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29a. 1 H NMR (400 MHz, CD3Cl) δ 11.25 - 11.44 (m, 1H), 8.04 (br d, J = 9.0 Hz, 1H), 8.01 - 8.08 (m, 1H), 7.02 (s, 1H), 6.78 (br d, J = 8.6 Hz, 1H), 3.63 - 3.71 (m, 1H), 3.07 - 3.13 (m, 1H), 3.01 - 3.05 (m, 3H), 1.46 (d, J = 6.6 Hz, 1H).

[0249] Synthesis of 5-bromo-N1-methylbenzene-1,2-diamine (29b) 5-bromo-N-methyl-2-nitroaniline (29a) (1.05 g, 4.54 mmol) was dissolved in EtOH (30 mL) and H2O (10 mL), to which NH4Cl (1.22 g, 22.7 mmol) and Fe (1.27 g, 22.7 mmol) were added. The mixture was stirred at 80°C for 2 hours. TLC showed that 29a had been completely consumed and a new spot had formed. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29b. 1H NMR (400 MHz, CDCl3) δ 6.66 - 6.72 (m, 1H), 6.63 - 6.66 (m, 1H), 6.46 - 6.51 (m, 1H), 2.99 - 3.35 (m, 2H), 2.71 - 2.82 (m, 3H).

[0250] Synthesis of 6-bromo-2-methoxy-1-methyl-1H-benzo[d]imidazole (29c) To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (29b) (400 mg, 1.99 mmol) in AcOH (6 mL), tetramethoxymethane (2.17 g, 15.9 mmol) was added. The mixture was stirred at 50°C for 1 hour. LC-MS showed that 29b had been completely consumed, and one major peak of the desired MS was detected. The reaction mixture was quenched at 0°C by the addition of NaHCO3 (30 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 29c. 1 H NMR (400 MHz, CDCl3) δ 7.29 - 7.37 (m, 1H), 7.15 - 7.24 (m, 2H), 4.10 - 4.15 (m, 3H), 3.43 - 3.49 (m, 3H).

[0251] Synthesis of 2-methoxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (29d) To a solution of 6-bromo-2-methoxy-1-methyl-1H-benzo[d]imidazole (29c) (330 mg, 1.37 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.04 g, 4.11 mmol) in dioxane (10 mL), Pd(PPh3)2Cl2 (96.1 mg, 136.9 μmol) and KOAc (1.34 g, 13.7 mmol) were added. The mixture was stirred at 120 °C for 16 hours. LC-MS showed that 29c was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29d. MSmas calculation value: [M+1] + (C 15 H 21 BN2O3), m / z 289.2, LCMS measured value m / z 289.2; 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.61 (m, 2H), 7.45 - 7.49 (m, 1H), 4.12 - 4.16 (m, 3H), 3.48 - 3.52 (m, 3H), 1.17 - 1.23 (m, 12H).

[0252] Synthesis of 2-methoxy-1-methyl-1H-benzo[d]imidazole-6-ol (29e) To a solution of 2-methoxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (29d) (240 mg, 1.17 mmol) in CH3CN (5 mL), solutions of NH4HCO3 (92.11 mg, 1.17 mmol, 95.9 μL) in H2O (2 mL) and H2O2 (264 mg, 2.33 mmol, 224 μL, 30% purity) were added. The mixture was stirred at 20°C for 2 hours. LC-MS showed that 29d was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was quenched by the addition of Na2S2O3 (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29e. MSmas calculation value: [M+1] + (C9H 10 N2O2), m / z 179.1, LCMS measured value m / z 179.1; 1 H NMR (400 MHz, CDCl3) δ7.24 - 7.33 (m, 1H), 6.55 - 6.66 (m, 2H), 4.08 - 4.11 (m, 3H), 3.38 - 3.49 (m, 3H), 1.94 - 2.05 (m, 3H), 1.76 - 1.91 (m, 3H).

[0253] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1-methyl-1H-benzo[d]imidazole (29f) 2-methoxy-1-methyl-1H-benzo[d]imidazole-6-ol (29e) (240 mg, 1.35 mmol) was dissolved in DMF (5 mL), to which K2CO3 (279 mg, 2.02 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (311 mg, 1.48 mmol) were added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 29e had been completely consumed, and one major peak of the desired MS was detected. The reaction mixture was quenched by the addition of H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to obtain 29f. MSmas calculation value: [M+1] + (C 15 H 11 Cl2N3O4), m / z 368.0, LCMS measured value m / z 368.0; 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.44 (m, 2H), 7.40 - 7.53 (m, 1H), 6.55 - 6.74 (m, 2H), 4.13 - 4.29 (m, 3H), 3.45 - 3.63 (m, 3H).

[0254] Synthesis of 3,5-dichloro-4-((2-methoxy-1-methyl-1H-benzo[d]imidazole-6-yl)oxyaniline (29g) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1-methyl-1H-benzo[d]imidazole (29f) (160 mg, 435 μmol) in EtOH (3 mL), solutions of Fe (121 mg, 2.17 mmol) and NH4Cl (116 mg, 2.17 mmol) in H2O (1 mL) were added. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 29f was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29 g. 1 H NMR (400 MHz, CDCl3) δ 7.31 - 7.36 (m, 1H), 6.63 - 6.65 (m, 2H), 6.55 - 6.62 (m, 2H), 4.07 - 4.12 (m, 3H), 3.60 - 3.75 (m, 2H), 3.35 - 3.46 (m, 3H).

[0255] Synthesis of N-(3,5-dichloro-4-((2-methoxy-1-methyl-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29) To a solution of 3,5-dichloro-4-((2-methoxy-1-methyl-1H-benzo[d]imidazole-6-yl)oxy)aniline (29 g) (10 mg, 29.6 μmol) in THF (1 mL), Et3N (15.0 mg, 148 μmol, 20.6 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (8.78 mg, 59.2 μmol) were added. The mixture was stirred at 20°C for 20 minutes. LC-MS showed that 29 g was completely consumed, and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (HCl conditions: column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04% HCl)-ACN]) to obtain Example 29. MSmas calculation value: [M+1] + (C 18 H 13 Cl2N5O5), m / z 450.0, LCMS measured value m / z 449.9; 1 H NMR (400 MHz, CD3OD) δ 7.74 - 7.85 (m, 2H), 7.20 - 7.24 (m, 1H), 6.59 - 6.60 (m, 1H), 6.55 - 6.58 (m, 1H), 4.03 - 4.06 (m, 3H), 3.33 - 3.37 (m, 3H).

[0256] Example 30 N-(3,5-dichloro-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 6-bromo-1-isopropyl-2-methoxy-1H-benzo[d]imidazole (30a) To a solution of 5-bromo-N1-isopropylbenzene-1,2-diamine (20b) (400 mg, 1.75 mmol) in AcOH (5 mL), tetramethoxymethane (1.90 g, 13.97 mmol) was added. The mixture was stirred at 50°C for 1 hour. LC-MS showed that 20b had been completely consumed, and one major peak of the desired mass was detected. The reaction mixture was quenched at 0°C by the addition of NaHCO3 (30 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 30a. MSmas calculation value: [M+1] + (C 11 H 13 BrN2O), m / z 269.0, LCMS measured value m / z 269.0; 1 H NMR (400 MHz, CDCl3) δ 7.31 - 7.53 (m, 2H), 7.26 (s, 1H), 4.52 - 4.71 (m, 1H), 4.20 (s, 3H), 1.50 - 1.60 (m, 6H).

[0257] Synthesis of 1-isopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (30b) To a solution of 6-bromo-1-isopropyl-2-methoxy-1H-benzo[d]imidazole (30a) (320 mg, 1.19 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (905.78 mg, 3.57 mmol) in dioxane (15 mL), Pd(PPh3)2Cl2 (83.45 mg, 118.90 μmol) and KOAc (1.17 g, 11.89 mmol) were added. The mixture was stirred at 120 °C for 16 hours. LC-MS showed that 30a was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was filtered, and then 30 mL of H2O was added to the filtrate. The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30b. MSmas calculation value: [M+1] + (C 17 H 25 BN2O3), m / z 317.2, LCMS measured value m / z 317.1.

[0258] Synthesis of 1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-ol (30c) To a solution of 1-isopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (30b) (375 mg, 1.19 mmol) in H2O (2 mL), solutions of NH4HCO3 (93.76 mg, 1.19 mmol, 97.67 μL), CH3CN (5 mL), and H2O2 (268.89 mg, 2.37 mmol, 227.88 μL, 30% purity) were added. The mixture was stirred at 20°C for 2 hours. LC-MS showed that 30b was completely consumed, and one major peak indicating the desired mass was detected. The reaction mixture was quenched by the addition of Na2S2O3 (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30c. MSmas calculation value: [M+1]+ (C 11 H 14 N2O2), m / z 207.1, LCMS measured value m / z 207.1.

[0259] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole (30d) To a solution of 1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-ol (30c) (244 mg, 1.18 mmol) in DMF (1 mL), K2CO3 (245.26 mg, 1.77 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (273.28 mg, 1.30 mmol) were added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 30c was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was quenched by the addition of H2O (5 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to obtain 30d. MSmas calculation value: [M+1] + (C 17 H 15 Cl2N3O4), m / z 396.0, LCMS measured value m / z 396.1; 1 H NMR (400 MHz, CDCl3) δ 8.28 - 8.38 (m, 2H), 7.39 - 7.44 (m, 1H), 6.86 - 6.89 (m, 1H), 6.52 - 6.56 (m, 1H), 4.51 - 4.60 (m, 1H), 4.16 - 4.19 (m, 3H), 1.50 - 1.55 (m, 6H).

[0260] Synthesis of 3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxyaniline (30e) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole (30d) (150 mg, 378.57 μmol) in EtOH (3 mL), a solution of Fe (105.71 mg, 1.89 mmol) and NH4Cl (101.25 mg, 1.89 mmol) in H2O (1 mL) was added. The mixture was stirred at 80°C for 2 hours. TLC showed that 30d was completely consumed. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30e. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.41 (m, 1H), 6.83 - 6.86 (m, 1H), 6.70 - 6.73 (m, 1H), 6.57 - 6.62 (m, 1H), 4.51 - 4.58 (m, 1H), 4.14 - 4.18 (m, 2H), 3.74 - 3.77 (m, 1H), 1.49 - 1.54 (m, 6H), 1.24 - 1.29 (m, 2H).

[0261] Synthesis of N-(3,5-dichloro-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 30) To a solution of 3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (30e) (30 mg, 81.91 μmol) in DCM (0.5 mL), TEA (24.87 mg, 245.73 μmol, 34.20 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (18.25 mg, 122.87 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that the 30e had been completely consumed, and trace amounts of the desired MS were detected. The mixture was stirred for a further 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was quenched with MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain the crude product. The crude product was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate) to obtain Example 30. MSmas calculation value: [M+1] + (C 19 H 15 Cl2N5O5), m / z 464.0, LCMS measured value m / z 464.0; 1 H NMR (400 MHz, CD3OD) δ 7.96 (s, 2H), 6.95 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.44 (dd, J = 8.6, 2.4 Hz, 1H), 4.61 (dq, J = 14.0, 6.8 Hz, 1H), 1.48 (d, J = 7.0 Hz, 6H).

[0262] Example 31 2-(3,5-dichloro-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (31a) 3,5-Dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (30e) (35 mg, 95.57 μmol) was added to a solution of HOAc (2 mL) and H2O (1 mL) at 0°C with ethyl (2-cyanoacetyl)carbamate (16.86 mg, 107.99 μmol). Next, HCl (1 M, 23.89 μL) was added dropwise at 2–4°C, and the mixture was then stirred at 0°C for 10 minutes. A solution of NaNO2 (8.57 mg, 124.24 μmol) in H2O (0.05 mL) was added dropwise to the reaction mixture at 0°C. The mixture was then stirred at 0°C for 6 hours. LCMS showed that 30e was completely consumed, and one major peak of the desired mass was detected. The reaction mixture was quenched by adding H2O (5 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 31a. MSmas calculation value: [M+1] + (C 23 H 22 Cl2N6O5), m / z 533.1, LCMS measured value m / z 533.1; 1 H NMR (400 MHz, DMSO-d6) δ 11.03 - 11.06 (m, 1H), 7.35 - 7.38 (m, 1H), 7.02 - 7.03 (m, 1H), 6.56 - 6.60 (m, 1H), 4.23 - 4.26 (m, 2H), 4.18 - 4.20 (m, 2H), 4.15 - 4.17 (m, 2H), 1.45 - 1.51 (m, 6H).

[0263] Synthesis of 2-(3,5-dichloro-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 31) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (31a) (20 mg, 37.50 μmol) was dissolved in DMA (1 mL) and KOAc (7.36 mg, 75.00 μmol) was added. The mixture was stirred at 110 °C for 6 hours. LC-MS showed that 31a was completely consumed and one major peak of the desired mass was detected. The reaction mixture was quenched by the addition of H2O (5 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 31. MS mass calculation value: [M+H] + (C 20 H 14 Cl2N6O4), m / z 473.0, MS measured value m / z 473.1; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (s, 1H), 7.80 (s, 2H), 7.00 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 6.25 (dd, J = 8.6, 2.4 Hz, 1H), 4.53 (dt, J = 13.8, 7.0 Hz, 1H), 2.67 - 2.84 (m, 1H), 2.52 - 2.57 (m, 3H), 1.41 (d, J = 7.0 Hz, 6 H).

[0264] Example 32 N-(3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32) To a solution of 3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (30e) (30 mg, 81.91 μmol) in DCM (0.5 mL), TEA (24.87 mg, 245.73 μmol, 34.20 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (18.25 mg, 122.87 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that the 30e was completely consumed, and the desired MS was detected. The mixture was quenched with NaHCO3 (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC ((FA), column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 32. MSmas calculation value: [M+1] + (C 20 H 17 Cl2N5O5), m / z 478.1, LCMS measured value m / z 477.9; 1H NMR (400 MHz, DMSO-d6) δ 10.49 (br s, 1H), 8.14 (s, 2H), 7.29 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.49 (dd, J = 8.62, 1.65 Hz, 1H), 4.61 (dt, J = 13.6, 6.8 Hz, 1H), 4.07 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H).

[0265] Example 33 N-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 33) To a solution of 3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)aniline (27e) (20 mg, 54.91 μmol) in DCM (0.5 mL), TEA (16.67 mg, 164.73 μmol, 22.93 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (12.23 mg, 82.37 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. LC-MS and HPLC showed that 27e was completely consumed, and the desired MS was detected. The mixture was quenched with NaHCO3 (10 mL) and stirred for 10 minutes. The mixture was extracted with DCM (15 mL x 2). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC ((NH4HCO3), column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]) to obtain Example 33. MSmas calculation value: [M+1] + (C 20 H 15 Cl2N5O5), m / z 476.0, LCMS measured value m / z 475.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (br s, 1H), 8.14 (s, 2H), 7.30 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.54 (dd, J = 8.6, 2.6 Hz, 1H), 4.07 (s, 3H), 3.08 (tt, J = 7.0, 3.6 Hz, 1H), 1.00 - 1.10 (m, 2H), 0.82 - 0.90 (m, 2H).

[0266] Example 34 2-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 2-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 34) 2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 28) (10 mg, 20.61 μmol) was dissolved in DCM (3 mL) and BCl3 (1 M, 41.21 μL) was added. The mixture was stirred at 40°C for 32 hours. LCMS showed that Example 28 had been completely consumed and the desired MS was detected. The mixture was quenched with MeOH (2 mL) and stirred at 25°C for 10 minutes. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Phenomenex Luna C18 200×40mm×10μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 34. MSmas calculation value: [M+1] + (C 20 H 12 Cl2N6O4), m / z 471.0, LCMS measured value m / z 470.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.81 (s, 2H), 6.82 - 6.87 (m, 2H), 6.31 (dd, J = 8.4, 2.4 Hz, 1H), 2.83 (tt, J = 7.0, 3.6 Hz, 1H), 0.95 - 1.01 (m, 2H), 0.80 - 0.86 (m, 2H).

[0267] Example 35 2-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of 4-ethyl-6-methoxyquinoline (35a) Dichloromanganese (12.58 mg, 0.1 mmol) was added to a solution of 4-chloro-6-methoxyquinoline (600 mg, 3.10 mmol) in THF (10 mL). EtMgBr (2 M, 2.32 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 1 hour. LC-MS showed that the starting material had been completely consumed, and one major peak at the desired mass was detected. The reaction mixture was quenched by the addition of aqueous NH4Cl (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 35a. MSmas calculation value: [M+1] + (C 12 H 13 NO), m / z 188.1, MS measured value m / z 188.0; 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 9.2, 2.8 Hz, 1H), 7.20 - 7.28 (m, 2H), 3.96 (s, 3H), 3.03 - 3.11 (m, 2H), 1.41 (t, J = 7.6 Hz, 3H).

[0268] Synthesis of 4-ethylquinoline-6-ol (35b) A solution of 4-ethyl-6-methoxyquinoline (35a) (537 mg, 2.87 mmol) in H2SO4 (3 mL) and H2O (3 mL) was stirred at 100°C for 24 hours. TLC and LCMS showed that 35a was completely consumed, and one major peak indicating the desired mass was detected. The mixture was adjusted to pH 9 with ammonium hydroxide. The mixture was filtered, and the filter cake was washed with H2O (20 mL x 3) and dried under vacuum to obtain 35b. MSmas calculation value: [M+1] + (C 11 H 11 NO), m / z 174.1, MS measured value m / z 174.2; 1 H NMR (400 MHz, CDCl3) δ ppm 8.67 (d, J = 4.6 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.37 - 7.42 (m, 1H), 7.33 (dd, J = 9.0, 2.57 Hz, 1H), 7.22 - 7.25 (m, 1H), 2.98 - 3.11 (m, 2H), 1.34 - 1.45 (m, 3H).

[0269] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4-ethylquinoline (35c) To a solution of 4-ethylquinoline-6-ol (35b) (423 mg, 2.44 mmol) in DMF (2 mL), 1,3-dichloro-2-fluoro-5-nitrobenzene (512.82 mg, 2.44 mmol) and K2CO3 (675.03 mg, 4.88 mmol) were added. The mixture was stirred at 20°C for 1 hour. TLC showed that 35c had been completely consumed and a new spot had formed. The reaction mixture was diluted with ethyl acetate (30 mL) and H2O (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 35c. MSmas calculation value: [M+1] + (C17 H 12 Cl2N2O3), m / z 363.0, MS measured value m / z 363.0; 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.4 Hz, 1H), 8.37 (s, 2H), 8.13 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.8 Hz, 1H), 7.22 - 7.29 (m, 3H), 2.95 (q, J = 7.6 Hz, 2H), 1.25 - 1.44 (m, 3H).

[0270] Synthesis of 3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)aniline (35d) To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-4-ethylquinoline (35c) (780 mg, 2.15 mmol) in EtOH (10 mL), solutions of Fe (599.67 mg, 10.74 mmol) and NH4Cl (574.39 mg, 10.74 mmol) in H2O (0.5 mL) were added. The mixture was stirred at 80°C for 2 hours. TLC showed that the 35c had been completely consumed and a new spot had formed. 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 diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 35d. MSmas calculation value: [M+1] + (C 17 H 14 Cl2N2O), m / z 333.0, MS measured value m / z 333.0; 1H NMR (400 MHz, CDCl3) δ ppm 8.71 (d, J = 4.2 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.38 (dd, J = 9.2, 2.6 Hz, 1H), 7.17 - 7.31 (m, 3H), 6.75 (s, 2H), 3.83 (br s, 2H), 2.95 (q, J = 7.4 Hz, 2H), 1.24 - 1.42 (m, 3 H).

[0271] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (35e) To a solution of 3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)aniline (35d) (20 mg, 60.02 μmol) in HOAc (1 mL) and H2O (0.5 mL), ethyl (2-cyanoacetyl)carbamate (14.06 mg, 90.03 μmol) and HCl (1 M, 150.05 μL) were added at 0°C. Then, NaNO2 (5.38 mg, 78.03 μmol) was added to the mixture. The mixture was stirred at 0°C for 1 hour. LC-MS showed that 35d was completely consumed, and one major peak indicating the desired mass was detected. The reaction mixture was diluted with ethyl acetate (10 mL) and H2O (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 35e. MSmas calculation value: [M+1] + (C 23 H 19 Cl2N5O4), m / z 500.0, MS measured value m / z 500.1.

[0272] Synthesis of 2-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 35) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (35e) (30 mg, 59.96 μmol) was dissolved in DMA (2 mL) and KOAc (11.77 mg, 119.92 μmol) was added. The mixture was stirred at 115 °C for 3 hours. LC-MS showed that 35e was completely consumed and one major peak of the desired mass was detected. The reaction mixture was diluted with ethyl acetate (10 mL) and H2O (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was prepared using prep-TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f The sample was purified using (=0.45) to obtain Example 35. MSmas calculation value: [M+1] + (C 21 H 13 Cl2N5O3), m / z 454.0, MS measured value m / z 454.1; 1 H NMR (400 MHz, CD3OD) δ 8.67 (d, J = 4.6 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.86 (s, 2H), 7.53 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 4.59 (br s, 1H), 2.98 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H).

[0273] Example 36 N-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of N-(3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 36) To a solution of 3,5-dichloro-4-((4-ethylquinoline-6-yl)oxy)aniline (35d) (30 mg, 90.03 μmol) in DCM (2 mL), TEA (27.33 mg, 270.10 μmol, 37.59 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (20.06 mg, 135.05 μmol) were added. The mixture was stirred at 20°C for 0.5 hours. LC-MS showed that 35d was completely consumed, and one major peak indicating the desired mass was detected. The mixture was quenched with MeOH (0.5 mL). The mixture was purified by prep-HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]; B%: 40%-70%, 10 min) to obtain Example 36. MSmas calculation value: [M+1] + (C 20 H 14 Cl2N4O4), m / z 445.0, MS measured value m / z 445.0; 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 8.01 - 8.10 (m, 1H), 7.44 (dd, J = 9.2, 2.8 Hz, 1H), 7.38 (d, J = 4.6 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 2.81 - 3.05 (m, 3H), 1.23 (t, J = 7.46 Hz, 3H).

[0274] Example 37 N-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-(tert-butyl)-2-nitroaniline (37a) To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) in CH3CN (10 mL), DIPEA (2.35 g, 18.18 mmol, 3.17 mL) and 2-methylpropan-2-amine (997.34 mg, 13.64 mmol, 1.43 mL) were added. The mixture was stirred at 50°C for 2 hours. TLC showed that the starting material had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to remove CH3CN. The residue was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 37a. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.36 - 8.50 (m, 1H), 7.95 - 8.07 (m, 1H), 7.25 - 7.27 (m, 1H), 6.72 (dd, J = 1.4, 9.2 Hz, 1H), 1.48 - 1.59 (m, 9H).

[0275] Synthesis of 5-bromo-N1-(tert-butyl)benzene-1,2-diamine (37b) To a solution of 5-bromo-N-(tert-butyl)-2-nitroaniline (37a) (1.24 g, 4.54 mmol) in EtOH (10 mL), Fe (1.27 g, 22.70 mmol) was added, and then a solution of NH4Cl (1.21 g, 22.70 mmol) in H2O (4 mL) was added dropwise to the mixture. The mixture was stirred at 80°C for 2 hours. TLC showed that 37a had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (15 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 obtain 37b. MSmas calculation value: [M+1] + (C 10 H 15 BrN2), m / z 243.04, LCMS measured value m / z 243.0; 1 H NMR (400 MHz, CDCl3) δ 6.98 - 7.05 (m, 1H), 6.82 - 6.88 (m, 1H), 6.56 - 6.64 (m, 1H), 3.34 - 3.60 (m, 2H), 2.78 - 3.19 (m, 1H), 1.31 - 1.35 (m, 9H).

[0276] Synthesis of 6-bromo-1-(tert-butyl)-1H-benzo[d]imidazole (37c) A solution of 5-bromo-N1-(tert-butyl)benzene-1,2-diamine (37b) (100 mg, 411.28 μmol) in CH(OMe)3 (3 mL) was stirred at 100°C for 2 hours. LC-MS indicated that the reaction was complete, and the desired MS was detected. The mixture was concentrated under vacuum to obtain 37c. MSmas calculation value: [M+1] + (C 11 H 13 BrN2), m / z 253.03, LCMS measured value m / z 253.0; 1H NMR (400 MHz, CD3OD) δ 8.21 - 8.28 (m, 1H), 7.96 - 7.99 (m, 1H), 7.54 - 7.60 (m, 1H), 7.35 - 7.41 (m, 1H), 1.73 - 1.80 (m, 9H).

[0277] Synthesis of 1-(tert-butyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (37d) To a solution of 6-bromo-1-(tert-butyl)-1H-benzo[d]imidazole (37c) (96 mg, 379.24 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (288.91 mg, 1.14 mmol) in dioxane (3 mL), KOAc (372.19 mg, 3.79 mmol) and Pd(PPh3)2Cl2 (26.62 mg, 37.92 μmol) were added under N2 at 20°C. The mixture was stirred at 90°C for 4 hours. TLC and LCMS showed that 37c was completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (3 mL x 3). The combined filtrate was concentrated under vacuum. The residue was diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to obtain 37d. MSmas calculation value: [M+1] + (C 17 H 25 BN2O2), m / z 301.2, LCMS measured value m / z 301.2; 1H NMR (400 MHz, CD3OD) δ 8.25 - 8.35 (m, 1H), 8.11 - 8.19 (m, 1H), 7.65 - 7.67 (m, 2H), 1.79 - 1.81 (m, 9H), 1.37 - 1.39 (m, 1H), 1.19 (s, 9H).

[0278] Synthesis of 1-(tert-butyl)-1H-benzo[d]imidazole-6-ol (37e) 1-(tert-butyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (37d) (80 mg, 266.49 μmol) was added to a mixture of H2O (1.5 mL) and CH3CN (3 mL) under N2, with ammonium carbonate (21.07 mg, 266.49 μmol, 21.94 μL) and H2O2 (60.42 mg, 532.97 μmol, 51.20 μL, 30% purity). The mixture was stirred at 20°C for 1 hour. LC-MS showed that 37d was completely consumed, and the desired MS was detected. The residue was poured into NaHSO3 (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain 37e. The crude product was used in the next step without further purification. MSmas calculation value: [M+1] + (C 11 H 14 N2O), m / z 191.11, LCMS measured value m / z 191.2; 1 H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 8.6, 2.20 Hz, 1H), 1.74 (s, 9H).

[0279] Synthesis of 1-(tert-butyl)-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (37f) To a solution of 1-(tert-butyl)-1H-benzo[d]imidazole-6-ol (37e) (50 mg, 262.82 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (60.71 mg, 289.11 μmol) in DMF (3 mL), K2CO3 (54.49 mg, 394.24 μmol) was added under N2 at 20°C. The mixture was stirred at 20°C for 1 hour. TLC and LCMS showed that 37e was completely consumed, and the desired MS was detected. The mixture was extracted with ethyl acetate (10 mL × 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 37f. MSmas calculation value: [M+1] + (C 17 H 15 Cl2N3O3), m / z 380.05, LCMS measured value m / z 380.1; 1 H NMR (400 MHz, CD3OD) δ 8.48 (m, 2H), 8.45 (m, 1H), 8.20 - 8.25 (m, 1H), 7.30 (d, J = 2.4 Hz, 1H), 6.79 - 6.84 (m, 1H), 1.73 (s, 9H).

[0280] Synthesis of 4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichloroaniline (37g) 1-(tert-butyl)-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (37f) (54 mg, 142.02 μmol) was dissolved in EtOH (3 mL) and H2O (1 mL) at 25 °C, to which Fe (39.66 mg, 710.11 μmol) and NH4Cl (37.98 mg, 710.11 μmol) were added. The mixture was then stirred at 80 °C for 1 hour. TLC and LCMS showed that 37f was completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL × 3). The combined filtrate was extracted with ethyl acetate (15 mL × 2) and H2O (5 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 37 g. The solid was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 17 H 17 Cl2N3O), m / z 350.07, LCMS measured value m / z 350.1; 1 H NMR (400 MHz, CD3OD) δ 8.12 - 8.23 ​​(m, 1H), 6.74 - 6.81 (m, 1H), 7.51 - 7.68 (m, 4H), 5.49 (s, 2H), 1.63 - 1.74 (m, 9H).

[0281] Synthesis of N-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 37) 4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichloroaniline (37 g) (20 mg, 57.10 μmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (25.44 mg, 171.31 μmol) were dissolved in CH2Cl2 (3 mL) and TEA (17.33 mg, 171.31 μmol, 23.84 μL) was added at 25°C. The mixture was then stirred at 25°C for 30 minutes. LC-MS showed that 37 g had been completely consumed, and the desired MS was detected. The mixture was quenched with MeOH (5 mL x 3) and stirred at 25°C for 5 minutes. The mixture was then concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Phenomenex Luna C18 200×40mm×10μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 37. MSmas calculation value: [M+1] + (C 20 H 17 Cl2N5O4), m / z 462.0, LCMS measured value m / z 462.0; 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.24 (s, 1H), 8.07 - 8.15 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 8.8, 2.45 Hz, 1H), 1.64 (s, 9H).

[0282] Example 38 2-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-(2-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate (38a) 4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichloroaniline (37 g) (20 mg, 57.10 μmol) and ethyl N-(2-cyanoacetyl)carbamate (9.81 mg, 62.81 μmol) were mixed in CH3CN (2 mL) and t-BuONO (17.67 mg, 171.31 μmol, 20.38 μL) was added at 0°C. The mixture was then stirred at 0°C for 1 hour. LC-MS showed that 37 g had been completely consumed and the desired MS was detected. The mixture was quenched with MeOH (15 mL) and stirred at 25°C for 5 minutes. The mixture was then concentrated under vacuum to obtain 38a. The solid was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 23 H 22 Cl2N6O4), m / z 517.1, LCMS measured value m / z 517.1.

[0283] Synthesis of 2-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 38) (E)-ethyl(2-(2-(4-((1-(tert-butyl)-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate (38a) (28 mg, 54.12 μmol) was dissolved in DMA (2 mL) and KOAc (10.62 mg, 108.24 μmol) was added. The mixture was stirred at 115 °C for 3 hours. LC-MS and HPLC showed that 38a was completely consumed and the desired MS was detected. The mixture was then concentrated under vacuum to obtain the residue. The residue was purified by Prep-HPLC ((FA), column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 38. MSmas calculation value: [M+1] + (C 21 H 16 Cl2N6O3), m / z 471.0, LCMS measured value m / z 470.9; 1 HNMR (400 MHz, DMSO-d6) δ8.19 - 8.31 (m, 1H), 7.78 - 7.91 (m, 2H), 7.56 - 7.68 (m, 1H), 7.27 - 7.40 (m, 1H), 6.61 - 6.76 (m, 1H), 1.59 - 1.71 (m, 9H).

[0284] Example 39 N-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 3-((5-bromo-2-nitrophenyl)amino)propan-1-ol (39a) To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) in DMF (10 mL), 3-aminopropan-1-ol (1.02 g, 13.64 mmol, 1.05 mL) was added under nitrogen at 25°C. The mixture was stirred under nitrogen at 25°C for 3 hours. LC-MS showed that the starting material had been completely consumed, and the desired MS was detected. The mixture was extracted with ethyl acetate (20 mL x 2) and H2O (5 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 39a. MSmas calculation value: [M+1] + (C9H 11 BrN2O3), m / z 275.0, LCMS measured value m / z 275.0; 1 H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 9.0, 2.0 Hz, 1H), 3.86 (t, J = 5.8 Hz, 2H), 3.42 - 3.49 (m, 2H), 2.00 (quin, J = 6.2 Hz, 2H).

[0285] Synthesis of 3-((2-amino-5-bromophenyl)amino)propan-1-ol (39b) A solution of 3-(5-bromo-2-nitro-anilino)propan-1-ol (39a) (900 mg, 3.27 mmol) in EtOH (10 mL) was added to a solution of Na2S2O4 (4.56 g, 26.17 mmol) in H2O (8 mL). The mixture was stirred at 25°C for 16 hours. LC-MS showed that 39a had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was concentrated under vacuum. The residue was extracted with ethyl acetate (25 mL x 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 39b. MSmas calculation value: [M+1] + (C9H 13 BrN2O), m / z 245.0, LCMS measured value m / z 245.1; 1 H NMR (400 MHz, CD3OD) δ 6.53 - 6.70 (m, 3H), 3.71 (t, J = 6.2 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 1.88 (quin, J = 6.6 Hz, 2H).

[0286] Synthesis of 6-bromo-1-(3-hydroxypropyl)-1H-benzo[d]imidazole-2(3H)-thion(39c) Di(imidazole-1-yl)methanethion (604.91 mg, 3.39 mmol) was added to a solution of 3-(2-amino-5-bromoanilino)propan-1-ol (39b) (640 mg, 2.61 mmol) in THF (5 mL) under N2 at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS and TLC showed that 39b was completely consumed, and the desired MS was detected. The mixture was extracted with ethyl acetate (25 mL x 2) and aqueous NH4Cl solution (15 mL). The combined organic phases were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 39c. MSmas calculation value: [M+1] + (C 10 H 11 BrN2OS), m / z 287.0, LCMS measured value m / z 287.0; 1 H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 8.4, 1.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.84 (s, 20H), 4.36 (t, J = 7.0 Hz, 2H), 3.59 (t, J = 6.0 Hz, 2H), 1.95 - 2.05 (m, 2H).

[0287] Synthesis of 3-(6-bromo-2-(methylthio)-1H-benzo[d]imidazole-1-yl)propan-1-ol (39d) 5-bromo-3-(3-hydroxypropyl)-1H-benzimidazole-2-thion (39c) (200 mg, 696.44 μmol) was dissolved in CH3CN (3 mL) and MeI (118.62 mg, 835.73 μmol, 52.03 μL) was added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS showed that 39c had been completely consumed and the desired MS 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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 39d. MSmas calculation value: [M+1] + (C 11 H 13 BrN2OS), m / z 301.0, LCMS measured value m / z 301.0; 1 H NMR (400 MHz, CD3OD) δ 7.70 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.6, 1.8 Hz, 1H), 4.86 (s, 39H), 4.25 (t, J = 7.2 Hz, 2H), 3.59 (t, J = 6.0 Hz, 2H), 2.76 (s, 3H), 1.99 (quin, J = 6.6 Hz, 2H).

[0288] Synthesis of 7-bromo-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine(39e) A solution of 3-(6-bromo-2-methylsulfanyl-benzimidazole-1-yl)propan-1-ol (39d) (193 mg, 640.77 μmol) in THF (5 mL) was degassed and purged three times with O2. NaH (51.26 mg, 1.28 mmol, 60% purity) was added at 0°C. The mixture was stirred under O2 at 0-25°C for 16 hours. LC-MS and TLC showed that 39d was completely consumed, and the desired MS was detected. The mixture was quenched with NH4Cl (20 mL), extracted with ethyl acetate (15 mL x 3), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 39e. MSmas calculation value: [M+1] + (C 10 H9BrN2O), m / z 253.0, LCMS measured value m / z 252.9; 1 H NMR (400 MHz, CD3OD) δ 7.50 (s, 1H), 7.28 (s, 2H), 4.55 - 4.61 (m, 2H), 4.14 (t, J = 6.0 Hz, 2H), 2.34 (quin, J = 5.6 Hz, 2H).

[0289] Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine(39f) To a solution of 7-bromo-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine (39e) (100 mg, 395.11 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (301.00 mg, 1.19 mmol) in dioxane (6 mL), KOAc (387.76 mg, 3.95 mmol) and Pd(PPh3)2Cl2 (27.73 mg, 39.51 μmol) were added under N2 at 20°C. The mixture was stirred at 90°C for 4 hours. LC-MS showed that 39e was completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with ethyl acetate (5 mL x 3). The combined filtrate was concentrated under vacuum. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 39f. MSmas calculation value: [M+1] + (C 16 H 21 BN2O3), m / z 301.2, LCMS measured value m / z 301.1.

[0290] Synthesis of 3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-ol (39g) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine (39f) (50 mg, 166.58 μmol) was added to a mixture of H2O (1 mL) and CH3CN (2 mL) under N2, with ammonium carbonate (13.17 mg, 166.58 μmol, 13.72 μL) and H2O2 (37.77 mg, 333.16 μmol, 32.01 μL, 30% purity). The mixture was stirred at 20°C for 1 hour. LC-MS showed that 39f was completely consumed, and the desired MS was detected. The residue was poured into NaHSO3 (20 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 39 g. The product was used in the next step without further purification. MSmas calculation value: [M+1] + (C 10 H 10 N2O2), m / z 191.2, LCMS measured value m / z 191.2.

[0291] Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine (39h) 3,4-Dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-ol (39g) (30mg, 157.73μmol) and 1,3-Dichloro-2-fluoro-5-nitrobenzene (36.43mg, 173.50μmol) are dissolved in DMF (2mL) with K2CO2. 3(32.70 mg (236.60 μmol) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 16 hours. LC-MS showed that 39 g was completely consumed, and the desired MS 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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 39h. MSmas calculation value: [M+1] + (C 16 H 11 Cl2N3O4), m / z 380.0, LCMS measured value m / z 380.1; 1 H NMR (400 MHz, CD3OD) δ 8.44 (s, 2H), 7.30 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.6, 2.6 Hz, 1H), 4.55 (dd, J = 10.8, 5.6 Hz, 3H), 4.08 (t, J = 6.2 Hz, 2H), 2.26 - 2.35 (m, 2H).

[0292] Synthesis of 3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxyaniline (39i) 7-(2,6-dichloro-4-nitro-phenoxy)-3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole (39h) (55 mg, 144.67 μmol) was dissolved in EtOH (2 mL) and H2O (0.5 mL), to which Fe (40.40 mg, 723.34 μmol) and NH4Cl (38.69 mg, 723.34 μmol) were added. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 39h had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (5 mL x 3). The combined filtrate was extracted with ethyl acetate (15 mL x 2) and H2O (5 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 39i. The product was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 16 H 13 Cl2N3O2), m / z 350.0, LCMS measured value m / z 350.1; 1 H NMR (400 MHz, CD3OD) δ 7.28 (br d, J = 9.2 Hz, 1H), 6.75 (s, 2H), 6.67 - 6.71 (m, 2H), 4.51 - 4.57 (m, 2H), 4.06 (t, J = 6.2 Hz, 2H), 2.31 (dt, J = 11.0, 5.8 Hz, 2H), 1.96 - 2.07 (m, 1H).

[0293] Synthesis of N-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 39) To a solution of 3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)aniline (39i) (15 mg, 42.83 μmol) in DCM (2 mL), TEA (13.00 mg, 128.50 μmol, 17.89 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (9.54 mg, 64.25 μmol) were added. The mixture was stirred at 25°C for 0.5 hours. The mixture was quenched with MeOH (5 mL) and stirred at 25°C for 10 minutes. The mixture was then concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 39. MSmas calculation value: [M+1] + (C 19 H 13 Cl2N5O5), m / z 462.0, LCMS measured value m / z 461.9; 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (br s, 1H), 8.02 - 8.12 (m, 2H), 7.27 (br d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 6.60 (br d, J = 8.6 Hz, 1H), 4.49 (br d, J = 4.2 Hz, 2H), 4.01 - 4.08 (m, 2H), 2.21 (br d, J = 4.8 Hz, 2H).

[0294] Example 40 2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate (40a) 3,5-Dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)aniline (39i) (15 mg, 42.83 μmol) and ethyl N-(2-cyanoacetyl)carbamate (7.36 mg, 47.12 μmol) were mixed in CH3CN (2 mL) and t-BuONO (8.83 mg, 85.67 μmol, 10.19 μL) was added at 0°C. The mixture was then stirred at 0°C for 1 hour. LC-MS indicated that the reaction was complete and the desired MS was detected. The mixture was quenched with MeOH (5 mL) and stirred for 5 minutes. The mixture was then concentrated under vacuum to obtain 40a. The product was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 22 H 18 Cl2N6O5), m / z 517.1, LCMS measured value m / z 517.1.

[0295] Synthesis of 2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrili (Example 40) (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate (40a) (20 mg, 38.66 μmol) was dissolved in DMA (2 mL) and KOAc (7.59 mg, 77.32 μmol) was added. The mixture was stirred at 115 °C for 3 hours. LC-MS indicated that the reaction was complete and the desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 40. MSmas calculation value: [M+1] + (C 20 H 12 Cl2N6O4), m / z 471.0, LCMS measured value m / z 470.9; 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 2H), 7.29 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.6, 2.52 Hz, 1H), 4.46 - 4.52 (m, 2H), 4.06 (t, J = 6.0 Hz, 2H), 2.17 - 2.24 (m, 2H).

[0296] Example 41 N-(4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 6-bromo-1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazole (41a) To a solution of 5-bromo-N1-(tert-butyl)benzene-1,2-diamine (37b) (1 g, 4.11 mmol) in HOAc (5 mL), C(OCH3)4 (2.24 g, 16.45 mmol) was added. The mixture was stirred at 50 °C for 16 hours. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was quenched at 20 °C by adding aqueous NaHCO3 solution (50 mL), and then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (15 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 obtain 41a. MSmas calculation value: [M+1] + (C 12 H 15 BrN2O), m / z 283.0, LCMS measured value m / z 283.0.

[0297] Synthesis of 1-(tert-butyl)-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (41b) 6-Bromo-1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazole (41a) (700 mg, 2.47 mmol), KOAc (1.21 g, 12.36 mmol), BPD (1.88 g, 7.42 mmol), and Pd(PPh3)2Cl 2( A mixture of 173.51 mg (247.21 μmol) of dioxane (3 mL) was degassed, purged three times with N2, and then stirred at 110°C for 16 hours under an N2 atmosphere. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the dioxane. The residue was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (15 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 obtain 41b. MSmas calculation value: [M+1] + (C 18 H27 BN2O3), m / z 331.2, LCMS measured value m / z 331.2; 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.59 - 7.64 (m, 1H), 7.51 - 7.55 (m, 1H), 4.19 (s, 3H), 1.79 - 1.83 (m, 9H), 1.36 (s, 12H).

[0298] Synthesis of 1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazole-6-ol (41c) To a solution of 1-(tert-butyl)-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (41b) (440 mg, 1.33 mmol) in ACN (10 mL), a solution of NH4HCO3 (105.34 mg, 1.33 mmol, 109.73 μL) in H2O (5 mL) was added at 20°C. Then, H2O2 (302.10 mg, 2.66 mmol, 256.02 μL, 30% purity) was added dropwise at 20°C. The resulting mixture was stirred at 20°C for 1 hour. TLC showed that 41b had been completely consumed and a new spot had formed. The mixture was poured into a saturated NaHSO3 solution (10 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 41c. MSmas calculation value: [M+1] + (C 12 H 16 N2O2), m / z 221.1, LCMS measured value m / z 221.1.

[0299] Synthesis of 1-(tert-butyl)-6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1H-benzo[d]imidazole (41d) To a solution of 1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazol-6-ol (41c) (340 mg, 1.54 mmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (356.55 mg, 1.70 mmol) in DMF (20 mL) was added K2CO3 (320.01 mg, 2.32 mmol). The mixture was stirred at 20°C for 1 hour. TLC indicated that 41c was completely consumed, and one new spot was formed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 41d. MS calculated mass: [M+1] + (C 18 H 17 Cl2N3O4), m / z 410.0, found LCMS m / z 410.0; 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 2.4, 8.6 Hz, 1H), 4.16 (s, 3H), 1.75 (s, 9H).

[0300] Synthesis of 4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichloroaniline (41e) To a solution of 1-(tert-butyl)-6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1H-benzo[d]imidazole (41d) (200 mg, 487.51 μmol) in EtOH (10 mL), Fe (136.12 mg, 2.44 mmol) was added, and then a solution of NH4Cl (130.39 mg, 2.44 mmol) in H2O (4 mL) was added dropwise to the mixture. The mixture was stirred at 80°C for 1 hour. TLC and LCMS showed that 41d had been completely consumed and a new spot had formed. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate) to obtain 41e. MSmas calculation value: [M+1] + (C 18 H 19 Cl2N3O2), m / z 380.1, LCMS measured value m / z 380.0.

[0301] Synthesis of N-(4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazole-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 41) A mixture of 4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichloroaniline (41e) (30 mg, 78.89 μmol), 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (58.58 mg, 394.46 μmol), and TEA (39.92 mg, 394.46 μmol, 54.90 μL) in THF (3 mL) was degassed and purged 3 times with N2. Then the mixture was stirred at 20°C for 1 hour under N2 atmosphere. TLC and LCMS indicated the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]) to give Example 41. MS calculated mass: [M+1] + (C 21 H 19 Cl2N5O5), m / z 492.10, LCMS found m / z 492.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.87 - 10.95 (m, 1H), 8.06 - 8.12 (m, 2H), 7.25 - 7.31 (m, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 2.3, 8.7 Hz, 1H), 4.05 (s, 3H), 1.66 (s, 9H).

[0302] Example 42 N-(4-((3-(tert-butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Formula

[0303] Example 43 N-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 5-bromo-N-(1-methylcyclopropyl)-2-nitroaniline (43a) A mixture of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol), 1-methylcyclopropanamine (978.03 mg, 9.09 mmol, HCl), and DIPEA (2.35 g, 18.18 mmol, 3.17 mL) in CH3CN (10 mL) was degassed, purged three times with N2, and then the mixture was stirred at 50°C for 3 hours under an N2 atmosphere. TLC showed that the reaction was complete and a new spot had formed. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (20 mL), washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 43a. MS mass calculation value: [M+H] + (C 10 H 11 Br2N2O2), m / z, 271.0, LCMS measured value m / z 271.0; 1 H NMR (400 MHz, CDCl3) δ 8.27 (br s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 9.0, 2.08 Hz, 1H), 1.46 (s, 3H), 0.90 (d, J = 4.8 Hz, 2H), 0.82 - 0.87 (m, 2H).

[0304] Synthesis of 5-bromo-N1-(1-methylcyclopropyl)benzene-1,2-diamine (43b) To a solution of 5-bromo-N-(1-methylcyclopropyl)-2-nitroaniline (43a) (1 g, 3.69 mmol) and Fe (1.03 g, 18.44 mmol) in H2O (4 mL) and MeOH (20 mL), Fe (1.03 g, 18.44 mmol) and NH4Cl (986.52 mg, 18.44 mmol) were added, and the mixture was stirred at 80°C for 1 hour under an N2 atmosphere. TLC showed that the reaction was complete. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 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 obtain 43b. 1 H NMR (400 MHz, CD3OD) 6.98 (d, J = 2.0 Hz, 1H), 6.54 - 6.62 (m, 2H), 1.36 (s, 3H), 0.74 - 0.77 (m, 2H), 0.65 - 0.69 (m, 2H).

[0305] Synthesis of 6-bromo-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (43c) A mixture of 4-bromo-N2-(1-methylcyclopropyl)benzene-1,2-diamine (43b) (250 mg, 1.04 mmol) and HC(OMe)3 (10 mL) was degassed, purged three times with N2, and then stirred at 100°C for 1 hour under an N2 atmosphere. TLC showed that the reaction was complete and a new spot had formed. The reaction mixture was concentrated under reduced pressure to obtain 43c. MS mass calculation value: [M+H] + (C 12 H 13 BrN2), m / z, 251.0, LCMS measured value m / z 251.0.

[0306] Synthesis of 1-(1-methylcyclopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (43d) A mixture of 6-bromo-1-(1-methylcyclopropyl)benzimidazole (43c) (260 mg, 1.04 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (394.37 mg, 1.55 mmol), KOAc (304.84 mg, 3.11 mmol), and Pd(PPh3)2Cl2 (72.67 mg, 103.54 μmol) in 20 mL of dioxane was degassed, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. TLC showed that the reaction was complete and a new spot had formed. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 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 obtain 43d. MS mass calculation value: [M+H] + (C 17 H 23 BN2O2), m / z, 299.1, LCMS measured value m / z 299.1.

[0307] Synthesis of 1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-ol (43e) 1-(1-methylcyclopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (43d) (300 mg, 1.01 mmol) and NH4HCO3 (79.54 mg, 1.01 mmol) were mixed with CH3CN (20 mL) and H2O (10 mL) to which H2O2 (228.14 mg, 2.01 mmol, 193.34 μL, 30% purity) was added. The mixture was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 1 hour. LCMS indicated that the reaction was complete, and the desired MS was detected. The reaction mixture was quenched at 0°C by adding Na2SO3 solution (20 mL), then diluted with H2O (20 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 43e. MS mass calculation value: [M+H] + (C 11 H 12 N2O), m / z, 189.1, LCMS measured value m / z 189.1.

[0308] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (43f) A mixture of 1-(1-methylcyclopropyl)benzimidazole-5-ol (43e) (240 mg, 1.28 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (294.53 mg, 1.40 mmol), and K2CO3 (352.44 mg, 2.55 mmol) in DMF (10 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 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 obtain 43f. MS mass calculation value: [M+H] + (C 17H 13 Cl2N3O3), m / z, 378.0, LCMS measured value m / z 378.0; 1 H NMR (400 MHz, CDCl3) 8.35 (s, 2H), 7.95 (s, 1H), 7.95 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.73 (dd, J = 8.8, 2.4 Hz, 1H), 1.59 (s, 3H), 1.17 - 1.22 (m, 2H), 1.01 - 1.05 (m, 2H).

[0309] Synthesis of 3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxyaniline (43g) A mixture of 6-(2,6-dichloro-4-nitro-phenoxy)-1-(1-methylcyclopropyl)benzimidazole (43f) (150 mg, 396.61 μmol), Fe (110.74 mg, 1.98 mmol), and NH4Cl (106.07 mg, 1.98 mmol) in EtOH (10 mL) and H2O (2 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 80°C for 1 hour. TLC showed that the reaction was complete and one major new spot had formed. The reaction mixture was filtered, then diluted with H2O (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 43 g. 1 H NMR (400 MHz, CDCl3) 7.95 (br s, 1H), 7.67 (br d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.8, 2.2 Hz, 1H), 6.73 (s, 2H), 1.58 (s, 3H), 1.16 - 1.22 (m, 2H), 0.98 - 1.04 (m, 2H).

[0310] Synthesis of N-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 43) 3,5-Dichloro-4-[3-(1-methylcyclopropyl)benzimidazole-5-yl]oxyaniline (43 g) (10 mg, 28.72 μmol) and TEA (8.72 mg, 86.15 μmol, 11.99 μL) were mixed with THF (2 mL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (8.53 mg, 57.43 μmol) was added, and the mixture was stirred at 25°C for 0.1 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions: column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 43. MS mass calculation value: [M+H] + (C 20 H 15 Cl2N5O4), m / z, 460.1, LCMS measured value m / z 460.1; 1 H NMR (400 MHz, CD3OD) 8.27 (br s, 1H), 7.99 (s, 2H), 7.04 (br s, 1H), 6.86 (br dd, J = 8.8, 2.4 Hz, 1H), 3.30 (dt, J = 3.4, 1.6 Hz, 1H), 1.56 (s, 3H), 1.19 (s, 2H), 1.06 (s, 2H).

[0311] Example 44 2-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (44a) 3,5-Dichloro-4-[3-(1-methylcyclopropyl)benzimidazole-5-yl]oxyaniline (43 g) (30 mg, 86.15 μmol) was added to a solution of HOAc (5 mL) and H2O (2 mL) at 0°C with ethyl N-(2-cyanoacetyl)carbamate (15.47 mg, 99.07 μmol) and HCl (12 M, 1.79 μL). After 10 minutes, a solution of NaNO2 (7.73 mg, 112.00 μmol) in H2O (2 mL) was added, and the mixture was stirred at 0°C under an N2 atmosphere for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 44a. MS mass calculation value: [M+H] + (C 23 H 20 Cl2N6O4), m / z, 515.1, LCMS measured value m / z 515.1.

[0312] Synthesis of 2-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 44) A mixture of ethyl N-[(2E)-2-cyano-2-[[3,5-dichloro-4-[3-(1-methylcyclopropyl)benzimidazole-5-yl]oxyphenyl]hydrazono]acetyl]carbamate (44a) (36 mg, 69.86 μmol) and KOAc (13.71 mg, 139.71 μmol) in DMA (3 mL) was degassed, purged three times with N2, and then stirred at 115°C for 3 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (FA conditions: column: Phenomenex Luna C18 200 × 40 mm × 10 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 44. MS mass calculation value: [M+H] + (C 21 H 14 Cl2N6O3), m / z, 469.1, LCMS measured value m / z 469.1. 1 H NMR (400 MHz, CD3OD) 8.21 (s, 1H), 7.82 (s, 2H), 7.61 (br d, J = 8.8 Hz, 1H), 7.10 (br d, J = 2.2 Hz, 1H), 6.86 (br dd, J = 8.8, 2.4 Hz, 1H), 4.59 (br s, 1H), 1.57 (s, 3H), 1.17 - 1.23 (m, 2H), 1.07 (br t, J = 6.0 Hz, 2H).

[0313] Example 45 N-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 6-bromo-2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (45a) To a solution of 5-bromo-N1-(1-methylcyclopropyl)benzene-1,2-diamine (43b) (200 mg, 829.44 μmol) in AcOH (5 mL), tetramethoxymethane (225.85 mg, 1.66 mmol) was added. The mixture was stirred at 50°C for 1 hour. LC-MS and TLC showed that 43b had been completely consumed, and a new spot had formed. The reaction mixture was concentrated under reduced pressure to remove the AcOH. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 45a. MSmas calculation value: [M+1] + (C 12 H 13 BrN2O), m / z 281.0, LCMS measured value m / z 281.0; 1 HNMR (400 MHz, CD3OD) δ 1.01 - 1.19 (m, 4H), 1.45 - 1.50 (m, 3H), 4.15 - 4.19 (m, 3H), 7.24 - 7.33 (m, 2H), 7.53 - 7.58 (m, 1H).

[0314] Synthesis of 2-methoxy-1-(1-methylcyclopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (45b) To a solution of 6-bromo-2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (45a) (210 mg, 746.94 μmol) and BPD (569.03 mg, 2.24 mmol) in dioxane (5 mL), Pd(PPh3)2Cl2 (52.43 mg, 74.69 μmol) and KOAc (733.06 mg, 7.47 mmol) were added under N2 at 20°C. The mixture was stirred at 90°C for 4 hours. TLC and LCMS showed that 45a was completely consumed and the desired MS 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 diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 45b. MSmas calculation value: [M+1] + (C 18 H 25 BN2O3), m / z 329.2, LCMS measured value m / z 329.1; 1 HNMR (400 MHz, CD3OD) δ 1.05 - 1.11 (m, 2H), 1.17 - 1.22 (m, 13H), 1.23 - 1.26 (m, 2H), 1.35 - 1.40 (m, 14H), 1.48 - 1.52 (m, 4H), 4.19 (s, 3H), 4.76 - 4.94 (m, 1H), 7.39 - 7.43 (m, 1H), 7.42 (s, 1H), 7.55 - 7.59 (m, 1H), 7.80 - 7.82 (m, 1H).

[0315] Synthesis of 2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-ol (45c) 2-Methoxy-1-(1-methylcyclopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (45b) (205 mg, 624.59 μmol) was added to a mixture of H2O (1.5 mL) and CH3CN (3 mL) under N2, with ammonium carbonate (49.38 mg, 624.59 μmol, 51.43 μL) and H2O2 (141.62 mg, 1.25 mmol, 120.01 μL, 30% purity). The mixture was stirred at 20°C for 1 hour. LC-MS showed that 45b had been completely consumed, and the desired MS was detected. The residue was poured into NaHSO3 solution (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 45c. The crude product was used in the next step without further purification. MSmas calculation value: [M+1] + (C 12 H 14 N2O2), m / z 219.1, LCMS measured value m / z 219.0; 1 HNMR (400 MHz, CD3OD) δ 7.20 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.6, 2.32 Hz, 1H), 4.12 (s, 3H), 1.46 (s, 3H), 1.11 - 1.17 (m, 3H), 0.98 - 1.04 (m, 2H).

[0316] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (45d) To a solution of 2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-ol (45c) (170 mg, 778.92 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (179.92 mg, 856.81 μmol) in DMF (3 mL), K2CO3 (161.48 mg, 1.17 mmol) was added under N2 at 20°C. The mixture was stirred at 20°C for 1 hour. TLC and LCMS showed that 45c was completely consumed, and the desired MS was detected. The mixture was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using Prep-TLC (petroleum ether: ethyl acetate) to obtain 45d. MSmas calculation value: [M+1] + (C 18 H 15 Cl2N3O4), m / z 408.0, LCMS measured value m / z 408.0; 1 HNMR (400 MHz, CD3OD) δ 8.44 - 8.46 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 8.6, 2.6 Hz, 1H), 4.15 - 4.18 (m, 2H), 2.98 - 3.00 (m, 1H), 2.85 - 2.87 (m, 1H), 1.44 - 1.47 (m, 2H), 1.19 - 1.21 (m, 3H).

[0317] Synthesis of 3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxyaniline (45e) 6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (45d) (170 mg, 416.43 μmol) was dissolved in EtOH (5 mL) and H2O (1 mL) at 25 °C, to which Fe (116.29 mg, 2.08 mmol) and NH4Cl (111.37 mg, 2.08 mmol) were added. The mixture was then stirred at 80 °C for 1 hour. LC-MS showed that 45d had been completely consumed, and the desired MS was detected. The suspension was filtered through a Celite pad, and the pad cake was washed with EtOH (10 mL x 3). The combined filtrate was extracted with ethyl acetate (30 mL x 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 45e. The solid was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 18 H 17 Cl2N3O2), m / z 378.1, LCMS measured value m / z 378.1; 1 HNMR (400 MHz, CD3OD) δ 7.26 - 7.30 (m, 1H), 6.74 - 6.81 (m, 2H), 4.06 - 4.17 (m, 3H), 1.43 (s, 3H), 1.24 (s, 1H), 1.05 - 1.13 (m, 2H), 0.93 - 1.00 (m, 2H).

[0318] Synthesis of N-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 45) 3,5-Dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)aniline (45e) (40 mg, 105.75 μmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (47.11 mg, 317.25 μmol) were dissolved in THF (4 mL) and TEA (32.10 mg, 317.25 μmol, 44.16 μL) was added at 25°C. The mixture was then stirred at 25°C for 0.5 hours. LC-MS showed that 45e had been completely consumed and the desired MS was detected. The mixture was quenched with MeOH (5 mL x 3) and stirred at 25°C for 5 minutes. The mixture was then concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]). The resulting solution was diluted with NaHCO3 (5 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain Example 45. MSmas calculation value: [M+1] + (C 21 H 17 Cl2N5O5), m / z 490.1, LCMS measured value m / z 489.9; 1 HNMR (400 MHz, DMSO-d6) δ10.45 - 10.55 (m, 1H), 8.11 - 8.23 ​​(m, 2H), 7.23 - 7.34 (m, 1H), 6.82 - 6.96 (m, 1H), 6.45 - 6.55 (m, 1H), 4.05 - 4.11 (m, 3H), 1.38 (s, 3H), 0.94 - 1.09 (m, 4H).

[0319] Example 46 2-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka] Synthesis of (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (46a) 3,5-Dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)aniline (45e) (10 mg, 26.44 μmol) and ethyl N-(2-cyanoacetyl)carbamate (12.38 mg, 79.31 μmol) were mixed in CH3CN (1 mL) and t-BuONO (8.18 mg, 79.31 μmol, 9.43 μL) was added at 0°C. The mixture was then stirred at 0°C for 1 hour. LC-MS showed that 45e had been completely consumed and the desired MS was detected. The mixture was quenched with MeOH (15 mL) and concentrated under reduced pressure to obtain 46a. The solid was used directly in the next step without further purification. MSmas calculation value: [M+1] + (C 24 H 22 Cl2N6O5), m / z 545.1, LCMS measured value m / z 545.1.

[0320] Synthesis of 2-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 46) To a solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (46a) (14 mg, 25.67 μmol) in DMA (2 mL) was added KOAc (5.04 mg, 51.34 μmol). The mixture was stirred at 115°C for 3 hours. LCMS indicated complete consumption of 46a, and the desired MS signal was detected. The mixture was diluted with MeOH (15 mL), concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC ((FA), column: Xtimate C18 100×30 mm×3 μm; mobile phase: [water (0.2% FA)-ACN]). The obtained solution was diluted with NaHCO3 (5 mL), and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (5 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give Example 46. MS calculated mass: [M+1] + (C 22 H 16 Cl2N6O4), m / z 499.1, LCMS found m / z 498.9; 1 HNMR (400 MHz, DMSO-d6) δ 7.80 - 7.86 (m, 2H), 7.30 (d, J = 8.6 Hz, 1H), 6.94 - 6.99 (m, 1H), 6.46 - 6.53 (m, 1H), 4.05 - 4.13 (m, 3H), 1.40 (s, 3H), 1.03 - 1.08 (m, 2H), 0.98 - 1.02 (m, 2H).

[0321] Example 47 N-(3,5-dichloro-4-((3-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [Chemical Formula] Synthesis of N-(3,5-dichloro-4-((3-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 47) 3,5-Dichloro-4-((2-Methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole-6-yl)oxy)aniline (45e) (30 mg, 79.31 μmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (35.33 mg, 237.94 μmol) were dissolved in THF (3 mL) and TEA (24.08 mg, 237.94 μmol, 33.12 μL) at 25°C. The mixture was then stirred at 25°C for 0.5 hours. LC-MS showed that 45e had been completely consumed and the desired MS was detected. The mixture was quenched with MeOH (15 mL) and stirred at 25°C for 5 minutes. The mixture was then concentrated under vacuum to obtain the residue. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 47. MSmas calculation value: [M+1] + (C 20 H 15 Cl2N5O5), m / z 476.0, LCMS measured value m / z 475.9; 1 HNMR (400 MHz, DMSO-d6) δ11.24 - 11.34 (m, 1H), 10.59 - 10.68 (m, 1H), 8.05 (s, 2H), 6.78 - 6.85 (m, 2H), 6.27 (dd, J = 8.50, 2.51 Hz, 1H), 1.35 (s, 3H), 0.88 - 0.98 (m, 4H).

[0322] Exampl...

Claims

1. Equation (I): 【Chemistry 1】 (I) [In the formula, A is, 【Chemistry 2】 And; 【Transformation 3】 is a five-membered heterocyclyl or a five- to six-membered heteroaryl, where each may optionally contain one or two additional ring heteroatoms selected from the group consisting of N and O. Here, each heteroatom of the heterocyclyl or heteroaryl is given one R if necessary to satisfy the valence of the heteroatom. １ It binds to the group, and, Here, each carbon atom of the heterocyclyl or heteroaryl is one R if necessary to satisfy the valence of the carbon atom. ２ It bonds with the group, provided that the R required to satisfy the valence of each carbon atom ２ There is only one base; Z １ Z ２ , and Z ３ These are independently N or CH; Y is either N or C; each R １ is independently H, C １ - C ６ alkyl, or C ３ - C ６ cycloalkyl, Here, each C １ -C ６ Alkyl or C ３ -C ６ Cycloalkyl groups may have 1 to 5 R groups. ３ It is also acceptable if it is substituted with the base; Each R ２ H and C are independent of each other. １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, -O(C １ -C ６ Alkyl), -O (C ３ -C ６ It is a cycloalkyl, hydroxyl, or oxo compound. Here, each C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, -O(C １ -C ６ Alkyl), or -O (C ３ -C ６ The cycloalkyl group may have 1 to 5 R groups. ３ It is also acceptable if it is substituted with the base; Or, R １ and R ２ They combine to form a 5-6 member heteroaryl or a 5-7 member heterocycline; Or, two R's ２ The bases combine to form a 5-6 member heteroaryl, a 5-7 member heterocyclyl, and C ５ -C ７ Cycloalkyl, or C ６ Form an aryl; and, Each R ３ These are, independently, halogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Haloalkyl, C １ -C ６ alkyl-OH, -NH ２ It is -CN or hydroxyl; However, the compound in question does not contain any of the compounds listed below, their tautomers, or their pharmaceutically acceptable salts. 【Transformation 3】 ］ The compound represented by , its tautomer, or pharmaceutically acceptable salt thereof.

2. the below described: 【Chemistry 4】 However, it may in some cases be a 5-6 membered heteroaryl compound that contains one or two additional ring heteroatoms selected from the group consisting of N and O. Here, each heteroatom of the above heteroaryl group has one R if necessary to satisfy the valence of the heteroatom. １ It binds to the group, and, Here, each carbon atom of the heteroaryl complex has one R if necessary to satisfy the valence of the carbon atom. ２ It bonds with the group, provided that the R required to satisfy the valence of each carbon atom ２ There is only one base. The compound according to claim 1, its tautomer, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is C.

4. the below described: 【Transformation 5】 but, 【Transformation 6】 The compound according to claim 3, its tautomer, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is N.

6. the below described: 【Transformation 7】 but, 【Transformation 8】 The compound according to claim 5, its tautomer, or a pharmaceutically acceptable salt thereof.

7. the below described: 【Chemistry 9】 However, it may, in some cases, contain one or two additional ring heteroatoms selected from the group consisting of N and O, and is a five-membered heterocycline. Here, each heteroatom in the above heterocycline has one R if necessary to satisfy the valence of the heteroatom. １ It binds to the group, and Here, each carbon atom of the heterocycline has one R if necessary to satisfy the valence of the carbon atom. ２ It bonds with the group, provided that the R required to satisfy the valence of each carbon atom ２ There is only one base. The compound according to claim 1, its tautomer, or a pharmaceutically acceptable salt thereof.

8. the below described: 【Chemistry 10】 but, 【Chemistry 11】 The compound according to claim 7, its tautomer, or a pharmaceutically acceptable salt thereof.

9. Z １ The compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is CH.

10. Z １ The compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein N is present.

11. Z ２ The compound according to any one of claims 1 to 10, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is CH.

12. Z ２ The compound according to any one of claims 1 to 10, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein N is present.

13. Z ３ The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is CH.

14. Z ３ The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein N is present.

15. Z １ Z ２ , and Z ３ The compounds described in any one of claims 1 to 8, their tautomers, or pharmaceutically acceptable salts thereof, wherein each is CH.

16. Z １ However, N is; and, Z ２ and Z ３ However, each of them is CH, A compound according to any one of claims 1 to 8, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. Z ２ However, N is; and, Z １ and Z ３ However, each of them is CH, A compound according to any one of claims 1 to 8, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

18. Each R １ However, independently, H and C １ -C ３ Alkyl, or C ３ -C ５ It is a cycloalkyl, Here, each C １ -C ３ Alkyl or C ３ -C ５ The cycloalkyl group may have 1 to 3 R ３ It may be substituted with the base, A compound according to any one of claims 1 to 17, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

19. Each R １ However, independently, H, cyclopropyl, -CH ３ , -CH(CH ３ ) ２ t-butyl, -CH ２ CH ３ , 【Chemistry 12】 The compound according to claim 18, its tautomer, or a pharmaceutically acceptable salt thereof.

20. each R ２ is independently H, C １ -C ３ alkyl, C ３ -C ５ cycloalkyl, -O(C １ -C ３ alkyl), -O(C ３ -C ５ cycloalkyl), hydroxyl, or oxo, Here, each C １ -C ３ alkyl, C ３ -C ５ cycloalkyl, -O(C １ -C ３ alkyl), or -O(C ３ -C ５ cycloalkyl) group is optionally substituted with 1 to 3 R ３ groups, A compound according to any one of claims 1 to 19, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

21. Each R ２ However, independently, H, -CH ３ ien-CH ２ CH ３ , -OCH ３ The compound according to claim 20, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is cyclopropyl or oxo.

22. R １ and R ２ The compound according to any one of claims 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compounds together form a 5-6 membered heteroaryl or a 5-7 membered heterocycline.

23. R １ and R ２ But together, 【Chemistry 13】 The compound according to claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, forming a compound.

24. Two R's ２ The bases combine to form 5-6 member heteroaryls, 5-7 member heterocyclines, and C ５ -C ７ Cycloalkyl, or C ６ A compound according to any one of claims 1 to 17, a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms an aryl group.

25. Each R ３ However, if present, halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ alkyl-OH, -NH ２ A compound according to any one of claims 1 to 24, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is -CN or hydroxyl.

26. Each R ３ However, independently, Cl, F, -CH ３ , -CF ３ ,-CHF ２ ien-CH ２ OH, -NH ２ The compound according to claim 25, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is -CN or hydroxyl.

27. Table 1 Table 1 Table 2 A compound selected from the compounds listed, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

29. The pharmaceutical composition according to claim 28 for agonizing thyroid hormone receptor beta (THR beta).

30. The pharmaceutical composition according to claim 28 for treating a THR beta-mediated disorder in a patient in need of treatment.

31. The pharmaceutical composition according to claim 30, wherein the disorder is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.

32. The pharmaceutical composition according to claim 30, wherein the disorder is non-alcoholic steatohepatitis (NASH).

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