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 to Related Applications This application claims priority to U.S. Provisional Application No. 62 / 891,078, filed Aug. 23, 2019, and U.S. Provisional Application No. 62 / 967,943, filed Jan. 30, 2020, the entire contents of each of which are hereby incorporated by reference in their entirety.

[0002] Field of the 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 disorders mediated by THR beta.

Background Art

[0003] Beneficial effects resulting from treating patients with hyperthyroidism or hypothyroidism with T3 / T4 endogenous ligands or early analogs of these endogenous ligands have been described in the literature (Richardson Hill Jr., S. et al. J. Clin. Invest. 1960, 39, 523 - 533). In these initial and similar subsequent studies, the heart has been shown as the major organ in which side effects occur in both hyperthyroidism and hypothyroidism (Klein, I. et al. Circulation, 2007, 1725 - 1735). In particular, tachycardia, hypertrophy, atrial arrhythmia, and atrial fibrillation are serious concerns. Furthermore, increased bone metabolism leading to a decrease in bone mineral density has also been noted. Negative effects at both the heart and bone sites are associated with agonism of the THR alpha isoform, while the beneficial effects of THR agonism in the liver are mainly associated with the THR beta isoform (Sinha, R. A. 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 those that act as THR beta agonists, preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism and maintain 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 new thyroid hormone analogs that are selective agonists of THR beta, preferably those that avoid the undesirable effects associated with THR alpha agonism and maintain the beneficial effects of thyroid hormones, for example, those that treat patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.

Summary of the Invention

[0005] In one aspect, herein, formula (I):

Chemical formula

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

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

[0008] In one aspect, provided is a method for treating a disorder mediated by THR beta in a patient, which comprises administering to the patient either a therapeutically effective amount of a compound provided herein or a therapeutically effective amount of a composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH).

DETAILED DESCRIPTION OF THE INVENTION

[0009] Definitions Unless otherwise specified, the following definitions apply throughout this specification. Further, terms or symbols used in this specification shall have their ordinary meaning in the art if not defined below.

[0010] "Comprising" is intended to mean that the compositions and methods include the recited elements but do not exclude others. "Consisting essentially of" is meant to exclude other elements of any importance to the combination when used to define the compositions and methods. For example, a composition consisting essentially of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel characteristics of the claimed invention. "Consisting of" is meant to exclude, for example, amounts exceeding trace amounts of other components and steps beyond the recited substantial method steps. Embodiments defined by each of these transitional terms are within the scope of the present invention.

[0011] An "effective amount" or dose of a compound or composition means an amount of the compound or composition that produces a desired intended result based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, but not limited to, LD 50 (the dose that is lethal to 50% of the population), and ED 50 (the therapeutically effective dose for 50% of the population).

[0012] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals such as tablets containing the compounds of the present invention as active ingredients. A variety of substances can be included in the term "excipient", including but not limited to, binders, disintegrants, coating agents, compression / capsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavors, suspending / gelling agents, or wet granulating agents. Examples of binders include, for example, carbomers, povidone, xanthan gum, etc.; examples of coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating agents, etc.; examples of compression / capsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; examples of disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include, for example, maltodextrin, carrageenan, etc.; examples of lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of materials for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; examples of suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; examples of wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

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

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

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

[0016] "Salt" means an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functional groups, 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. Cations useful in pharmaceutically acceptable salts include, but are not limited to, for example, Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functional groups, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, and salts of inorganic acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Anions useful in pharmaceutically acceptable salts include, but are not limited to, for example, oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic phosphate, dibasic phosphate, and tribasic phosphate, mesylate, tosylate, etc.

[0017] The "therapeutically effective amount" or dose of a compound or composition means the amount of the compound or composition that results in alleviation or suppression 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 "therapy" of a disease in a patient means: 1) preventing the disease from occurring in a patient who has a predisposition to the disease or who does not yet exhibit symptoms of the disease; 2) suppressing the disease or preventing its onset; or 3) causing amelioration or regression of the disease. As used herein, "treatment" or "therapy" is an approach for obtaining beneficial or desirable results, including clinical outcomes. For the purposes of the present invention, beneficial or desirable results include, but are not limited to, one or more of the following: a decrease in one or more symptoms attributable to the disease or disorder, a decrease in the degree of the disease or disorder, stabilization of the disease or disorder (e.g., preventing or delaying worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or reducing the rate of progression of the disease or disorder, improvement in the condition of the disease or disorder, providing remission (partial or total) of the disease or disorder, a decrease in the dosage of one or more other drugs required to treat the disease or disorder, enhancement of the effect of another drug used to treat the disease or disorder, delaying the progression of the disease or disorder, improving the quality of life, and / or prolonging the survival of the patient. Further, "treatment" includes 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 "isotopomer" of a compound is a compound in which one or more atoms of the compound are replaced by isotopes of those same atoms. For example, when H is replaced by D or T, 12 C is, 11 replaced by 14 C, or when 15It may be replaced by N. For example, but not limited to this, when replaced by D, in some examples, the metabolic rate may decrease and the half-life may become longer. When H is replaced by T, a radioligand that may be useful for binding research can be provided. 12 Replacing C with a short-lived isotope 11 C can provide a ligand useful for positron emission tomography (PET) scans. 14 Replacing N with 15 N gives 15 Compounds that can be detected / monitored by 15N-NMR spectroscopy are provided. For example, an isotopomer of a compound containing -CH2CH3 is a compound containing -CD2CD3 instead of -CH2CH3.

[0020] Unless a specific isotope of an element is indicated in the formula, the present disclosure includes all isotopic substituents of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H can be 2 H, i.e., D). Isotopic substituents can be isotopically substituted at any or all sites within the structure, or atoms can be present at any or all sites within the structure in natural abundance ratios.

[0021] "Stereoisomer" or "plural stereoisomers" means, but is not limited to this, compounds with different stereogenicity of the constituent atoms, such as chirality at one or more stereocenters, or compounds related to the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0022] "Tautomers" means alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both a ring-NH- moiety and a ring=NH- moiety, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0023] "Alkyl" means 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 way of example, straight-chain or branched-chain 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-). C x Alkyl means an alkyl group having x carbon atoms.

[0024] "Aryl" or "Ar" means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic (e.g., phenyl (Ph)) or fused polycyclic (e.g., naphthyl or anthryl) ring, and the fused ring may or may not be aromatic provided that the point of attachment is to an aromatic carbon atom (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0025] "Cycloalkyl" means a saturated or unsaturated but non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having a monocyclic or polycyclic ring including fused, bridged and spiro ring systems. C x Cycloalkyl means a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic provided that the point of attachment is via a non-aromatic, non-heterocyclic ring of a saturated carbocyclic ring.

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

[0027] "Hydroxy" or "hydroxyl" means a 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 within the ring. Such heteroaryl groups can have a monocyclic ring (e.g., pyridinyl or furyl) or a fused polycyclic ring (e.g., indolizinyl or benzothienyl), where the fused ring may or may not be aromatic as long as the bonding moiety passes through an atom of the aromatic heteroaryl group and / or may or may not contain a heteroatom. 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- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0029] "Heterocycle" or "heterocyclic" 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 selected from the group consisting of nitrogen, sulfur, or oxygen, preferably 1 to 3 heteroatoms, more preferably 1 to 2 heteroatoms. C xHeterocycloalkyl means a heterocycloalkyl group having x ring atoms including ring heteroatoms. The heterocycle encompasses a monocyclic or a fused polycyclic ring system including fused, bridged and spiro ring systems. In a fused ring system, if the linking moiety is through a non-aromatic ring, one or more rings can be cycloalkyl, aryl, or heteroaryl. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group may optionally be oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0030] Heterocyclyl and heteroaryl include, but are not limited to, for example, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isothiazolyl, 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 referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

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

[0032] As used throughout this specification, the terms "any" or "optionally" mean that the event or situation described thereafter may occur but need not occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "a nitrogen atom may optionally be oxidized to provide an N-oxide (N→O) moiety" means that the nitrogen atom can be oxidized but need not be oxidized, and this description includes the situation where the nitrogen atom is not oxidized and the situation where the nitrogen atom is oxidized.

[0033] "Optionally substituted" means that, unless otherwise specified, the group may be unsubstituted or may be the same or different substituents that do not exceed the normal valence of the group, and may be substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an 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 in this specification is made by naming the terminal portion of the functional group and then naming the adjacent functional group towards the point of attachment. For example, the substituent "alkoxycarbonylalkyl" means a group represented by (alkoxy)-C(O)-(alkyl)-.

[0035] It is understood that polymers made by defining substituents having further substituents on themselves in all of the substituted groups defined above (for example, substituted aryls having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended to be included herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is restricted, for example, by the limitation that a substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0036] It is understood that the above definitions are not intended to include unacceptable substitution patterns (for example, a methyl substituted with four fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0037] It is understood that specific features of the invention described in the context of another embodiment for purposes of clarification may also be provided in combination in a single embodiment. Conversely, for purposes of brevity, the various features of the invention described in the context of a single embodiment may also be provided in another or any suitable sub-combination. All combinations of embodiments related to chemical groups represented by variable groups are specifically included by the present invention, and are disclosed herein to the same extent that each of such combinations is individually and explicitly disclosed, in the range of compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Further, all sub-combinations of the chemical groups listed in the embodiments describing such variable groups are also specifically included by the present invention, and are disclosed herein to the same extent that each of such sub-combinations of chemical groups is individually and explicitly disclosed herein.

[0038] Compound In one aspect, herein, Formula (I):

Chemical formula

[0039] In some embodiments, there is provided a compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, A is

Chemical formula

Chemical formula

Chemical formula

[0041] In some embodiments, the compound of formula (I) is of formula (II):

Chemical formula

[0042] In some embodiments, the compound of formula (I) is of formula (III):

Chemical formula

[0043] In some embodiments, the compound of formula (I) is of formula (IV):

Chemical formula

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

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

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

[0047] In some embodiments of the compound of formula (I) or a variation thereof, Z 1 is CH, and Z 2 is CH. In some embodiments, Z 1 is CH, and Z 2 is N. In some embodiments, Z 1 is N, and Z 2 is CH. In some embodiments, Z 1 is N, and Z 2 is N. In some embodiments, Z 1 is CH, and Z 3 is CH. In some embodiments, Z 1 is CH, and Z 3 is N. In some embodiments, Z 1 is N, and Z 3 is CH. In some embodiments, Z 1 is N, and Z 3 is N. In some embodiments, Z 2 is CH, and Z 3 is CH. In some embodiments, Z 2 is CH, and Z 3 is N. In some embodiments, Z 2 is N, and Z 3 is CH. In some embodiments, Z 2 is N, and Z 3 is N. In some embodiments, Z 1 is CH; Z 2 is CH; and Z 3 is CH. In some embodiments, Z 1 is CH; Z 2 is CH; and Z 3 is N. In some embodiments, Z 1 is CH; 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 a compound represented by formula (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 a variation thereof,

Chemical formula

Chemical formula

[0051] In some embodiments of the compound of formula (I) or its variations, [Chemical formula] is a 5-membered heterocyclyl which may optionally contain one or two additional ring heteroatoms selected from the group consisting of N and O, wherein each heteroatom of the heterocyclyl is, if necessary to satisfy the valence of the heteroatom, one R 1is bonded to the base and, where each carbon atom of the above heterocyclyl, if necessary to satisfy the valence of the carbon atom, one R 2 is bonded to the group, provided that the R 2 group necessary to satisfy the valence of each carbon atom is only one. In some embodiments of the compound of formula (I) or its variations,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

Chemical formula

[0053] In some embodiments, the compound of formula (I) is a compound represented by formula (I-4) to (I-9), (II-4) to (II-9), (III-4) to (III-9), and (IV-4) to (IV-9): [Chemical formula] [Chemical formula] [wherein A, Z 1 , Z 2 , Z 3 , R 1 , and R 2 are as defined in formula (I).] is any of the compounds represented by

[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 1is independently H, C1-C3 alkyl, or C3-C5 cycloalkyl, where each C1-C3 alkyl or C3-C5 cycloalkyl group may optionally be substituted with 1 to 3 R 3 groups. In some embodiments, each R 1 is independently H, -CH3, or -CH2CH3. In some embodiments, each R 1 is independently H, cyclopropyl, -CH3, -CH(CH3)2, t-butyl, or -CH2CH3. In some embodiments, when R 1 is present, at least one R 1 is H. In some embodiments, when R 1 is present, at least one R 1 is optionally C1-C6 alkyl that may be substituted with 1 to 5 R 3 groups. In some embodiments, when R 1 is present, at least one R 1 is unsubstituted C1-C6 alkyl. In some embodiments, when R 1 is present, at least one R 1 is optionally C1-C3 alkyl that may be substituted with 1 to 3 R 3 groups. In some embodiments, when R 1 is present, at least one R 1 is unsubstituted C1-C3 alkyl. In some embodiments, when R 1 is present, at least one R 1 is -CH3, or -CH2CH3. In some embodiments, when R 1 is present, at least one R 1 is -CH3, -CH(CH3)2, t-butyl, or -CH2CH3. In some embodiments, when R 1 is present, at least one R 1 is -CH3. In some embodiments, when R 1 is present, at least one R 1is -CH2CH3. In some embodiments, R 1 when present, at least one R 1 is -CH(CH3)2. In some embodiments, R 1 when present, at least one R 1 is t-butyl. In some embodiments, R 1 when present, at least one R 1 is optionally C3-C6 cycloalkyl, optionally substituted with 1 to 5 R 3 groups. In some embodiments, R 1 when present, at least one R 1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 1 when present, at least one R 1 is optionally C3-C5 cycloalkyl, optionally substituted with 1 to 3 R 3 groups. In some embodiments, R 1 when present, at least one R 1 is unsubstituted C3-C5 cycloalkyl. In some embodiments, R 1 when present, at least one R 1 is cyclopropyl. In some embodiments, R 1 when present, at least one R 1 is cyclopropyl substituted with one R 3 group. In some embodiments, R 1 when present, at least one R 1 is cyclopropyl substituted with one R 3 group, where the R 3 group is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 1 when present, at least one R 1 is

Chemical formula

Chem.

Chem.

Chem.

[0056] In some embodiments of the compound of formula (I) or its variations, each R 2 is 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 optionally be substituted with 1 to 3 R 3 groups. In some embodiments, each R 2 is 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 optionally be substituted with 1 to 3 R 3 groups. In some embodiments, each R 2 is independently H, -CH3, -CH2CH3, -OCH3, or oxo. In some embodiments, each R 2 is independently H, -CH3, -CH2CH3, -OCH3, cyclopropyl, or oxo. In some embodiments, R 2When present, at least one R 2 is H. In some embodiments, R 2 When present, at least one R 2 is optionally C1-C6 alkyl which may be substituted with 1 to 5 R 3 groups. In some embodiments, R 2 When present, at least one R 2 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 When present, at least one R 2 is optionally C1-C3 alkyl which may be substituted with 1 to 3 R 3 groups. In some embodiments, R 2 When present, at least one R 2 is unsubstituted C1-C3 alkyl. In some embodiments, R 2 When present, at least one R 2 is -CH3 or -CH2CH3. In some embodiments, R 2 When present, at least one R 2 is -CH3. In some embodiments, R 2 When present, at least one R 2 is -CH2CH3. In some embodiments, R 2 When present, at least one R 2 is optionally C3-C6 cycloalkyl which may be substituted with 1 to 5 R 3 groups. In some embodiments, R 2 When present, at least one R 2 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 2 When present, at least one R 2 is optionally C3-C5 cycloalkyl which may be substituted with 1 to 3 R 3 groups. In some embodiments, R 2 When present, at least one R 2is an unsubstituted C3-C5 cycloalkyl. In some embodiments, R 2 , if present, at least one R 2 is cyclopropyl. In some embodiments, R 2 , if present, at least one R 2 is optionally -O(C1-C6 alkyl) which may be substituted with 1 to 5 R 3 groups. In some embodiments, R 2 , if present, at least one R 2 is unsubstituted -O(C1-C6 alkyl). In some embodiments, R 2 , if present, at least one R 2 is optionally -O(C1-C3 alkyl) which may be substituted with 1 to 3 R 3 groups. In some embodiments, R 2 , if present, at least one R 2 is unsubstituted -O(C1-C3 alkyl). In some embodiments, R 2 , if present, at least one R 2 is -OCH3. In some embodiments, R 2 , if present, at least one R 2 is optionally -O(C3-C6 cycloalkyl) which may be substituted with 1 to 5 R 3 groups. In some embodiments, R 2 , if present, at least one R 2 is unsubstituted -O(C3-C6 cycloalkyl). In some embodiments, R 2 , if present, at least one R 2 is optionally -O(C3-C5 cycloalkyl) which may be substituted with 1 to 3 R 3 groups. In some embodiments, R 2 , if present, at least one R 2 is unsubstituted -O(C3-C5 cycloalkyl). In some embodiments, R 2When present, at least one R 2 is hydroxyl. In some embodiments, R 2 When present, at least one R 2 is oxo.

[0057] In some embodiments of the compound of formula (I) or its variations, R 1 and R 2 together form a 5- to 6-membered heteroaryl or a 5- to 7-membered heterocyclyl. In some embodiments, R 1 and R 2 together form a 5- to 6-membered heteroaryl, such as pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, or furanyl. In some embodiments, R 1 and R 2 together form a 5-membered heteroaryl. In some embodiments, R 1 and R 2 together form a 6-membered heteroaryl. In some embodiments, R 1 and R 2 together form a 5- to 7-membered heterocyclyl, such as tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, oxazinanyl, or thiomorpholinyl. In some embodiments, R 1 and R 2 together form a 5- to 6-membered heterocyclyl. In some embodiments, R 1 and R 2 together form a 5-membered heterocyclyl. In some embodiments, R 1 and R 2 together form a 6-membered heterocyclyl. In some embodiments, R 1 and R 2combine to form a 7-membered heterocycle. In some embodiments, R 1 and R 2 combine to form

Chemical formula

[0058] In some embodiments of the compound of formula (I) or its variations, two R 2 groups combine to form a 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycle, a C5-C7 cycloalkyl, or a C6 aryl. In some embodiments, two R 2 groups combine to form a 5- to 6-membered heteroaryl, such as pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, or furanyl. In some embodiments, two R 2 groups combine to form a 5-membered heteroaryl. In some embodiments, two R 2 groups combine to form a 6-membered heteroaryl. In some embodiments, two R 2 groups combine to form a 5- to 7-membered heterocycle, such as tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or thiomorpholinyl. In some embodiments, two R 2 groups combine to form a 5- to 6-membered heterocycle. In some embodiments, two R 2 groups combine to form a 5-membered heterocycle. In some embodiments, two R 2 groups combine to form a 6-membered heterocycle. In some embodiments, two R 2 groups combine to form a 7-membered heterocycle. In some embodiments, two R 2together form a C5-C7 cycloalkyl. In some embodiments, two Rs 2 together form a C5-C6 cycloalkyl. In some embodiments, two Rs 2 together form a C5 cycloalkyl. In some embodiments, two Rs 2 together form a C6 cycloalkyl. In some embodiments, two Rs 2 together form a C7 cycloalkyl. In some embodiments, two Rs 2 together form a C6 aryl.

[0059] In some embodiments of the compounds of formula (I), each R 3 , when present, is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-OH, -NH2, -CN, or hydroxyl. In some embodiments, each R 3 , when present, is independently Cl, F, -CH3, -CF3, -CHF2, -CH2OH, -NH2, -CN, or hydroxyl. In some embodiments, when R 3 is present, at least one R 3 is halogen, for example, Cl, or F. In some embodiments, when R 3 is present, at least one R 3 is Cl. In some embodiments, when R 3 is present, at least one R 3 is F. In some embodiments, when R 3 is present, at least one R 3 is C1-C3 alkyl, for example, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, when R 3 is present, at least one R 3 is -CH3. In some embodiments, when R 3 is present, at least one R3 is C3-C6 cycloalkyl. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 haloalkyl. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 haloalkyl having 1 to 3 halogen atoms. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 haloalkyl having 1 halogen atom. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 haloalkyl having 2 halogen atoms. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 haloalkyl having 3 halogen atoms. In some embodiments, R 3 , when present, at least one R 3 is -CF3. In some embodiments, R 3 , when present, at least one R 3 is -CHF2. In some embodiments, R 3 , when present, at least one R 3 is C1-C3 alkyl-OH. In some embodiments, R 3 , when present, at least one R 3 is -CH2OH. In some embodiments, R 3 , when present, at least one R 3 is -NH2. In some embodiments, R 3 , when present, at least one R 3 is -CN. In some embodiments, R 3 , when present, at least one R 3 is hydroxyl.

[0060] In some embodiments of the compound of formula (I), [Chemical formula] is [Chemical formula] as follows. In other embodiments of the compound of formula (I), [Chemical formula] is [Chemical formula] as follows.

[0061] In some embodiments, a compound of formula (I) or a variation thereof is provided, wherein the compound has any one or more of the following characteristics: (I) A is [Chemical formula] as follows; (II) The combination of Z 1 , Z 2 , Z 3 is (iv) Z 1 , Z 2 , Z 3 are each CH, or (v) Z 1 is N, and Z 2 and Z 3 are each CH, or (vi) Z 2 is N, and Z 1 and Z 3 are each CH; (III) [Chemical formula] is (vii) Optionally, a 5- to 6-membered heteroaryl which may contain 1 to 2 additional ring heteroatoms selected from the group consisting of N and O, for example,

Chem.

Chem.

[0062] In some embodiments, (II) is applied. In some embodiments, (IV) is applied. In some embodiments, (V) is applied. In some embodiments, (i) is applied. In some embodiments, (ii) is applied. In some embodiments, (iii) is applied. In some embodiments, (iv) is applied. In some embodiments, (v) is applied. In some embodiments, (vi) is applied. In some embodiments, (vii) is applied. In some embodiments, (viii) is applied. In some embodiments, (i) and (II) are applied. In some embodiments, (ii) and (II) are applied. In some embodiments, (iii) and (II) are applied. In some embodiments, (vii) and (II) are applied. In some embodiments, (viii) and (II) are applied. In some embodiments, (iv) and (vii) are applied. In some embodiments, (iv) and (viii) are applied. In some embodiments, (v) and (vii) are applied. In some embodiments, (v) and (viii) are applied. In some embodiments, (vi) and (vii) are applied. In some embodiments, (vi) and (viii) are applied. In some embodiments, (I), (II), (III), (IV), and (V) are applied. In some embodiments, (i), (II), (III), (IV), and (V) are applied. In some embodiments, (ii), (II), (III), (IV), and (V) are applied. In some embodiments, (iii), (II), (III), (IV), and (V) are applied. In some embodiments, (I), (iv), (III), (IV), and (V) are applied. In some embodiments, (I), (v), (III), (IV), and (V) are applied. In some embodiments, (I), (vi), (III), (IV), and (V) are applied.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 2-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 5-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 10-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 20-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 50-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 75-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 100-fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100-fold selectivity for THR beta over 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 the description of this specification, all descriptions, variants, embodiments, or aspects of a part can be combined with all descriptions, variants, embodiments, or aspects of other parts, just as if each and every combination were individually and specifically described. For example, regarding A in formula (I), all descriptions, variants, embodiments, or aspects provided in this specification can be combined with all descriptions, variants, embodiments, or aspects of Z 1 Z 2 Z 3 R 1 R 2 R 3 B, and all descriptions, variants, embodiments, or aspects of Y, just as if all combinations were individually and specifically described. Also, all descriptions, variants, embodiments, or aspects of formula (I) are equally applicable to other formulas described in this specification, if applicable, and it is understood that all descriptions, variants, embodiments, or aspects are equally described, just as if each and every description, variant, embodiment, or aspect were individually and specifically described for all formulas. For example, all descriptions, variants, embodiments, or aspects of formula (I) are equally applicable to any of the formulas detailed in this specification, such as formulas (I-1) to (I-9), (II), (II-1) to (II-9), (III), (III-1) to (III-9), (IV), (IV-1) to (IV-9), if applicable, and it is understood that all descriptions, variants, embodiments, or aspects are equally described, just as if each and every description, variant, embodiment, or aspect were individually and specifically described for all formulas.

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

[0066] In one embodiment, provided herein is a compound selected from those represented in Table 1 (Tables 1-1 to 1-5) below, or a tautomer, N-oxide, isotopomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0067] In some embodiments, provided herein is a compound selected from those listed in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound selected from Examples 1 to 59 or a pharmaceutically acceptable salt thereof.

[0068] The present invention also includes all salts of the compounds referred to herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms, as well as any tautomers, or other forms such as N-oxides, solvates, or isotopomers of the described compounds. Unless stereochemistry is explicitly indicated by chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the indicated compound. Further, 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 compounds, such as crystalline or amorphous forms of the compounds, are also included in the present invention. Compositions containing the compounds of the present invention, for example, compositions of substantially pure compounds including their particular stereochemical forms, are also contemplated. Also, compositions containing mixtures of the compounds of the present invention in any ratio are encompassed by the present invention, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, whereby racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds are included.

[0069] Synthesis method Scheme 1a:

Chemical formula

[0070] Scheme 1b:

Chemical formula

[0071] Scheme 1c:

Chemical formula

[0072] Scheme 2:

Chemical formula

[0073] Scheme 3:

Chemical Structure

[0074] Scheme 4:

Chemical Structure

[0075] Scheme 4a:

Chemical Structure

[0076] Scheme 5:

Chemical formula

[0077] The synthesis of the specific compounds provided herein is outlined above and provided in the Examples section below. The variable groups described in the above schemes are defined for the compounds of formula (I) or any variations, embodiments, or aspects thereof. The synthesis of the other compounds provided herein will be apparent to those skilled in the art based on the guidance provided herein and on synthetic methods well known to those skilled in the art.

[0078] If it is desired to obtain a specific enantiomer of a compound, it can be obtained from the corresponding mixture of enantiomers using any suitable conventional method for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer recovered. In another separation process, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described.

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

[0080] Solvates of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain a stoichiometric or non-stoichiometric amount of a solvent and are often formed during the crystallization process. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed.

[0081] It is understood that the synthetic processes disclosed herein can be modified to obtain the various compounds of the invention by selecting appropriate reagents and starting materials. Where protection of certain reactive or incompatible groups (e.g., amines or carboxylic acids) is required, the formulas, for example, the formulas of the schemes provided herein, are intended to and include compounds in which such reactive or incompatible groups are in appropriately protected form. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

[0082] Pharmaceutical Compositions and Formulations Pharmaceutical compositions of any of the compounds detailed herein are included in the invention. Accordingly, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions according to the invention can take a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or a form suitable for administration by inhalation.

[0083] In one aspect, the compounds detailed herein can be in a purified form, and compositions containing the compounds in purified form are detailed herein. Compositions are provided that contain a compound detailed herein or a salt thereof, such as a composition of a substantially pure compound. In some embodiments, the compositions containing a compound detailed herein or a salt thereof are in substantially pure form. In one variation, "substantially pure" is intended to mean a composition having an impurity content of 35% or less, where the impurity means a compound other than the compound or its salt that constitutes the major part of the composition. For example, a composition of a substantially pure compound selected from the compounds in Table 1 is intended to mean a composition having an impurity content of 35% or less, where the impurity means a compound other than that compound or its salt. In one variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 25% or less. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 20% or less. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 10% or less. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 5% or less. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 3% or less. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 1% or less. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the impurity content of the composition is 0.5% or less. In still other variations, a composition of a substantially pure compound has an impurity content of the composition of 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, and this impurity can be a compound in a different stereochemical form. For example, but not limited to, a composition of a substantially pure (S) compound means that the content of the (R) form 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 of the present specification are synthetic compounds manufactured for administration to an individual such as a human. In another variation, a composition is provided that includes the compound in a substantially pure form. In another variation, the present invention encompasses a pharmaceutical composition that includes a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, a method of administering the compound is provided. The purified form, the pharmaceutical composition, and the method of administering the compound are suitable for any of the compounds or forms thereof detailed herein.

[0085] The compound can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound can be formulated with a suitable carrier to provide the delivery form, including, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or elastic soft gelatin capsules, etc.), cachets, troches, 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, etc.

[0086] One or several of the compounds described herein can be used in the manufacture of pharmaceutical formulations such as pharmaceutical preparations by combining the compound or compounds as the active ingredient with a pharmaceutically acceptable carrier as described above. Depending on the form of treatment of the system (e.g., comparison between a transdermal patch and an oral tablet), the carrier can be in various forms. Further, the pharmaceutical preparation can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, coloring agents, regulators, and salts, buffers, coating agents, or antioxidants for adjusting the osmotic pressure. The formulation containing the compound can also contain other substances having valuable therapeutic properties. The pharmaceutical preparation can be manufactured by known pharmaceutical methods. Appropriate formulations can be referred to, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is incorporated herein by reference.

[0087] The compounds described herein can 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 are lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers acceptable for soft shell gel capsules are, for example, vegetable oils, waxes, fats, semi - solids and liquid polyols, etc. Further, the pharmaceutical preparation can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, coloring agents, regulators, and salts, buffers, coating agents, or antioxidants.

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

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

[0090] Method of Use / Treatment The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any of the formulas provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be used in in vitro methods, for example, in in vitro methods of administering the compound or composition to cells to perform screening purposes and / or quality control assays.

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

[0092] In one aspect, provided herein is a method of treating a THR beta-mediated disorder in a patient comprising administering to the patient in need thereof 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.

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

[0094] In one aspect, provided herein is a method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting THR beta with an effective amount of any of the compounds provided herein or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein. In one aspect, provided herein is a method of selectively agonizing THR beta over THR alpha comprising contacting THR beta with an effective amount of any of the compounds provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein. In such an aspect, the method selectively agonizes THR beta over THR alpha by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100-fold. 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 aspect, provided herein is a method of treating a THR beta-mediated disease or disorder in a patient in need thereof, 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 aspect, the disease or disorder is a liver disease or disorder. In one aspect, provided herein is a method of treating a liver disease or disorder associated with sub-optimal THR beta agonism in a patient in need thereof, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes THR beta over THR alpha.

[0096] In one aspect, provided herein is a method for treating non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method for treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient an effective amount of 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 aspect, provided herein is a method for treating metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method for treating dyslipidemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method for treating hypertriglyceridemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method for treating hypercholesterolemia in a patient in need thereof, 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, a patient having a disease or disorder associated with THR beta agonism may include, but is not limited to, a patient having an underlying hypothyroid disorder.

[0098] In another aspect, there is provided a method of delaying the onset and / or progression of a THR-beta-mediated disease or disorder in a patient (e.g., a human) at risk of developing the disease or disorder. It is understood that delaying the onset may include prevention in the case where an individual does not develop the disease or disorder. In one aspect, an individual at risk of developing a THR-beta-mediated disease or disorder has one or more risk factors for developing the disease or disorder, such as age, increasing waist circumference, increasing body mass index, or related co-morbidities.

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

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

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

[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 any one of about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old, or any age greater than or equal to that. In some embodiments, the human is a child. In some embodiments, the human is any one of about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old, or any age less than or equal to that.

[0103] Dosage and Administration The dosage of the compounds described herein, or stereoisomers, tautomers, solvates, or salts thereof, administered to an individual (such as a human), can vary depending on the specific compound or its salt, 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, etc. In some embodiments, the amount of the compound, or stereoisomer, tautomer, solvate, or salt thereof, 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] In one aspect, the effective amount of the compound can be a dosage of about 0.01 to about 100 mg / kg. The effective amount or dosage of the compounds of the present disclosure can be determined, for example, by 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 agent, the severity and course of the disease being treated, and the health status, symptoms, and body weight of the subject. The dosage can be, for example, in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0106] In one aspect, any method provided herein can include administering to an individual a pharmaceutical composition comprising a therapeutically effective amount of a 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 according to an effective dosing regimen for a desired time or period, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, which in some variations may be over the lifetime of the individual. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered continuously to the individual over a period of time (e.g., at least once a day). The dosing frequency can also be less than once a day, such as, for example, about once a week. The dosing frequency can also be more than once a day, such as, for example, twice or three times a day. The dosing frequency can also be intermittent, including a "drug holiday" (e.g., 14 days of once-daily dosing for 7 days followed by 7 days of no dosing is repeated, for example, for about 2 months, about 4 months, about 6 months or more). Any dosing frequency can be used with any of the compounds or pharmaceutically acceptable salts thereof described herein at any of the dosages described herein.

[0108] Products and Kits The present disclosure further provides a product comprising a compound or a salt thereof described herein, a composition described herein, or one or more unit dosages described herein in a suitable package. In certain embodiments, the product is for use in any of the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampules, bottles, jars, flexible packaging, and the like. The product can further be sterilized and / or sealed.

[0109] The present disclosure further provides a kit for practicing the methods of the present disclosure, comprising one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described herein. The kit can use the compounds or pharmaceutically acceptable salts thereof disclosed herein. In one variation, the kit uses the compounds or pharmaceutically acceptable salts thereof described herein. The kit can be used for any one or more of the uses described herein and thus may include instructions for the treatment of any disease described herein, for example, for the treatment of non-alcoholic steatohepatitis (NASH).

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

[0111] The kit can be in unit dosage form, bulk package (e.g., multi-dose package), or sub-unit dosage. For example, a kit can be provided that includes a sufficient dose of a compound or a pharmaceutically acceptable salt thereof disclosed herein and / or an additional pharmaceutically active compound useful for the diseases detailed herein, and can provide effective treatment of an individual for an extended period, for example, for 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 include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use at a pharmacy (such as a hospital pharmacy or a dispensing pharmacy).

[0112] The kit may optionally include a set of instructions, general descriptive instructions, but an electronic storage medium (e.g., magnetic disk or optical disk) containing instructions is also acceptable and relates to the use of the components of the methods of the present disclosure. The instructions included in the kit typically include information regarding the components and their administration to an individual.

Example

[0113] This disclosure is made by way of example only, and it is understood that numerous changes in the combination and arrangement of parts may be made by those skilled in the art without departing 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 exemplified by this disclosure can be carried out by appropriate modifications apparent to those skilled in the art, such as appropriately protecting interfering groups, by using other suitable reagents known to those skilled in the art other than those described, or by making certain changes to the reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as applicable for producing other compounds of this disclosure.

[0115] The following abbreviations may be relevant to this application. Abbreviations Ac: Acetyl ACN, or MeCN: Acetonitrile BAST: Bis(2-methoxyethyl)aminosulfur trifluoride BINAP: 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl BPD: Bis(pinacolato)diboron Boc: Tert-butoxycarbonyl 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: Disuccinimidyl 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: Saturated 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] Synthesis Example Scheme A Synthesis of 3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)oxy)aniline (Compound 1e)

Chem.

[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 at 0 °C to SEM-Cl (451.83 mg, 2.71 mmol, 479.65 μL) and DIEA (420.30 mg, 3.25 mmol, 566.45 μL). The mixture was then stirred at 20 °C for 4 h. TLC indicated that 1a was completely consumed and two new spots were formed. LCMS 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, concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to obtain 1b. MS mass calculated value: [M+1] + (C 15 H23 BrN2OSi), m / z 355.1, LCMS measured value m / z 355.1; 1 1H 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 - indazol - 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 - indazol - 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 and purged with N2 three times, then the mixture was stirred at 100 °C for 3.5 h under a N2 atmosphere. TLC showed that 1b was completely consumed and many new spots were formed. LCMS showed the desired MS. The suspension was filtered through a pad of celite and the pad cake was washed with EtOAc (5 ml×3). The combined filtrate was extracted with ethyl acetate (20 mL×2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by prep - TLC (SiO2, ethyl acetate: petroleum ether) to obtain 1c. MS mass calculated value: [M + 1] + ( C 15 H24 N2O2Si), m / z 293.2, LCMS measured value m / z 293.2; 1 1H 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) To a solution of 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ol (1c) (115 mg, 393.23 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (90.83 mg, 432.56 μmol) in DMF (5 mL) was added K2CO3 (81.52 mg, 589.85 μmol). The mixture was degassed and purged with N2 three times, and stirred at 20 °C for 1 hour. TLC showed that 1c was completely consumed and one new spot was formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 1d. MS mass calculated value: [M+1] + (C 21 H 25 Cl2N3O4Si), m / z 482.1, LCMS measured value m / z 482.2; 11H 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-indazol-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 h. TLC indicated that 1d was completely consumed and one new spot was formed. LCMS showed the desired MS. The suspension was filtered through a pad of celite and the pad cake was washed with EtOAc (5 mL × 3). The combined filtrate was extracted with ethyl acetate (20 mL × 2) and washed with 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 give a residue. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to give 1e. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chem.

[0122] Synthesis of 2-(3,5-dichloro-4-((3-ethyl-1H-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 1) To a mixture of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-ethyl-1H-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (1 g) (18 mg, 36.79 μmol) in HOAc (1 mL), NaOAc (15.09 mg, 183.93 μmol) was added under N2. The mixture was stirred at 120 °C for 3 h. LCMS indicated that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×30 mm×5 μm; mobile phase: [water (0.04% HCl)-MeCN]) to afford Example 1. MS calculated for [M+1] + ( C 19 H 12 Cl2N6O3), m / z 443.0, LCMS found m / z 443.0; 1 1H 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-indazol-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Chemical formula

[0124] Synthesis of 6-(3,5-dichloro-4-((3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H),-dione (2b) 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) were added to a mixture of H2O (0.5 mL) and THF (2 mL), followed by K3PO4 (7.54 mg, 35.50 μmol), and di-tert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (1.16 mg, 1.77 μmol). The mixture was degassed and purged three times with N2, and then the mixture was stirred at 90 °C for 3 h under a 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 × 2) and H2O (15 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The mixture was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 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-indazol-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-indazol-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 h. HPLC and LCMS indicated that 2b was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (FA), column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.04% HCl)-MeCN] to give Example 2. MS mass calculated 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-indazol-5-yl)oxy)aniline (Compound 3f)

Chemical formula

[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) was added NaH (386.59 mg, 9.67 mmol, 990.33 μL, 60% purity) at 0 °C under N2, and then SEM-Cl (1.34 g, 8.05 mmol, 1.43 mL) was added to the mixture. The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into NH4Cl (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate) to give 3b. 11H 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-indazol-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) under N2, hypodiboric acid (1.34 g, 14.94 mmol), DIPEA (1.93 g, 14.94 mmol, 2.60 mL), and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butylphosphane (33.30 mg, 49.81 μmol) were added. The mixture was stirred at 50 °C for 1.5 h. LCMS indicated complete consumption of 3b and the desired MS was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3c. MS mass calculated value: [M+1] + (C 14 H 23 BN2O3Si), m / z 307.1, LCMS found m / z 307.1.

[0129] Synthesis of 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ol (3d) (3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-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, followed by 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 h. LCMS indicated complete consumption of 3c and detection of the desired MS. TLC showed complete consumption of the starting material and formation of new spots. The residue was poured into NaHS2O3 (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with brine (30 mL × 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 give 3d. MS mass calculated: [M+1] + (C 14 H 22 N2O2Si), m / z 279.1, LCMS found m / z 279.1.

[0130] Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3e) To a mixture of 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-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 added K2CO3 (789.26 mg, 5.71 mmol) under N2. The mixture was stirred at 20 °C for 1 h. TLC showed complete consumption of the starting material and formation of two spots. The residue was poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate) to give 3e. 1 1H 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-indazol-5-yl)oxy)aniline (3f) To a mixture of 5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3e) (200 mg, 426.98 μmol) in EtOH (5 mL) and H2O (1 mL) were added NH4Cl (114.20 mg, 2.13 mmol) and Fe (119.22 mg, 2.13 mmol). The mixture was stirred at 80 °C for 2 h. TLC and LCMS indicated complete consumption of 3e 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 × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3f. MS mass calculated value: [M+1] + (C 20 H 25 Cl2N3O2Si), m / z 438.0, LCMS found m / z 438.0; 11H 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [Chemical Structure] Synthesis of 3,5-dichloro-4-((3-methyl-1H-indazol-5-yl)oxy)aniline (3g) A solution of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-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 h. LCMS indicated that 3f was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 3g. MS mass calculated 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-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (3h) A solution of 3,5-dichloro-4-((3-methyl-1H-indazol-5-yl)oxy)aniline (3g) (35mg, 113.58 μmol) in HCl (1 mL) and H2O (2 mL) was added with NaNO2 (10.19mg, 147.65 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then the mixture was quickly filtered to obtain a solution. The solution was added to a solution of ethyl N-(2-cyanoacetyl)carbamate (19.51mg, 124.93 μmol) in H2O (2 mL) and Pyr (1 mL) at 0 °C, and then the reaction mixture was stirred at 0 °C for an additional 0.5 h. LCMS indicated that 3g was completely consumed and the desired MS was detected. The suspension was filtered and then washed with H2O (5 mL×3). The filter cake was dried under reduced pressure to obtain 3h. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 3) To a solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)-carbamate (3h) (50mg, 105.20 μmol) in HOAc (3 mL) was added NaOAc (43.15mg, 526.00 μmol). The mixture was stirred at 120 °C for 16 h. LCMS and HPLC indicated that 3h was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (FA), column: Phenomenex Luna C18 150×30mm×5μm; mobile phase: [water (0.2% FA)-MeCN] to obtain Example 3. MS mass calculated value: [M + 1] + (C 18 H10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0. 1 1H 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-indazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0136] Synthesis of N-(3,5-dichloro-4-((3-methyl-1H-indazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 4) To a mixture of N-(3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (4a) (20 mg, 36.33 μmol) in DCM (1.5 mL) was added TFA (0.5 mL) under N2. The mixture was stirred at 25 °C for 16 h. LCMS indicated 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 × 2). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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 4. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [Chemical formula] 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-indazol-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 under N2 at 0 °C, t-BuONO (23.52 mg, 228.09 μmol, 27.13 μL, 2 eq) was added. The mixture was stirred at 20 °C for 16 h. TLC and LCMS indicated that 3f was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether / ethyl acetate) to give 5a. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (5b) 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 a mixture of THF (2 mL) was added with a mixture of K3PO4 (30.91 mg, 145.62 μmol, 2 eq) in H2O (0.5 mL) and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium (4.75 mg, 7.28 μmol) under N2. The mixture was stirred at 90 °C for 2 h. LCMS 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 × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO2, petroleum ether / ethyl acetate) to give 5b. MS mass calculated 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-indazol-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-indazol-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 h. LCMS indicated 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 × 3). The combined organic phases were washed with brine (10 mL × 2), 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)-ACN]) to obtain Example 5. MS mass calculated 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]pyridin-5-yl)oxy)aniline (Compound 6e)

Chemical formula

[0141] (3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (6b) synthesis 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 and purged with N2 three times, and then the mixture was stirred at 50 °C for 1 h under a N2 atmosphere. LCMS indicated that 6a was completely consumed and detected one major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent, and 6b was obtained and used directly in the next step without purification. MS mass calculated 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]pyridin-5-ol (6c) To a solution of (3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (6b) (300 mg, 976.47 μmol) in ACN (2 mL) was added a solution of H2O2 (221.43 mg, 1.95 mmol, 187.65 μL, 30% purity) and NH4HCO3 (77.20 mg, 976.47 μmol, 80.41 μL) in H2O (1 mL). The mixture was stirred at 20 °C for 1 h. TLC and LCMS indicated that 6b was completely consumed and detected one major peak of the desired mass. The reaction mixture was diluted with EtOAc (20 mL) and Na2SO3 (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to obtain 6c. MS mass calculated value: [M+1] + (C 13 H 21 N3O2Si), m / z 280.1, MS measured value m / z 280.1; 1 1H 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) To a solution of 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ol (6c) (175 mg, 626.32 μmol, 1 eq) in DMF (2 mL) were added K2CO3 (129.84 mg, 939.48 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (144.67 mg, 688.95 μmol). The mixture was stirred at 20 °C for 1 h. TLC and LCMS indicated complete consumption of 6c and detected one major peak of the desired mass. The reaction mixture was diluted with EtOAc (10 mL) and H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 6d. MS mass calculated value: [M+1] + (C 19 H 22 Cl2N4O4Si), m / z 469.0, MS measured value m / z 469.1; 11H 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]pyridin-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) was added a solution of Fe (107.08 mg, 1.92 mmol) and NH4Cl (102.56 mg, 1.92 mmol) in H2O (0.1 mL). The mixture was stirred at 80 °C for 1 h. TLC and LCMS indicated complete consumption of 6d and detected one major peak of the desired mass. The suspension was filtered through a pad of celite gel and the pad was washed with EtOH (20 mL). The filtrate was concentrated to dryness to afford a residue. The residue was diluted with EtOAc (10 mL) and H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6e. MS mass calculated: [M+1] + (C 19 H 24 Cl2N4O2Si), m / z 439.1, MS found m / z 439.1; 11H 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]pyridin-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-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (6f) To a solution of 3,5-dichloro-4-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)aniline (6e) (50 mg, 113.79 μmol) in THF (3 mL) was added 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). The mixture was stirred at 20 °C for 0.5 h. TLC and LCMS indicated consumption of 6e 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 EtOAc (10 mL) and H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate *0.2% HOAc) to give 6f. MS mass calculated: [M+1] + (C 22 H 24 Cl2N6O5Si), m / z 551.1, LCMS found m / z 551.1.

[0146] Synthesis of N-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridin-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]pyridin-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 a N2 atmosphere. LCMS indicated that 6f was 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 to remove the solvent. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]) and prep-HPLC (column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 6. MS mass calculated: [M+1] + (C 16 H 10 Cl2N6O4), m / z 421.0, LCMS found 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]pyridin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0148] Synthesis of 2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 7) To a solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (7a) (40 mg, 83.99 μmol) in HOAc (2 mL) was added NaOAc (34.45 mg, 419.93 μmol). The mixture was stirred at 120 °C for 3 h. LCMS indicated that 7a was completely consumed and detected one major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.2% FA)-MeCN]) to give Example 7. MS mass calculated value: [M+1] + (C 17 H9Cl2N7O3), m / z 430.0, MS measured value m / z 429.9; 1 1H 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-indazol-5-yl)oxy)aniline (Compound 8d)

Chemical Structure

[0150] Synthesis of 3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-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 (64.07 mg, 69.97 μmol), and t-Bu Xphos (44.57 mg, 104.95 μmol) in a mixture of dioxane (5 mL) and H2O (5 mL) were degassed and purged with N2 three times, then the mixture was stirred at 100 °C for 16 h under a N2 atmosphere. TLC indicated that 8a had been completely consumed and many new spots were formed. LCMS showed the desired MS. The suspension was filtered through a pad of celite and the pad cake was washed with EtOAc (5 ml × 3). The combined filtrate was extracted twice with 15 mL of ethyl acetate and 5 mL of H2O. The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, ethyl acetate: petroleum ether) to give 8b. MS mass calculated 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) A solution of 3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ol (8b) (30 mg, 101.90 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (23.54 mg, 112.08 μmol) in DMF (2 mL) was added with K2CO3 (21.12 mg, 152.84 μmol). The mixture was degassed and purged three times with N2, and stirred at 20 °C for 1 hour. TLC indicated that 8c was completely consumed and one new spot was formed. The mixture was extracted with ethyl acetate (15 mL) and H2O (5 mL). The combined organic phases were washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a 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-indazol-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) were added iron powder (11.53 mg, 206.44 μmol) and NH4Cl (11.04 mg, 206.44 μmol). The mixture was stirred at 80 °C for 2 hours. TLC indicated that 8d was completely consumed and one new spot was formed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (5 mL×3). The combined filtrates were extracted with DCM (15 mL×2) and H2O (5 mL). The combined organic phases were washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, and dried by blowing with nitrogen gas to obtain 8d. MS calculated value for [M+1] + (C 20 H 25 Cl2N3O3Si), m / z 454.1, LCMS measured value m / z 454.1; 11H 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-indazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0154] Synthesis of N-(3,5-dichloro-4-((3-methoxy-1H-indazol-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-indazol-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 h. LCMS and HPLC indicated 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. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0156] Synthesis of 2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (9b) To a solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (9a) (25 mg, 40.22 μmol) in DMA (3 mL) was added KOAc (7.89 mg, 80.44 μmol). The mixture was stirred at 115 °C for 2 h. LCMS and HPLC indicated that 9a was completely consumed and the desired MS was detected. The reaction mixture was extracted with ethyl acetate (15 mL × 2) and H2O (5 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (FA), column: Phenomenex Synergi C18 150×25×10 μm; mobile phase: [water (0.2% FA)-MeCN] to give 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 9) A solution of 2-(3,5-dichloro-4-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-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 h. LCMS and HPLC indicated that 9b was completely consumed and the desired MS was detected. The mixture was concentrated under vacuum to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25×10 μm; mobile phase: [water (0.2% FA)-MeCN]) to give Example 9. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0159] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (10b) A solution of 1-methyl-1H-benzo[d]imidazol-6-ol (10a) (200 mg, 1.35 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (311.81 mg, 1.48 mmol) in DMF (10 mL) was added with K2CO3 (279.85 mg, 2.02 mmol). The mixture was degassed and purged three times with N2 and stirred at 20 °C for 1 hour. TLC indicated that 10a was completely consumed and one new spot was formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate:MeOH) to obtain 10b. MS mass calculated: [M+1] + (C 14 H9Cl2N3O3), m / z 338.0, LCMS found 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]imidazol-6-yl)oxy)aniline (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) were added Fe (148.65 mg, 2.66 mmol) and NH4Cl (142.37 mg, 2.66 mmol). The mixture was stirred at 80 °C for 2 h. TLC indicated that 10b was completely consumed and one new spot was formed. LCMS showed the desired MS. The suspension was filtered through a pad of celite and the pad cake was washed with EtOAc (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 give 10c. MS mass calculated value: [M+1] + (C 14 H 11 Cl2N3O), m / z 308.0, LCMS found 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]imidazol-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]imidazol-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 hour. TLC (ethyl acetate:MeOH) indicated that one new spot was formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (15 mL) and saturated aqueous NH4Cl (5 mL). The combined organic phases were washed with brine (5 mL × 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. MS mass calculated 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]pyridin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0163] Synthesis of 2-(4-amino-2,6-dichlorophenoxy)-N-methyl-5-nitropyridin-4-amine (11b) To a solution of 2-chloro-N-methyl-5-nitropyridin-4-amine (11a) (580 mg, 3.09 mmol) and 4-amino-2,6-dichlorophenol (605.46 mg, 3.40 mmol) in DMF (10 mL) were added K2CO3 (1.71 g, 12.37 mmol) and CuI (353.32 mg, 1.86 mmol) at 20 °C. The mixture was then stirred at 90 °C for 16 h. TLC indicated that the reaction was complete. The mixture was adjusted to pH = 4 - 5 with HCl (1 M) and extracted with EtOAc (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. 11H 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) Iron powder (373.31 mg, 6.68 mmol) and NH4Cl (357.53 mg, 6.68 mmol) were added to a solution of 2-(4-amino-2,6-dichlorophenoxy)-N-methyl-5-nitropyridin-4-amine (11b) (440 mg, 1.34 mmol) in EtOH (8 mL). The mixture was stirred at 80 °C for 16 h. LCMS indicated the complete consumption of 11b. The suspension was filtered through a pad of celite, and the pad cake was washed with EtOAc (5 mL × 3). The combined filtrate was extracted with ethyl acetate (20 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 11c. MS mass calculated 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]pyridin-6-yl)oxy)aniline (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 h. TLC indicated that 11c was completely consumed and one new spot was formed. LCMS showed the desired MS. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, ethyl acetate:methanol) to give 11d. MS mass calculated: [M+1] + (C 13 H 10 Cl2N4O), m / z 309.0, LCMS found 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]pyridin-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]pyridin-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 hour. TLC indicated that one new spot was formed. The mixture was extracted with ethyl acetate (20 mL × 2) and saturated aqueous NH4Cl solution (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a 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. MS mass calculated value: [M+1] + (C 16 H 10 Cl2N6O4), m / z 421.0, LCMS measured value m / z 421.0; 1 1H 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0168] Synthesis of 5-bromo-N1-ethylbenzene-1,2-diamine (12b) To a mixture of 5-bromo-N-ethyl-2-nitroaniline (12a) (2 g, 8.16 mmol) in EtOH (30 mL) and H2O (10 mL) were added NH4Cl (1.75 g, 32.64 mmol) and iron powder (1.82 g, 32.64 mmol). The mixture was stirred at 80 °C for 2 h. TLC indicated that the reaction was completed. 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) in trimethoxymethane (2 mL) was degassed and purged with N2 three times. Then, the mixture was stirred at 100 °C for 2 h under an N2 atmosphere. TLC indicated that 12c was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 12c. MS mass calculated value: [M+1] + (C9H9BrN2), m / z 224.9, LCMS measured value m / z 224.9; 11H 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]imidazol-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 and purged three times with N2, and then the mixture was stirred at 50 °C for 1 hour under a N2 atmosphere. TLC and LCMS indicated that 12c was completely consumed and detected one major peak of the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give 12d. MS mass calculated 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]imidazol-6-ol (12e) A solution of (1 - ethyl - 1H - benzo[d]imidazol - 6 - yl)boronic acid (12d) (580 mg, 3.05 mmol) in ACN (6 mL) was added to 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). The mixture was stirred at 20 °C for 2 hours. TLC and LCMS indicated that 12d was completely consumed and detected one major peak of the desired mass. The reaction mixture was diluted with EtOAc (10 mL) and Na2S2O3 (10 mL), and extracted with EtOAc (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. MS mass calculated 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]imidazol - 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 and purged three times with N2, and then the mixture was stirred at 20 °C for 1 hour under a N2 atmosphere. TLC and LCMS indicated that 12e was completely consumed and detected one major peak of the desired mass. The reaction mixture was diluted with EtOAc (10 mL) and H2O (10 mL), and extracted with EtOAc (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 a residue. The residue was purified by prep - TLC (SiO2, DCM / MeOH) to obtain 12f. MS mass calculated 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 = 7.4 Hz, 3H).

[0173] Synthesis of 3,5-dichloro-4-((1-ethyl-1H-benzo[d]imidazol-6-yl)oxy)aniline (12 g) 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) was added a solution of iron powder (74.53 mg, 1.33 mmol) and NH4Cl (71.39 mg, 1.33 mmol) in H2O (0.1 mL). The mixture was stirred at 80 °C for 1 hour. TLC and LCMS indicated that 12f was completely consumed and detected one major peak of the desired mass. The suspension was filtered through a pad of celite gel and the pad was washed with EtOH (20 mL). The filtrate was concentrated to dryness to give a residue. The residue was diluted with EtOAc (10 mL) and H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 12g. MS mass calculated value: [M+1] + (C 15 H 13 Cl2N3O), m / z 322.0, LCMS measured value m / z 322.0; 11H 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]imidazol-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]imidazol-6-yl)oxy)aniline (12 g) (60 mg, 186.23 μmol) in THF (2 mL) was added 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). The mixture was stirred at 20 °C for 0.5 h. TLC and LCMS indicated that 12 g was completely consumed and detected one major peak of the desired mass. The reaction mixture was quenched by the addition of H2O (0.5 mL). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.2% FA)-MeCN]) to give Example 12. MS mass calculated: [M+1] + (C 18 H 13 Cl2N5O4), m / z 434.0, LCMS found m / z 434.0; 11H 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-(quinolin-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0176] Synthesis of 3,5-Dichloro-4-(quinolin-6-yloxy)aniline (13b) A solution of 6-(2,6-dichloro-4-nitrophenoxy)quinoline (13a) (180 mg, 537.09 μmol) in EtOH (5 mL) and H2O (2 mL) was added with NH4Cl (143.65 mg, 2.69 mmol) and iron powder (149.97 mg, 2.69 mmol). The mixture was then stirred at 80 °C for 2 h. LCMS indicated the completion of the reaction. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was extracted with EtOAc (10 mL) and H2O (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 13b. MS mass calculated 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-(quinolin-6-yloxy)phenyl)hydrazono)acetyl)carbamate (13c) 3,5-Dichloro-4-(quinolin-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, and NaNO2 (13.57 mg, 196.62 μmol) was added. The mixture was then stirred at 0 °C for 20 minutes. The mixture was then added at 0 °C to a solution of ethyl N-(2-cyanoacetyl)carbamate (16.88 mg, 108.14 μmol) in Pyr (1 mL). The mixture was then stirred at 0 °C for an additional 20 minutes. LCMS indicated that the reaction was complete and the desired MS was detected. The mixture was extracted with EtOAc (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 as is in the next step. MS mass calculated: [M+1] + (C 21 H 15 Cl2N5O4), m / z 472.0, LCMS found m / z 471.9.

[0178] Synthesis of 2-(3,5-dichloro-4-(quinolin-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 13) (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-(quinolin-6-yloxy)phenyl)hydrazono)acetyl)carbamate (13c) (40 mg, 84.70 μmol) in a solution of HOAc (2 mL) was added NaOAc (27.79 mg, 338.78 μmol). The mixture was then stirred at 120 °C for 2 hours. LCMS indicated that the reaction was complete and the desired MS was seen among the major peaks. The mixture was concentrated under vacuum. The residue was extracted with EtOAc (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 100×30mm×5μm; mobile phase: [water (0.2% FA)-MeCN]) to obtain Example 13. MS mass calculated: [M+1] + (C19 H9Cl2N5O3), m / z 426.0, LCMS measured value m / z 426.1; 1 1H 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-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0180] Synthesis of 3,5-dichloro-4-((2-methylquinolin-6-yl)oxy)aniline (14b) A solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-methylquinoline (14a) (100 mg, 286.40 μmol) in EtOH (5 mL) and H2O (2 mL) was added with NH4Cl (76.60 mg, 1.43 mmol) and iron powder (79.98 mg, 1.43 mmol). The mixture was stirred at 90 °C for 2 hours. LCMS indicated the completion of the reaction. 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 × 2) and dried under vacuum to obtain 14b. MS mass calculated 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-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (14c) To a mixture of 3,5-dichloro-4-((2-methylquinolin-6-yl)oxy)aniline (14b) (50 mg, 156.65 μmol) in HCl (1 mL) and H2O (0.5 mL) at 0 °C was added NaNO2 (21.62 mg, 313.30 μmol). The mixture was stirred at 0 °C for 20 minutes. Then the mixture was added at 0 °C to a solution of ethyl N-(2-cyanoacetyl)carbamate (26.90 mg, 172.31 μmol) in Pyr (1 mL). Then the mixture was stirred at 0 °C for an additional 20 minutes. LCMS 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 give 14c. The residue was used directly in the next step. MS mass calculated 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-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 14) To a solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (14c) (35 mg, 71.97 μmol) in HOAc (2 mL) was added NaOAc (23.62 mg, 287.88 μmol). Then the mixture was stirred at 120 °C for 2 hours. LCMS indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was extracted with EtOAc (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 give Example 14. MS mass calculated value: [M+1] + (C 20 H 11Cl2N5O3), m / z 440.0, LCMS measured value m / z 440.0; 1 H NMR (400 MHz, 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-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

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

[0185] (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (15c) synthesis To a mixture of 3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)aniline (15b) (30 mg, 93.99 μmol) in HCl (0.5 mL) and H2O (1 mL) was added NaNO2 (8.43 mg, 122.19 μmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, then the resulting mixture was added at 0 °C under N2 to a solution of ethyl (2-cyanoacetyl)carbamate (16.14 mg, 103.39 μmol) in Py (0.5 mL) and H2O (1 mL), and the mixture was stirred at 0 °C for an additional 0.5 h. TLC and LCMS indicated that 15b was completely consumed and one major peak of the desired MS was detected. The reaction mixture was filtered and the filter cake was dried under vacuum to give 15c. MS mass calculated: [M+1] + (C 22 H 17 Cl2N5O4), m / z 486.1, LCMS found m / z 486.1.

[0186] Synthesis of 2-(3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 15) (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (15c) (45.71 mg, 93.99 μmol) in a mixture of HOAc (2 mL) was added NaOAc (38.55 mg, 469.97 μmol) under N2. The mixture was stirred at 120 °C for 2.5 h. LCMS indicated that 15c was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25×10 μm; mobile phase: [water (0.2% FA)-MeCN]) to give Example 15. MS mass calculated: [M+1] + (C 20 H 11 C l2N5O3), m / z 440.0, LCMS measured value m / z 439.9. 1 1H NMR (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-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[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) was added dropwise Pyr (43.50 mg, 549.91 μmol, 44.39 μL) at 55 °C, and the mixture was stirred for 0.5 h. 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 h. TLC showed that 16a was completely consumed and many new spots were formed. LCMS 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 phases were 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 give 16b. 1 1H NMR (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-methylquinolin-6-yl)boronic acid (16c) To a mixture of 6-bromo-3-methylquinoline (16b) (25 mg, 112.57 μmol) in MeOH (2 mL) were added under N2 hypodiboric acid (30.28 mg, 337.71 μmol), DIPEA (43.65 mg, 337.71 μmol, 58.82 μL), and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (752.69 μg, 1.13 μmol). The mixture was stirred at 50 °C for 1.5 h. LCMS showed that 16b was completely consumed and the desired MS was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with MeOH (5 mL × 3). The combined filtrates were concentrated under reduced pressure to give 16c. MS mass calculated value: [M+1] + (C10 H 10 BNO2), m / z 188.0, LCMS measured value m / z 188.1.

[0190] Synthesis of 3-methylquinolin-6-ol (16d) (3-Methylquinolin-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, followed by ammonia; carbonic acid (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 indicated that 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 × 3). The combined organic phases were washed with brine (10 mL × 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. MS mass calculated 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) A solution of 3-methylquinolin-6-ol (16d) (10 mg, 62.82 μmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (14.51 mg, 69.10 μmol) in DMF (2 mL) was added with K2CO3 (13.02 mg, 94.23 μmol). The mixture was degassed and purged three times with N2, and stirred at 20 °C for 1 hour. TLC indicated that 16d was completely consumed and one new spot was formed. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (15 mL) and H2O (5 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate) to obtain 16e. MS mass calculated 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-methylquinolin-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) were added Fe (8.00 mg, 143.20 μmol) and NH4Cl (7.66 mg, 143.20 μmol). The mixture was stirred at 80 °C for 1 hour. TLC indicated that 16e was completely consumed and one new spot was formed. LCMS showed the desired MS. The suspension was filtered through a pad of celite and the pad cake was washed with EtOH (5 ml × 3). The combined filtrates were concentrated under reduced pressure to obtain a 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 × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain 16f. MS mass calculated 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] (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (16g) synthesis To a solution of 3,5-dichloro-4-((3-methylquinolin-6-yl)oxy)aniline (16f) (5 mg, 15.66 μmol) in HCl (0.5 mL) and H2O (1 mL) at 0 °C, NaNO2 (1.41 mg, 20.36 μmol) was added and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was 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). Then the reaction mixture was stirred at 0 °C for an additional 0.5 h. LCMS indicated complete consumption of 16f and the desired MS was detected. The suspension was filtered and then washed with H2O (5 mL × 3). The filter cake was concentrated under reduced pressure to give 16g. MS mass calculated 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-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 16) A solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-methylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (16 g) (5 mg, 10.28 μmol) in HOAc (1.5 mL) was added with NaOAc (4.22 mg, 51.41 μmol). The mixture was stirred at 120 °C for 2.5 h. LCMS indicated that 16 g was 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. MS mass calculated 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-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0196] Synthesis of 2-methyl-2H-indazol-5-ol (17b) To a solution of (2-methyl-2H-indazol-5-yl)boronic acid (17a) (120 mg, 681.90 μmol) in ACN (2 mL) was added 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). The mixture was stirred at 20 °C for 1 h. TLC and LCMS indicated that 17a was completely consumed and detected one major peak of the desired mass. The reaction mixture was diluted with EtOAc (20 mL) and Na2SO3 (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH) to give 17b. MS mass calculated value: [M+1] + (C8H8N2O), m / z 149.0, LCMS measured value m / z 149.1; 11H 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-indazol-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 h under a N2 atmosphere. TLC indicated that 17c was completely consumed and one new spot was formed. H2O (2 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was washed with 5 mL of H2O and dried under vacuum to obtain 17c. MS mass calculated value: [M+1] + (C 14 H9Cl2N3O3), m / z 338.0, LCMS measured value m / z 338.0; 1 1H 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-indazol-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), and NH4Cl (79.09 mg, 1.48 mmol) in EtOH (2 mL) was stirred at 80 °C for 1 hour under a N2 atmosphere. LCMS indicated that 17c was completely consumed and detected one major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H2O and dried under vacuum to obtain 17d. MS mass calculated: [M+1] + (C 14 H 11 Cl2N3O), m / z 308.0, LCMS found m / z 308.0.

[0199] Synthesis of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-2H-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (17e) To a solution of 3,5-dichloro-4-((2-methyl-2H-indazol-5-yl)oxy)aniline (17d) (40 mg, 129.80 μmol) in HCl (0.5 mL) and H2O (1 mL) at 0 °C was added NaNO2 (11.64 mg, 168.74 μmol). The mixture was stirred at 0 °C for 10 minutes. Then the mixture was added at 0 °C to a solution of ethyl N-(2-cyanoacetyl)carbamate (22.29 mg, 142.78 μmol) in H2O (1 mL) and Pyr (0.5 mL). The reaction mixture was stirred at 0 °C for an additional 10 minutes. LCMS indicated that 17d was completely consumed and detected one major peak of 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. MS mass calculated: [M+1] + (C 20 H 16 Cl2N6O4), m / z 475.0, MS found m / z 475.1.

[0200] Synthesis of 2-(3,5-dichloro-4-((2-methyl-2H-indazol-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-indazol-5-yl)oxy)phenyl)hydrazono)acetyl)carbamate (17e) (60 mg, 126.24 μmol) in HOAc (2 mL) solution, NaOAc (51.78 mg, 631.20 μmol) was added. The mixture was stirred at 120 °C for 2 hours. LCMS showed that 17e was completely consumed and detected one major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. 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. MS mass calculated value: [M+1] + (C 18 H 10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0; 1 1H 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0202] Synthesis of 5-bromo-N1-methylbenzene-1,2-diamine (18b) To a solution of 5-bromo-N-methyl-2-nitroaniline (18a) (1.8 g, 7.79 mmol) in EtOH (30 mL) and H2O (10 mL) were added NH4Cl (2.08 g, 38.95 mmol) and iron powder (2.18 g, 38.95 mmol). Then, the mixture was stirred at 80 °C for 16 h. LCMS indicated that the reaction was completed and the desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum to obtain 18b. MS mass calculated 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]imidazol-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) were added TEA (1.81 g, 17.90 mmol, 2.49 mL) and DSC (1.68 g, 6.57 mmol). Then, the mixture was stirred at 20 °C for 16 h. TLC indicated that the reaction was completed. The mixture was concentrated under vacuum. The residue was diluted with H2O (15 mL) and EtOAc (15 mL). The mixture was filtered and the solid was collected. The solid was extracted with EtOAc (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]imidazol-2(3H)-one (18d) To a mixture of 6-Bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (18c) (1.1 g, 4.84 mmol) in DMF (15 mL) was added NaH (213.14 mg, 5.33 mmol, 60% purity) at 20 °C. The mixture was then stirred at 20 °C for 10 minutes. Then 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 indicated consumption of the starting material and formation of one new spot. The mixture was added to H2O (45 mL) and extracted with EtOAc (20 mL × 2). 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 silica gel column chromatography (petroleum ether:ethyl acetate) to give 18d. 1 H 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]imidazol-5-yl)boronic acid (18e) A mixture of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (18d) (200 mg, 559.73 μmol) and hypodiboric acid (150.54 mg, 1.68 mmol) in MeOH (5 mL) was added with DIEA (217.02 mg, 1.68 mmol, 292.48 μL) and cataCXium A-Pd-G2 (3.74 mg, 5.60 μmol) under N₂. The mixture was stirred at 50 °C for 1.5 h. LCMS indicated that 18d was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, and 18e was obtained. MS mass calculated 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]imidazol-2(3H)-one (18f) To a mixture of (3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)boronic acid (18e) (130 mg, 403.43 μmol) in CH₃CN (2 mL) was added a solution of NH₄HCO₃ (31.89 mg, 403.43 μmol, 33.22 μL) in H₂O (1 mL) and H₂O₂ (91.48 mg, 806.85 μmol, 77.53 μL, 30% purity) under N₂. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into NaHSO₃ (10 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 18f. MS mass calculated value: [M+1] + (C 14 H 22 N2O3Si), m / z 295.1, LCMS measured value m / z 295.2;1 1H NMR (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]imidazol-2(3H)-one (18g) To a mixture of 5-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (18f) (130 mg, 441.55 μmol) in DMF (3 mL) under N2, K2CO3 (91.54 mg, 662.32 μmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (101.99 mg, 485.70 μmol) were added. The mixture was stirred at 20 °C for 1 h. LCMS indicated that 18f was completely consumed and the desired MS was detected. TLC indicated 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 × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate) to give 18g. MS mass calculated value: [M+1] + (C 20 H 23 Cl2N3O5Si), m / z 484.1, LCMS measured value m / z 484.1; 11H 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]imidazol-2(3H)-one (18h) To a mixture of 5-(2,6-Dichloro-4-nitrophenoxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (18g) (100 mg, 206.44 μmol) in EtOH (4 mL) was added 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 h. LCMS indicated 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 give a residue. The residue was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (15 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 18h. MS mass calculated 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]imidazol-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]imidazol-2(3H)-one (18h) (20 mg, 44.01 μmol) in THF (1.5 mL) under N2, 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. The mixture was stirred at 20 °C for 20 minutes. LCMS indicated that 18h was completely consumed and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]) to give 18i. MS mass calculated value: [M+1] + (C 23 H 25 Cl2N5O6Si), m / z 566.1, LCMS measured value m / z 566.2; 11H 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 18) To a mixture of N-(3,5-dichloro-4-((3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (18i) (8.5 mg, 15.01 μmol) in dioxane (0.5 mL) was added HCl (2 mL) under N2. The mixture was stirred at 65 °C for 6 h. LCMS indicated the consumption of 18i. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]) to give Example 18. MS mass calculated value: [M+1] + (C 17 H 11 Cl2N5O5), m / z 436.0, LCMS measured value m / z 435.9; 11H 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chem.

[0212] Synthesis of 2-(3,5-dichloro-4-((1-methyl-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (19a) (20 mg, 42.1 μmol) in a mixture of HOAc (2 mL) was added NaOAc (17.3 mg, 210 μmol) under N2. The mixture was stirred at 120 °C for 3 h. LCMS indicated that 19a was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 μm; mobile phase: [water (0.2% FA)-ACN]; 20%-60%, 10 min) to give Example 19. MS mass calculated value: [M+1] + (C 18 H 10 Cl2N6O3), m / z 429.0, LCMS measured value m / z 429.0; 1 1H 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[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) in EtOH (10 mL) was added a solution of NH4Cl (1.34 g, 25.1 mmol) in H2O (3 mL) and Fe (1.40 g, 25.1 mmol) under N2. The mixture was stirred at 80 °C for 2 h. TLC indicated 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 × 2). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 20b. 1 1H 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 at 100 °C for 2 h under N2. TLC (petroleum ether:ethyl acetate) indicated that 20b was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give 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]imidazol-6-yl)boronic acid (20d) To a mixture of 6-bromo-1-isopropyl-1H-benzo[d]imidazole (20c) (1 g, 4.18 mmol) in MeOH (6 mL) were added 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) under N2. The mixture was stirred at 50 °C for 0.5 h. TLC indicated that 20c was completely consumed and one new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give 20d.

[0217] Synthesis of isopropyl-1H-benzo[d]imidazol-6-ol (20e) 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 to a mixture of isopropyl-1H-benzo[d]imidazol-6-yl)boronic acid (20d) (853 mg, 4.18 mmol) in CH3CN (10 mL) under N2. The mixture was stirred at 25 °C for 1 h. LCMS indicated 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 × 2). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 20e. MS mass calculated 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) K2CO3 (753 mg, 5.45 mmol) was added to a mixture of 1-isopropyl-1H-benzo[d]imidazol-6-ol (20e) (640 mg, 3.63 mmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (839 mg, 4.00 mmol) in DMF (10 mL) under N2. The mixture was stirred at 25 °C for 1 h. TLC indicated that 20e was completely consumed and many new spots were formed. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were 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 give 20f. 11H 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]imidazol-6-yl)oxy)aniline (20g) To a mixture of 6-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-1H-benzo[d]imidazole (20f) (500 mg, 1.37 mmol) in EtOH (8 mL) was added a solution of NH4Cl (365 mg, 6.83 mmol) in H2O (2 mL) and Fe (381 mg, 6.83 mmol) under N2. The mixture was stirred at 80 °C for 2 h. TLC indicated that 20f was completely consumed and one new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was washed with water to give 20g. 1 1H 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 20) A mixture of 3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazol-6-yl)oxy)aniline (20 g) (50 mg, 149 μmol) in THF (3 mL) was added with 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) under N2. The mixture was stirred at 25 °C for 1 h. LCMS indicated 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 × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was washed with water (2 mL × 2) and ethyl acetate (2 mL × 4) to obtain Example 20. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0222] Synthesis of 2-(3,5-dichloro-4-((1-isopropyl-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (21a) (100 mg, 199 μmol) in HOAc (4 mL) was added NaOAc (81.5 mg, 993 μmol) under N2. The mixture was stirred at 120 °C for 3 h. LCMS indicated that 21a was completely consumed and one major peak of the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a 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 afford Example 21. MS mass calculated value: [M+1] + (C 20 H 14 Cl2N6O3), m / z 457.1, LCMS found 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[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) were added Fe (1.09 g, 19.45 mmol) and NH4Cl (1.04 g, 19.45 mmol). The mixture was stirred at 80 °C for 5 h. LCMS indicated that 22a was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with EtOH (5 mL × 3). The combined filtrates were concentrated under reduced pressure. The residue was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 22b. MS mass calculated value: [M+1] + (C9H 11BrN2), m / z 227.0, LCMS found m / z 227.1; 1 1H 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 h. LCMS indicated complete consumption of 22b 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 give 22c. MS calculated value: [M+1] + (C 10 H9BrN2), m / z 237.0, LCMS found m / z 237.1; 1 1H 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]imidazol-6-yl)boronic acid (22d) A mixture of 6-bromo-1-cyclopropyl-1H-benzo[d]imidazole (22c) (420 mg, 1.77 mmol) in MeOH (10 mL) was added with hypodiboric acid (476.43 mg, 5.31 mmol), DIPEA (686.82 mg, 5.31 mmol, 925.63 μL), and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (11.84 mg, 17.71 μmol) under N2. The mixture was stirred at 50 °C for 1 hour. LCMS indicated that 22c was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with MeOH (5 mL×3). The combined filtrate was concentrated under reduced pressure to give 22d. MS mass calculated 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]imidazol-6-ol (22e) To a mixture of (1-cyclopropyl-1H-benzo[d]imidazol-6-yl)boronic acid (22d) (350 mg, 1.73 mmol) in H2O (2 mL) and CH3CN (4 mL) were added ammonium carbonate (136.97 mg, 1.73 mmol, 142.67 μL) and H2O2 (392.82 mg, 3.47 mmol, 332.90 μL, 30% purity) under N2. The mixture was stirred at 20 °C for 1 hour. LCMS indicated 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×3). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 22e. MS mass calculated value: [M+1] + (C 10 H 10 N2O), m / z 175.1, LCMS measured value m / z 175.2;1 1H 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) To a solution of 1-cyclopropyl-1H-benzo[d]imidazol-6-ol (22e) (300 mg, 1.72 mmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (397.80 mg, 1.89 mmol) in DMF (10 mL) was added K2CO3 (357.03 mg, 2.58 mmol). The mixture was degassed and purged with N2 three times and stirred at 20 °C for 1 h. LCMS and TLC indicated 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 phases were 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 give 22f. MS mass calculated value: [M+1] + (C 16 H 11 Cl2N3O3), m / z 364.0, LCMS measured value m / z 364.0; 11H 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]imidazol-6-yl)oxy)aniline (22g) To a solution of 1-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (22f) (410 mg, 1.13 mmol) in EtOH (10 mL) and H2O (3 mL) were added Fe (314.38 mg, 5.63 mmol) and NH4Cl (301.10 mg, 5.63 mmol). The mixture was stirred at 80 °C for 2 h. LCMS indicated complete consumption of 22f and detection of the desired MS. The suspension was filtered through a pad of Celite 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 phases were 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 afford 22g. MS mass calculated value: [M+1] + (C 16 H 13 Cl2N3O), m / z 334.0, LCMS measured value m / z 334.1; 11H 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 22) To a solution of 3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazol-6-yl)oxy)aniline (22 g) (25 mg, 74.81 μmol) in THF (3 mL) were added 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). The mixture was stirred at 25 °C for 0.5 h. LCMS indicated 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 min. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((NH4HCO3), column: Waters Xbridge BEH C18 100×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN)] to obtain Example 22. MS mass calculated value: [M+1] + (C 16 H 13 Cl2N3O), m / z 446.0, LCMS measured value m / z 445.9; 11H 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chem.

[0232] Synthesis of 2-(3,5-dichloro-4-((1-cyclopropyl-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (23a) (40 mg, 79.79 μmol) in a solution of DMA (3 mL) was added KOAc (15.66 mg, 159.58 μmol). The mixture was stirred at 115 °C for 3 h. LCMS indicated that 23a was completely consumed and the desired MS was detected. The mixture was added dropwise to H2O (4 mL) with stirring in 10 min. The mixture was filtered, and the filter cake was washed with H2O (1 mL×3) and dried under vacuum. The residue was purified by Prep-HPLC; column: Waters Xbridge BEH C18 100×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain Example 23. MS calculated value: [M+1] + (C 20 H 12 Cl2N6O3), m / z 455.0, LCMS measured value m / z 454.9; 11H 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-cyclopropylquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[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 and purged with N2 three times, and then the mixture was stirred at 100 °C for 16 h under a 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 × 2). The combined organic layers were washed with brine (20 mL × 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 24b. MS mass calculated 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-cyclopropylquinolin-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 a mixture of EtOH (20 mL) and H2O (4 mL) was degassed and purged three times with N2, and then the mixture was stirred at 90 °C for 3 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was filtered, concentrated, 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 a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain 24c. MS calculated mass: [M+H] + (C 18 H 14 Cl2N2O), m / z, 345.0, LCMS found 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-cyclopropylquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 24) A mixture of 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) in THF (2 mL) was added with 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (17.21 mg, 115.87 μmol). The mixture was degassed and purged three times with N2, and then the mixture was stirred at 25 °C for 0.5 h under an N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions: column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 24. MS mass calculated 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-methylquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0238] Example 26 2-(3,5-Dichloro-4-((2-cyclopropylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0239] Synthesis of 2-(3,5-dichloro-4-((2-cyclopropylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (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 and purged three times with N2. Then the mixture was stirred at 115 °C for 3 h under an N2 atmosphere. LCMS indicated the completion of the reaction 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 150×25mm×5μm; mobile phase: [water (0.2% FA)-ACN]) to obtain Example 26. MS mass calculated 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[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-dioxaborolane (114.08 mg, 449.23 μmol) in dioxane (3 mL) was added KOAc (183.70 mg, 1.87 mmol) and Pd(PPh3)2Cl2 (26.28 mg, 37.44 μmol) at 20 °C under N2. The mixture was stirred at 90 °C for 4 h. LCMS indicated complete consumption of 27a and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with ethyl acetate (5 mL × 3). The combined filtrate was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 27b. MS mass calculated value: [M+1] + (C 17 H 23 BN2O3), m / z 315.2, LCMS measured value m / z 315.1; 11H 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]imidazol-6-ol (27c) To a mixture of H2O (1.5 mL) and CH3CN (3 mL) of 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) under N2, 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) were added. The mixture was stirred at 20 °C for 1 h. LCMS indicated that 27b was completely consumed and the desired MS was detected. The residue was poured into NaHSO3 (30 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 27c. MS mass calculated 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) A solution of 1-cyclopropyl-2-methoxy-1H-benzo[d]imidazol-6-ol (27c) (70 mg, 342.76 μmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (79.17 mg, 377.04 μmol) in DMF (3 mL) was added with K2CO3 (71.06 mg, 514.14 μmol). The mixture was degassed, purged three times with N2, and stirred at 20 °C for 1 hour. LCMS and TLC indicated 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 phases were 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. MS mass calculated 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]imidazol-6-yl)oxy)aniline (27e) A solution of 1-cyclopropyl-6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1H-benzo[d]imidazole (27d) (120 mg, 304.41 μmol) in EtOH (3 mL) and H2O (1 mL) was added to Fe (85.01 mg, 1.52 mmol) and NH4Cl (81.41 mg, 1.52 mmol). The mixture was stirred at 80 °C for 2 h. LCMS indicated that 27d was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite 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 phases were 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 give 27e. MS mass calculated: [M+1] + (C 17 H 15 Cl2N3O2), m / z 364.1, LCMS found 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 27) A solution of 3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)aniline (27e) (50 mg, 137.28 μmol) in DCM (2 mL) was added with 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). The mixture was stirred at 25 °C for 0.5 h. LCMS indicated 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 100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]) to obtain Example 27. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0247] Synthesis of 2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (28a) (260 mg, 489.32 μmol) in DMA (3 mL) was added KOAc (96.04 mg, 978.64 μmol). The mixture was stirred at 115 °C for 3 h. LCMS indicated that 28a was completely consumed and the desired MS was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with MeOH (5 mL×3). The combined filtrates were concentrated under reduced pressure. The residue was purified by Prep-HPLC ((FA), column: Welch Ultimate C18 150×25 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]) to afford Example 28. MS mass calculated value: [M+1] + (C 21 H 14 Cl2N6O4), m / z 485.0, LCMS found m / z 484.9; 1 1H 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chem.

[0249] Synthesis of 5-bromo-N1-methylbenzene-1,2-diamine (29b) To a solution of 5-bromo-N-methyl-2-nitroaniline (29a) (1.05 g, 4.54 mmol) in EtOH (30 mL) and H2O (10 mL) were added NH4Cl (1.22 g, 22.7 mmol) and Fe (1.27 g, 22.7 mmol). The mixture was stirred at 80 °C for 2 h. TLC indicated complete consumption of 29a and formation of one new spot. The reaction mixture was filtered, and then 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 afford 29b. 11H 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) was added tetramethoxymethane (2.17 g, 15.9 mmol). The mixture was stirred at 50 °C for 1 h. LCMS indicated the complete consumption of 29b and detected one major peak of the desired MS. The reaction mixture was quenched at 0 °C by the addition of NaHCO3 (30 mL), then extracted with ethyl acetate (30 mL × 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 afford 29c. 1 1H 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, 3 H).

[0251] Synthesis of 2-methoxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (29d) 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) was added with Pd(PPh3)2Cl2 (96.1 mg, 136.9 μmol) and KOAc (1.34 g, 13.7 mmol). The mixture was stirred at 120 °C for 16 h. LCMS indicated 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 × 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 29d. MS mass calculated: [M+1] + (C 15 H 21 BN2O3), m / z 289.2, LCMS found 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]imidazol-6-ol (29e) 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) was added to a solution 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). The mixture was stirred at 20 °C for 2 h. LCMS indicated 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 × 3). The combined organic layers were washed with saturated NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 29e. MS mass calculated: [M+1] + (C9H 10 N2O2), m / z 179.1, LCMS found 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) A solution of 2-methoxy-1-methyl-1H-benzo[d]imidazol-6-ol (29e) (240 mg, 1.35 mmol) in DMF (5 mL) was added to K2CO3 (279 mg, 2.02 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (311 mg, 1.48 mmol). The mixture was stirred at 20 °C for 1 h. LCMS indicated complete consumption of 29e and detected one major peak of the desired MS. The reaction mixture was quenched by the addition of H2O (5 mL) and 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. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to give 29f. MS mass calculated 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]imidazol-6-yl)oxy)aniline (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) was added a solution of Fe (121 mg, 2.17 mmol) and NH4Cl (116 mg, 2.17 mmol) in H2O (1 mL). The mixture was stirred at 80 °C for 2 h. LCMS indicated that 29f was completely consumed and one major peak of the desired MS was detected. The reaction mixture was filtered and then 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 give 29g. 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29) A solution of 3,5-dichloro-4-((2-methoxy-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)aniline (29 g) (10 mg, 29.6 μmol) in THF (1 mL) was added with 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). The mixture was stirred at 20 °C for 20 minutes. LCMS indicated 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 condition: column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (0.04% HCl)-ACN]) to obtain Example 29. MS mass calculated 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0257] Synthesis of 1-isopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (30b) 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) was added with Pd(PPh3)2Cl2 (83.45 mg, 118.90 μmol) and KOAc (1.17 g, 11.89 mmol). The mixture was stirred at 120 °C for 16 h. LC-MS indicated 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 × 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30b. MS mass calculated 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]imidazol-6-ol (30c) 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) was added with a solution of NH4HCO3 (93.76 mg, 1.19 mmol, 97.67 μL) in CH3CN (5 mL) and H2O2 (268.89 mg, 2.37 mmol, 227.88 μL, 30% purity). The mixture was stirred at 20 °C for 2 h. LCMS indicated that 30b was completely consumed and one major peak of 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 × 3). The combined organic layers were washed with saturated NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30c. MS mass calculated 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]imidazol-6-ol (30c) (244 mg, 1.18 mmol) in DMF (1 mL) were added K2CO3 (245.26 mg, 1.77 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (273.28 mg, 1.30 mmol). The mixture was stirred at 20 °C for 1 hour. LCMS indicated 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), then 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. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to give 30d. MS mass calculated 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]imidazol-6-yl)oxy)aniline (30e) 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) was added to a solution of Fe (105.71 mg, 1.89 mmol) and NH4Cl (101.25 mg, 1.89 mmol) in H2O (1 mL). The mixture was stirred at 80 °C for 2 h. TLC indicated 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 give 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]imidazol-5-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 30) A solution of 3,5-dichloro-4-((1-isopropyl-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)aniline (30e) (30 mg, 81.91 μmol) in DCM (0.5 mL) was added with 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). The mixture was stirred at 25 °C for 0.5 h. LCMS indicated that 30e was completely consumed and a trace amount of the desired MS was detected. The mixture was stirred for an additional 2 h. LCMS indicated 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 150×25 mm×5 μm; 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. MS mass calculated value: [M+1] + ( C 19 H 15 Cl2N5O5), m / z 464.0, LCMS measured value m / z 464.0; 1 1H 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]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0263] Synthesis of 2-(3,5-dichloro-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (31a) (20 mg, 37.50 μmol) in DMA (1 mL) was added KOAc (7.36 mg, 75.00 μmol). The mixture was stirred at 110 °C for 6 h. LCMS indicated complete consumption of 31a and detected one major peak of the desired mass. 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, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]) to give Example 31. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0265] Example 33 N-(3,5-Dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0266] Example 34 2-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [Chem.] Synthesis of 2-(3,5-dichloro-4-((3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 34) To a solution of 2-(3,5-dichloro-4-((1-cyclopropyl-2-methoxy-1H-benzo[d]imidazol-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) in DCM (3 mL) was added BCl3 (1 M, 41.21 μL). The mixture was stirred at 40 °C for 32 h. LCMS indicated that Example 28 was completely consumed and the desired MS was detected. The mixture was quenched with MeOH (2 mL) and stirred at 25 °C for 10 min. 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 give Example 34. MS mass calculated 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-ethylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chem.

[0268] Synthesis of 4-ethylquinolin-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 h. TLC and LCMS indicated that 35a was completely consumed and one major peak of 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 × 3) and dried under vacuum to give 35b. MS mass calculated: [M+1] + (C 11 H 11 NO), m / z 174.1, MS found 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, 3 H).

[0269] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4-ethylquinoline (35c) To a solution of 4-ethylquinolin-6-ol (35b) (423 mg, 2.44 mmol) in DMF (2 mL) were added 1,3-dichloro-2-fluoro-5-nitro-benzene (512.82 mg, 2.44 mmol) and K2CO3 (675.03 mg, 4.88 mmol). The mixture was stirred at 20 °C for 1 h. TLC indicated that 35c was completely consumed and one new spot was formed. The reaction mixture was diluted with ethyl acetate (30 mL) and H2O (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 35c. MS mass calculated: [M+1] + (C17 H 12 Cl2N2O3), m / z 363.0, MS measured value m / z 363.0; 1 1H 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-ethylquinolin-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) was added a solution of Fe (599.67 mg, 10.74 mmol) and NH4Cl (574.39 mg, 10.74 mmol) in H2O (0.5 mL). The mixture was stirred at 80 °C for 2 hours. TLC indicated that 35c was completely consumed and one new spot was formed. The suspension was filtered through a pad of celite and the pad cake was washed with ethyl acetate (10 mL × 3). The combined filtrate was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were 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 give 35d. MS mass calculated value: [M+1] + (C 17 H 14 Cl2N2O), m / z 333.0, MS measured value m / z 333.0; 11H 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] (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((4-ethylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (35e) synthesis To a solution of 3,5-dichloro-4-((4-ethylquinolin-6-yl)oxy)aniline (35d) (20 mg, 60.02 μmol) in HOAc (1 mL) and H2O (0.5 mL) at 0 °C were added ethyl (2-cyanoacetyl)carbamate (14.06 mg, 90.03 μmol) and HCl (1 M, 150.05 μL). Then, NaNO2 (5.38 mg, 78.03 μmol) was added to the mixture. The mixture was stirred at 0 °C for 1 hour. LCMS indicated that 35d 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 to obtain 35e. MS mass calculated 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-ethylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 35) A solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((4-ethylquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (35e) (30 mg, 59.96 μmol) in DMA (2 mL) was added to KOAc (11.77 mg, 119.92 μmol). The mixture was stirred at 115 °C for 3 h. LCMS indicated that 35e was completely consumed and detected one major peak of the desired mass. 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 purified by prep-TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f = 0.45) to afford Example 35. MS mass calculated 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, 3 H).

[0273] Example 36 N-(3,5-Dichloro-4-((4-ethylquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0274] Example 37 N-(4-((1-(tert-butyl)-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide [Chemical formula] Synthesis of 5-Bromo-N-(tert-butyl)-2-nitroaniline (37a) To a solution of 4-Bromo-2-fluoro-1-nitrobenzene (1g, 4.55 mmol) in CH3CN (10 mL) were added DIPEA (2.35 g, 18.18 mmol, 3.17 mL) and 2-methylpropan-2-amine (997.34 mg, 13.64 mmol, 1.43 mL). The mixture was stirred at 50 °C for 2 hours. TLC showed that the starting material was completely consumed and one new spot was 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 × 2). The combined organic layers were washed with brine (15 mL × 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) was added Fe (1.27 g, 22.70 mmol), 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 h. TLC indicated that 37a was completely consumed and one new spot was 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 × 3). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 37b. MS mass calculated: [M+1] + (C 10 H 15 BrN2), m / z 243.04, LCMS found 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 h. LCMS indicated that the reaction was complete and the desired MS was detected. The mixture was concentrated under vacuum to give 37c. MS mass calculated: [M+1] + (C 11 H 13 (BrN2), m / z 253.03, LCMS found m / z 253.0; 11H 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-dioxaborolane (288.91 mg, 1.14 mmol) in dioxane (3 mL) was added KOAc (372.19 mg, 3.79 mmol) and Pd(PPh3)2Cl2 (26.62 mg, 37.92 μmol) at 20 °C under N2. The mixture was stirred at 90 °C for 4 h. TLC and LCMS indicated complete consumption of 37c and the desired MS was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (3 mL × 3). The combined filtrates were concentrated in vacuo. The residue was diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate) to afford 37d. MS mass calculated: [M+1] + (C 17 H 25 BN2O2), m / z 301.2, LCMS found m / z 301.2; 11H 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]imidazol-6-ol (37e) To a mixture of 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) in H2O (1.5 mL) and CH3CN (3 mL) under N2, ammonium carbonate (21.07 mg, 266.49 μmol, 21.94 μL), and H2O2 (60.42 mg, 532.97 μmol, 51.20 μL, 30% purity) were added. The mixture was stirred at 20 °C for 1 h. LCMS indicated that 37d was completely consumed and the desired MS was detected. The residue was poured into NaHSO3 (30 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give 37e. The crude product was used in the next step without further purification. MS mass calculated value: [M+1] + (C 11 H 14 N2O), m / z 191.11, LCMS measured value m / z 191.2; 1 1H 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) A solution of 1-(tert-butyl)-1H-benzo[d]imidazol-6-ol (37e) (50 mg, 262.82 μmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (60.71 mg, 289.11 μmol) in DMF (3 mL) was added with K2CO3 (54.49 mg, 394.24 μmol) at 20 °C under N2. The mixture was stirred at 20 °C for 1 hour. TLC and LCMS indicated 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 phases were 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. MS mass calculated 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]imidazol-6-yl)oxy)-3,5-dichloroaniline (37g) A solution of 1-(tert-butyl)-6-(2,6-dichloro-4-nitrophenoxy)-1H-benzo[d]imidazole (37f) (54 mg, 142.02 μmol) in EtOH (3 mL) and H2O (1 mL) was added with Fe (39.66 mg, 710.11 μmol) and NH4Cl (37.98 mg, 710.11 μmol) at 25 °C. Then the mixture was stirred at 80 °C for 1 h. TLC and LCMS indicated that 37f was completely consumed and the desired MS was detected. The suspension was filtered through a pad of Celite 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 phases were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 37g. The solid was used directly in the next step without further purification. MS mass calculated 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]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 37) A solution of 4-((1-(tert-butyl)-1H-benzo[d]imidazol-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) in CH2Cl2 (3 mL) was added with TEA (17.33 mg, 171.31 μmol, 23.84 μL) at 25 °C. Then the mixture was stirred at 25 °C for 30 minutes. LCMS indicated that 37 g was completely consumed and the desired MS was detected. The mixture was quenched with MeOH (5 mL × 3) and stirred at 25 °C for 5 minutes. Then 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 37. MS mass calculated 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]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0283] Synthesis of 2-(4-((1-(tert-butyl)-1H-benzo[d]imidazol-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]imidazol-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate (38a) (28 mg, 54.12 μmol) in DMA (2 mL) was added KOAc (10.62 mg, 108.24 μmol). The mixture was stirred at 115 °C for 3 h. LCMS and HPLC indicated that 38a was completely consumed and the desired MS was detected. The mixture was then concentrated under vacuum to give a 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 give Example 38. MS calculated mass: [M+1] + (C 21 H 16 Cl2N6O3), m / z 471.0, LCMS found m / z 470.9; 1 1H NMR (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]oxazin-7-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[0285] Synthesis of 3-((2-amino-5-bromophenyl)amino)propan-1-ol (39b) To a solution of 3-(5-bromo-2-nitro-anilino)propan-1-ol (39a) (900 mg, 3.27 mmol) in EtOH (10 mL) was added a solution of Na2S2O4 (4.56 g, 26.17 mmol) in H2O (8 mL). The mixture was stirred at 25 °C for 16 hours. LCMS indicated complete consumption of 39a and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with EtOH (5 mL × 3). The combined filtrates were concentrated under vacuum. The residue was extracted with ethyl acetate (25 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 39b. MS mass calculated value: [M+1] + (C9H 13 BrN2O), m / z 245.0, LCMS measured value m / z 245.1; 1 1H 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)-thione (39c) To a solution of 3-(2-amino-5-bromo-anilino)propan-1-ol (39b) (640 mg, 2.61 mmol) in THF (5 mL) was added bis(imidazol-1-yl)methanethione (604.91 mg, 3.39 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 h. LCMS and TLC indicated complete consumption of 39b and detection of the desired MS. The mixture was extracted with ethyl acetate (25 mL × 2) and aqueous NH4Cl solution (15 mL). The combined organic phases were washed with brine (15 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 give 39c. MS mass calculated value: [M+1] + (C 10 H 11 BrN2OS), m / z 287.0, LCMS measured value m / z 287.0; 1 1H 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]imidazol-1-yl)propan-1-ol (39d) To a solution of 5-bromo-3-(3-hydroxypropyl)-1H-benzimidazole-2-thione (39c) (200 mg, 696.44 μmol) in CH3CN (3 mL) was added MeI (118.62 mg, 835.73 μmol, 52.03 μL) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS indicated complete consumption of 39c and the desired MS was detected. The mixture was extracted with ethyl acetate (20 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 39d. MS mass calculated 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-benzimidazol-1-yl)propan-1-ol (39d) (193 mg, 640.77 μmol) in THF (5 mL) was degassed and purged with O2 three times. 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 h. LCMS and TLC indicated 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 × 3), and the combined organic phases were 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 give 39e. MS mass calculated 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) 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-dioxaborolane (301.00 mg, 1.19 mmol) in dioxane (6 mL) was added with KOAc (387.76 mg, 3.95 mmol) and Pd(PPh3)2Cl2 (27.73 mg, 39.51 μmol) at 20 °C under N2. The mixture was stirred at 90 °C for 4 h. LCMS indicated that 39e was completely consumed and the desired MS was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with ethyl acetate (5 mL × 3). The combined filtrate was concentrated under vacuum. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 39f. MS mass calculated 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) To a mixture 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) (50 mg, 166.58 μmol) in H2O (1 mL) and CH3CN (2 mL) under N2, ammonium carbonate (13.17 mg, 166.58 μmol, 13.72 μL), and H2O2 (37.77 mg, 333.16 μmol, 32.01 μL, 30% purity) were added. The mixture was stirred at 20 °C for 1 h. LCMS indicated that 39f was completely consumed and the desired MS was detected. The residue was poured into NaHSO3 (20 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 39g. The product was used in the next step without further purification. MS mass calculated value: [M+1] + (C 10 H 10 N2O2), m / z 191.2, LCMS observed 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) To a solution of 3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-ol (39g) (30 mg, 157.73 μmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (36.43 mg, 173.50 μmol) in DMF (2 mL), K2CO 3(32.70 mg (236.60 μmol) was added. The mixture was degassed and purged three times with N2, and stirred at 20 °C for 16 h. LCMS indicated that 39 g was completely consumed and the desired MS was detected. The mixture was extracted with ethyl acetate (20 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 39 h. MS mass calculated 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]oxazin-7-yl)oxy)aniline (39i) To a solution of 7-(2,6-dichloro-4-nitro-phenoxy)-3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole (39h) (55 mg, 144.67 μmol) in EtOH (2 mL) and H2O (0.5 mL) were added Fe (40.40 mg, 723.34 μmol) and NH4Cl (38.69 mg, 723.34 μmol). The mixture was stirred at 80 °C for 2 h. LCMS indicated that 39h was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite 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 phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 39i. The product was used directly in the next step without further purification. MS mass calculated: [M+1] + (C 16 H 13 Cl2N3O2), m / z 350.0, LCMS found 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]oxazin-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]oxazin-7-yl)oxy)aniline (39i) (15 mg, 42.83 μmol) in DCM (2 mL) were added 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). The mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with MeOH (5 mL) and stirred at 25 °C for 10 min. The mixture was then concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]) to give Example 39. MS calculated for: [M+1] + (C 19 H 13 Cl2N5O5), m / z 462.0, LCMS found 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]oxazin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0295] Synthesis of 2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 40) A solution of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate (40a) (20 mg, 38.66 μmol) in DMA (2 mL) was added KOAc (7.59 mg, 77.32 μmol). The mixture was stirred at 115 °C for 3 h. LCMS indicated 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 give Example 40. MS mass calculated 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]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[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) A mixture of 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( 173.51 mg, 247.21 μmol) in dioxane (3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110 °C for 16 h under an N2 atmosphere. TLC and LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 41b. MS mass calculated: [M+1] + (C 18 H27 BN2O3), m / z 331.2, LCMS measured value m / z 331.2; 1 1H 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]imidazol-6-ol (41c) A solution of NH4HCO3 (105.34 mg, 1.33 mmol, 109.73 μL) in H2O (5 mL) was added 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) 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 h. TLC showed that 41b was completely consumed and one new spot was formed. The mixture was poured into saturated NaHSO3 solution (10 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 41c. MS mass calculated 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) 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 with 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 mass calculated value: [M+1] + (C 18 H 17 Cl2N3O4), m / z 410.0, LCMS measured value 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) was added Fe (136.12 mg, 2.44 mmol), 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 indicated that 41d was completely consumed and one new spot was 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 × 2). 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-TLC (SiO2, petroleum ether:ethyl acetate) to afford 41e. MS mass calculated 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]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 41) 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) were degassed and purged three times with N2. The mixture was then stirred at 20 °C for 1 h under a N2 atmosphere. TLC and LCMS indicated that 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 mass calculated value: [M+1] + (C 21 H 19 Cl2N5O5), m / z 492.10, LCMS measured value 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

Chemical Structure

[0303] Example 43 N-(3,5-Dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical Structure

[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 a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was 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. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 43b. 1 1H 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 and purged with N2 three times, and then the mixture was stirred at 100 °C for 1 hour under a N2 atmosphere. TLC indicated that the reaction was complete and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give 43c. MS mass calculated 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-dioxaborolane (394.37 mg, 1.55 mmol), KOAc (304.84 mg, 3.11 mmol), and Pd(PPh3)2Cl2 (72.67 mg, 103.54 μmol) in dioxane (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 90 °C for 16 h under a N2 atmosphere. TLC indicated that the reaction was complete and one new spot was formed. The reaction mixture was 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. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 43d. MS mass calculated: [M+H] + (C 17 H 23 BN2O2), m / z, 299.1, LCMS found m / z 299.1.

[0307] Synthesis of 1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-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), NH4HCO3 (79.54 mg, 1.01 mmol) were added to a mixture of CH3CN (20 mL) and H2O (10 mL), and then H2O2 (228.14 mg, 2.01 mmol, 193.34 μL, 30% purity) was added. The mixture was degassed and purged three times with N2, and then the mixture was stirred at 25 °C for 1 h under a N2 atmosphere. LCMS indicated that the reaction was complete and the desired MS was detected. The reaction mixture was quenched at 0 °C by the addition of a Na2SO3 solution (20 mL), then diluted with H2O (20 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 43e. MS mass calculated 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)benzimidazol-5-ol (43e) (240 mg, 1.28 mmol), 1,3-dichloro-2-fluoro-5-nitro-benzene (294.53 mg, 1.40 mmol), and K2CO3 (352.44 mg, 2.55 mmol) in DMF (10 mL) was degassed and purged three times with N2, and then the mixture was stirred at 25 °C for 1 h under a N2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was 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. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 43f. MS mass calculated value: [M+H] + (C 17H 13 Cl2N3O3), m / z, 378.0, LCMS measured value m / z 378.0; 1 H NMR (400 MHz, CDCl3) δ 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]imidazol-6-yl)oxy)aniline (43 g) 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 and purged with N2 three times, and then the mixture was stirred at 80 °C for 1 hour under a N2 atmosphere. TLC indicated that the reaction was complete, and one major new spot was 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) δ 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 43) To a mixture of 3,5-dichloro-4-[3-(1-methylcyclopropyl)benzimidazol-5-yl]oxy-aniline (43 g) (10 mg, 28.72 μmol) and TEA (8.72 mg, 86.15 μmol, 11.99 μL) in THF (2 mL) was added 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (8.53 mg, 57.43 μmol), and the mixture was stirred at 25 °C for 0.1 h under a N2 atmosphere. LCMS 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 calculated 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical formula

[0312] Synthesis of 2-(3,5-dichloro-4-((1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-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)benzimidazol-5-yl]oxy-phenyl]hydrazono]acetyl]carbamate (44a) (36 mg, 69.86 μmol) and KOAc (13.71 mg, 139.71 μmol) in DMA (3 mL) was degassed and purged three times with N2. Then the mixture was stirred at 115 °C for 3 hours under a N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a 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 give Example 44. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[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) 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) was added with Pd(PPh3)2Cl2 (52.43 mg, 74.69 μmol) and KOAc (733.06 mg, 7.47 mmol) under N2 at 20 °C. The mixture was stirred at 90 °C for 4 h. TLC and LCMS indicated that 45a was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with ethyl acetate (10 mL × 3). The combined filtrate was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to give 45b. MS mass calculated value: [M + 1] + (C 18 H 25 BN2O3), m / z 329.2, LCMS measured value m / z 329.1; 1 1H NMR (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]imidazol-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, followed by 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 h. LCMS indicated complete consumption of 45b and the desired MS was detected. The residue was poured into a NaHSO3 solution (30 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 45c. The crude product was used in the next step without further purification. MS mass calculated value: [M+1] + (C 12 H 14 N2O2), m / z 219.1, LCMS found m / z 219.0; 1 1H NMR (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) A solution of 2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-6-ol (45c) (170 mg, 778.92 μmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (179.92 mg, 856.81 μmol) in DMF (3 mL) was added with K2CO3 (161.48 mg, 1.17 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 1 hour. TLC and LCMS indicated 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 phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate) to obtain 45d. MS mass calculated value: [M+1] + (C 18 H 15 Cl2N3O4), m / z 408.0, LCMS measured value m / z 408.0; 1 1H NMR (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]imidazol-6-yl)oxy)aniline (45e) A solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazole (45d) (170 mg, 416.43 μmol) in EtOH (5 mL) and H2O (1 mL) was added with Fe (116.29 mg, 2.08 mmol) and NH4Cl (111.37 mg, 2.08 mmol) at 25 °C. Then the mixture was stirred at 80 °C for 1 h. LCMS indicated that 45d was completely consumed and the desired MS was detected. The suspension was filtered through a pad of celite and the pad cake was washed with EtOH (10 mL × 3). The combined filtrate was extracted with ethyl acetate (30 mL × 2) and H2O (10 mL). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 45e. The solid was used directly in the next step without further purification. MS mass calculated value: [M + 1] + (C 18 H 17 Cl2N3O2), m / z 378.1, LCMS measured value m / z 378.1; 1 1H NMR (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]imidazol-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]imidazol-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) in a solution of THF (4 mL) was added with TEA (32.10 mg, 317.25 μmol, 44.16 μL) at 25 °C. Then, the mixture was stirred at 25 °C for 0.5 h. LCMS indicated that 45e was completely consumed and the desired MS was detected. The mixture was quenched with MeOH (5 mL×3) and stirred at 25 °C for 5 min. Then, the mixture was concentrated under vacuum. The residue was purified by Prep-HPLC ((FA), column: Welch Xtimate C18 150×25 mm×5 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 obtain Example 45. MS mass calculated value: [M+1] + (C 21 H 17 Cl2N5O5), m / z 490.1, LCMS measured value m / z 489.9; 1 1H NMR (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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [Chemistry] (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) Synthesis To a mixture of 3,5-dichloro-4-((2-methoxy-1-(1-methylcyclopropyl)-1H-benzo[d]imidazol-6-yl)oxy)aniline (45e) (10 mg, 26.44 μmol) and ethyl N-(2-cyanoacetyl)carbamate (12.38 mg, 79.31 μmol) in CH3CN (1 mL) at 0 °C was added t-BuONO (8.18 mg, 79.31 μmol, 9.43 μL). The mixture was then stirred at 0 °C for 1 hour. LCMS indicated that 45e was completely consumed and the desired MS was detected. The mixture was quenched with MeOH (15 mL) and concentrated under reduced pressure to give 46a. The solid was used directly in the next step without further purification. MS mass calculated 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]imidazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 46) (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 treated with KOAc (5.04 mg, 51.34 μmol). The mixture was stirred at 115 °C for 3 h. LCMS indicated complete consumption of 46a and the desired MS was detected. The mixture was diluted with MeOH (15 mL) and 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 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 give Example 46. MS mass calculated value: [M+1] + (C 22 H 16 Cl2N6O4), m / z 499.1, LCMS found m / z 498.9; 1 1H NMR (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 Structure

[0322] Example 48 2-(3,5-Dichloro-4-((3-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chem.

[0323] Example 49 2-(4-((1-(tert-Butyl)-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Chemical Structure

[0324] Synthesis of 2-(4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 49) A solution of (E)-ethyl (2-(2-(4-((1-(tert-butyl)-2-methoxy-1H-benzo[d]imidazol-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate (49a) (50 mg, 91.34 μmol) in DMA (5 mL) was added KOAc (17.93 mg, 182.69 μmol). The mixture was stirred at 115 °C for 3 hours. LCMS indicated that 49a was completely consumed. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The com...

Claims

1. Formula (I): 【Chemical 1】 (I) [wherein, A is [Chemical 2] ; [Chemical Formula 3] is a 5-membered heterocyclyl or a 5- to 6-membered heteroaryl, where each of them may optionally contain 1 to 2 additional ring heteroatoms selected from the group consisting of N and O, Here, each heteroatom of the above heterocyclyl or heteroaryl is bonded to one R group, if necessary to satisfy the valence of the heteroatom, and, １ and, Here, each carbon atom of the above heterocyclyl or heteroaryl is bonded to one R group, if necessary to satisfy the valence of the carbon atom, provided that there is only one R group necessary to satisfy the valence of each carbon atom; ２ group, provided that there is only one R ２ group necessary to satisfy the valence of each carbon atom; Z １ 、Z ２ 、and Z ３ is, independently, N, or CH; Y is N or C; Each R １ is, independently, H, C １ -C ６ alkyl, or C ３ -C ６ cycloalkyl, and Here, each C １ -C ６ alkyl or C ３ -C ６ cycloalkyl group may optionally be substituted with 1 to 5 R ３ groups; Each R ２ is, independently, H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, -O(C １ -C ６ alkyl), -O(C ３ -C ６ cycloalkyl), hydroxyl, or oxo, and Here, each C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, -O(C １ -C ６ alkyl), or -O(C ３ -C ６ cycloalkyl) group may optionally be substituted with 1 to 5 R ３ groups; or R １ and R ２ together form a 5- or 6-membered heteroaryl or 5- to 7-membered heterocyclyl; or two Rs ２ groups together form a 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl, C ５ -C ７ cycloalkyl, or C ６ aryl; Each R ３ is 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 , -CN, or hydroxyl.] a compound represented by, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is [Chemical Formula 4] .

3. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is [Chemical Formula 5] .

4. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is 【Chemical Formula 6】 .

5. The following: 【Chemical Formula 7】 is a 5- to 6-membered heteroaryl which may optionally contain 1 to 2 additional ring heteroatoms selected from the group consisting of N and O, Here, each heteroatom of the above heteroaryl is bonded to one R group, if necessary to satisfy the valence of the heteroatom, and, １ and, Here, each carbon atom of the above heteroaryl is bonded to one R group when necessary to satisfy the valence of the carbon atom, provided that only one R group is necessary to satisfy the valence of each carbon atom. ２ group, provided that the R group necessary to satisfy the valence of each carbon atom is only one, ２ ​ The compound according to any one of claims 1 to 4, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

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

7. The following: 【Chemical 8】 is 【Chemical Formula 9】 The compound according to claim 6, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

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

9. The following: 【Chemical Formula 10】 is 【Chemical 11】 The compound according to claim 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. The following: 【Chemical Formula 12】 is a 5-membered heterocyclyl which may optionally contain 1 to 2 additional ring heteroatoms selected from the group consisting of N and O, Here, each heteroatom of the above heterocyclyl is bonded to one R group, if necessary to satisfy the valence of the heteroatom, and １ and Here, each carbon atom of the above heterocyclyl is bonded to one R group when necessary to satisfy the valence of the carbon atom, provided that only one R group is necessary to satisfy the valence of each carbon atom. ２ group, provided that the R ２ group necessary to satisfy the valence of each carbon atom is only one. The compound according to any one of claims 1 to 4, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. The following: 【Chemical 13】 is 【Chemical 14】 The compound according to claim 10, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

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

13. Z １ The compound according to any one of claims 1 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is N.

14. Z ２ The compound according to any one of claims 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

15. Z ２ The compound according to any one of claims 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is N.

16. Z ３ The compound according to any one of claims 1 to 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

17. Z ３ The compound according to any one of claims 1 to 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is N.

18. Z １ , Z ２ , and Z ３ is CH in each case, a compound according to any one of claims 1 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

19. Z １ is N; and, Z ２ and Z ３ are each CH, The compound according to any one of claims 1 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. 。

20. Z ２ is N; and, Z １ and Z ３ are each CH, The compound according to any one of claims 1 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

21. Each R １ is independently H, C １ -C ３ alkyl, or C ３ -C ５ cycloalkyl, and Here, each C １ -C ３ alkyl or C ３ -C ５ cycloalkyl group may optionally be substituted with 1 to 3 R ３ groups, The compound according to any one of claims 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

22. Each R １ is independently H, cyclopropyl, -CH ３ , -CH(CH ３ ), ２ t-butyl, -CH ２ CH ３ , 【Chemical Formula 15】 The compound according to claim 21, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is as defined.

23. 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, and 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 may optionally be substituted with 1 to 3 R ３ groups, The compound according to any one of claims 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

24. Each R ２ is independently H, -CH ３ , -CH ２ CH ３ , -OCH ３ , cyclopropyl, or oxo, the compound according to claim 23, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

25. R １ and R ２ which together form a 5- to 6-membered heteroaryl or a 5- to 7-membered heterocyclyl, the compound according to any one of claims 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

26. R １ and R ２ together form 【Chemical 16】 The compound according to claim 25, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms...

27. Two Rs ２ groups together form a 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl, C ５ -C ７ cycloalkyl, or C ６ aryl, and the compound according to any one of claims 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

28. Each R ３ when present, independently, is halogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkyl-OH, -NH ２ , -CN, or hydroxyl, the compound according to any one of claims 1 to 27, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

29. Each R ３ is independently Cl, F, -CH ３ , -CF ３ , -CHF ２ , -CH ２ OH, -NH ２ , -CN, or hydroxyl, the compound according to claim 28, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

30. A compound selected from the compounds described in Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or a tautomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

32. A method for agonizing thyroid hormone receptor beta (THR beta) comprising contacting THR beta with an effective amount of the compound according to any one of claims 1 to 30 or a tautomer thereof or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition according to claim 31.

33. A method for treating a THR beta-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 30 or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition according to claim 31.

34. The method according to claim 33, wherein the disorder is non-alcoholic steatohepatitis (NASH).

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