Modulators of THR-β and methods of use thereof

Abstract

To provide compounds that are effective modulators of THR-β activity, which can be used for the treatment of THR-β related disorders.SOLUTION: Disclosed herein are compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where TL is a moiety of Formula IIa, IIb, IIIa to IIId; CE is a moiety of a group having a benzene ring or the like; and HD is a moiety of Formula V or VI.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 005,661, filed April 6, 2020, U.S. Provisional Patent Application No. 62 / 944,052, filed December 5, 2019, and U.S. Provisional Patent Application No. 62 / 845,252, filed May 8, 2019, the entire disclosures of each of which are incorporated herein by reference.

[0002] The present invention is in the field of pharmaceutical compounds and their formulation and methods of use in the treatment of disease. Specifically, the present invention is in the field of THR-β modulators and their uses. [Background technology]

[0003] In parallel with the global rise in obesity, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease and liver transplants worldwide [1, 2]. NAFLD is thought to affect 30% of the adult population and 70-80% of obese and diabetic patients. NAFLD is defined as excess hepatic fat accumulation greater than 5% induced by causes other than alcohol consumption. NAFLD progresses to hepatitis (nonalcoholic steatohepatitis, NASH) and fibrosis in a variable proportion of individuals, ultimately leading to liver failure and hepatocellular carcinoma (HCC) in susceptible individuals [3].

[0004] In the United States alone, NASH is the third most common indication for liver transplantation and is on track to become the most common.[4] The most important medical need in patients with NAFLD and NASH is effective treatment to halt progression and potentially reverse fibrosis, the main predictor of liver disease evolution.[5, 6]

[0005] Thyroid hormones (TH) are essential for normal development, growth, and metabolism in all vertebrates. Their effects are primarily mediated through triiodothyronine (T3), which functions as a ligand for TH receptors (TR, or THR) β1, β2, and α1 [7]. In the absence of ligand, TRs first bind as heterodimers or homodimers to TH response elements (TREs) located in the promoter regions of target genes, where the TREs interact with corepressors. Upon ligand binding, the TR homodimers dissociate in favor of heterodimerization with the retinoid X receptor (RXR), resulting in the release of corepressors and the recruitment of coactivators. This new complex attracts numerous proteins involved in RNA polymerase II transcription of the targeted genes.

[0006] Two distinct genetic loci, designated THRA and THRB, are responsible for encoding multiple interrelated TR isoforms with distinct tissue distributions and biological functions. The two major isoforms with the widest levels of tissue expression are TRα1 and TRβ1 [8]. TRα1 is first expressed during fetal development and is widely expressed in adult tissues, whereas TRβ1 appears later in development and is most highly expressed in adult liver, kidney, and lung [9]. TRα1 is a key regulator of cardiac output, while TRβ1 helps control metabolism in the liver. Importantly, the natural thyroid hormone T3 activates both TRα1 and TRβ1 without significant selectivity.

[0007] The design of thyromimetic small molecule agents has led to the identification of TR (or THR) agonists with varying levels of TRβ selectivity, despite the high structural similarity between the ligand-binding domains for TRβ and TRα. The TRβ selectivity achieved by some of these compounds has resulted in improved therapeutic indices for lipid lowering compared to cardiac effects such as heart rate, cardiac hypertrophy, and contractility [10-12].

[0008] Another strategy to avoid activation of TRα in cardiac tissue is to design phosphonate-containing TR agonist prodrugs that are specifically converted to active agonists in the liver but remain stable as inactive prodrugs in extrahepatic tissues, including the blood and heart.13 TRα and TRβ agonists are also used for indications other than liver-related diseases, as is known in the art. Summary of the Invention

[0009] Disclosed herein are compounds of formula I': (I')TL-L a -CE-HD or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein i) T L is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) L a are independently bonded;-(C(R a )2) n -;Oxygen;Sulfur;-NR a -, iii) CE is a moiety of formula IV, and iv) HD is a moiety of formula V or VI, wherein the substituents are as defined herein, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof. Pharmaceutical compositions comprising the above-described compounds, as well as methods of treating diseases by administering or contacting a patient with one or more of the above-described compounds, are also disclosed. [ka] [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows the chemical structure of compound 67 as confirmed by X-ray crystallography. [Figure 2] 1 shows the chemical structure of compound 67-A as confirmed by X-ray crystallography. DETAILED DESCRIPTION OF THE INVENTION

[0011] Disclosed herein are novel compounds that are effective modulators of THR-β activity and can be used to treat various THR-β-related disorders.Compounds and their methods of use are discussed in detail below.Some compounds disclosed herein are agonists of TRα and / or TRβ receptors, and other compounds are antagonists of TRα and / or TRβ receptors, and are used to treat liver-related disorders mediated by TRα and / or TRβ receptors and other indications known in the art.

[0012] definition Various embodiments are described below. It should be noted that a particular embodiment is not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. An aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment.

[0013] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0014] The use of the terms "a," "an," and "the" and similar referents in the context of describing elements (particularly in the context of the claims that follow) should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values ​​herein is intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually referred to herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to better illustrate embodiments and does not present a limitation on the scope of the claims unless otherwise specified. No language in the specification should be construed as indicating any non-claimed element as essential.

[0015] In the definition of a chemical substituent, R x and R y Each of is independently hydrogen, alkyl, carbocycle, heterocycle, aryl, or heteroaryl, all of which, except hydrogen, are optionally substituted.

[0016] Unless otherwise indicated, the abbreviations "TR" and "THR" refer to thyroid hormone receptor.

[0017] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to a patient to whom the compound is administered and does not abolish the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound disclosed herein with an acid or base. Base-forming salts include, but are not limited to, ammonium salts (NH +alkali metal salts, such as, but not limited to, sodium or potassium salts; alkaline earth salts, such as, but not limited to, calcium or magnesium salts; salts of organic bases, such as, but not limited to, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; salts with the amino group of amino acids, such as, but not limited to, arginine and lysine. Useful acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and salicylate.

[0018] As used herein, "pharmaceutically acceptable ester" refers to an ester of a compound that does not cause significant irritation to a patient to whom it is administered. The ester is metabolized in the body to yield the parent compound, e.g., a claimed compound. Thus, the ester does not abolish the biological activity and properties of the compound. Pharmaceutical esters can be obtained by reacting the compounds disclosed herein with an alcohol. Methyl, ethyl, and isopropyl esters are some of the common esters prepared. Other suitable esters are well known to those skilled in the art (e.g., Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, New York, NY, 2014 (hereby incorporated by reference in its entirety).

[0019] When the compounds disclosed herein have at least one chiral center, they can exist as racemates or individual enantiomers.It should be noted that all such isomers and their mixtures are included in the scope of the present disclosure.Therefore, the illustration of a chiral center without specifying R or S means that the scope of the present disclosure includes the R isomer, the S isomer, the racemic mixture of isomers, or the mixture in which one isomer is present in a greater amount than the other.

[0020] If the preparation process for the compounds disclosed herein results in a mixture of stereoisomers, such isomers can be separated by conventional techniques, such as preparative chiral chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with optically active acids, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

[0021] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted," it means that the substituent may be substituted with one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, O-cyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Protecting groups that can form the protective derivatives of the above-described substituents are known to those of skill in the art and can be found in references such as Wuts, cited above.

[0022] As used herein, a "carbocycle" is a ring structure in which all atoms in the ring are carbon atoms. If any of the atoms in the ring are other than carbon atoms, the ring is a "heterocycle." Examples of atoms in the ring include sulfur, oxygen, and nitrogen. A carbocycle or heterocycle may be polycyclic, e.g., a fused ring system, a spiro ring system, or a bridged ring system. These polycyclic rings include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Additional non-limiting examples include: [ka] Examples include:

[0023] As used herein, "aryl" refers to a carbocyclic (all carbon) ring having a fully delocalized pi-electron system. An "aryl" group can consist of two or more fused rings (rings that share two adjacent carbon atoms). When an aryl is a fused ring system, the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring within the fused ring system may or may not have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, radicals of benzene, naphthalene, and azulene. Additional non-limiting examples include: [ka] Examples include:

[0024] As used herein, "heteroaryl" refers to a ring having a fully delocalized π-electron system and containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur within the ring. A "heteroaryl" group may be composed of two or more fused rings (rings that share two adjacent carbon atoms). When a heteroaryl is a fused ring system, the ring connected to the rest of the molecule has a fully delocalized π-electron system. The other ring within the fused ring system may or may not have a fully delocalized π-electron system. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0025] When "hetero" is used, it is intended to mean certain groups, such as alkyl or aryl groups, in which at least one carbon atom has been replaced with a heteroatom selected from nitrogen, oxygen, and sulfur.

[0026] As used herein, "alkyl" refers to a straight-chain or branched, fully saturated (no double or triple bonds) hydrocarbon group. The alkyl groups of the compounds of the present disclosure may contain 1 to 20 carbon atoms. The alkyl groups herein may also be medium-sized, having 1 to 10 carbon atoms. The alkyl groups herein may also be lower alkyls having 1 to 5 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

[0027] The alkyl group of the compounds of the present disclosure may be substituted or unsubstituted. If substituted, the substituents may be cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR x R y and protected amino.

[0028] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The alkenyl groups of the compounds of the present disclosure may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups as those disclosed above for alkyl group substitution or for any substitution.

[0029] As used herein, "alkenyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl groups of the compounds of the present disclosure may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups as those disclosed above for alkyl group substitution or for any substitution.

[0030] As used herein, "acyl" refers to an acyl group formed from a group consisting of "R × It refers to the "C(=O)-" group.

[0031] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) hydrocarbon ring. The cycloalkyl groups of the compounds of the present disclosure can range from C3 to C8. The cycloalkyl groups can be substituted or unsubstituted. If substituted, the substituents can be selected from those set forth above for alkyl group substitution. A "cycloalkyl" group can consist of two or more fused rings (rings that share two adjacent carbon atoms). When a cycloalkyl is a fused ring system, the ring connected to the remainder of the molecule is a cycloalkyl as defined above. The other ring in the fused ring system can be a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0032] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds within the ring, provided that if more than one double bond is present, they cannot form a completely delocalized π-electron system within the ring (otherwise, the group is an "aryl" as defined herein). The cycloalkenyl groups of the compounds of the present disclosure may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups disclosed above for alkyl group substitution. A "cycloalkenyl" group may consist of two or more fused rings (rings that share two adjacent carbon atoms). When a cycloalkenyl is a fused ring system, the ring connected to the remainder of the molecule is a cycloalkenyl as defined above. The other ring in the fused ring system may be a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0033] The term "alkylene" refers to an alkyl group, as defined herein, which is diradical and is connected to two other moieties. Thus, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), isopropylene (IUPAC: (methyl)ethylene) (-CH-CH(CH)-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH-CH(CH)-CH-) are examples, but not limited to, of alkylene groups. Similarly, the term "cycloalkylene" refers to a cycloalkyl group, as defined herein, which is connected to two other moieties in an analogous manner. When the alkyl and cycloalkyl groups contain unsaturated carbons, the terms "alkenylene" and "cycloalkenylene" are used.

[0034] As used herein, "heterocycloalkyl," "heteroarylcyclic," or "heteroalicyclyl" refers to a ring having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur within the ring system. The ring may also contain one or more double bonds, provided that the ring does not form a completely delocalized π-electron system. Rings, as defined herein, can be stable 3- to 18-membered rings consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroalicyclyl groups of the compounds of the present disclosure can be unsubstituted or substituted. If substituted, the substituents can be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamide, and trifluoromethanesulfonamide. A "heterocycloalkyl" group can consist of two or more fused rings (rings that share two adjacent carbon atoms). When a heterocycloalkyl is a fused ring system, the ring connected to the rest of the molecule is a heterocycloalkyl as defined above. The other ring in the fused ring system may be a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0035] As used herein, "aralkyl" refers to an alkylene substituted with an aryl group.

[0036] As used herein, "carbocyclic alkyl" or "(carbocyclic) alkyl" refers to an alkylene substituted with a carbocyclic group.

[0037] As used herein, "heterocyclic alkyl" or "(heterocyclic) alkyl" refers to an alkylene substituted with a heterocyclic group. Similarly, "(heterocycloalkyl) alkyl" refers to an alkylene substituted with a heterocycloalkyl group.

[0038] As used herein, "heteroarylalkyl" or "(heteroaryl)alkyl" refers to an alkylene substituted with a heteroaryl group.

[0039] The "O-carboxy" group is x It refers to the "C(=O)O-" group.

[0040] A "C-carboxy" group refers to a "-C(=O)R" group.

[0041] An "acetyl" group refers to a CH3C(=O)- group.

[0042] A "C-amido" group is defined as "-C(=O)NR x R y " refers to the group.

[0043] The "N-amide" group is defined as "RC(=O)NR x -" refers to the group.

[0044] The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced by halogen atoms.

[0045] Using techniques well known to those skilled in the art, any unsubstituted or monosubstituted amine group on the compounds herein can be converted to an amide, any hydroxy group can be converted to an ester, and any carboxyl group can be converted to either an amide or an ester (see, e.g., Wuts, supra).

[0046] In any of the compounds of the present disclosure that have one or more chiral centers, where the absolute stereochemistry is not explicitly indicated, it is understood that each center can independently be R or S or a mixture thereof. Additionally, in any of the compounds of the present disclosure that have one or more double bond-forming geometric isomers that can be defined as E or Z, it is understood that each double bond can independently be E or Z, or a mixture thereof.

[0047] It is understood that the disclosure of a compound herein inherently includes the disclosure of its tautomers, where applicable. For example, the disclosure of: [ka] also discloses the following: [ka] and vice versa, even if only one of the two structures is disclosed.

[0048] It should be understood that isotopically enriched analogs of compounds are also contemplated when illustrating or naming compounds throughout this disclosure. For example, a compound may have deuterium incorporated in place of hydrogen, or carbon-13 in place of carbon with a natural isotopic distribution. Isotopic enrichment may occur at a single position on the compound, i.e., only one hydrogen is replaced with deuterium, or at more than one position. This disclosure also encompasses compounds in which all analogous atoms are replaced by their less common isotopes, such as perdeutero compounds in which all hydrogen atoms are replaced by deuterium. Isotopically enriched compounds are useful when obtaining NMR spectra or utilizing isotope effects in controlling the reaction rate of a compound undergoing such an enrichment.

[0049] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of compounds to an organism. Multiple techniques for administering compounds exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0050] The term "carrier" defines a chemical compound that facilitates the uptake of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of living organisms.

[0051] The term "diluent" defines a compound diluted in water that dissolves the compound of interest and stabilizes the compound's biologically active form. Salts dissolved in buffer solutions are utilized as diluents in the art. One commonly used buffer solution is phosphate buffered saline, which mimics the salt conditions of human blood. Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0052] In certain embodiments, the same substance may act as a carrier, a diluent, or an excipient, or may serve any two or all three roles. Thus, a single additive to a pharmaceutical composition may have multiple functions.

[0053] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0054] compound In one aspect, disclosed herein is a compound of formula I: (I)TL-L a -CE-HD or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] JPEG2025011262000008.jpg35141- In the formula, - each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 independently represents nitrogen or -CR b - and each R bare independently hydrogen, halogen, or lower alkyl; - R1 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted carbocyclic alkyl, optionally substituted aralkyl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl alkyl, optionally substituted amino, optionally substituted C-carboxy or O-carboxy, -CN, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or —CN; R3 is hydrogen or lower alkyl; - R4 is an optionally substituted alkyl, an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic alkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is the heteroatom in the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; ii) CE is a moiety of formula IV, [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; optionally, R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; - Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; -(TL) is a compound in which the moiety of formula IV is TL-L a - indicates the point where it connects to -(HD) indicates the point at which the moiety of formula IV is attached to -HD; iii) HD is a moiety of formula V or VI, [ka] During the ceremony, - R9 is hydrogen, -(C(R d )2) n -C(R d )3, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2)n -S(=O) q R d , -(C(R d )2) n -CN, -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, ·Each R d is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; -R 10 is hydrogen, -C(R e )3, and each R e are independently hydrogen, halogen, or optionally substituted lower alkyl; -R 11 is an aryl group optionally substituted with lower alkyl, halogen, cycloalkyl; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring system, iv) L a are independently a bond, -(C(R a )2) n -, oxygen, sulfur, -NR a - in which -Each R a are independently hydrogen or lower alkyl; -n is 0, 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof.

[0055] In some embodiments, R is an optionally substituted alkyl, an optionally substituted carbocyclic group, an optionally substituted aryl group, or an optionally substituted C-carboxy or O-carboxy group. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In certain embodiments, the carbocyclic group is cyclohexane or cyclopentane. In various embodiments, the aryl group is phenyl. In some embodiments, the C-carboxy group is a moiety of the formula -C(=O)-OR and the O-carboxy group is a moiety of the formula -OC(=O)-R, where R is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0056] In some embodiments, R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0057] In some embodiments, Q1, Q2, Q3, and Q4 are -CR b - and each R b are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0058] In some embodiments, R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0059] In some embodiments, R5 is hydroxy.

[0060] In some embodiments, the TL is [ka] This is the part selected from JPEG2025011262000012.jpg44156.

[0061] In some embodiments, the TL is [ka] This is the portion selected from JPEG2025011262000014.jpg109153.

[0062] In some embodiments of the compound of Formula I, R and R are each independently chlorine, bromine, and iodine. In other embodiments, R and R are each independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, wherein the alkyl groups of the lower alkyl and lower alkoxy are each independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. In some embodiments, R and R are the same. In certain embodiments, R and R are each independently chlorine or methyl.

[0063] In some embodiments of the compound of Formula I, R8 is hydrogen.

[0064] In some embodiments, R c is hydrogen or methyl.

[0065] In some embodiments, disclosed herein are compounds of Formula I, wherein: -TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 is independently nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is an optionally substituted alkyl, an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic alkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy group or O-carboxy group, —CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is optionally a heteroatom in the ring structure, R2 is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen, R4 is an optionally substituted alkyl, an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic alkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is the heteroatom in the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atom to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; or a tautomer of the moiety of formula III when Q6 is nitrogen and R5 is hydroxy, Alk is hydrogen or optionally substituted alkyl; -CE is a moiety of formula IV [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; ·(TL) is the part of formula IV that is TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV joins with -HD; HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is -NH2 and R 10 is -CH3, L a is oxygen.

[0066] In other embodiments, disclosed herein are compounds of Formula I, wherein: TL is a moiety of formula II, [ka] During the ceremony, Each of Q1, Q2, and Q3 independently represents nitrogen or -CR b - and each R bare independently hydrogen, halogen, or lower alkyl; R1 is an optionally substituted alkyl, an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic alkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy group or O-carboxy group, —CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is optionally a heteroatom in the ring structure, R2 is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen, -CE is a moiety of formula IV [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; ·(TL) is the part of formula IV that is TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV joins with -HD; -HD is a moiety of formula V, [ka] During the ceremony, R9 is hydrogen, -CN, or -C≡CR d and R d is hydrogen or lower alkyl, L a is oxygen.

[0067] In some embodiments, L a is a bond, —(C(R a )2) n -, oxygen, sulfur, or -NR a -A combination of two or more of the following.

[0068] In another aspect, disclosed herein is a compound of formula I': (I')TL-L a -CE-HD or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein: i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 independently represents nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl group, optionally substituted (heteroaryl)alkyl group, optionally substituted amino group, optionally substituted C-carboxy group or O-carboxy group, -CN, optionally substituted carbamoyl group, or optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen or lower alkyl; R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom within the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system; or a bicyclic heterocyclic ring system, ii) CE is a moiety of formula IV, [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; optionally, R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL), but the part of formula IV is TL-L a - indicates the point where it connects to (HD) represents the point where the portion of formula IV connects to -HD; iii) HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is hydrogen, -(C(R d )2) n -C(R d )3, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2) n -S(=O) q R d , -(C(R d )2) n -CN, -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, Each R d is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; R 10 is hydrogen or -C(R e )3, and each R e are independently hydrogen, halogen, or optionally substituted lower alkyl; L a are independently a bond, -(C(R a )2) z -, oxygen, sulfur, or -NR a - in which Each R a are independently hydrogen or lower alkyl; z is 0, 1, 2, 3, 4, or 5; however, (1) When TL is a moiety of formula IIIa, wherein Q4, Q5, and Q6 are -CH-, R4 is an optionally substituted C1-C3 alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted carbamoyl group, and HD is a moiety of formula V, wherein R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxy; (2) When TL is a moiety of formula IIa, wherein Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is a moiety of formula V, wherein R9 is hydrogen, Q7 is -CH-, and R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group; (3) TL is a moiety of formula IIIa, wherein Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is —CH—, then R cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene; (4) When T L is a moiety of formula IIIb, wherein Q is -CH-, Q is nitrogen, and HD is a moiety of formula V, wherein R is hydrogen, -CN, or -COH, Q is -CH-, and R and R are independently halogen or methyl, or R and R together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R cannot be isopropyl or 2-hydroxy-1-methyl-ethyl; (5) TL is a moiety of formula IIIb, wherein Q4 is -CR c -, Q5 is nitrogen, and HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is -O-, (a) none of R6, R7, and R8 can be deuterium; (b) Q4 cannot be -CD-, where D is deuterium; (c) R4 cannot be a 3- to 5-membered cycloalkyl ring optionally substituted with one or more halogens; a non-aromatic (carbocyclic) alkyl optionally substituted with methyl or hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxy, or methoxy; phenethyl optionally substituted with halogen; C1-C4 alkyl optionally substituted with 1 to 6 substituents selected from halogen, hydroxyl, and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or a 3- to 5-membered heterocycloalkyl optionally substituted with benzyl; (6) T L is a moiety of formula IIIb, and (i) Q and Q are nitrogen, or (ii) Q and Q are -CR b -, or (iii) Q4 is nitrogen and Q5 is -CR c - and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R4 cannot be -CH(CH3)2 or -CH(CD3)2; (7) TL is a moiety of formula IIIa where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3; (8) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is -O-, Q7 is -CH- and HD is a moiety of formula V, then R9 cannot be methyl; (9) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, R is isopropyl, and L a is -O-, Q7 is -CH-, and HD is a moiety of formula V, then R9 cannot be isopropyl; (10) T L is a moiety of formula IIa, wherein Q, Q, and Q are -CH-; and L a is -O-, Q7 is -CH-, R6 and R7 are independently chlorine or trifluoromethyl, and HD is a moiety of formula V, where R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl, or -C(O)NH2; (11) T L is a moiety of formula IIa, wherein Q and Q are —CH—, Q is nitrogen, and L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, and HD is a moiety of formula V, wherein R9 is -CN, then R1 cannot be isopropyl; (12) T L is a moiety of formula IIb, wherein Q, Q, and Q are -CH-; and L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, and HD is a moiety of formula V, wherein R9 is -CN, then R1 cannot be isopropyl; (13) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is —O—, Q7 is —CH—, R6 and R7 are chlorine, and HD is a moiety of formula VI, wherein R 10 is H, Me, Et, isopropyl, —CHCF, or —CHCHF, then R cannot be C-C alkyl or C-C hydroxyalkyl; (14) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is —O—, Q7 is —CH—, R6 and R7 are chlorine, and HD is a moiety of formula VI, wherein R 10 is H or Me, then R4 cannot be cyclopropyl; (15) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L ais -CH2-, Q7 is -CH-, R6 and R7 are both chlorine or both methyl, and HD is a moiety of formula VI, wherein R 10 When is H or Me, R4 cannot be isopropyl. In some embodiments, when T L is a moiety of formula IIIb, where Q is -CH-, Q is nitrogen, and HD is a moiety of formula V, where R is -CHCN or -C≡CH, Q is -CH-, and R and R are chlorine, then R cannot be isopropyl.

[0069] In another aspect, disclosed herein is a compound of formula I': (I')TL-L a -CE-HD or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein: i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 independently represents nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl group, optionally substituted (heteroaryl)alkyl group, optionally substituted amino group, optionally substituted C-carboxy group or O-carboxy group, -CN, optionally substituted carbamoyl group, or optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen or lower alkyl; R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom within the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system; or a bicyclic heterocyclic ring system, ii) CE is a moiety of formula IV, [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; optionally, R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL) is the part of formula IV, TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV connects to -HD; iii) HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is hydrogen, -(C(R d )2) n -C(R d )3, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2) n -S(=O) q R d , -(C(R d )2) n -CN, -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, Each R d is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; R 10 is hydrogen or -C(R e )3, and each R e are independently hydrogen, halogen, or optionally substituted lower alkyl; (iv)L a are independently a bond, -(C(R a )2) z -, oxygen, sulfur, or -NR a - in which Each R a are independently hydrogen or lower alkyl; z is 0, 1, 2, 3, 4, or 5; however, (1) When TL is a moiety of formula IIIa, wherein Q4, Q5, and Q6 are -CH-, R4 is an optionally substituted C1-C3 alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted carbamoyl group, and HD is a moiety of formula V, wherein R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxy; (2) When TL is a moiety of formula IIa, wherein Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is a moiety of formula V, wherein R9 is hydrogen, Q7 is -CH-, and R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group; (3) TL is a moiety of formula IIIa, wherein Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is —CH—, then R cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene; (4) When T L is a moiety of formula IIIb, wherein Q is -CH-, Q is nitrogen, and HD is a moiety of formula V, wherein R is hydrogen, -CN, or -COH, Q is -CH-, and R and R are independently halogen or methyl, or R and R together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R cannot be isopropyl or 2-hydroxy-1-methyl-ethyl; (5) TL is a moiety of formula IIIb, wherein Q4 is -CR c -, Q5 is nitrogen, and HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is -O-, (a) none of R6, R7, and R8 can be deuterium; (b) Q4 cannot be -CD-, where D is deuterium; (c) R4 cannot be a 3- to 5-membered cycloalkyl ring optionally substituted with one or more halogens; a non-aromatic (carbocyclic) alkyl optionally substituted with methyl or hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxy, or methoxy; phenethyl optionally substituted with halogen; C1-C4 alkyl optionally substituted with 1 to 6 substituents selected from halogen, hydroxyl, and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or a 3- to 5-membered heterocycloalkyl optionally substituted with benzyl; (6) T L is a moiety of formula IIIb, and (i) Q and Q are nitrogen, or (ii) Q and Q are -CR b -, or (iii) Q4 is nitrogen and Q5 is -CR c - and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R4 cannot be -CH(CH3)2 or -CH(CD3)2; (7) TL is a moiety of formula IIIa where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3; (8) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is -O-, Q7 is -CH- and HD is a moiety of formula V, then R9 cannot be methyl; (9) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, R is isopropyl, and L a is -O-, Q7 is -CH-, and HD is a moiety of formula V, then R9 cannot be isopropyl; (10) T L is a moiety of formula IIa, wherein Q, Q, and Q are -CH-; and L a is -O-, Q7 is -CH-, R6 and R7 are independently chlorine or trifluoromethyl, and HD is a moiety of formula V, where R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl, or -C(O)NH2; (11) T L is a moiety of formula IIa, wherein Q and Q are —CH—, Q is nitrogen, and L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, and HD is a moiety of formula V, wherein R9 is -CN, then R1 cannot be isopropyl; (12) T L is a moiety of formula IIb, wherein Q, Q, and Q are -CH-; and L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, and HD is a moiety of formula V, wherein R9 is -CN, then R1 cannot be isopropyl; (13) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is —O—, Q7 is —CH—, R6 and R7 are chlorine, and HD is a moiety of formula VI, wherein R 10 is H, Me, Et, isopropyl, —CHCF, or —CHCHF, then R cannot be C-C alkyl or C-C hydroxyalkyl; (14) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L a is —O—, Q7 is —CH—, R6 and R7 are chlorine, and HD is a moiety of formula VI, wherein R 10 is H or Me, then R4 cannot be cyclopropyl; (15) T L is a moiety of formula IIIb, wherein Q is —CH—, Q is nitrogen, and L ais -CH2-, Q7 is -CH-, R6 and R7 are both chlorine or both methyl, and HD is a moiety of formula VI, wherein R 10 is H or Me, then R4 cannot be isopropyl; (16) When TL is a moiety of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, and HD is a moiety of formula V, where R9 is -CHCN or -C≡CH, Q7 is -CH-, and R6 and R7 are chlorine, then R4 cannot be isopropyl.

[0070] In another aspect, disclosed herein is a compound of formula I': (I')TL-L a -CE-HD or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein: i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 independently represents nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl group, optionally substituted (heteroaryl)alkyl group, optionally substituted amino group, optionally substituted C-carboxy group or O-carboxy group, -CN, optionally substituted carbamoyl group, or optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen or lower alkyl; R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom within the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and cycloalkyl; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring system; ii) CE is a moiety of formula IV, [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; optionally, R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL) is the part of formula IV, TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV connects to -HD; iii) HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is hydrogen, -(C(R d )2) n -C(Rd )3, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2) n -S(=O) q R d , -(C(R d )2) n -CN, -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, Each R d is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; R 10 is hydrogen or -C(R e )3, and each R e are independently hydrogen, halogen, or optionally substituted lower alkyl; L a are independently a bond, -(C(R a )2) z -, oxygen, sulfur, or -NR a - in which Each R a are independently hydrogen or lower alkyl; z is 0, 1, 2, 3, 4, or 5; however, (1) When TL is a moiety of formula IIIa, wherein Q4, Q5, and Q6 are -CH-, R4 is an optionally substituted C1-C3 alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted carbamoyl group, and HD is a moiety of formula V, wherein R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxy; (2) When TL is a moiety of formula IIa, wherein Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is a moiety of formula V, wherein R9 is hydrogen, Q7 is -CH-, and R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group; (3) TL is a moiety of formula IIIa, wherein Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is —CH—, then R cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene; (4) When T L is a moiety of formula IIIb, wherein Q is -CH-, Q is nitrogen, and HD is a moiety of formula V, wherein R is hydrogen, -CN, or -COH, Q is -CH-, and R and R are independently halogen or methyl, or R and R together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R cannot be isopropyl or 2-hydroxy-1-methyl-ethyl; (5) TL is a moiety of formula IIIb, wherein Q4 is -CR c -, Q5 is nitrogen, and HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is -O-, (a) none of R6, R7, and R8 can be deuterium; (b) Q4 cannot be -CD-, where D is deuterium; (c) R4 cannot be a 3- to 5-membered cycloalkyl ring optionally substituted with one or more halogens; a C1-C4 alkyl optionally substituted with one to six substituents selected from halogen, hydroxyl, and deuterium; or a 3- to 5-membered heterocycloalkyl; (6) T L is a moiety of formula IIIb, and (i) Q and Q are nitrogen, or (ii) Q and Q are -CR b -, or (iii) Q4 is nitrogen and Q5 is -CR c - and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R4 cannot be -CH(CH3)2 or -CH(CD3)2; (7) When TL is a moiety of formula IIIa where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3. In some embodiments, when T L is a moiety of formula IIIb, where Q is -CH-, Q is nitrogen, and HD is a moiety of formula V, where R is -CHCN or -C≡CH, Q is -CH-, and R and R are chlorine, then R cannot be isopropyl.

[0071] In another aspect, disclosed herein is a compound of formula I': (I')TL-L a -CE-HD or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein: i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 independently represents nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl group, optionally substituted (heteroaryl)alkyl group, optionally substituted amino group, optionally substituted C-carboxy group or O-carboxy group, -CN, optionally substituted carbamoyl group, or optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen or lower alkyl; R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom within the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and cycloalkyl; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring system; ii) CE is a moiety of formula IV, [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; optionally, R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL) is the part of formula IV, TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV connects to -HD; iii) HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is hydrogen, -(C(R d )2) n -C(R d )3, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2) n -S(=O) q R d , -(C(R d )2) n -CN, -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, Each R d is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; R 10 is hydrogen or -C(R e )3, and each R e are independently hydrogen, halogen, or optionally substituted lower alkyl; (iv)L a are independently a bond, -(C(R a )2) z -, oxygen, sulfur, or -NR a - in which Each R a are independently hydrogen or lower alkyl; z is 0, 1, 2, 3, 4, or 5; however, (1) When TL is a moiety of formula IIIa, wherein Q4, Q5, and Q6 are -CH-, R4 is an optionally substituted C1-C3 alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted carbamoyl group, and HD is a moiety of formula V, wherein R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxy; (2) When TL is a moiety of formula IIa, wherein Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is a moiety of formula V, wherein R9 is hydrogen, Q7 is -CH-, and R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group; (3) TL is a moiety of formula IIIa, wherein Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is —CH—, then R cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene; (4) When TL is a moiety of formula IIIb, wherein Q4 is -CH-, Q5 is nitrogen, and HD is a moiety of formula V, wherein R9 is hydrogen, -CN, -CHCN, -C≡CH, or -COH, Q7 is -CH-, and R6 and R7 are independently halogen or methyl, or R7 and R8 together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 cannot be isopropyl or 2-hydroxy-1-methyl-ethyl; (5) TL is a moiety of formula IIIb, wherein Q4 is -CR c-, Q5 is nitrogen, and HD is a moiety of formula V, wherein R9 is -CN, Q7 is -CH-, and L a is -O-, (a) none of R6, R7, and R8 can be deuterium; (b) Q4 cannot be -CD-, where D is deuterium; (c) R4 cannot be a 3- to 5-membered cycloalkyl ring optionally substituted with one or more halogens; a C1-C4 alkyl optionally substituted with one to six substituents selected from halogen, hydroxyl, and deuterium; or a 3- to 5-membered heterocycloalkyl; (6) T L is a moiety of formula IIIb, and (i) Q and Q are nitrogen, or (ii) Q and Q are -CR b -, or (iii) Q4 is nitrogen and Q5 is -CR c - and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R4 cannot be -CH(CH3)2 or -CH(CD3)2; (7) When TL is a moiety of formula IIIa where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is a moiety of formula V where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3.

[0072] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId: [ka] During the ceremony, Each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8 is independently nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy group or O-carboxy group, -CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen; R4 is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, and the nitrogen of the carbamoyl group or carbamoylalkyl group is a heteroatom within the ring structure; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino; or R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or R4 and R5 together with the carbon atoms to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; CE is a moiety of formula IV; [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL) is the part of formula IV, TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV connects to -HD; HD is a moiety of formula V or VI, [ka] During the ceremony, R9 is selected from -NH2, -CN, -CH2-S-CH3, or -CH2-S(=O)2-CH3; R 10 is -CH3, L a is oxygen or -CH2-.

[0073] In some embodiments of the compound of Formula I', TL is a moiety of formula IIa, [ka] HD is part of formula V [ka]

[0074] In some embodiments of the compound of Formula I', TL is a moiety of formula IIa, [ka] HD is a moiety of formula VI [ka]

[0075] In some embodiments of the compound of Formula I', TL is a moiety of formula IIb, [ka] HD is part of formula V [ka]

[0076] In some embodiments of the compound of Formula I', TL is a moiety of formula IIb, [ka] HD is a moiety of formula VI [ka]

[0077] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIa; [ka] HD is part of formula V [ka]

[0078] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIa; [ka] HD is a moiety of formula VI [ka]

[0079] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIb; [ka] HD is the part of formula V, [ka] During the ceremony, R9 is hydrogen, -(C(R d )2) n -OR d , -(C(R d )2) n -N(R d )2, -(C(R d )2) n -S(=O) q R d , -(C(R d )2) n -C≡CR d , -(C(R d )2) n -C(=O)-OR d , -(C(R d )2) n -HeAr, or -(C(R d )2) n -C(=O)-N(R d )2 is selected, Each R d are independently hydrogen or optionally substituted C1-C5 alkyl; each q is independently 0 or 2; Each n is independently 0 or 1.

[0080] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIb, [ka] HD is a moiety of formula VI [ka]

[0081] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIc; [ka] HD is part of formula V [ka]

[0082] In some embodiments of the compound of Formula I', TL is a moiety of formula IIIc; [ka] HD is a moiety of formula VI [ka]

[0083] In some embodiments of the compound of Formula I', TL is a moiety of formula IIId, [ka] HD is part of formula V [ka]

[0084] In some embodiments of the compound of Formula I', TL is a moiety of formula IIId, [ka] HD is a moiety of formula VI [ka]

[0085] In some embodiments of the compound of Formula I', TL is the moiety of formula II [ka] During the ceremony, Q1, Q2, and Q3 each independently represent nitrogen or -CR b - and each R b are independently hydrogen, halogen, or lower alkyl; R1 is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy group or O-carboxy group, -CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; R2 is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R3 is hydrogen; CE is a moiety of formula IV; [ka] During the ceremony, each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q7 is nitrogen or -CR c -, wherein R c is hydrogen, halogen, or lower alkyl; (TL) is the part of formula IV, TL-L a - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV connects to -HD; HD is the part of formula V [ka] During the ceremony, R9 is hydrogen, -CN, -NH2, -C(R d )2-SR d , -C(R d )2-S(=O)2R d , or -C≡CR d and each R d are independently hydrogen or lower alkyl; L a is oxygen or -CH2-.

[0086] In some embodiments of the compound of Formula I', Q1, Q2, Q3, and Q4 are -CR b - and each R b are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In some embodiments of the compound of Formula I', Q1, Q2, and Q3 are -CH-.

[0087] In some embodiments of the compound of Formula I', Q1 is -CH- and Q2 and Q3 are nitrogen. In some embodiments of the compound of Formula I', Q2 is -CH- and Q1 and Q3 are nitrogen. In some embodiments of the compound of Formula I', Q3 is -CH- and Q1 and Q2 are nitrogen.

[0088] In some embodiments of the compound of Formula I', Q1 is nitrogen and Q2 and Q3 are -CH-. In some embodiments of the compound of Formula I', Q2 is nitrogen and Q1 and Q3 are -CH-. In some embodiments of the compound of Formula I', Q3 is nitrogen and Q1 and Q2 are -CH-.

[0089] In some embodiments of the compound of Formula I', Q4, Q5, and Q6 are -CR b - and each R b are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In some embodiments of the compound of Formula I', Q4, Q5, and Q6 are -CH-.

[0090] In some embodiments of the compound of Formula I', Q4 is -CH- and Q5 and Q6 are nitrogen. In some embodiments of the compound of Formula I', Q5 is -CH- and Q4 and Q6 are nitrogen. In some embodiments of the compound of Formula I', Q6 is -CH- and Q4 and Q5 are nitrogen.

[0091] In some embodiments of the compound of Formula I', Q4 is nitrogen and Q5 and Q6 are -CH-. In some embodiments of the compound of Formula I', Q5 is nitrogen and Q4 and Q6 are -CH-. In some embodiments of the compound of Formula I', Q6 is nitrogen and Q4 and Q5 are -CH-.

[0092] In some embodiments of the compound of Formula I', Q4 is -CH- and Q5 is nitrogen.

[0093] In some embodiments of the compound of Formula I', Q5 and Q6 are nitrogen.

[0094] In some embodiments of the compound of Formula I', Q5 is nitrogen and Q8 is -CH-.

[0095] In some embodiments of the compound of Formula I', Q5, Q6, and Q8 are -CR b - and each R b are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In some embodiments of the compound of Formula I', Q5, Q6, and Q8 are -CH-.

[0096] In some embodiments of the compound of Formula I', Q5 is -CH- and Q6 and Q8 are nitrogen. In some embodiments of the compound of Formula I', Q6 is -CH- and Q5 and Q8 are nitrogen. In some embodiments of the compound of Formula I', Q8 is -CH- and Q5 and Q6 are nitrogen.

[0097] In some embodiments of a compound of Formula I', R1 is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, and an optionally substituted C-carboxy group. In some embodiments of a compound of Formula I', the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In some embodiments of a compound of Formula I', at least one carbon atom of the recited alkyl moiety is perfluorinated. In some embodiments of a compound of Formula I', the alkyl is substituted with a cycloalkyl or aryl. In some embodiments of a compound of Formula I', the cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl. In some embodiments of a compound of Formula I', the aryl is an optionally substituted phenyl. In some embodiments of a compound of Formula I', the carbocyclic group is cyclohexane or cyclopentane. In some embodiments of a compound of Formula I', the aryl group is phenyl. In some embodiments of the compound of Formula I', the C-carboxy group is a moiety of formula -C(=O)-OR, where R is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0098] In some embodiments of the compound of Formula I', R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, non-aromatic C3-C 12 carbocyclic group, C6-C 10 an aryl group, a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, an amino group, a C-carboxy group or an O-carboxy group, -CN, or a carbamoyl group, wherein R1 is hydroxy, halogen, -CN, amino, oxo, an O-carboxy group, a C-carboxy group, a C-amido group, an N-amido group, a C1-C6 alkoxy, a C6-C10 an alkoxy group, a C3-C9 cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroaryl groups independently selected from oxygen, sulfur, or nitrogen, or a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroaryl groups independently selected from oxygen, sulfur, or nitrogen, and a C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0099] In some embodiments of the compound of Formula I', R1 is hydrogen. In some embodiments of the compound of Formula I', R1 is -CN.

[0100] In some embodiments of the compound of Formula I', R1 is optionally substituted C1-C6 alkyl. In some embodiments of the compound of Formula I', R1 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k In some embodiments of the compound of Formula I', R is C 1- It is a C6 alkyl.

[0101] In some embodiments of the compound of Formula I', R1 is an optionally substituted non-aromatic carbocyclic group. In some embodiments of the compound of Formula I', R1 is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k non-aromatic C3-C optionally substituted by 12 It is a carbocyclic group.

[0102] In some embodiments of the compound of Formula I', R1 is an optionally substituted aryl group. In some embodiments of the compound of Formula I', R1 is hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k C6-C optionally substituted with 10 It is an aryl group.

[0103] In some embodiments of compounds of Formula I', R1 is an optionally substituted heterocycloalkyl group. In some embodiments of compounds of Formula I', R1 is a 3- to 6-membered heterocycloalkyl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring is selected from hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0104] In some embodiments of compounds of Formula I', R1 is an optionally substituted heteroaryl group. In some embodiments of compounds of Formula I', R1 is a 5- to 10-membered heteroaryl group containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heteroaryl group is selected from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0105] In some embodiments of compounds of Formula I', R1 is an optionally substituted (carbocyclic) alkyl group. In some embodiments of compounds of Formula I', R1 is (cyclopentyl)C1-C6 alkyl, (cyclobutyl)C1-C6 alkyl, (cyclopentyl)C1-C6 alkyl, (cyclohexyl)C1-C6 alkyl, (cycloheptyl)C1-C6 alkyl, (cyclooctyl)C1-C6 alkyl, or (cyclononyl)C1-C6 alkyl. 1- C alkyl, and R1 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C 1-C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0106] In some embodiments of the compound of Formula I', R1 is an optionally substituted aralkyl group. In some embodiments of the compound of Formula I', R1 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is a benzyl group optionally substituted by

[0107] In some embodiments of the compound of Formula I', R1 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of the compound of Formula I', R1 is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is a (heterocycloalkyl)alkyl group optionally substituted by

[0108] In some embodiments of the compound of Formula I', R1 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of the compound of Formula I', R1 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is a (heteroaryl)alkyl group optionally substituted by

[0109] In some embodiments of the compound of Formula I', R1 is an optionally substituted amino group. In some embodiments of the compound of Formula I', R1 is C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C9 cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a C6-C 10 Aryl, C-carboxy, C-amido, -(SO2)(C 1- C6 alkyl), -C(O)O(C1- C6 alkyl), -C(O)O(C 1- C6 haloalkyl), -C(O)O(C 3- -C(O)O(C6-C9 cycloalkyl), -C(O)O(3- to 6-membered heterocycloalkyl), -C(O)O(5- to 10-membered heteroaryl), and -C(O)O(C6-C 10 In some embodiments of the compound of Formula I', R1 is an amino group optionally substituted with 1 to 2 substituents independently selected from the group consisting of -NR m R n where R m and R n is a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a C6-C 10 Aryl, C-carboxy, C-amido, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -C(O)O(C 3- -C(O)O(C6-C9 cycloalkyl), -C(O)O(3- to 6-membered heterocycloalkyl), -C(O)O(5- to 10-membered heteroaryl), and -C(O)O(C6-C 10 aryl); or R m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 101 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0110] In some embodiments of the compound of formula I', R1 is an optionally substituted C-carboxy group. In some embodiments of the compound of formula I', R1 is -C(O)(C 1- C6 alkyl), -C(O)(C 3- -C(C9 cycloalkyl), -C(O)(3- to 6-membered heterocycloalkyl), -C(O)(5- to 10-membered heteroaryl), and -C(O)(C6-C 10 aryl), and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of acrylic k is optionally replaced by

[0111] In some embodiments of the compound of Formula I', R1 is an optionally substituted O-carboxy group. In some embodiments of the compound of Formula I', R1 is -OC(O)(C 1- C6 alkyl), -OC(O)(C 3- C9 cycloalkyl), -OC(O)(3- to 6-membered heterocycloalkyl), -OC(O)(5- to 10-membered heteroaryl), and -OC(O)(C6-C 10 aryl), and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen or sulfur, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0112] In some embodiments of the compound of Formula I', R1 is an optionally substituted carbamoyl group. In some embodiments of the compound of Formula I', R1 is -C(O)NR m R n where R m and R n is a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; and a C6-C 10 aryl; or R m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl k is optionally replaced by

[0113] In some embodiments of the compound of Formula I', R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted non-aromatic C3-C 12 Carbocyclic groups, optionally substituted C-C 10 aryl groups, and optionally substituted C-carboxy groups.

[0114] In some embodiments of the compound of Formula I', R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted non-aromatic C3-C 12 Carbocyclic groups, optionally substituted C-C 10 aryl groups, optionally substituted C-carboxy groups, and optionally substituted carbamoyl groups.

[0115] In some embodiments of the compound of Formula I', R1 is selected from the group consisting of hydrogen; -CN; C1-C6 alkyl; non-aromatic C3-C 12 Carbocycle, C6-C 10 an aryl group; a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group, or -C(O)-R j where R j is -NR m R n -OR m and;R m is hydrogen or C1-C6 alkyl; R n is C1-C6 alkyl; or R m and R n together with the nitrogen to which they are attached form a ring structure; R1 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C6-C 10 one to five R independently selected from aralkoxy; k is optionally replaced by

[0116] In some embodiments of the compound of Formula I', R1 is hydrogen, -CN, C1-C6 alkyl, non-aromatic C3-C 12 Carbocyclic, C6-C 10 an aryl group; a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group; or -C(O)-R j where R j is -NR m R n -OR m and;R m is hydrogen or C1-C6 alkyl; R n is C1-C6 alkyl; or R m and R n together with the nitrogen to which they are attached form a ring structure; R1 is one to three R1 independently selected from phenyl and haloalkyl; k is optionally replaced by

[0117] In some embodiments of the compound of Formula I', R1 is hydrogen, -CN, C1-C6 alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, or -C(O)-R j where R j is -NR m R n -OR m and R m is hydrogen or C1-C6 alkyl, and R n is C1-C6 alkyl, or R m and R n together with the nitrogen to which they are attached form 1,2,3,4-tetrahydroisoquinoline, and R1 is one to three R1 independently selected from phenyl and haloalkyl. k is optionally replaced by

[0118] In some embodiments of the compound of Formula I', R1 is hydrogen, -CN, C1-C6 alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, isopropylamino, or -C(O)-R j where R j is -NR m R n -OR m and;R m is hydrogen or C1-C6 alkyl; R n is C1-C6 alkyl, or R m and R n together with the nitrogen to which they are attached form 1,2,3,4-tetrahydroisoquinoline, and R1 is one to three R1 independently selected from phenyl and haloalkyl. k is optionally replaced by

[0119] In some embodiments of the compound of Formula I', R2 is hydrogen, halogen, C 1- C6 alkyl, C 3- C cycloalkyl, or -CN; R is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl.

[0120] In some embodiments of the compound of Formula I', R2 is hydrogen. In some embodiments of the compound of Formula I', R2 is halogen. In some embodiments of the compound of Formula I', R2 is -CN.

[0121] In some embodiments of the compound of Formula I', R2 is optionally substituted C1-C6 alkyl. In some embodiments of the compound of Formula I', R2 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C-C 10 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl.

[0122] In some embodiments of the compound of Formula I', R2 is optionally substituted C3-C9 cycloalkyl. In some embodiments of the compound of Formula I', R2 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 3- In some embodiments of compounds of Formula I', R2 is C3-C9 cycloalkyl optionally substituted with 1 to 10 substituents independently selected from the group consisting of hydroxy, halogen, and C1-C6 alkoxy.

[0123] In some embodiments of the compound of Formula I', R2 is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments of the compound of Formula I', R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0124] In some embodiments of compounds of Formula I', R2 is hydrogen, halogen, hydroxy, C1-C6 alkyl optionally substituted with 1-5 substituents independently selected from halogen, and C1-C6 alkoxy, C3-C9 cycloalkyl optionally substituted with 1-10 substituents independently selected from hydroxy, halogen, and C1-C6 alkoxy, or -CN.

[0125] In some embodiments of the compound of Formula I', R3 is hydrogen. In some embodiments of the compound of Formula I', R3 is lower alkyl.

[0126] In some embodiments of compounds of formula I', R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, or an optionally substituted (heterocycloalkyl)alkyl group.

[0127] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C 12 Carbocycle, C6-C 10an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group, an aralkyl group, or a (heterocycloalkyl)alkyl group; and R4 is hydroxy, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R selected from the group consisting of aralkoxy; g or two R g together with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0128] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C 12 Carbocycle, C6-C 10 an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group, an aralkyl group, or a (heterocycloalkyl)alkyl group; and R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g or two R g together with the atoms to which they are attached form a ring.

[0129] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C12 a 3- to 6-membered heterocyclic alkyl ring containing 1 to 4 ring heteroatoms independently selected from carbocycle, oxygen, sulfur, or nitrogen, a (carbocyclic) alkyl group, an aralkyl group, or a (heterocyclic alkyl) alkyl group; R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 one to five R independently selected from aralkoxy; g or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring optionally containing one or two cyclic heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0130] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C 12 a 3- to 6-membered heterocyclic alkyl ring containing 1 to 4 ring heteroatoms independently selected from carbocycle, oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, or a (heterocyclic alkyl)alkyl group; R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is optionally replaced by

[0131] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)alkyl, (cyclopentyl)alkyl, benzyl, (tetrahydrofuranyl)alkyl, or (tetrahydropyranyl)alkyl; R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloxyalkyl, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy g or two R g together with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0132] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (cyclobutyl)alkyl group, (cyclopentyl)alkyl group, benzyl group, (tetrahydrofuranyl)alkyl group, or (tetrahydropyranyl)alkyl group; R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is optionally replaced by

[0133] In some embodiments of the compound of Formula I', R4 is optionally substituted alkyl. In some embodiments of the compound of Formula I', R4 is optionally substituted C1-C6 alkyl. In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g In some embodiments of the compound of Formula I', R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. In some embodiments of the compound of Formula I', R4 is C 1- In some embodiments of the compound of Formula I', R4 is C 1- In some embodiments of the compound of Formula I', R4 is C5-C6 alkyl.

[0134] In some embodiments of the compound of Formula I', R4 is optionally substituted alkenyl. In some embodiments of the compound of Formula I', R4 is optionally substituted C2-C 10In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g C2-C optionally substituted with 10 In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g C2-C optionally replaced by 10 It is alkenyl.

[0135] In some embodiments of the compound of Formula I', R4 is an optionally substituted non-aromatic carbocyclic group. In some embodiments of the compound of Formula I', R4 is an optionally substituted non-aromatic C3-C 12 In some embodiments of the compound of Formula I', R4 is hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g non-aromatic C3-C optionally substituted by 12 a carbocyclic group or two R g together with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g non-aromatic C3-C optionally substituted by 12 In some embodiments of the compound of Formula I', R4 is a carbocyclic group. In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g non-aromatic C3-C optionally substituted by 12 a carbocyclic group or two R gtogether with the atoms to which they are attached to form a 3- to 6-membered aromatic or non-aromatic ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g non-aromatic C3-C optionally substituted by 12 It is a carbocyclic group.

[0136] In some embodiments of compounds of Formula I', R4 is an optionally substituted heterocycloalkyl group. In some embodiments of compounds of Formula I', R4 is an optionally substituted 3- to 6-membered heterocycloalkyl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring is selected from hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3- a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from C9 cycloalkyl, oxygen, sulfur, or nitrogen, oxygen, or sulfur, and C6-C 10 1 to 5 R independently selected from the group consisting of 5- to 10-membered heteroaryl groups, including 1 to 4 ring heteroaryls independently selected from aryl; g or two R gtogether with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is an optionally substituted 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring is selected from hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R selected from the group consisting of aryl g In some embodiments of compounds of Formula I', R4 is an optionally substituted 3- to 6-membered heterocycloalkyl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring is selected from hydroxy, halogen, CN, oxo, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g In some embodiments of compounds of Formula I', R4 is an optionally substituted 3- to 6-membered heterocycloalkyl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heterocycloalkyl ring is selected from hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; gis optionally replaced by

[0137] In some embodiments of compounds of Formula I', R4 is an optionally substituted (carbocyclic)alkyl group. In some embodiments of compounds of Formula I', R4 is (cyclopropyl)C1-C6 alkyl, (cyclobutyl)C1-C6 alkyl, (cyclopentyl)C1-C6 alkyl, (cyclohexyl)C1-C6 alkyl, (cycloheptyl)C1-C6 alkyl, (cyclooctyl)C1-C6 alkyl, or (cyclononyl)C1-C6 alkyl. 1- C alkyl, and R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g or two R g together with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is (cyclopropyl)C1-C6 alkyl, (cyclobutyl)C1-C6 alkyl, (cyclopentyl)C1-C6 alkyl, (cyclohexyl)C1-C6 alkyl, (cycloheptyl)C1-C6 alkyl, (cyclooctyl)C1-C6 alkyl, or (cyclononyl)C1-C6 alkyl. 1- C alkyl, and R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C 1-C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R selected from the group consisting of aryl g In some embodiments of the compound of Formula I', R4 is optionally substituted by (cyclopropyl)C 1- C6 alkyl, (cyclobutyl)C 1- C6 alkyl, (cyclopentyl)C 1- C6 alkyl, (cyclohexyl)C 1- C6 alkyl, (cycloheptyl)C 1- C6 alkyl, (cyclooctyl)C 1- C6 alkyl, or (cyclononyl)C 1- C6 alkyl, and R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is optionally replaced by

[0138] In some embodiments of the compound of Formula I', R4 is an optionally substituted aralkyl group. In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g or a benzyl group optionally substituted by two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring containing 1 to 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g In some embodiments of the compound of Formula I', R4 is a benzyl group optionally substituted by hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; gis a benzyl group optionally substituted by

[0139] In some embodiments of the compound of Formula I', R4 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of the compound of Formula I', R4 is hydroxy, oxo, halogen, amino, CN, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from aryl g or a (heterocycloalkyl)alkyl group optionally substituted by two R g together with the two atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl gIn some embodiments of the compound of Formula I', R4 is a (heterocycloalkyl)alkyl group optionally substituted by hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is a (heterocycloalkyl)alkyl group optionally substituted by

[0140] In some embodiments of the compound of Formula I', R4 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g or a (heteroaryl)alkyl group optionally substituted by two R g together with the atom to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g In some embodiments of the compound of Formula I', R4 is a (heteroaryl)alkyl group optionally substituted by hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g In some embodiments of the compound of Formula I', R4 is a (heteroaryl)alkyl group optionally substituted by hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is a (heteroaryl)alkyl group optionally substituted by

[0141] In some embodiments of the compound of Formula I', R4 is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g or two R gtogether with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is a C6-C 10 an aryl group or a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; R4 is hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is optionally replaced by

[0142] In some embodiments of the compound of Formula I', R4 is an optionally substituted C6-C 10 In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g C6-C optionally substituted by 10 an aryl group or two R gtogether with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g C6-C optionally substituted by 10 In some embodiments of the compound of Formula I', R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g C6-C optionally substituted by 10 an aryl group or two R g together with the atoms to which they are attached to form a 3- to 6-membered aromatic or non-aromatic ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g C6-C optionally substituted by 10 It is an aryl group.

[0143] In some embodiments of the compound of Formula I', R4 is selected from the group consisting of 1 to 5 R g or two R g together with the atoms to which they are attached form a 3- to 6-membered aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is selected from 1 to 5 R g or two R g form a ring together with the atoms to which they are attached.

[0144] In some embodiments of the compound of Formula I', R4 is selected from the group consisting of 1 to 5 R g is naphthalene optionally substituted by

[0145] In some embodiments of compounds of Formula I', R4 is an optionally substituted heteroaryl group. In some embodiments of compounds of Formula I', R4 is a 5- to 10-membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heteroaryl ring is selected from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl groups; g or two R g together with the atoms to which they are attached form a 3- to 6-membered non-aromatic or non-aromatic ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of Formula I', R4 is an optionally substituted 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heteroaryl ring is selected from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C1-C6 alkoxy, C6-C10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g In some embodiments of compounds of Formula I', R4 is a 5-10 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heteroaryl ring is optionally substituted with hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; gIn some embodiments of compounds of Formula I', R4 is an optionally substituted 5-10 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is selected from hydroxy, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of aralkoxy; g is optionally replaced by

[0146] In some embodiments of the compound of Formula I', R4 is an optionally substituted amino group. In some embodiments of the compound of Formula I', R4 is C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C9 cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a C6-C 10 Aryl, C-carboxy, C-amido, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -C(O)O(C 1- C6 haloalkyl), -C(O)O(C 3- -C(O)O(C6-C9 cycloalkyl), -C(O)O(3- to 6-membered heterocycloalkyl), -C(O)O(5- to 10-membered heteroaryl), and -C(O)O(C6-C 10 In some embodiments of the compound of Formula I', R4 is an amino group optionally substituted with 1 to 2 substituents independently selected from the group consisting of -NR m R n where R m and R nis a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a C6-C 10 Aryl, C-carboxy, C-amido, (SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), C(O)O(C 3- -C(O)O(C6-C9 cycloalkyl), -C(O)O(3- to 6-membered heterocycloalkyl), -C(O)O(5- to 10-membered heteroaryl), and -C(O)O(C6-C 10 aryl); or R m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g is optionally replaced by

[0147] In some embodiments of the compound of Formula I', R4 is an optionally substituted sulfamoyl group. In some embodiments of the compound of Formula I', R4 is -SO2NR m R n where R m and R n is hydrogen, C 1- C6 alkyl, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 aryl; or R m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryl g is optionally replaced by

[0148] In some embodiments of the compound of Formula I', R4 is an optionally substituted carbamoyl group. In some embodiments of the compound of Formula I', R4 is C(O)NR m R n where R m and R n is a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; and a C6-C 10 aryl; or R m and R ntogether with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring, and R1 is hydroxy, halogen, -CN, amino, C1-C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and a C6-C 10 1 to 5 R independently selected from the group consisting of aryl g is optionally replaced by

[0149] In some embodiments of the compound of Formula I', R5 is hydroxy. In some embodiments of the compound of Formula I', R5 is NH2.

[0150] In some embodiments of the compound of Formula I', R5 is alkylamino. In some embodiments of the compound of Formula I', R5 is -NR u R v where R u is hydrogen or C 1- C6 alkyl, and R v is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 1- C 12 It is alkyl.

[0151] In some embodiments of the compound of Formula I', R5 is alkanoylamino. In some embodiments of the compound of Formula I', R5 is -NR u C(O)R v where R u is hydrogen or C1-C6 alkyl, and R v is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 1- C 12 It is alkyl.

[0152] In some embodiments of the compound of Formula I', R5 is alkylsulfonylamino. In some embodiments of the compound of Formula I', R5 is -NR u SO2R v and R u is hydrogen or C 1- C6 alkyl, and R v is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 aralkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 1- C 12 It is alkyl.

[0153] In some embodiments of the compound of Formula I', R5 is hydroxy or NH2. In some embodiments of the compound of Formula I', R5 is hydroxy, NH2, C1-C6 alkylamino, C1-C6 alkanoylamino, or C1-C6 alkylsulfonylamino.

[0154] In some embodiments of compounds of Formula I′, R4 and R5, together with the carbon atom to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic C3-C 12 Carbocyclic, optionally substituted C-C 10 In some embodiments of the compound of Formula I', R4 and R5 together with the carbon atoms to which they are attached form a 5- or 6-membered non-aromatic C3-C6 alkyl group. 12 Carbocycle, C6-C 10 and forming 4- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from aryl groups, oxygen, sulfur, or nitrogen, and 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the carbocycle, aryl groups, heterocycloalkyl groups, and heteroaryl groups are not substituted with hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 Optionally substituted with 1 to 5 substituents selected from the group consisting of aryl.

[0155] In some embodiments of the compounds of Formula I', R4 and R5, together with the carbon atom to which they are attached, form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring. In some embodiments of the compounds of Formula I', R4 and R5, together with the carbon atom to which they are attached, form a 7- to 11-membered spirocyclic ring or a 7- to 11-membered spiroheterocyclic ring, and the spirocyclic ring and spiroheterocyclic ring are selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl.

[0156] In some embodiments of compounds of Formula I', R4 and R5, together with the carbon atom to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic ring, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group.

[0157] In some embodiments of compounds of Formula I', R4 and R5, together with the carbon atoms to which they are attached, form a 5- or 6-membered non-aromatic carbocyclic group; C6-C 10an aryl group; a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; or a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the carbocyclic group, aryl group, heterocycloalkyl ring, and heteroaryl ring are joined by 1 to 5 R independently selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and oxo. g and / or two R g together with the atoms to which they are attached form a 3- to 6-membered carbocyclic group.

[0158] In some embodiments of compounds of Formula I', R4 and R5, together with the carbon atom to which they are attached, form a 3- to 6-membered heterocycloalkyl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring contains 1-5 R1-R2 independently selected from the group consisting of C1-C6 alkyl and oxo. g and / or two R g together with the atoms to which they are attached form a 3- to 6-membered non-aromatic carbocyclic ring.

[0159] In some embodiments of compounds of Formula I', R4 and R5, together with the carbon atom to which they are attached, form 1 to 5 R independently selected from C1-C6 alkyl and oxo. g and / or two R g together with the atoms to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group.

[0160] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIIaa: [ka] In the formula, each R g are independently C1-C6 alkyl, or two R gtogether with the atoms to which they are attached form an alkene optionally substituted with C1-C6 alkyl, or two R g together with the atoms to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group. In some embodiments of the compound of Formula I', two R g together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0161] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIIaa: [ka] In the formula, each R g are independently C1-C6 alkyl, or two R g together with the atoms to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group. In some embodiments of the compound of Formula I', two R g together with the atoms to which they are attached form a cyclopentyl or cyclohexyl group.

[0162] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIIab: [ka] R g is C1-C6 alkyl. In some embodiments of the compound of Formula I', R g is isopropyl.

[0163] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIIac: [ka] R g is C1-C6 alkyl. In some embodiments of the compound of Formula I', R g is methyl.

[0164] In some embodiments of the compound of Formula I', T L is a moiety of Formula IIIad: [ka] In the formula, each R g are independently hydrogen or C1-C6 alkyl.

[0165] In some embodiments of compounds of formula I', R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted carbamoyl group, and R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino.

[0166] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C 12 Carbocycle, C6-C 10 an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or —C(O)NR m R n and; R m and R n is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkoxy, C6-C 10R is independently selected from the group consisting of an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring; R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 one to five R independently selected from aralkoxy; g is optionally replaced by; R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino.

[0167] In some embodiments of the compound of Formula I', R4 is C1-C6 alkyl, C2-C 10 Alkenyl, non-aromatic C3-C 12 Carbocycle, C6-C 10 an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or —C(O)NR m R n and; R m and R n is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkoxy, C6-C 10R is independently selected from the group consisting of an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; m and R n together with the nitrogen to which they are attached form a 3- to 18-membered heterocycloalkyl ring; R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 one to five R independently selected from aralkoxy; g is optionally replaced by; R5 is hydroxy.

[0168] In some embodiments of the compound of Formula I', Alk is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments of the compound of Formula I', Alk is hydrogen or hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 1- In some embodiments of the compound of Formula I', Alk is hydrogen. In some embodiments of the compound of Formula I', Alk is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-Calkoxy, C-C10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 C optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl 1- In some embodiments of the compound of Formula I', Alk is C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, and C1-C6 alkoxy.

[0169] In some embodiments of the compound of Formula I', R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring system. In some embodiments of compounds of Formula I', R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and C3-C9 cycloalkyl; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring system. In some embodiments of compounds of Formula I', R 11 is a C6-C optionally substituted by 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl; 10aryl group or a 5- to 10-membered heteroaryl group containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted with 1-5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl, or a 7- to 12-membered bicyclic ring system containing either an aromatic or saturated ring, or a 7- to 12-membered bicyclic heterocycle containing either an aromatic or saturated ring system. In some embodiments of the compound of Formula I', R 11 is a C6-C optionally substituted by 1 to 5 substituents independently selected from lower alkyl, halogen, and C3-C9 cycloalkyl; 10 or a 7-12 membered bicyclic ring system containing either an aromatic or saturated ring; or a 7-12 membered bicyclic heterocycle containing either an aromatic or saturated ring system. In some embodiments of the compound of Formula I', R 11 is a C6-C optionally substituted by 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl; 10 In some embodiments of the compound of Formula I', R 11 is a C6-C optionally substituted by 1 to 5 substituents independently selected from lower alkyl, halogen, and C3-C9 cycloalkyl; 10 In some embodiments of the compound of Formula I', R 11 is a 5- to 10-membered heteroaryl group containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted with 1-5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C-C cycloalkyl. In some embodiments of the compound of Formula I', R 11 is a 7- to 12-membered bicyclic ring system containing either an aromatic or saturated ring. In some embodiments of the compound of Formula I', R 11is a 7- to 12-membered bicyclic heterocycle containing either an aromatic or saturated ring system. In some embodiments of the compound of Formula I', R 11 is benzene optionally substituted with 1 to 5 substituents independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, halogen, and C3-C9 cycloalkyl; pyridine optionally substituted with C1-C5 alkyl; cinnoline; isoquinoline; quinoline; pyrazolo[1,5-a]pyridine; imidazo[1,5-a]pyridine; benzo[b]thiophene; chroman; 1,2,3,4-tetrahydronaphthalene; or naphthalene. In some embodiments of the compound of Formula I', R 11 is benzene optionally substituted with 1 to 5 substituents independently selected from C1-C5 alkyl, halogen, and C3-C9 cycloalkyl, 1,2,3,4-tetrahydronaphthalene, or naphthalene.

[0170] In some embodiments of compounds of Formula I', each of R6 and R7 is halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and C1-C6 alkoxy; R8 is hydrogen; or R6 is halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and C1-C6 alkoxy; and R7 and R8 together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered carbocyclic ring.

[0171] In some embodiments of a compound of Formula I', each of R6 and R7 is independently chlorine, bromine, and iodine. In some embodiments of a compound of Formula I', each of R6 and R7 is independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, wherein the alkyl groups of the lower alkyl and lower alkoxy are each independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. In some embodiments of a compound of Formula I', R6 and R7 are the same. In some embodiments of a compound of Formula I', each of R6 and R7 is independently chlorine or methyl. In some embodiments of a compound of Formula I', R6 is Cl, R7 is Cl, and R8 is hydrogen. In some embodiments of a compound of Formula I', R6 is Cl, R7 is Cl, and R8 is methyl. In some embodiments of compounds of Formula I', R6 is halogen, and R7 and R8 together with the carbon atoms to which they are attached form a four-membered carbocyclic ring.

[0172] In some embodiments of the compound of Formula I', R8 is hydrogen. In some embodiments of the compound of Formula I', R8 is optionally substituted lower alkyl. In some embodiments of the compound of Formula I', R8 is hydroxy, halogen, amino, -CN, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C 3- and R is a lower alkyl optionally substituted by 1 to 5 substituents selected from the group consisting of C5 cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing one heteroatom independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compound of Formula I', R is an optionally substituted lower alkoxy. In some embodiments of the compound of Formula I', R is hydroxy, halogen, amino, -CN, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C 3-and R is a lower alkoxy optionally substituted by 1 to 5 substituents selected from the group consisting of C cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing one heteroatom independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compound of Formula I', R is cyano. In some embodiments of the compound of Formula I', R is halogen.

[0173] In some embodiments of the compound of Formula I', R7 and R8, together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered non-aromatic carbocyclic ring, a 3- to 5-membered heterocycloalkyl, a C6-C6 10 It forms an aryl or 5- to 10-membered heteroaryl ring.

[0174] In some embodiments of the compound of Formula I', Q7 is nitrogen. In some embodiments of the compound of Formula I', Q7 is -CR c In some embodiments of the compound of Formula I', R c is hydrogen. In some embodiments of the compound of Formula I', R c is halogen. In some embodiments of the compound of Formula I', R c is lower alkyl. In some embodiments of the compound of Formula I', R c is hydrogen or methyl. In some embodiments of the compound of Formula I', Q7 is -CH-.

[0175] In some embodiments of the compound of Formula I', R9 is hydrogen, —(C(R d )2) n -N(R d )2, -(C(R d )2) n -CN, or -(C(R d )2) n -C≡CR d In some embodiments of the compound of Formula I', R9 is hydrogen, -(CH2) n -N(R d )2, -(CH2) n -CN, or -(CH2) n -C≡CR dIn some embodiments of the compound of Formula I', R9 is hydrogen, —N(R d )2, -CN, or -C≡CR d In some embodiments of the compound of Formula I', R9 is selected from hydrogen, -NH2, -CN, or -C≡CH.

[0176] In some embodiments of the compound of Formula I', R9 is hydrogen. In some embodiments of the compound of Formula I', R9 is (C(R d )2) n -C(R d )3. In some embodiments of the compound of Formula I', R9 is (C(R d )2) n -OR d In some embodiments of the compound of Formula I', R9 is (C(R d )2) n -N(R d )2. In some embodiments of the compound of Formula I', R9 is -NH2. In some embodiments of the compound of Formula I', R9 is -(C(R d )2) n -S(=O) q R d In some embodiments of the compound of Formula I', R9 is -(C(R d )2) n In some embodiments of the compound of Formula I', R9 is -CN. In some embodiments of the compound of Formula I', R9 is -(C(R d )2) n -C≡CR d In some embodiments of the compound of Formula I', R9 is -C≡CH. In some embodiments of the compound of Formula I', R9 is (C(R d )2) n -C(=O)-OR d In some embodiments of the compound of Formula I', R9 is -(C(R d )2) n In some embodiments of the compound of Formula I', R9 is -(C(R d )2) n -C(=O)-N(Rd )2.

[0177] In some embodiments of the compound of Formula I′, each R d are independently hydrogen or hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-Calkoxy, C-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 In some embodiments of the compound of Formula I', each R is a lower alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl. d is hydrogen. In some embodiments of the compound of Formula I', each R d are independently hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C6 alkoxy, C6-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 and lower alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl.

[0178] In some embodiments of the compound of Formula I', q is 0. In some embodiments of the compound of Formula I', q is 1. In some embodiments of the compound of Formula I', q is 2.

[0179] In some embodiments of the compound of Formula I', n is 0. In some embodiments of the compound of Formula I', n is 1. In some embodiments of the compound of Formula I', n is 2. In some embodiments of the compound of Formula I', n is 3. In some embodiments of the compound of Formula I', n is 4. In some embodiments of the compound of Formula I', n is 5.

[0180] In some embodiments of compounds of Formula I', HeAr is a 5- or 6-membered heteroaryl group containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0181] In some embodiments of the compound of Formula I', R 10 is hydrogen or -C(R e )3, and each R e are independently hydrogen, halogen, or hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-Calkoxy, C-C 10 Aralkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 In some embodiments of the compound of Formula I', R is a lower alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl. 10 is hydrogen. In some embodiments of the compound of Formula I', R 10 -C(R e )3, and each R e are independently hydrogen, halogen, or hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C-Calkoxy, C-C 10 Aralkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 In some embodiments of the compound of Formula I', R is a lower alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl. 10 -C(R e )3, and each R e is independently hydrogen, halogen, or lower alkyl. In some embodiments of the compound of Formula I', R 10 is hydrogen, -CHF2, -CH3, or ethyl.

[0182] In some embodiments of the compound of Formula I', L a is a bond, -(C(R a )2) z -, oxygen, sulfur, or -NR a In some embodiments of the compound of Formula I', L a is a bond. In some embodiments of the compounds of Formula I', L a is -(C(R a )2) z In some embodiments of the compound of Formula I', L a In some embodiments of the compound of Formula I', L a is oxygen. In some embodiments of the compound of Formula I', L a is sulfur. In some embodiments of the compound of Formula I', L a Ha-NR a In some embodiments of the compound of Formula I', each R a is hydrogen. In some embodiments of the compound of Formula I', each R a is independently lower alkyl. In some embodiments of the compound of Formula I', each R a is independently hydrogen or lower alkyl.

[0183] In some embodiments of the compound of Formula I', z is 0. In some embodiments of the compound of Formula I', z is 1. In some embodiments of the compound of Formula I', z is 2. In some embodiments of the compound of Formula I', z is 3. In some embodiments of the compound of Formula I', z is 4. In some embodiments of the compound of Formula I', z is 5.

[0184] In another embodiment, disclosed herein is a compound selected from the group consisting of: [ka] JPEG2025011262000069.jpg213149JPEG2025011262000070.jpg230154JPEG2025011262000071.jpg222156JPEG202 5011262000072.jpg216154JPEG2025011262000073.jpg204157JPEG2025011262000074.jpg236157JPEG20250112620 00075.jpg202157JPEG2025011262000076.jpg222157JPEG2025011262000077.jpg223156JPEG2025011262000078.j pg206155JPEG2025011262000079.jpg206155JPEG2025011262000080.jpg232156JPEG2025011262000081.jpg222157

[0185] Compound synthesis The compounds of the present disclosure were synthesized using the general synthetic procedures set forth in Schemes 1-10 below. Performance of each illustrated step is within the skill of one of ordinary skill in the art who also knows how to modify the synthetic procedures of the following schemes to synthesize the full range of compounds disclosed herein. Synthetic procedures for each compound are provided in the Examples section below.

[0186] As depicted in Scheme 1, an aromatic amine compound of formula S-II is converted to an aza-uracil compound of formula S-III by first generating the corresponding diazonium salt, followed by reaction with N-(2-cyanoacetyl)-carbamate, and finally cyclization to form a compound of formula S-III. The nitrile of formula S-III is then hydrolyzed to a carboxylic acid compound of formula S-IV. The compound of formula S-IV is then reacted with diphenylphosphoryl azide (DPPA) to form a compound of formula SV. Finally, the compound of formula SV is deprotected. [ka]

[0187] As depicted in Scheme 2, aromatic amine compounds of formula S-II can be converted to boronic acid compounds of formula S-VII by first generating a diazonium salt and then reacting with tetrahydroxydiborane. The corresponding boronic acid is then coupled with a suitably protected (by a protecting group "PG") bromo-azauracil compound of formula Int-I. The resulting bromide compound of formula S-VIII is then further transformed by either a substitution reaction or a transition metal-catalyzed transformation, as exemplified in the Examples section below. Removal of the protecting group "PG" affords compounds of formula SX. [ka] JPEG2025011262000084.jpg65150

[0188] The synthesis of aromatic amine compounds of formula S-XIV is described in Scheme 3. Reaction of a compound of formula S-XI with a compound of formula S-XII (where "X" represents a halogen, such as F or Cl), followed by protection with a protecting group "PG", gives a compound of formula S-XIII. Reduction of the nitro functionality of the compound of formula S-XIII results in the formation of an aromatic amine compound of formula S-XIV. [ka]

[0189] Scheme 4 describes the synthesis of a compound of formula S-XIX. Following the transmetallation reaction of a compound of formula S-XVI (where "X" represents a halogen, e.g., Br or I), it is added to an aldehyde of general formula S-XV to obtain an alcohol compound of formula S-XVII, which is then reduced to a compound of formula S-XVIII. Deprotection of PG2 of a compound of formula S-XVIII results in the formation of a compound of formula S-XIX. [ka] JPEG2025011262000087.jpg72152

[0190] As depicted in Scheme 5, compounds of formula S-XX can be obtained by coupling compounds of formula S-VII with bromide compounds of formula Int-II. [ka]

[0191] Scheme 6a shows an alternative synthesis of compounds of general formula S-XIX. A compound of formula S-XXI (where the structure represents a halogen, e.g., Cl, Br, or I) is coupled with a compound of formula S-XXII via Suzuki-type coupling to form a compound of formula S-XXIII. The protecting group PG, e.g., a benzyl moiety, can then be removed to give a compound of formula S-XXIV. The resulting phenol functionality can then be replaced with a triflate group to give a compound of general formula S-XXV. The -OTf group can then be replaced with an -NH2 moiety via a transition metal-catalyzed reaction, e.g., a Buchwald coupling with t-butyl carbamate or benzophenone imine, followed by deprotection to give a compound of general formula S-XIX. The method described in Scheme 6a can also be applied when an indazole halide is used as the starting material instead of S-XXI. Alternatively, the indazole halide can undergo lithium-halogen exchange. The resulting aryllithium species can be reacted with aldehydes of type S-XXVIII to form compounds of formula S-XXIX. Further details of the structure of formula S-XXIX are provided in Scheme 7. [ka]

[0192] Scheme 6b shows the synthesis of a compound of formula S-XXII from a compound of formula S-XXVI in a Suzuki reaction with 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane. [ka]

[0193] Scheme 7 describes the synthesis of a compound of formula S-XXXI. Following the transmetallation reaction of a compound of formula S-XXVII (where "X" represents a halogen, e.g., Br or I), it is added to an aldehyde of general formula S-XXVIII to obtain an alcohol compound of formula S-XXIX, which is then reduced to a compound of formula S-XXX. Deprotection of PG2 of a compound of formula S-XXX results in the formation of a compound of formula S-XXXI. [ka]

[0194] Scheme 8 describes a general synthesis of compounds of formula S-XXI and their products. For example, when R1 is hydrogen and Y is hydrogen, R1 can be converted to the corresponding acyl group via an acid chloride and a Lewis acid (e.g., InBr3) in a nonpolar aprotic solvent (e.g., dichloroethane). The newly formed ketone group can be partially reduced to an alcohol or fully reduced to the corresponding alkane. Further transformations of the ketone group will be apparent to those skilled in the art. In a second example, where R1 is hydrogen and Y is a suitable protecting group (e.g., tosyl), R1 can then be converted to an iodide via an iodinating agent (e.g., NIS) using available literature procedures. [ka]

[0195] Scheme 9 describes a general synthesis of compounds of formula S-XXXIII. 4-Bromo-6-chloropyridazin-3-amines can be converted to the corresponding 4-aryl-6-chloropyridazin-3-amines (S-XXXII) using typical Suzuki-Miyaura conditions, for example, using ArB(OH) (e.g., phenylboronic acid) and a palladium catalyst (e.g., PdCl(PPh)). Subsequent conversion of the amino group to Cl via typical Sandmeyer reaction conditions (e.g., CuCl, t-Bu-ONO, acetonitrile, heat) provides compounds of type S-XXXIII. [ka]

[0196] Scheme 10 describes a general synthesis of compounds of formula S-XXXVI. Compounds of formula S-XXXIV can be coupled with phenols HO-CE-HD at elevated temperatures in a Cu(I)-mediated coupling reaction in DMSO with a base (e.g., KCO) to give intermediates of type S-XXXV. Subsequent hydrolysis of the chloropyridazine via acetic acid and an acetate salt (e.g., NaOAc) gives products of formula S-XXXVI, from which the desired regioisomer can be isolated. In the context of Scheme 10, the group HD can comprise a general protecting group that can be cleaved at the stage of intermediate S-XXXV or at the end of the synthesis to give compounds of formula S-XXXVI. [ka]

[0197] The synthesis of the compound of formula S-XXXVII can be carried out using literature procedures. For example, an alkynyl ester can be combined with a protected aniline using a Ru catalyst under the conditions described in Org. Lett. 2014, 16, 3568-3571 to give a 6-bromoquinolone. Alternatively, the compound of formula S-XXXVII can be formed by other procedures reported in the literature, including, but not limited to, the following examples: (a)Kadnikov,DV;et al.J.Org.Chem.2004,69,6772.(b)Manley,PJ;et al.Org.Lett.2004,6,2433.(c)Jia,C.;Piao,D.;et al.J.Org.Chem.2000,65,7516.(d)Inamoto,K.;et al.J.Org.Chem.2010,75,3900.(e)Ferguson,J.;et al.Org.Lett.2013,15,1998.(f)Fan,H;Org.Lett.2018,20,7929-7932. [ka]

[0198] Alternatively, Scheme 11 shows the synthesis of compounds of formula S-XXXVII, which can begin with an aminoaryl dihalide (S-XXXVII-a). The amine is then protected (e.g., trimethylacetamide) to give the amide intermediate (S-XXXVII-b). Under strongly basic conditions (e.g., n-buLi, THF), S-XXXVII-b reacts with an aldehyde containing the desired Rg substitution to give the alcohol product S-XXXVI-c, which is oxidized in the next step (via a common oxidizing agent, e.g., Dess-Martin reagent) to give the ketone S-XXXVII-d. The ketone undergoes an aldol-type reaction with a protected ester (e.g., t-butyl ether) to give the intermediate S-XXXVII-e. In the final step, intramolecular cyclization can occur to give compounds of formula S-XXXVII. [ka]

[0199] Incorporation of compounds of formula S-XXXVII to form the final product can occur using similar methods described in Schemes 6a and 6b. [ka]

[0200] There are several methods for accessing compounds of formula XXXVIII, including, but not limited to, those found in or referenced in the following references: (a) Hajra, S; et al. Org. Lett. 2018, 20, 4540-4544. (b) Zaytsev, S. et al. Journal of Organic Chemistry (2018), 83(15), 8695-8709. (c) Wu, C; et al. Organic Letters (2014), 16(7), 1960-1963. (d) Ye, N; et al. ACS Infect Dis. 2016, 2(6), 382-392. Incorporation of compounds of formula S-XXXVIII to form the final product can occur using similar methods described in Schemes 6a and 6b.

[0201] As depicted in Scheme 12, compounds of formula S-XXXIX can be obtained by coupling compounds of formula S-VII with azauracil compounds of formula Int-A. The benzyloxymethyl acetal can then be deprotected using a variety of methods described in the literature. [ka]

[0202] Pharmaceutical Composition In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound described herein and at least one pharmaceutically acceptable excipient.

[0203] In another aspect, disclosed herein are pharmaceutical compositions comprising a compound of Formula I described herein and a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound of Formula I described herein and at least one pharmaceutically acceptable diluent, excipient, or carrier.

[0204] In another aspect, disclosed herein is a pharmaceutical composition comprising, consisting essentially of, or consisting of a compound of Formula I' described herein and at least one pharmaceutically acceptable excipient.

[0205] The pharmaceutical compositions disclosed herein may include pharmaceutically acceptable carriers such as diluents, disintegrants, sweeteners, glidants, or flavoring agents, and may be formulated into oral dosage forms such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups, or parenteral dosage forms such as liquids for external use, suspensions for external use, emulsions for external use, gels (ointments, etc.), inhalants, dusting powders, injections, etc. The dosage forms may be formulated in various forms, for example, dosage forms for single administration or multiple administrations.

[0206] The pharmaceutical compositions disclosed herein may contain excipients such as lactose, corn starch, glidants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonicity agents. If desired, sweeteners and / or flavoring agents may be added. Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO), Cremophor, carbohydrates, starches (e.g., corn starch), inorganic salts, antibacterial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), fluids such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0207] Specific carbohydrate excipients include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, myo-inositol, and the like.

[0208] Inorganic salts or buffers include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

[0209] Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl formate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0210] Additional exemplary excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80," and pluronic acid agents such as F68 and F88 (all available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc, and other such suitable cations.

[0211] Furthermore, the compositions disclosed herein may optionally contain one or more acids or bases.Non-limiting examples of usable acids include those selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Non-limiting examples of suitable bases include those selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0212] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active ingredient, and the specific needs of the composition. Generally, however, the excipient is present in the composition in an amount of about 1% to about 99% by weight of the excipient, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight. Generally, the amount of excipient present in the compositions of the present disclosure is selected from at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.

[0213] The pharmaceutical compositions described herein can be administered to a human patient themselves, or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or mixed with suitable carriers or excipients. Techniques for formulating and administering the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 18th edition, 1990.

[0214] Suitable routes of administration may include, for example, oral, transdermal, rectal, transmucosal, or intestinal administration, and may include parenteral delivery, including intramuscular, subcutaneous, intravenous, and intramedullary injection, as well as inhalation, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection.

[0215] The pharmaceutical compositions disclosed herein can be prepared in a known manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, wet grinding, emulsifying, encapsulating, encapsulating or tableting process.Then, these pharmaceutical compositions can be formulated in a conventional manner using one or more known physiologically acceptable carriers, including excipients and / or adjuvants, which facilitates the processing of active compound into pharmaceutically usable preparations.Any well-known technique, carrier and excipient can be used as suitable and understood in the art, for example, in the above-mentioned Remington's Pharmaceutical Sciences.

[0216] Pharmaceutical compositions suitable for use in the formulations of the present disclosure include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of compound effective to prevent, alleviate or improve the symptoms of a disease, or prolong the survival of the subject being treated. In some embodiments, a therapeutically effective amount refers to an amount of compound effective to alleviate or improve the symptoms of a disease, or prolong the survival of the subject being treated.

[0217] While exact dosages can be determined on a drug-by-drug basis, in most cases, some generalizations regarding dosage can be made. A daily dosage regimen for an adult human patient may be, for example, an oral dose of 0.001 mg to 1000 mg, preferably 0.01 mg to 500 mg, e.g., 1 to 200 mg, of each active ingredient of the pharmaceutical compositions disclosed herein, or a pharmaceutically acceptable salt thereof, calculated as the free base or free acid, with the composition administered 1 to 4 times daily or once weekly. Alternatively, the compositions disclosed herein may be administered via continuous release, such as sustained-release, delayed-release, or extended-release, preferably at a dose of up to 500 mg of each ingredient per day. Thus, the total daily oral dosage of each ingredient typically ranges from 0.1 mg to 2000 mg.

[0218] Treatment method In another aspect, disclosed herein is a method of treating a thyroid hormone receptor-associated disorder in a patient, the method comprising, consisting essentially of, or consisting of identifying a patient in need of treatment for a thyroid hormone receptor-associated disorder, and administering to or contacting the patient with a compound described herein.

[0219] In another aspect, disclosed herein are methods of treating a thyroid hormone receptor-associated disorder in a patient, the method comprising identifying a patient in need of treatment for a thyroid hormone receptor-associated disorder and administering to or contacting the patient with a compound of Formula I described herein. In some embodiments, the method of treating a thyroid hormone receptor-associated disorder in a patient consists essentially of, or consists of, identifying a patient in need of treatment for a thyroid hormone receptor-associated disorder and administering to or contacting the patient with a compound of Formula I described herein.

[0220] In another aspect, disclosed herein is a method of treating a thyroid hormone receptor-associated disorder in a patient, the method comprising, consisting essentially of, or consisting of identifying a patient in need of treatment for a thyroid hormone receptor-associated disorder, and administering to or contacting the patient with a compound of formula I' as described herein.

[0221] In some embodiments, a medical professional, such as a physician, physician's assistant, nurse, or the like, identifies individuals in need of treatment for a thyroid hormone receptor-associated disorder and / or as candidates for treatment with the compounds disclosed herein. Identification may be based on medical test results, non-responsiveness to other first-line therapies, the specific nature of a particular liver disorder, etc.

[0222] In some embodiments, the thyroid hormone receptor-associated disorder is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0223] In another aspect, disclosed herein is a method of treating a disorder or disease in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein, wherein the disorder or disease is selected from non-alcoholic fatty liver disease (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0224] In another aspect, disclosed herein is a method of treating NASH in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0225] In another aspect, disclosed herein is a method of treating obesity in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0226] In another aspect, disclosed herein is a method of treating hyperlipidemia in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0227] In another aspect, disclosed herein is a method of treating hypercholesterolemia in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0228] In another aspect, disclosed herein is a method of treating diabetes in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0229] In another aspect, disclosed herein is a method of treating hepatic steatosis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0230] In another aspect, disclosed herein are methods for selectively modulating the activity of thyroid hormone receptor β (THR-β), comprising, consisting essentially of, or consisting of contacting a compound described herein with a thyroid hormone receptor. In some embodiments, the contacting is in vitro or ex vivo, while in other embodiments, the contacting is in vivo.

[0231] In another aspect, disclosed herein is a method of selectively modulating the activity of thyroid hormone receptor β (THR-β), comprising contacting a compound of Formula I, as described herein, with a thyroid hormone receptor. In some embodiments, the contacting is in vitro or ex vivo, while in other embodiments, the contacting is in vivo. In some embodiments, the method of selectively modulating the activity of thyroid hormone receptor β (THR-β) consists essentially of, or consists of, contacting a compound of Formula I, as described herein, with a thyroid hormone receptor.

[0232] In another aspect, disclosed herein are methods for selectively modulating the activity of thyroid hormone receptor β (THR-β), comprising, consisting essentially of, or consisting of contacting a compound of Formula I' described herein with a thyroid hormone receptor. In some embodiments, the contacting is in vitro or ex vivo, while in other embodiments, the contacting is in vivo.

[0233] In another aspect, disclosed herein are methods for selectively modulating the activity of thyroid hormone receptor β (THR-β), comprising, consisting essentially of, or consisting of contacting a composition described herein with a thyroid hormone receptor. In some embodiments, the contacting is in vitro or ex vivo, while in other embodiments, the contacting is in vivo. [Example]

[0234] The following illustrates aspects of the present invention without limiting its scope. Conditions for the preparation of some of the compounds disclosed herein are presented. Procedures for the synthesis of common intermediates are presented only once. Chemical names were generated using Marvin 17.28.0 or Chemdraw 18.1.

[0235] Abbreviation table: The following abbreviations are used in this disclosure: [Table 1] JPEG2025011262000100.jpg162151

[0236] Synthesis of building blocks Synthesis of 1,3-isopropyl-1H-indol-5-ol [ka] To a stirred mixture of (4-methoxyphenyl)hydrazine (10.00 g, 72.375 mmol, 1.0 equiv) in 100 mL of AcOH was added isovalaldehyde (6.23 g, 0.072 mmol, 1 equiv) dropwise at 80 °C. The resulting mixture was stirred at 120 °C for 2 h. The resulting mixture was concentrated in vacuo. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-5-methoxy-1H-indole (2.6 g, 19%) as a brown solid.

[0237] To a solution of 3-isopropyl-5-methoxy-1H-indole (9.03 g, 47.713 mmol, 1.0 equiv) in DCM (100.00 mL) was added boron tribromide (35.88 g, 143.217 mmol, 3 equiv) dropwise at −78° C. for 1 h. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched by adding HO at 0° C. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-1H-indol-5-ol (5.86 g, 56%) as a black oil.

[0238] 2a. Synthesis of 5-bromo-3-isopropyl-1H-indole [ka] To a stirred solution of 4-bromophenyl-hydrazine (50.00 g, 267.32 mmol, 1.00 equiv) in AcOH (500 mL) was added isovalaldehyde (23.03 g, 267.37 mmol, 1.00 equiv) dropwise at 80 °C. The resulting mixture was stirred at 120 °C for 3 h. The resulting mixture was concentrated in vacuo. The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-3-isopropyl-1H-indole (28 g, 44%) as a brown solid.

[0239] 2b. Synthesis of 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine: [ka] To a stirred solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (2.0 g, 8.36 mmol, 1 equiv.), DMAP (20.44 mg, 167.29 μmol, 0.02 equiv.), and DIPEA (2.38 g, 18.40 mmol, 2.2 equiv.) in DCM (60 mL) was added ToSCl (1.91 g, 10.04 mmol, 1.2 equiv.) at 20 °C. The resulting mixture was then stirred at 20 °C for 12 h. TLC (petroleum ether / ethyl acetate = 5 / 1, UV) showed that the starting material was completely consumed. The mixture was diluted with HO (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0 to 10%) to give 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (2.6 g, 5.61 mmol, 67.0% yield) as an off-white solid.

[0240] 2c. Synthesis of 5-bromo-3-pentyl-1H-indazole [ka] To a solution of 5-bromo-2-fluoro-benzaldehyde (25 g, 123.15 mmol, 1 equiv) in THF (100 mL) was added bromo(pentyl)magnesium (1 M, 184.73 mL, 1.5 equiv) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with saturated NH Cl (50 mL) at 0 °C, then diluted with HO (50 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether) to give 1-(5-bromo-2-fluoro-phenyl)hexan-1-ol (9.5 g, 34.53 mmol, 28% yield) as a colorless oil.

[0241] To a solution of 1-(5-bromo-2-fluoro-phenyl)hexan-1-ol (9.5 g, 34.53 mmol, 1 equiv.) in DCM (100 mL) at 20 °C was added 4A MS (10 g) and PDC (25.98 g, 69.05 mmol, 2 equiv.). The mixture was stirred at 20 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether) to give 1-(5-bromo-2-fluoro-phenyl)hexan-1-one (8.2 g, 30.02 mmol, 87% yield) as a pale yellow solid.

[0242] To a solution of 1-(5-bromo-2-fluoro-phenyl)hexan-1-one (5 g, 18.31 mmol, 1 equiv.) in NMP (2 mL) was added hydrazine hydrate (2.16 g, 36.61 mmol, 2.09 mL, 85% purity, 2 equiv.) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was added to ice water (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (eluent: 0–20% ethyl acetate / petroleum ether) to give 5-bromo-3-pentyl-1H-indazole (2 g, 7.49 mmol, 41% yield) as a white solid.

[0243] Synthesis of 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde [ka] To a stirred solution of 5-bromo-3-isopropyl-1H-indole (3.0 g, 12.6 mmol, 1.00 equiv) in toluene (50 mL) was added BuNHSO (0.43 g, 1.27 mmol, 0.10 equiv) portionwise at 0 °C. TsCl (2.90 g, 15.26 mmol, 1.2 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4.0 g, 67%) as a pale yellow solid.

[0244] To a stirred solution of 5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4 g, 10.2 mmol, 1.00 equiv) in THF was added n-BuLi (31.2 ml, 51.0 mmol, 5.0 equiv, 1.6 M in hexane) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 40 min under a nitrogen atmosphere. DMF (3.70 g, 0.051 mmol, 5.0 equiv) was added at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1.5 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (1.1 g, 31%) as a pale yellow oil.

[0245] Synthesis of 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione [ka] 6-Bromo-2,4-dihydro-1,2,4-triazine-3,5-dione (10.00 g, 52.091 mmol, 1.00 equiv.) was refluxed (140 °C) in acetic anhydride (50 mL) for 5 hours. After concentration of the reaction medium to dryness, the precipitate was isolated and then recrystallized from ether to give the desired product. The desired product was isolated as a pale yellow solid (11.6 g, 95% pure, 90% yield).

[0246] Under nitrogen, NaH (2.19 g, 54.755 mmol, 1.10 equiv., 60%) was placed in DMF (50 mL). A solution of 2-acetyl-6-bromo-4H-1,2,4-triazine-3,5-dione (11.60 g, 49.571 mmol, 1.0 equiv.) in DMF (150 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then [(chloromethoxy)methyl]benzene (8.54 g, 54.53 mmol, 1.1 equiv.) was added, followed by stirring at room temperature for 18 h. After concentration to dryness, the resulting residue was dissolved in HO (200 mL) and extracted with ethyl acetate (EA) (3 × 500 mL). After drying over NaSO, the organic phase was evaporated, and the resulting clear oil was purified, yielding 15 g of crystals. The crystals were placed in EtOH (400 mL) in the presence of TsOH (100.0 mg, 0.581 mmol, 0.01 equiv). The mixture was heated at reflux for 4 h and then concentrated to dryness. The residue was dissolved in HO and then extracted with EA. After drying and evaporation of the organic phase, the desired product was obtained as a yellow oil (9.5 g, yellow oil, 90% pure, 61% yield).

[0247] 5a. Synthesis of 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione [ka] To a stirred solution of 6-bromo-2,4-dihydro-1,2,4-triazine-3,5-dione (200.0 mg, 1.04 mmol, 1.0 equiv) in ACN (5 mL) was added BSA (529.8 mg, 2.61 mmol, 2.5 equiv) dropwise at 0° C. under an argon atmosphere. The resulting mixture was stirred at 82° C. for 3 hours under an argon atmosphere, and then CHCl (251.4 mg, 1.77 mmol, 1.7 equiv) was added dropwise at 82° C. and stirring was continued at 82° C. for 20 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and then dissolved in DCM, washed with water and brine, and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (870 mg, 69%) as a yellow solid.

[0248] 5b. Synthesis of 6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione 6-Bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione was prepared similarly as described for 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione, using 2.5 equivalents of iodoethane instead of 1.7 equivalents of CH3I.

[0249] 6. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole [ka] To a stirred solution of 3-isopropyl-1H-indol-5-ol (1.00 g, 5.71 mmol, 1.00 equiv) in THF, potassium tert-butoxide (0.64 g, 5.70 mmol, 1.0 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the resulting mixture was concentrated in vacuo and redissolved in DMF. To a second reaction flask: a stirred solution of 1,2,3-trichloro-5-nitrobenzene (1.29 g, 5.70 mmol, 1.0 equiv) in DMF was added the first reaction flask at 0 °C. The resulting mixture was stirred at 0 °C for 5 minutes, then warmed to 100 °C and stirred for 1 hour. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography to give 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.3 g, 55%) as a yellow solid.

[0250] 7. Synthesis of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole [ka] To a stirred mixture of 3-isopropyl-1H-indol-5-ol (5.10 g, 29.10 mmol, 1.0 equiv.) in 50 mL of DMSO, K2CO3 (4.42 g, 32.0 mmol, 1.1 equiv.) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (4.92 g, 29.1 mmol, 1.0 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (6 g, 64%) as a pale yellow solid.

[0251] 8. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole [ka] To a solution of 5-hydroxyindole (16.0 g, 120.2 mmol, 1.0 equiv) in acetonitrile (320 mL) was added potassium tert-butoxide (13.48 g, 120.2 mmol, 1.0 equiv) at 0° C. After 20 minutes, the mixture was concentrated to remove acetonitrile and dissolved in N,N-dimethylformamide (320 mL). 1,2,3-trichloro-5-nitrobenzene (27.21 g, 120.2 mmol, 1.00 equiv) was then added at 0° C. The resulting solution was stirred at 100° C. overnight and then quenched with water (300 mL). The resulting solution was extracted with ethyl acetate (3×500 mL), and the combined organic layers were washed with brine (2×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 28 g (68% yield) of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole as a yellow solid.

[0252] 9. Synthesis of 5-dichloro-4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]aniline [ka] To a stirred solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.29 g, 3.532 mmol, 1.0 equiv) in toluene (50.00 mL), TsCl (0.81 g, 4.239 mmol, 1.2 equiv), KOH (50%) (21.4 mL), and BuNHSO (0.12 g, 0.353 mmol, 0.1 equiv) in toluene (10 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 6 h. After completion of the reaction, the resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (1.40 g, 75%) as a yellow solid.

[0253] To a stirred solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (1.40 g, 2.73 mmol, 1.0 equiv) and NHCl (1.16 g, 21.62 mmol, 8.0 equiv) in EtOH (50 mL) and HO (25 mL) under a nitrogen atmosphere, Fe powder (0.75 g, 13.514 mmol, 5.00 equiv) was added portionwise at room temperature. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with EA and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3,5-dichloro-4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)-indol-5-yl]oxy]aniline (1.11 g, 78%) as a white solid.

[0254] 10. Synthesis of 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylaniline [ka] To a stirred mixture of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (5.00 g, 15.414 mmol, 1.00 equiv.) in 50 mL of toluene, TsCl (3.53 g, 0.018 mmol, 1.2 equiv.), BuNHSO (0.52 g, 0.002 mmol, 0.1 equiv.), and KOH (50 mL) were added dropwise at 0 °C. The mixture was stirred at room temperature overnight and quenched with water (50 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in hexane to give 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (5.8 g, 79%) as a pale yellow solid.

[0255] To a stirred mixture of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (5.80 g, 12.120 mmol, 1.0 equiv.) in MeOH (70 mL) was added Pd / C (1.74 g) in portions. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (1×500 mL). The filtrate was concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to give 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethyl-aniline (3.2 g, 59%) as a pale yellow solid.

[0256] 11. Synthesis of 4-[[(3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline [ka] To a stirred solution of N-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (260.16 mg, 0.879 mmol, 1.0 equiv.) in THF (5 mL) was added MeLi-LiBr (1.7 mL, 1.76 mmol, 2.0 equiv., 1 M in ether) under nitrogen at −78° C. Then, t-BuLi (1.6 mL, 2.64 mmol, 3.00 equiv., 1.6 M in hexane) was added dropwise at −78° C. The mixture was stirred at −78° C. for 20 minutes. 3-Isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (300 mg, 0.879 mmol, 1.0 equiv.) was added at −78° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified to give 2,2,2-trifluoro-N-(4-[hydroxy]3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300 mg, 61%) as a white solid.

[0257] A solution of 2,2,2-trifluoro-N-(4-[hydroxy]3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300.0 mg, 0.537 mmol, 1.00 equiv) in DCM (5 mL) was stirred at 0 °C under nitrogen. Then, a solution of EtSiH (374.7 mg, 3.22 mmol, 6.0 equiv) in DCM (15 mL) and TMSOTf (7.16 mg, 0.032 mmol, 0.06 equiv) in DCM (5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was quenched with saturated NaHCO solution (20 mL). The resulting solution was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was isolated as a yellow solid (260 mg, 85% pure, 76% yield) containing 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide.

[0258] To a solution of 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (260.0 mg, 0.479 mmol, 1.0 equiv) in MeOH (10 mL) and HO (2 mL) stirred at room temperature under nitrogen was added NaOH (76.66 mg, 1.917 mmol, 4.0 equiv). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with dichloromethane (3×50 mL), and the organic layers were combined, washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was isolated as a yellow solid containing 4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline (230 mg, 90% pure, 97% yield).

[0259] 12. Synthesis of 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline [ka] To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (28.0 g, 86.65 mmol, 1.0 equiv.) in toluene (720 mL) was added tetrabutylammonium hydrogen sulfate (2.94 g, 8.665 mmol, 0.10 equiv.) and potassium hydroxide (120.00 g, 2138.8 mmol, 25.0 equiv.) in water (120 mL) at 0° C. 4-Toluenesulfonyl chloride (19.82 g, 103.98 mmol, 1.20 equiv.) in toluene (720 mL) was added dropwise at 0° C. The reaction was then stirred at room temperature for 3 hours and quenched with water (200 mL). The mixture was extracted with ethyl acetate (3×500 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified to give 5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole (34 g, 78% yield) as a yellow solid.

[0260] To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-indole (26.00 g, 54.47 mmol, 1.0 equiv.) in ethanol (500 mL) and water (250 mL), iron powder (15.21 g, 272.36 mmol, 5.0 equiv.) and ammonium chloride (23.31 g, 435.78 mmol, 8.0 equiv.) were added. The resulting solution was stirred at 50° C. for 2 hours. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (6×100 mL). The filtrate was extracted with dichloromethane (3×500 mL). The combined organic layers were combined, washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline (23 g, 88% yield) as a pale yellow solid.

[0261] 13a. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one [ka] To a solution of 3,6-dichloropyridazine (50.00 g, 335.64 mmol, 1.0 equiv.) in HO (1.20 L), AgNO (57.02 g, 335.64 mmol, 1.0 equiv.) and isobutyric acid (29.57 g, 335.64 mmol, 1.0 equiv.) were added portionwise at room temperature under an air atmosphere, followed by stirring at 50 °C under a nitrogen atmosphere. HSO (98.76 g, 1006.9 mmol, 3.0 equiv.) was added portionwise at 50 °C and the mixture was stirred at 60 °C. Then, (NH)SO (229.78 g, 1006.914 mmol, 3.0 equiv.) was added and the mixture was stirred at 70 °C for 30 min under a nitrogen atmosphere. The mixture was neutralized to pH 9 with NaOH solution. The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (2×1 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3,6-dichloro-4-isopropylpyridazine (30 g, 47%) as a pale yellow oil.

[0262] To a solution of 3,6-dichloro-4-isopropylpyridazine (20.00 g, 104.679 mmol, 1.0 equiv.) in DMSO (200 mL), phenol, 4-amino-2,6-dichloro- (18.63 g, 104.68 mmol, 1.0 equiv.), K2CO3 (58.16 g, 420.81 mmol, 4.02 equiv.), and CuI (11.96 g, 62.81 mmol, 0.60 equiv.) were added portionwise. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The mixture was acidified to pH 8 with concentrated HCl. The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline (17 g, 49%) as a green solid.

[0263] To a solution of 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (17.00 g, 51.111 mmol, 1.0 equiv) in HOAc (200 mL) was added NaOAc (24.33 g, 178.89 mmol, 3.50 equiv) in portions. The mixture was stirred overnight at 100° C. under a nitrogen atmosphere. To the mixture were added NaOH (12.27 g, 306.77 mmol, 6.0 equiv) and MeOH (200 mL) in portions. The resulting mixture was stirred overnight at 120° C. under a nitrogen atmosphere. The resulting mixture was extracted with EA (3×500 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (11 g, 69%) as an off-white solid.

[0264] 13b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline [ka] A mixture of 3,6-dichloro-4-isopropylpyridazine (80.0 g, 419 mmol, 1.00 equiv.), 4-amino-2,6-dichlorophenol (74.5 g, 419 mmol, 1.0 equiv.), K2CO3 (232 g, 1675 mmol, 4.0 equiv.), and CuI (47.9 g, 251 mmol, 0.6 equiv.) in DMSO (800 mL) was stirred at 60 °C overnight. After cooling to 25 °C, the solution was poured into ice water (3 L), and the pH of the mixture was adjusted to 8 with hydrochloric acid (3 N). The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether and ethyl acetate (PE:EA) 5:1) to give 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (35.0 g, 24% yield) as an off-white solid. LCMS (ESI, m / z): 332 [M+H] + .

[0265] A mixture of 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (10.0 g, 30.1 mmol, 1.00 equiv.) and potassium methoxide (21.1 g, 301 mmol, 10.0 equiv.) in MeOH (50 mL) was stirred at 65 °C for 48 h. After cooling to 25 °C, the pH of the mixture was adjusted to 6-7 with hydrochloric acid (1 N). The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 5:1 PE:EA) to give 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline (6.80 g, 65% yield) as a white solid. LCMS(ESI,m / z):328[M+H] + .

[0266] 14a. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid [ka] A 1000 mL round-bottom flask was charged with 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (14.13 g, 44.98 mmol, 1.0 eq) in MeOH (200 mL). HCl (4.10 mL, 112.439 mmol, 3 eq) was added dropwise at 0 °C. HO (100 mL) was added at 0 °C. The mixture was stirred for 10 min, then NaNO (3.72 g, 53.971 mmol, 1.20 eq) was added and stirred for an additional 30 min at 0 °C. Tetrahydroxydiborane (40.32 g, 449.749 mmol, 10.0 eq) was added. The reaction was stirred at 60 °C for 1 h. The resulting solution was quenched with water (50 mL). The resulting solution was extracted with dichloromethane (3 × 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (6.3 g, 37%) as a white solid.

[0267] 14b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronic acid [ka] To a stirred mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]aniline (5.80 g, 17.7 mmol, 1.00 equiv.) and CuBr (7.89 g, 35.3 mmol, 2.00 equiv.) in ACN (40 mL) was added tert-butyl nitrite (4.24 mL, 35.4 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was then warmed to room temperature and stirred for an additional 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10:1 PE:EA) to afford 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (3.50 g, 48% yield) as a yellow solid. LCMS (ESI, m / z): 391 [M+H] + .

[0268] A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methyloxypyridazine (1.00 g, 2.55 mmol, 1.00 equiv), bis(pinacolato)diboron (972 mg, 3.83 mmol, 1.50 equiv), Pd(dppf)Cl (187 mg, 0.256 mmol, 0.10 equiv), and KOAc (750 mg, 7.64 mmol, 3.00 equiv) in 1,4-dioxane (10 mL) was stirred at 90 °C for 2 h. After cooling to 25 °C, the solid was filtered and the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column: C18 silica gel; mobile phase, A: water (containing 0.5% TFA), and B: ACN (20% to 95% in 20 min) to give 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronic acid (610 mg, 64% yield) as a brown solid. LCMS (ESI, m / z): 359 [M+H] + .

[0269] 15. Synthesis of 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile [ka] To a solution of 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline (15.00 g, 33.532 mmol, 1.0 equiv) in water (700 mL), concentrated hydrochloric acid (336 mL), and acetic acid (942 mL) was added sodium nitrite (4.86 g, 70.418 mmol, 2.1 equiv) in water (50 mL) dropwise at 0° C. After the addition, the reaction was stirred at 0° C. for 45 minutes. The reaction mixture was then quickly poured into a solution of ethyl N-(2-cyanoacetyl)carbamate (7.85 g, 50.30 mmol, 1.5 equiv) and pyridine (336 mL) in water (600 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and filtered. The filter cake was washed with water (100 mL) and petroleum ether (200 mL) and dried under reduced pressure to give ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazinylidene)-acetyl)carbamate (18.4 g, 80% yield) as a red solid.

[0270] To a solution of ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (18.40 g, 29.95 mmol, 1.0 equiv) in N,N-dimethylacetamide (300 mL) was added potassium acetate (11.76 g, 119.782 mmol, 4.0 equiv). The reaction was stirred at 120° C. for 2 hours and quenched with water (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), and the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (14 g, 80% yield) as a brown solid.

[0271] To a stirred solution of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (7.0 g, 12.32 mmol, 1.0 equiv) and p-toluenesulfonic acid (0.210 g, 1.232 mmol, 0.1 equiv) in dichloromethane (300 mL) was added N-iodosuccinimide (4.16 g, 18.47 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 6 h and quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3 × 200 mL), and the combined organic layers were combined, washed with saturated sodium thiosulfate solution (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (5.30 g, 43% yield) as a brown solid.

[0272] 16. Synthesis of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile [ka] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (500 mg, 1.591 mmol, 1.0 equiv.) in HOAc (43.8 mL, 764.03 mmol) and HCl (15.3 mL, 503.55 mmol), NaNO (230.59 mg, 3.34 mmol, 2.1 equiv.) in HO (33.4 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The above solution was rapidly poured into a second reaction flask, and ethyl N-(2-cyanoacetyl)carbamate (372.75 mg, 2.387 mmol, 1.5 equiv.) in pyridine (20 mL) and HO (40.9 mL) were placed at 0 °C. The resulting mixture was kept at 0 °C for 30 min. The precipitated solid was collected by filtration and washed with PE and HO (3 × 300 mL) to give N-[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazin-1-ylidene)-carbonyl]-carbamate ethyl, which may also be referred to as (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-hydrazinylidene)acetyl)-carbamate (name produced by ChemDraw) (640 mg, 84%) as an orange solid.

[0273] To a solution of N-[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazin-1-ylidene)carbonyl]carbonyl]carbamate (also referred to as ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate) (640.00 mg, 1.330 mmol, 1.00 equiv) in DMA (13.36 mL) was added KOAc (261.01 mg, 2.660 mmol, 2.0 equiv) in portions at room temperature. The mixture was stirred at 120° C. under a nitrogen atmosphere for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (4 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated. This gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (590 mg, 102%) as a dark orange solid.

[0274] 17. Synthesis of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-1,2,4-triazine-3,5-dione [ka] To a solution of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (5.00 g, 11.663 mmol, 1.0 equiv.) in DCM (200 mL) stirred at room temperature was added 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (4.37 g, 13.995 mmol, 1.2 equiv.), Cu(OAc) (4.24 g, 23.326 mmol, 2 equiv.), and pyridine (1.85 g, 23.326 mmol, 2 equiv.). The reaction mixture was stirred at room temperature under oxygen for 2 days and then concentrated under reduced pressure to give the crude product. Purification gave 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-1,2,4-triazine-3,5-dione (2.2 g, 28% yield) as an off-white solid.

[0275] 18. Synthesis of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide [ka] An 8 mL vial was charged with 6-chloro-2-methyl-3-nitropyridine (20.00 g, 115.895 mmol, 1.0 equiv), phenol, 4-amino-2,6-dichloro- (24.76 g, 139.07 mmol, 1.2 equiv), K2CO3 (48.05 g, 347.69 mmol, 3.0 equiv), and DMF (200 mL). The resulting mixture was stirred at 60 °C overnight. The reaction mixture was quenched with water (400 mL). The resulting mixture was extracted with EA (3 × 500 mL), and the organic layers were combined, washed with brine (2 × 400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with EA:PE (0% to 40% in 30 min) to give the desired product 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]aniline (36.4 g, 91%) as a yellow solid. LCMS (ESI, m / z): 314 [M+H] + .

[0276] To a solution of 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]-aniline (36.40 g, 115.88 mmol, 1.0 equiv.) and (dimethoxymethyl)dimethylamine (33.14 g, 278.1 mmol, 2.4 equiv.) in dimethylformamide (400 mL) was added TEA (11.73 g, 115.9 mmol, 1.0 equiv.). The resulting mixture was stirred at 100 °C for 4 h. The mixture was cooled to 60 °C and concentrated under reduced pressure to remove half of the DMF. The resulting solution was carried on to the next step without further treatment.

[0277] To a solution of (E)-N'-(3,5-dichloro-4-((6-((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)oxy)phenyl)-N,N-dimethylformimidamide (49.17 g, 115.89 mmol, 1.0 equiv) in DMF (200 mL) and MeOH (400 mL) was added Pd / C (10.0 g, 93.967 mmol, 0.81 equiv) and NaOAc (9.51 g, 115.89 mmol, 1.0 equiv) under hydrogen. The resulting mixture was stirred at room temperature overnight. The mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with EA:PE (0% to 70% in 30 min) to give the desired product (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylmethanimidamide (21.5 g, 45%) as a brown solid. LCMS (ESI, m / z): 349 [M+H] + .

[0278] To a solution of (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylmethanimidamide (5.00 g, 14.32 mmol, 1.0 equiv.) and I2 (4.00 g, 15.75 mmol, 1.1 equiv.) in dimethylformamide (50 mL) was added KOH (3.21 g, 57.27 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature overnight and quenched with water (80 mL). The resulting mixture was extracted with EA (3 × 100 mL), and the organic layers were combined, washed with brine (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was triturated with 5:1 PE:EA to give the desired product (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide (5.9 g, 78%) as a yellow solid. LCMS (ESI, m / z): 475 [M+H] + .

[0279] 19. Synthesis of 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline [ka] To a solution of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide (3.0 g, 6.31 mmol, 1.0 equiv.), KPO (2.01 g, 9.471 mmol, 1.5 equiv.), and 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (0.410 g, 0.631 mmol, 0.10 equiv.) in dioxane (75 mL) and HO (15 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.24 g, 25.26 mmol, 4.0 equiv.) under nitrogen. The resulting mixture was stirred at 60°C overnight and quenched with water (100 mL). The resulting mixture was extracted with EA (3 x 150 mL), and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography eluting with EA:PE (0% to 50% in 30 min) to give the desired product (E)-N'-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-N,N-dimethylmethanimidamide (430 mg, 14%) as a yellow solid. LCMS (ESI, m / z): 389 [M+H] + .

[0280] To a solution of (E)-N'-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-N,N-dimethylmethanimidamide (400.0 mg, 1.028 mmol, 1.0 equiv.) in MeOH (25 mL) was added Pd / C (250.0 mg, 2.349 mmol, 2.3 equiv.). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The mixture was filtered through a Celite pad and washed with MeOH (20 mL). The combined organic layers were concentrated under reduced pressure to give the crude product (E)-N'-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]-oxy)phenyl]-N,N-dimethylmethanimidamide (380 mg, crude) as a yellow solid. LCMS (ESI, m / z): 391 [M+H] + .

[0281] To a solution of (E)-N'-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide (380.0 mg, 0.97 mmol, 1.0 equiv.) in ethyl alcohol (25 mL) was added ethylenediamine (262.6 mg, 4.37 mmol, 4.5 equiv.). The resulting mixture was stirred and refluxed overnight. The reaction mixture was concentrated under reduced pressure to give the crude product, 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline (350 mg, crude) as a yellow semi-solid. LCMS (ESI, m / z): 336 [M+H] + .

[0282] 20. Synthesis of 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione [ka] A mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronic acid (400 mg, 1.12 mmol, 1.0 equiv), 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (398 mg, 1.28 mmol, 1.15 equiv), PdAmphos(Cl) (79.3 mg, 0.112 mmol, 0.1 equiv), and KPO (713 mg, 3.36 mmol, 3.0 equiv) in 1,4-dioxane (8 mL) / water (0.8 mL) was stirred at 90 °C for 2 h. After cooling to 25 °C, the solid was filtered, and the filter cake was washed with EA (3 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1:1 PE:EA) to give 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]-phenyl]-2H-1,2,4-triazine-3,5-dione (190 mg, 30% yield) as a pale yellow solid. LCMS (ESI, m / z): 544 [M+H] + .

[0283] 21. Procedure for the synthesis of 2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: [ka] To a solution of 5-benzyloxy-2-bromo-1,3-dimethyl-benzene (1 g, 3.43 mmol) and 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl-yl]-1,3,2-dioxaborolane (1.84 g, 6.87 mmol) in dioxane (10 mL) was added 8N aqueous KOH (858.57 μL, 6.86 mmol), followed by heating at room temperature (approximately 15 min) under N protection. ℃ ) and Pd[P(t-Bu)3] 2(To the crude product, 2-(4-benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-boronane (870 mg, 72% yield) was added. The mixture was then stirred at 30 °C for 18 h. TLC (PE:EA, 10:1, I2 stain) showed complete consumption of the bromide and the formation of two new spots. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 × 2 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (eluent: 0–2% ethyl acetate / petroleum ether) to give the desired 2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-boronane (870 mg, 72% yield) as a white solid.

[0284] 22. Synthesis of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate [ka] To a solution of 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.0 g, 2.54 mmol, 1 equiv.) and 2-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.79 g, 5.09 mmol, 2 equiv.) in dioxane (30 mL) and HO (6 mL), dichloropalladium; tris-o-tolylphosphane (299.79 mg, 381.39 μmol, 0.15 equiv.) and KPO (1.62 g, 7.63 mmol, 3 equiv.) were added under N protection at 20 °C. The resulting mixture was then stirred at 100 °C for 15 h under N atmosphere. The combined mixture (combined with the 300 mg batch) was diluted with HO (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0 to 10%) to give 5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.44 mmol, 74% yield, 96.5% purity) as a yellow solid.

[0285] To a solution of 5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.52 mmol, 1 equiv.) in MeOH (20 mL) and THF (10 mL) was added Pd-C (10%, 1.07 g) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 35 °C for 18 h. The mixture was filtered, and the filtrate was concentrated and purified by flash silica gel chromatography (0–100% ethyl acetate in petroleum ether) to give 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol (1 g, 2.23 mmol, 88% yield) as a white solid.

[0286] To a solution of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol (1 g, 2.23 mmol, 1 equiv.) and pyridine (440.84 mg, 5.57 mmol, 2.5 equiv.) in DCM (25 mL) at 0 °C, TfO (754.76 mg, 2.68 mmol, 441.38 μL, 1.2 equiv.) was slowly added dropwise. After the addition, the mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between HO (30 mL) and DCM (30 mL). The organic phase was separated, washed with brine (10 mL × 3), dried over anhydrous MgSO4, filtered, and concentrated to give the crude product, which was purified by flash silica gel chromatography (0–10% ethyl acetate in petroleum ether) to give [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (1.25 g, 2.15 mmol, 97% yield) as a colorless gum.

[0287] 23. Synthesis of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline: [ka] To a solution of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (300 mg, 516.67 μmol, 1 equiv.) and tert-butyl carbamate (121.05 mg, 1.03 mmol, 2 equiv.) in dioxane (8 mL), Pd(dba) (47.31 mg, 51.67 μmol, 0.1 equiv.), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (59.79 mg, 103.33 μmol, 0.2 equiv.), and CsCO (505.03 mg, 1.55 mmol, 3 equiv.) were added under the protection of N at 20 °C. The resulting mixture was then stirred at 100°C under N2 for 15 h. LCMS indicated the reaction was complete. The mixture was diluted with HO (50 mL) and extracted with EA (50 × 3 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0-10%) to give tert-butyl N-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]carbamate (200 mg, 350.19 μmol, 68% yield, 95.9% purity) as a pale yellow solid.

[0288] To a solution of tert-butyl N-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]carbamate (170 mg, 310.39 μmol, 1 equiv.) in MeOH (3 mL) was added 4 M HCl gas in MeOH (8 mL) at 20 °C. The resulting mixture was then stirred at 20 °C for 12 h. MeOH was removed under reduced pressure, and the residue was partitioned between EA (50 mL) and HO (50 mL). The EA phase was washed again with HO (50 mL). The combined aqueous layers were adjusted to pH 7–8 with saturated aqueous NaHCO and then extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline (120 mg, 261.40 μmol, 84% yield, 97.5% purity) as a pale yellow solid.

[0289] 24. Synthesis of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide [ka] To a solution of 4-iodo-3,5-dimethylaniline (1 eq., 5 g, 20.24 mmol) in anhydrous DCM (150 mL) was added trifluoroacetic anhydride (2 eq., 5.63 mL) under N at 0° C. The reaction mixture was then stirred at 25° C. for 2.5 h. Water (200 mL) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (2×150 mL). The combined organic layers were dried over MgSO, filtered, and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (DCM) to give 2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (6.35 g, 91%) as a white solid.

[0290] Anhydrous THF (35 mL) was added to a mixture of 2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (1 equivalent, 2.40 g, 7 mmol) and NaH 60% (1.5 equivalents, 420 mg) under N at 0 °C. The reaction mixture was stirred at 25 °C for 1.5 h, then cooled to -78 °C, and t-BuLi (2.4 equivalents, 9.88 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 40 min. Anhydrous DMF (5 equivalents, 2.71 mL) was then added, and the reaction was further stirred at -78 °C for 1 h. The reaction mixture was hydrolyzed with saturated aqueous NH Cl (5 mL), poured into DCM (250 mL), and washed four times with brine. The combined organic layers were dried over MgSO, filtered, and evaporated to dryness. The crude mixture was recrystallized from hot EtOH to give 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (317 mg, 19%) as a yellow solid. The supernatant was recrystallized from hot toluene to give more 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (909 mg, 53%) as a pale yellow solid.

[0291] 25. Synthesis of 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline [ka] Anhydrous THF (8.3 mL) was added to a mixture of 5-bromo-3-pentyl-1H-indazole (1 eq, 668 mg, 2.5 mmol) and NaH 60% (1.5 eq, 150 mg) under N at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The mixture was then cooled to -78 °C, n-BuLi (1.5 eq, 2.34 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 2 h. A solution of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (1 eq, 613 mg) in anhydrous THF (8.3 mL) was then added dropwise to the reaction mixture at -78 °C. The reaction was further stirred at this temperature for 1.75 h and finally hydrolyzed with saturated aqueous NH Cl (5 mL), poured into DCM (100 mL), and washed three times with water. The organic phase was dried over MgSO, filtered, and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (20% to 40% EA in cyclohexane) to give 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide (317 mg, 29%) as a white solid.

[0292] A solution of EtSiH (6 equiv., 0.71 mL) in anhydrous DCM (20 mL) followed by TMSOTf (0.075 equiv., 0.01 mL) in anhydrous DCM (7 mL) was added dropwise under N to a solution of 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide (1 equiv., 317 mg, 0.73 mmol) in anhydrous DCM (7 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h, at which point the ice bath was removed and the reaction was stirred at 25 °C. After 19 h, additional EtSiH (6 equiv., 0.71 mL) and TMSOTf (0.075 equiv., 0.01 mL) were added and the reaction mixture was further stirred at 25 °C for 5 h. The reaction was then quenched with saturated aqueous NaHCO3 (20 mL), and the aqueous phase was extracted three times with DCM (3 x 50 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0% to 30% EA in cyclohexane) to give N-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (144 mg, 47%) as a white solid.

[0293] NaOH (4 equiv., 54 mg) was added to a solution of N-(3,5-di-methyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (1 equiv., 141 mg, 0.34 mmol) in MeOH (7 mL) and water (1.4 mL) under N. The reaction mixture was stirred at 60° C. for 90 h. The reaction mixture was then quenched with water (30 mL). The resulting solution was extracted with DCM (3×20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over MgSO, filtered, and evaporated to dryness to give 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline (105 mg, 97%) as a white solid, which was used without further purification.

[0294] Example 1: Synthesis of Compound 1 [ka] To a stirred solution of 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]aniline (1.11 g, 2.277 mmol, 1.00 equiv.) in HCl (21.90 mL), HOAc (62.50 mL), and HO (47.68 mL), NaNO (0.32 g, 4.566 mmol, 2 equiv.) in HO (4.2 mL) was added dropwise at 0 °C for 1 h. In a second reaction flask, ethyl N-(2-cyanoacetyl)carbamate (0.53 g, 3.424 mmol, 1.5 equiv.) in HO (58.41 mL) and pyridine (22.35 mL) was placed at 0 °C for 10 min. The above solution was quickly poured into the second reaction flask at 0 °C for 30 min. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This gave N-[(Z)-cyano[2-(3,5-dichloro-4-[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]phenyl)-hydrazin-1-ylidene]carbonyl]carbamate, which can also be named as ethyl (Z)-(2-cyano-(2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate as a red solid.

[0295] To a stirred solution of ethyl N-[(Z)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]-oxy]phenyl)hydrazin-1-ylidene]-carbonyl]carbamate (which may also be referred to as ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate) (1.16 g, 1.773 mmol, 1.00 equiv.) in DMA (20.00 mL) was added KOAc (0.35 g, 3.546 mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The solid was dried at room temperature overnight to give 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (521.2 mg, 45%) as a red solid.

[0296] To a stirred solution of 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (521.20 mg, 0.854 mmol, 1.00 equiv) in THF (20.00 mL) was added TBAF (20 mL) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65° C. for 20 h under a nitrogen atmosphere. The reaction was quenched with HO. The resulting mixture was extracted with EA, washed with brine, and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH 16:1) to give the crude product (200 mg). The crude product (200 mg) was purified by preparative HPLC to give 2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (11.5 mg, 3%, Compound 1) as a yellow solid. 1 H-NMR:(300MHz,DMSO-d6)δ ppm:10.67-10.60(m,1H),7.77(s,2H),7.30(d,J=8.7Hz,1H),7.07(s,1H),6.82(d,J= 2.5Hz, 1H), 6.67 (dd, J = 8.9, 2.5Hz, 1H), 2.94 (p, J = 7.0Hz, 1H), 1.18 (d, J = 6.8Hz, 6H).

[0297] Example 2: Synthesis of Compound 2 [ka] A 100 mL three-necked round-bottom flask maintained under an inert atmosphere of nitrogen was charged with concentrated HCl (9.60 mL), AcOH (27.40 mL), and 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethyl-aniline (450.00 mg, 1.003 mmol, 1.00 equiv) in HO (20.9 mL). To the stirred solution was added NaNO (145.35 mg, 2.107 mmol, 2.1 equiv) in HO (1.8 mL) dropwise at 0 °C for 45 min. In a second reaction flask, methyl N-(2-cyanoacetyl)carbamate (213.85 mg, 1.505 mmol, 1.50 equiv) in HO (25.6 mL) and pyridine (9.80 mL) was placed at 0° C. for 10 min. The above solution was quickly poured into the second reaction flask at 0° C. for 30 min. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This gives N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbonyl]carbamate, which may also be named as ethyl (Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate as a red solid.

[0298] To a stirred solution of ethyl N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbonyl]carbamate (also known as (Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate (name generated by Chemical Draw) (560.0 mg, 0.910 mmol, 1.00 equiv) in DMA (10.00 mL) was added KOAc (178.52 mg, 1.819 mmol). To the resulting mixture was added EA (3×100 mL) in portions. The resulting mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water (10 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (350 mg, 56%) as a red solid.

[0299] To a stirred solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrile (330.00 mg, 1 equiv.) in THF was added TBAF (1 M in THF) (8.00 mL) at room temperature. The resulting mixture was stirred at 65° C. for 48 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. Purification gave 2-[4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethyl-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (132.3 mg, 54%) as a yellow solid. 1 H-NMR:(300MHz,DMSO-d6)δ ppm:10.66(s,1H),7.29-7.20(m,3H),7.04(d,J=2.2Hz,1H),6.77(d,J=2.4Hz,1H),6 .60(dd,J=8.8,2.5Hz,1H),2.94(p,J=6.9Hz,1H),2.10(s,6H),1.19(d,J=6.8Hz,6H).

[0300] Example 3: Synthesis of Compound 3 [ka] To a solution of 4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline (480.00 mg, 1.075 mmol, 1.00 equiv) in concentrated HCl (9.60 mL), HOAc (28.80 mL), and HO (22.4 mL) stirred under nitrogen at 0 °C, NaNO (155.72 mg, 2.257 mmol, 2.1 equiv) in HO (22.4 mL) was added. The reaction mixture was stirred at 0 °C for 45 min. A second reaction flask containing a solution of ethyl N-(2-cyanoacetyl)carbamate (251.72 mg, 1.612 mmol, 1.50 equiv) in HO (27.2 mL) and pyridine (9.60 mL) was stirred at 0 °C for 10 min. The first reaction flask was rapidly poured into the second reaction flask, and the reaction mixture was stirred at 0° C. for 30 minutes. The precipitated solid was collected by filtration and washed with water (3×50 mL) and PE (3×50 mL). The resulting mixture was concentrated under vacuum. The crude product was isolated as a yellow solid, 520 mg, 80% pure, 63% yield.

[0301] To a solution of ethyl N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbonyl]carbamate (2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazinylidene)carbamate (350.00 mg, 0.570 mmol, 1.0 equiv) in DMA (8.0 mL) stirred at room temperature was added KOAc (111.94 mg, 1.141 mmol, (2.0 equiv.) was added. The reaction mixture was stirred at 120° C. for 3 hours. The reaction was quenched by adding water (10 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3×10 mL). The solid was dried under vacuum at 60° C. for 2 hours to give 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile. The desired product was isolated as a dark orange solid, 250 mg, 80% pure, 62% yield.

[0302] To a solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (200.00 mg, 0.352 mmol, 1.00 equiv) in THF (5.00 mL) stirred under nitrogen at 0° C. was added TBAF (10.57 mL, 10.570 mmol, 30.00 equiv, 1 M in THF). The reaction mixture was stirred at 65° C. for 3 days. The reaction mixture was concentrated under reduced pressure to give the crude product. The sample was purified to give 2-(4-((3-isopropyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile as a yellow solid (compound 3, 29.7 mg, 99% pure, 20% yield). 1H NMR(400MHz,DMSO-d6)δ ppm:13.00(br,1H),10.63(s,1H),7.19-7.22(m,2H),7.14(s,2H),7.01(d,J=2.0Hz,1 H),6.68-6.71(m,1H),4.11(s,2H),3.00-3.04(m,1H),2.27(s,6H),1.24-1.25(m,6H).

[0303] Example 4: Synthesis of Compound 4 [ka] A 50 mL autoclave was charged with 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (1.00 g, 1.44 mmol, 1.00 equiv.), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]-palladium(II) (0.11 g, 0.144 mmol, 0.10 equiv.), triethylamine (0.44 g, 4.32 mmol, 3.00 equiv.), and methanol (10 mL). The contents of the autoclave were placed under an atmosphere of carbon monoxide (30 atm). The reaction was stirred at 90°C overnight. The catalyst was filtered. The filtrate was concentrated under reduced pressure. The residue was purified to give 500 mg (67% yield) of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)-indole-3-carboxylate as a brown solid.

[0304] A 40 mL vial was charged with methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)indole-3-carboxylate (400 mg, 0.639 mmol, 1.00 equiv.), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (6.39 mL, 1 M in tetrahydrofuran, 6.39 mmol, 10.0 equiv.). The reaction was stirred at 65° C. overnight and quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3×20 mL), and the combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 30.4 mg (15% yield) of methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxylate as a yellow solid. 1 H NMR (300MHz, Methanol-d4) δ ppm: 7.97 (s, 1H), 7.80 (s, 2H), 7.41-7.44 (m, 2H), 6.88-6.92 (m, 1H), 3.84 (s, 3H).

[0305] Example 5: Synthesis of Compound 5 [ka] A 250 mL round-bottom was charged with 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (1.00 g, 1.759 mmol, 1.00 equiv), tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (52.78 mL, 1 M in tetrahydrofuran, 52.78 mmol, 30.00 equiv). The resulting solution was stirred at 65° C. overnight and then quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL), and the combined organic layers were washed with brine (3×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 500 mg (69% yield) of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a yellow solid.

[0306] To a solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (300 mg, 0.724 mmol, 1.00 equiv), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 equiv), and triethylsilane (337 mg, 2.90 mmol, 4.0 equiv) in toluene (10 mL) stirred under nitrogen at 100° C., cyclopentanone (366 mg, 4.35 mmol, 6.00 equiv) was added. The reaction mixture was stirred at 100° C. overnight and concentrated under reduced pressure. Purification gave 20.2 mg (6% yield) of 2-[3,5-dichloro-4-[(3-cyclopentyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrile as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ ppm:10.77(s,1H),7.81(s,2H),7.30-7.34(m,1H),7.13(d,J=1.8Hz,1H),6.90(d,J=2 .4Hz,1H),6.64-6.68(m,1H),3.06-3.14(m,1H),1.99-2.03(m,2H),1.60-1.78(m,6H).

[0307] Example 6: Synthesis of Compound 6 [ka] A 50 mL round-bottom flask was charged with 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (300 mg, 0.724 mmol, 1.00 equiv.), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 equiv.), toluene (10.00 mL), and triethylsilane (504.10 mg, 4.35 mmol, 6.00 equiv.) under nitrogen. Acetophenone (261 mg, 2.17 mmol, 3.00 equiv.) was added at 100 °C. The resulting solution was stirred at 100 °C overnight and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with dichloromethane (3 × 50 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 63.2 mg (17% yield) of 2-(3,5-dichloro-4-[[3-(1-phenylethyl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ ppm:10.88(s,1H),7.75(s,2H),7.21-7.29(m,2H),7.13-7.21(m,4H),7.06-7.11( m,1H),6.63-6.67(m,1H),6.38-6.39(m,1H),4.11-4.18(m,1H),1.56-1.59(m,3H).

[0308] Example 7: Synthesis of Compound 7 [ka] To a stirred solution of 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (400 mg, 0.576 mmol, 1.00 equiv.) and phenylboronic acid (91.3 mg, 0.749 mmol, 1.30 equiv.) in dioxane (4 mL) and water (0.8 mL), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (42.2 mg, 0.0580 mmol, 0.10 equiv.) and potassium carbonate (238.88 mg, 1.728 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C overnight and concentrated under reduced pressure. The residue was purified to give 170 mg (42% yield) of 2-(3,5-dichloro-4-[[1-(4-methyl-benzenesulfonyl)-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a light brown solid.

[0309] To a stirred solution of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (160 mg, 0.248 mmol, 1.00 equiv.) in tetrahydrofuran (4 mL) was added t-butylammonium fluoride (4.96 mL, 1 M in tetrahydrofuran, 4.96 mmol, 20.00 equiv.) at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred at 65° C. overnight and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL), and the combined organic layers were washed with brine (3×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification gave 2-[3,5-dichloro-4-[(3-phenyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (compound 7, 39 mg, 32%) as a pale orange solid.1 H NMR (300MHz, Methanol-d4) δ ppm: 7.78 (s, 2H), 7.50-7.56 (m, 2H), 7.49 (s, 1H), 7.35-7.41 (m, 3H), 7.18-7.23 (m, 2H), 681-6.84 (m, 1H).

[0310] Example 8: Synthesis of Compound 8 [ka] To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (200.00 mg, 0.460 mmol, 1.00 equiv) in HOAc (4.43 mL, 0.074 mmol, 0.16 equiv) was added HCl (2.00 mL, 0.055 mmol, 0.12 equiv) in portions at room temperature. The resulting mixture was stirred at 120° C. under a nitrogen atmosphere overnight. The crude product (160 mg) was purified to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (78.3 mg, 38%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ ppm: 13.82 (s, 1H), 12.70 (s, 1H), 12.19 (s, 1H), 7.82 (s, 2H), 7.44 (s, 1H), 3.05 (p, J = 6.8 Hz, 1H), 1.20 (d, J = 6.9 Hz, 6H).

[0311] Example 9: Synthesis of Compound 9 [ka] To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (200.00 mg, 0.460 mmol, 1.00 equiv) in DMSO (5 mL) was added KCO (190.53 mg, 1.379 mmol, 3.00 equiv) and HO (2 mL, 30% in water) in portions at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with saturated NaSO solution at room temperature and concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions (column: C18; mobile phase: ACN in water, gradient: 10% to 80% in 30 min) to give the crude product (150 mg), which was then purified by preparative HPLC (column: XBridge Prep OBD C18 column, mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 33% B in 9 min) to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxamide (112.1 mg, 54%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.76(s,1H),12.20(s,1H),8.14(br,1H),7.85-7.90(m,3H),7.44(s,1H),3.05(p,J=6.8Hz,1H),1.20(d,J=6.8Hz,6H).

[0312] Example 10: Synthesis of Compound 10 [ka] To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (200.00 mg, 0.440 mmol, 1.00 equiv.) in t-BuOH (20.00 mL, 210.465 mmol), DPPA (375.64 mg, 1.365 mmol, 3.10 equiv.) and EtN (138.12 mg, 1.365 mmol, 3.10 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 85 °C under a nitrogen atmosphere for 24 hours. The resulting mixture was concentrated. The residue was dissolved in CHCl (100 mL) and then washed with NHCl (4 × 200 mL), NaHCO, and brine. The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with CHCl:MeOH (50:1) to give tert-butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate (110 mg, 48%) as a white solid. LCMS (ESI, m / z): 525 [M+H] + .

[0313] A solution of t-butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate (90.0 mg, 1 equivalent) in 4N HCl in 1,4-dioxane (5.00 mL) was stirred at room temperature overnight. The resulting mixture was concentrated. The crude product (70 mg) was purified by preparative HPLC (column: XBridge Prep OBD C 18, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10 B to 40 B in 8 min) to give 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-tri-azine-3,5-dione (18.8 mg, 26%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm: 12.26 (s, 1H), 12.18 (s, 1H), 7.85 (s, 2H), 7.41 (s, 1H), 6.45 (s, 2H), 2.95-3.10 (m, 1H), 1.19 (d, J = 6.9Hz, 6H).

[0314] Example 11: Synthesis of Compound 11 [ka] To a stirred solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (430.00 mg, 0.706 mmol, 1.00 equiv) and trimethylsilylacetylene (207.96 mg, 2.117 mmol, 3.0 equiv) in DMF (10 mL) under a nitrogen atmosphere at room temperature, CuI (26.88 mg, 0.141 mmol, 0.20 equiv), EtN (214.25 mg, 2.117 mmol, 3.00 equiv), and Pd(dppf)Cl (103.28 mg, 0.141 mmol, 0.20 equiv) were added portionwise. The reaction mixture was stirred at 80° C. overnight and quenched with water (10 mL). The resulting mixture was extracted with EA (3×40 mL). The combined organic layers were washed with water (1×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione (260 mg, 52%) as an off-white solid.

[0315] To a stirred solution of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione (240.00 mg, 0.383 mmol, 1.00 equiv) in DCM (5 mL) was added BBr3 (383.84 mg, 1.532 mmol, 4.00 equiv) dropwise under a nitrogen atmosphere at 0° C. The reaction was stirred at room temperature for 4 h and quenched with MeOH (5 mL). The resulting mixture was concentrated under reduced pressure to give 100 mg (crude) 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)-ethynyl]-4H-1,2,4-triazine-3,5-dione as a light brown solid.

[0316] To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-4H-1,2,4-triazine-3,5-dione (100.00 mg, 0.197 mmol, 1.00 equiv) in MeOH (10 mL) was added KCO (109.16 mg, 0.790 mmol, 4.00 equiv) and stirred at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give a residue. Purification gave 19.4 mg (22% yield) of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-ethynyl-4H-1,2,4-triazine-3,5-dione as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.75(s,1H),12.23(s,1H),7.77(s,2H),7.44(s,1H),4.70(s,1H),3.03-3.10(m,1H),1.20(d,J=6.8Hz,6H)

[0317] Example 12: Synthesis of Compound 12 [ka] To a solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (300.00 mg, 0.492 mmol, 1.00 equiv.) and tert-butyl 2-cyanoacetate (208.54 mg, 1.477 mmol, 3.0 equiv.) in DMF (5.00 mg) stirred at room temperature, KCO (272.21 mg, 1.970 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at 90 °C overnight. The reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 190 mg (95% pure) of tert-butyl 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate (190 mg, 58%) as a yellow solid.

[0318] A 50 mL round-bottom flask was charged with tert-butyl 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate (190.00 mg, 0.284 mmol, 1.00 equiv), TsOH (24.43 mg, 0.142 mmol, 0.5 equiv), and toluene (5 mL). The resulting solution was stirred at 90° C. for 4 h and quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL), and the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 190 mg of crude (70% pure) 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile (190 mg, 82% yield) as a yellow oil.

[0319] To a solution of 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile (190.00 mg, 0.334 mmol, 1.00 equiv) in DCM (3 mL) stirred at −78° C. under nitrogen was added BBr3 (501.57 mg, 2.002 mmol, 6.0 equiv). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3×20 mL), and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification gave 24.9 mg (16% yield) of 2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)acetonitrile as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm: 12.71 (s, 1H), 12.20 (s, 1H), 7.81 (s, 2H), 7.46 (s, 1H), 4.05 (s, 2H), 3.03-3.07 (m, 1H), 1.11-1.31 (m, 6H).

[0320] Example 13: Synthesis of Compound 13 [ka] To a solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (350.00 mg, 0.574 mmol, 1.00 equiv.) and diethyl malonate (184.02 mg, 1.149 mmol, 2.00 equiv.) in DMSO (5 mL) stirred at room temperature under nitrogen, CsCO (561.52 mg, 1.723 mmol, 3.0 equiv.) was added. The reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with dichloromethane (3 x 50 mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (50 mL) and slurried on 100-200 mesh silica gel (2 g). The sample was purified and the desired product was isolated as a yellow oil. 270 mg, 90% purity, 61% yield.

[0321] To a solution of 1,3-diethyl 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-propanedioate (250.00 mg, 0.363 mmol, 1.00 equiv.) in DCM (5.00 mL) stirred at 0 °C under nitrogen, BBr3 (363.86 mg, 1.452 mmol, 4.00 equiv.) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (15 mL). The resulting solution was extracted with dichloromethane (3 × 30 mL), and the organic layers were combined, washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This material was not subjected to further purification. The crude product was isolated as a yellow solid, 210 mg, 70% pure, 71% yield.

[0322] To a solution of 1,3-diethyl 2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)propanedioate (210.00 mg, 0.369 mmol, 1.00 equiv) in MeOH (5.00 mL) and HO (1.00 mL) stirred at room temperature, NaOH (147.78 mg, 3.695 mmol, 10.00 equiv) was added. The reaction mixture was stirred at 60 °C for 4 h. The pH value of the mixture was adjusted to approximately 5–6 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane (3 × 30 mL), and the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified to give 2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetra-hydro-1,2,4-triazin-6-yl)acetic acid. The desired product was isolated as a white solid (54.0 mg, 99.5% pure, 31% yield). 1H NMR (300MHz, DMSO-d6) δ ppm: 7.82 (s, 1H), 7.44 (s, 1H), 3.44 (s, 2H), 3.01-3.10 (m, 1H), 1.19-1.24 (m, 6H).

[0323] Example 14: Synthesis of Compound 14 [ka] To a stirred solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (400.00 mg, 0.657 mmol, 1.00 equiv) in N-BuOH (5 mL) was added methylamine (3.3 mL, 6.565 mmol, 10.00 equiv, 2 M in THF) at room temperature. The reaction mixture was stirred at 110° C. overnight. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified to give 220 mg (53% yield) of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-6-(dimethylamino)-1,2,4-triazine-3,5-dione as a solid in light yield.

[0324] To a stirred solution of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-1,2,4-triazine-3,5-dione (400.00 mg, 0.715 mmol, 1.00 equiv) in DCM was added BBr3 (716.55 mg, 2.860 mmol, 4.00 equiv) at −78° C. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification gave 86.9 mg (54% yield) of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-4H-1,2,4-triazine-3,5-dione as a white solid. 1H NMR(300MHz,DMSO-d6)δ ppm:12.99(s,1H),12.23(s,1H),8.82(d,J=4.8Hz,1H),8.16(s,2H),7.4 2(s,1H),3.03-3.08(m,1H),2.79(d,J=4.8Hz,3H),1.20(d,J=6.9Hz,6H).

[0325] Example 15: Synthesis of Compound 15 [ka] To a 50 mL round-bottom flask was added 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (400.00 mg, 0.657 mmol, 1.00 equiv.) and dimethylamine (3.3 mL, 6.565 mmol, 10.00 equiv., 2 M in THF) in n-BuOH (8 mL) at room temperature. The reaction mixture was stirred at 110° C. overnight. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified to give 170 mg (41% yield) of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)-oxy]phenyl]-6-(dimethylamino)-1,2,4-triazine-3,5-dione as a pale pink solid.

[0326] A 50 mL round-bottom flask was charged with 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethylamino)-1,2,4-triazine-3,5-dione (160.00 mg, 0.279 mmol, 1.00 equiv.) and DCM (10.00 mL). BBr3 (279.61 mg, 1.116 mmol, 4.00 equiv.) was added at −78° C. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification gave 54.3 mg (42% yield) of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethylamino)-4H-1,2,4-triazine-3,5-dione. 1 HNMR (300MHz, DMSO-d6) δ ppm:7.91(s,2H),7.43(s,1H),3.03-3.10(m,1H),2.99(d,J=8.1Hz,6H),1.20(d,J=6.9Hz,6H).

[0327] Example 16: Synthesis of Compounds 16 and 23 compound 16 [ka] To a stirred mixture of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (250.00 mg, 0.729 mmol, 1.00 equiv.), 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (180.19 mg, 0.875 mmol, 1.20 equiv.), and KCO (201.48 mg, 1.458 mmol, 2.00 equiv.) in dioxane (10 mL) and HO (1 mL) was added Pd(PPh) (168.46 mg, 0.146 mmol, 0.20 equiv.) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was quenched with water (15 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with 1:5 EA:PE and MeCN (5 mL) and washed with ether (5 mL) to give the desired product, 6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-methyl-4H-1,2,4-triazine-3,5-dione (103.8 mg, 34%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ ppm: 12.45 (br, 1H), 12.21 (s, 1H), 8.10 (s, 2H), 7.43 (s, 1H), 3.58 (s, 3H), 3.11-2.97 (m, 1H), 1.20 (d, J = 6.9Hz, 6H).

[0328] compound 23 [ka] Compound 23 was prepared similarly as described for compound 16, using 6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione instead of 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione. 1H NMR(300MHz,DMSO-d6)δ:12.39(s,1H),12.18(s,1H),8.09(s,2H),7.40-7.41(m,1H) ,3.95-4.03(m,2H),3.00-3.07(m,1H),1.28(t,J=7.0Hz,3H),1.28(t,J=6.9Hz,6H). LCMS(ESI,m / z):438[M+H] + .

[0329] Example 17: Synthesis of Compound 17 [ka] To a solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (250.0 mg, 0.604 mmol, 1.00 equiv.) in acetonitrile (4 mL) was added chlorosulfonyl isocyanate (102.5 mg, 0.724 mmol, 1.2 equiv.) in acetonitrile (0.4 mL) dropwise at −45° C. under nitrogen. A fine precipitate formed during the addition. The mixture was stirred at −45° C. under nitrogen for 10 minutes. N,N-dimethylformamide (4 mL) was then added slowly, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water / ice (10 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (3 × 10 mL), saturated NaHCO3, and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by preparative TLC with dichloromethane:methanol (12:1) to give the crude product (160 mg). The crude product (160 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30 × 150, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B to 50% B over 8 min) to give 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carbonitrile (75.9 mg, 29% yield) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ 13.30(s,1H),12.28(s,1H),8.28(d,J=3.0Hz,1H),7.84(s,2H),7.58(d,J=9.0Hz,1H),6.97-7.01(m,1H),6.86(d,J=2.4Hz,1H).

[0330] Example 18: Synthesis of Compounds 18 and 19 [ka] NaNO (150.8 mg, 2.19 mmol, 2.1 equiv) in HO (12 mL) was added dropwise to a solution of 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline (350.0 mg, 1.04 mmol, 1.0 equiv) in HCl (5.5 mL, concentrated), AcOH (16 mL), and HO (12 mL). The mixture was stirred at 0 °C for 30 min. The reaction mixture was then quickly poured into a solution of ethyl N-(2-cyanoacetyl)carbamate (243.8 mg, 1.56 mmol, 1.5 equiv) in HO (16 mL) and pyridine (5.5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and filtered. The filter cake was washed with water (2 x 15 mL) and petroleum ether (2 x 15 mL) and dried under reduced pressure to give (350 mg, crude) ethyl N-[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazin-1-ylidene])carbonyl]carbamate as a yellow solid. LCMS (ESI, m / z): 503 [M+H] + .

[0331] To a solution of ethyl N-[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazin-1-ylidene])carbonyl]carbamate (350.00 mg, 0.695 mmol, 1.00 equiv) in DMA (20 mL) was added KOAc (341.22 mg, 3.477 mmol, 5.00 equiv). The resulting mixture was stirred at 120° C. overnight and quenched with water (30 mL). The resulting mixture was extracted with EA (3×40 mL), and the organic layers were combined, washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH / DCM = 1:7; Rf = 0.4; detection: UV) to give the crude product (180 mg). The product was separated using a preparative chiral HPLC column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.1% FA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B over 21 min. Purification afforded the desired product, 2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (86.3 mg, 26%), as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 13.25(br,1H),11.00(s,1H),7.82(d,J=8.7Hz,1H),7.76(s,2H),7.28(d,J= 2.4Hz, 1H), 6.89 (d, J = 8.7Hz, 1H), 2.78-2.95 (m, 1H), 1.13 (d, J = 6.6Hz, 6H). LCMS(ESI,m / z):457.0[M+H] + .

[0332] This reaction also produces the by-product compound 2-[3,5-dichloro-4-([3-propyl-1H-pyrrolo[3,2-b]-pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (20.8 mg, 6%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ 13.26(br,1H),11.03(s,1H),7.82(d,J=8.4Hz,1H),7.76(s,2H),7.33(d,J=2.4Hz,1H) ,6.87(d,J=8.7Hz,1H),2.42(t,J=7.5Hz,2H),1.45-1.58(m,2H),0.77(t,J=7.5Hz,3H). LCMS(ESI,m / z):457.0[M+H] + .

[0333] Example 19: Synthesis of Compounds 20, 21 and 22 Compound 21

change

[0334] To a stirred solution of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamide (200.00 mg, 0.313 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1.25 mL, 1 M in tetrahydrofuran, 1.251 mmol, 4.00 equiv.) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 65°C overnight and quenched with water (5 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic layers were washed with brine (5 × 10 mL) and hydrochloric acid (1 M), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC using the following conditions (Column: XBridge Shield RP 18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 27% B to 47% B in 7 min) to give 52 mg (34% yield) of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1H-indole-3-carboxamide as a pale yellow solid. 1 H NMR(300MHz,Methanol-d4)δ 7.76(s,1H),7.68(s,2H),7.41(d,J=9.0Hz,1H),7.08(d,J=2.1Hz,1H),6.90-6.94(m,1H),3.13(s,6H). LCMS(ESI,m / z):485[M+H] + .

[0335] compound 20 [ka] Compound 20 was prepared similarly as described for compound 21, using 2 equivalents of isopropylamine instead of 6 equivalents of dimethylamine and reacting at 80° C. overnight. 1H NMR(300MHz,Methanol-d4)δ 7.89(s,1H),7.77(s,2H),7.50(d,J=2.4Hz,1H),7.38(d,J=9.3Hz,1H),6.87-6.91(m,1H),4.12-4.16(m,1H),1.21(d,J=6.6Hz,6H). LCMS(ESI,m / z):499[M+H] + .

[0336] compound 22 [ka] Compound 22 was prepared similarly as described for compound 21, using 1.5 equivalents of tetrahydroisoquinoline instead of 6 equivalents of dimethylamine. 1 H NMR(400MHz,Methanol-d4)δ 7.70(d,J=8.4Hz,3H),7.45(d,J=8.8Hz,1H),7.15-7.17(m,3H),7.07(br,1H),6.93-6. 99(m,1H),6.91-6.92(m,1H),4.78(s,2H),3.86(t,J=6.0Hz,2H),2.87(t,J=5.8Hz,2H). LCMS:573[M+H] + .

[0337] Example 20: Synthesis of Compounds 24, 25, and 26 compound 25 [ka] To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (500 mg, 1.101 mmol, 1.00 equiv) and N,N-diisopropylethylamine (298.77 mg, 2.312 mmol, 2.10 equiv) in tetrahydrofuran (30 mL) under nitrogen at 0° C. was added chloroformate (126.62 mg, 1.167 mmol, 1.06 equiv) dropwise. The mixture was stirred at room temperature for 1 hour and treated dropwise with a solution of sodium borohydride (124.94 mg, 3.302 mmol, 3.00 equiv) in water (2 mL) at 0° C. The resulting solution was stirred at room temperature overnight and then slowly quenched with saturated NaHCO solution (10 mL). The resulting mixture was extracted with chloroform / isopropanol (3 / 1) (5 × 30 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product (400 mg) was purified by preparative HPLC using the following gradient conditions: Column: XSelect CSH Prep C 18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 31% B in 8 min) to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl-yl)-4H-1,2,4-triazine-3,5-dione (100.6 mg, 21% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 12.48(br,1H),12.22(br,1H),7.86(s,2H),7.44(s,1H),5.30(t,J=6.0Hz,1H),4.40(d,J=6.0Hz,2H),3.02-3.11(m,1H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):440[M+H] + .

[0338] compound 24 [ka] A 50 mL round-bottom flask was charged with 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2,4-triazine-3,5-dione (1.60 g, 3.634 mmol, 1.00 equiv.) and acetonitrile (15 mL). Phosphorus tribromide (0.3 mL) was added at 0° C. under nitrogen. The resulting solution was stirred at 75° C. for 1 hour. The mixture was cooled to room temperature and then quenched with saturated aqueous NaHCO (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL), and the organic layers were combined, washed with brine (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.1 g (39% yield) of 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione as a yellow solid. LCMS (ESI, m / z): 502 [M+H] + .

[0339] A 50 mL round-bottom flask was charged with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-tri-azine-3,5-dione (400 mg, 0.795 mmol, 1.00 equiv.), methylamine (1.2 mL, 2 M in tetrahydrofuran, 2.385 mmol, 3.00 equiv.), and N,N-dimethylformamide (8 mL). The mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature and diluted with water (5 mL). At this time, it was acidified by the addition of 1 N hydrochloric acid (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was discarded. The aqueous layer was made basic by adding saturated NaHCO3 solution (15 mL) and extracted with a 3:1 (5 × 30 mL) mixture of chloroform:isopropanol. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C 18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 35% B in 8 min. Purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[(methylamino)methyl]-4H-1,2,4-triazine-3,5-dione (64.8 mg, 18% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 12.23(br,1H),7.88(s,2H),7.43(s,1H),3.83(s,2H),3.01-3.19(m,1H),2.51(s,3H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):453[M+H] + .

[0340] compound 26 [ka] Compound 26 was prepared similarly as described for compound 24 by using dimethylamine instead of methylamine and reacting at 60° C. for 1 hour. 1 H NMR(300MHz,DMSO-d6)δ 12.21(br,1H),7.80(s,2H),7.45(s,1H),3.37(br,2H),3.03-3.08(m,1H),2.25(s,6H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):467[M+H] + .

[0341] Example 21: Synthesis of Compound 27 [ka] A 100 mL round-bottom flask was charged with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (400.00 mg, 0.795 mmol, 1.00 equiv.), imidazole (64.95 mg, 0.954 mmol, 1.20 equiv.), potassium carbonate (219.75 mg, 1.590 mmol, 2.00 equiv.), and N,N-dimethylformamide (8 mL). The mixture was stirred at 70 °C for 1 h, then cooled to room temperature and diluted with water (5 mL). At this time, it was acidified by the addition of 1 N hydrochloric acid (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was discarded. The aqueous layer was made basic by adding saturated NaHCO3 solution (15 mL) and extracted with a 3:1 (5 × 30 mL) mixture of chloroform:isopropanol. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product (150 mg) was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C 18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 37% B in 8 min. Purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(imidazol-1-ylmethyl)-4H-1,2,4-triazine-3,5-dione (14.5 mg, 4% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 12.19(s,1H),7.74(s,2H),7.69(s,1H),7.43(s,1H),7.21(s,1H),6.90(s,1H),5.15(s,2H),3.02-3.09(m,1H),1.19(d,J=6.9Hz,6H). LCMS(ESI,m / z):490[M+H] + .

[0342] Example 22 Synthesis of Compound 28 [ka] Difluorochloromethane was bubbled into a stirred mixture of 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione (310 mg, 0.569 mmol, 1.00 equiv.) and K2CO3 (630 mg, 4.56 mmol, 8.00 equiv.) in DMF (20 mL) for 4 hours, and the mixture was stirred at 50 °C for 5 hours. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with water (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2:1 PE:EA) to give 230 mg (65% yield) of 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazine-3,5-dione as a pale yellow solid. LCMS (ESI, m / z): 594 [M+H] + .

[0343] 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazine-3,5-dione (230 mg, 0.387 mmol, 1.00 equiv) in hydrogen chloride solution (4 mL, 4 M in 1,4-dioxane) was stirred at 60° C. for 2 hours. After cooling to 25° C., the resulting mixture was concentrated in vacuo. The residue was then diluted with DCM (5 mL), and a solution of BBr3 (1.5 mL, 1 M in DCM) was added dropwise at 25° C. The final reaction mixture was stirred at 25° C. for 45 minutes. The reaction was quenched by adding water (1 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column: C18 silica gel; mobile phase, A: water (containing 10 mM NH4HCO3), and B: ACN (0% to 50% over 15 min); detector: UV 220 / 254 nm). The product was lyophilized to give 113.4 mg (63% yield) of 6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-4H-1,2,4-triazine-3,5-dione as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.78(br s,1H),12.22(br s,1H),7.99(s,2H),7.83(t,J=57.2Hz,1H),7.45(s,1H),3.13-2.98(m,1H),1.20(d,J=7.2Hz,6H). LCMS(ESI,m / z):460[M+H] + .

[0344] Example 23: Synthesis of Compound 29 [ka] A 50 mL round-bottom flask was charged with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (400 mg, 0.795 mmol, 1.00 equiv.) and N,N-dimethylformamide (8 mL) under nitrogen. Sodium methylate (0.50 mL, 30% w / w in methanol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was acidified by the addition of 1 N hydrochloric acid (5 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with dichloromethane / methanol (10 / 1) to give the crude product (150 mg), which was then purified by preparative HPLC using the following gradient conditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 31% B to 51% B in 8 min. Purification afforded 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methoxymethyl)-4H-1,2,4-triazine-3,5-dione (26.2 mg, 7% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 12.53(s,1H),12.22(s,1H),7.80(s,2H),7.45(s,1H),4.32(s,2H),3.03-3.07(m,1H),2.48(s,3H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):454[M+H] + .

[0345] Example 24 Synthesis of Compound 30 [ka] A 100 mL round-bottom flask was charged with 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (300.00 mg, 0.689 mmol, 1.00 equiv.), concentrated hydrochloric acid (2 mL), Pd / C (30.00 mg, 0.282 mmol, 0.41 equiv.), and methanol (30.00 mL, 0.936 mmol, 1.36 equiv.) under hydrogen. The resulting solution was stirred overnight at room temperature and then filtered through Celite. The Celite pad was washed with methanol (5 × 30 mL), and the filtrate was collected and concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 solution (10 mL) and extracted with chloroform:isopropanol (3:1) (5 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: Column: Kinetex EVO C 18 column, 30 × 150, 5 μm; Mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O); Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 5% B to 30% B over 9 min. Purification gave 6-(aminomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (29.6 mg, 10% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 7.93 (s, 2H), 7.42 (s, 1H), 3.84 (br, 2H), 3.02-3.07 (m, 1H), 1.20 (d, J = 6.9Hz, 6H). LCMS(ESI,m / z):439[M+H] + .

[0346] Example 25 Synthesis of Compound 31 [ka] To a mixture of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline (70 mg, 156.39 μmol, 1 equiv.), concentrated HCl (87.97 μL, 6.75 equiv.) in HO (1 mL) was added dropwise a solution of sodium nitrite (14.84 mg, 215.04 μmol, 1.38 equiv.) in HO (1 mL), maintaining the temperature below 0° C. After the addition was complete, the reaction mixture was stirred for 0.5 h. A mixture of ethyl N-(2-cyanoacetyl)carbamate (27.47 mg, 175.94 μmol, 1.13 equiv) and NaOAc (43.30 mg, 527.83 μmol, 3.38 equiv) in EtOH (3 mL) was added dropwise to the resulting diazonium salt solution below 0 °C and stirred for an additional 2 h. The reaction mixture (combined with another 50 mg batch) was diluted with HO (10 mL), adjusted to pH 7-8 with saturated aqueous NaHCO, and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0 to 35%) to give ethyl N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo][3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazono]acetyl]carbamate (75 mg, 31% yield) as a yellow solid.

[0347] A mixture of ethyl N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazono]-acetyl]carbamate (55 mg, 89.47 μmol, 1 equiv.) and NaOAc (36.70 mg, 447.36 μmol, 5 equiv.) in AcOH (5 mL) was stirred at 130° C. for 5 h. The AcOH was removed under reduced pressure, and the residue was diluted with HO (50 mL), adjusted to pH 7–8 with saturated aqueous NaHCO, and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to afford 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (65 mg) as a yellow solid, which was used directly in the next step without further purification.

[0348] To a solution of 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (60 mg, 105.51 μmol, 1 equiv.) in THF (5 mL) was added TBAF (1 M in THF, 2.53 mL, 24 equiv.) in one portion at 20 °C. The resulting mixture was then stirred at 65 °C under N for 8 h. LCMS showed the reaction was complete. The mixture was diluted with HO (100 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC [Column: Welch Xtimate C18 150 × 30 mm, 5 μm; Mobile phase: 15% ACN in water (0.225% FA) to 45% ACN in water (0.225% FA)] to give 2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (25 mg, 56% yield, 98.3% purity) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ13.11-12.66(m,1H),10.83(br s,1H),7.57(d,J=8.4Hz,1H),7.30(d,J=2.1Hz,1H),7.15(s,2H),6.70(d,J=8.4Hz, 1H),4.24(s,2H),3.20(td,J=6.8,13.7Hz,1H),2.39(s,6H),1.33(d,J=6.9Hz,6H).

[0349] Example 26 Synthesis of Compound 32 [ka] A solution of NaNO2 (2.1 equiv., 45 mg) in water (6.5 mL) was added to a solution of 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline (1 equiv., 100 mg, 0.31 mmol) in HCl 37% (106 equiv., 2.7 mL), acetic acid (8.3 mL), and water (6.5 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h. In parallel, a solution of N-(2-cyanoacetyl)carbamate ethyl (1.5 equiv., 73 mg) in water (7.8 mL) and pyridine (2.7 mL) was stirred at 0 °C for 15 min. The first reaction mixture was quickly added to the second reaction mixture. The resulting reaction mixture was stirred at 0 °C for 2 h.

[0350] The precipitate was filtered and washed with water and petroleum ether to give ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)-phenyl)hydrazinylidene)acetyl)carbamate (13 mg) as a yellow solid. The filtrate was extracted with DCM (3 × 50 mL) and the combined organic phases were dried over MgSO, filtered and evaporated to dryness to give ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)hydrazinylene)acetyl)-carbamate (225 mg) as a yellow solid. The crude material was used as is in the next step.

[0351] Sodium acetate (4 equiv., 102 mg) was added to a solution of ethyl (2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)hydrazinyl-ene)acetyl)carbamate (1 equiv., 152 mg, 0.31 mmol) in acetic acid (5 mL) under N. The reaction mixture was heated to reflux for 4 h, then cooled to 0 °C, water (10 mL) was added, and the mixture was stirred for 30 min. The precipitate was then filtered, washed with water and petroleum ether, and purified by flash chromatography on silica gel (0–10% MeOH in DCM) to give 40 mg of a red solid, which was further triturated in EtO and iPrO to give compound 32 (20 mg, 15%) as an orange solid. 1 H-NMR(DMSO,400MHz):0.83(t,J=2.5Hz,3H);1.27(br,s,4H);1.63-1.70(quint,J=7.7Hz,2H);2.28(s,6H);2.80(t,J=7. 2Hz,2H);4.15(s,2H);7.00(d,J=8.8Hz,1H);7.18(s,2H);7.27(s,1H);7.35(d,J=8.8Hz,1H);12.51(s,1H);12.99(s,1H)

[0352] Example 27 Synthesis of Compound 33 [ka] A 50 mL round-bottom flask was charged with 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl-6-(hydroxymethyl)-4H-1,2,4-triazine-3,5-dione (1.60 g, 3.63 mmol) and CH3CN (15 mL). PBr3 (0.3 mL) was added at 0 °C under N2. The resulting solution was stirred at 75 °C for 1 h. The mixture was cooled to room temperature and then quenched with NaHCO3 (saturated, aqueous, 10 mL). The resulting mixture was extracted with EA (3 × 15 mL), and the organic layers were combined, washed with brine (1 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione as a yellow solid (1.1 g, 39%).

[0353] A 50 mL round-bottom flask was charged with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (300 mg, 0.60 mmol) and DMF (8 mL). NaSCH (125 mg, 1.79 mmol) was added at 0 °C. The mixture was acidified by adding 1 N aqueous HCl (5 mL) and extracted with EA (3 × 15 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (1:3) to give the crude product (150 mg), which was then purified by preparative HPLC. Purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[(methylsulfanyl)-methyl]-4H-1,2,4-triazine-3,5-dione as an off-white solid (32.9 mg, 12%). 1H NMR(300MHz,DMSO-d6)δ 12.55(br,1H),12.21(s,1H),7.81(s,2H),7.45(s,1H),3.54(s,2H),3.01-3.10(m,1H),2.11(s,3H),1.20(d,J=6.6Hz,6H). LCMS(ESI,m / z):470[M+H] + .

[0354] Example 28 Synthesis of Compound 34 [ka] A 50 mL round-bottom flask was charged with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (480 mg, 0.954 mmol), DMF (8 mL), and CHSONa (292 mg, 2.86 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was acidified by the addition of HCl (aq., 1 N, 5 mL) and extracted with EA (3 × 15 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column with DCM:MeOH (10:1) to give the crude product, which was then purified by preparative HPLC to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-6-(methanesulfonylmethyl)-4H-1,2,4-triazine-3,5-dione as a white solid (70.8 mg, 15%). 1 H NMR(300MHz,DMSO-d6)δ 12.74(br,1H),12.22(s,1H),7.84(s,2H),7.45(s,1H),4.48(s,2H),3.01-3.11(m,4H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):502[M+H] + .

[0355] Example 29: Synthesis of Compound 35 [ka] A 500 mL round bottom was charged with 3-methyl-4-nitrophenol (4.50 g, 29.4 mmol), benzyltrimethylammonium tetrachloroiodate (24.6 g, 58.8 mmol), and AcOH (600 mL). The reaction was stirred at 70 °C for 18 h. The solids were removed by filtration and washed with AcOH (300 mL). The organic layer was concentrated under reduced pressure. The residue was dissolved in EA:water (500 mL:250 mL). The organic layer was separated, washed with brine (2 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified on a silica gel column with EA:PE (4:94) to give 2,6-dichloro-3-methyl-4-nitrophenol as a brown solid (4.9 g, 64%).

[0356] A 250 mL vial was charged with 2,6-dichloro-3-methyl-4-nitrophenol (5.00 g, 22.5 mmol), Fe powder (6.29 g, 113 mmol), NHCl (9.64 g, 180 mmol), EtOH (50 mL), and water (25 mL). The reaction was stirred at 50 °C overnight. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel with EA:PE (2:5) to give 4-amino-2,6-dichloro-3-methylphenol (3.45 g, 59%) as a light brown solid.

[0357] 3,5-Dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-2-methylaniline was prepared similarly as described for 3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline starting from 4-amino-2,6-dichloro-3-methylphenol to give a brown solid (3.9 g, 73%).

[0358] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2H-pyridazin-3-one was prepared similarly as described for 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one starting from 4-amino-2,6-dichloro-3-methylphenol to give an off-white solid (2.5 g, 56%).

[0359] (E)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate was prepared similarly as described for ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate to give an orange solid (140 mg, 72%).

[0360] 2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (Compound 35-A) was prepared similarly as described for 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile to give a brown solid (2.1 g, 64%).

[0361] 2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid was prepared similarly as described for 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid to give a brown solid (1.0 g, 52%).

[0362] t-Butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate was prepared similarly as described for t-butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate to give a brown solid (600 mg, 71%).

[0363] A 100 mL round-bottom flask was charged with t-butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate (600 mg, 1.11 mmol) and DCM (15.0 mL). TFA (5 mL) was added dropwise at 0 °C. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in EA (50 mL). The pH of the solution was adjusted to 8 with NaHCO (saturated, aq.) and then extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous NaSO, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]-4H-1,2,4-triazine-3,5-dione (compound 35) as a white solid (105 mg, 39%). 1 H NMR(300MHz,DMSO-d6)δ 12.18(br,2H),7.72(s,1H),7.45(s,1H),6.39(br,2H),3.01-3.10(m,1H),2.20(s,3H),1.20(d,J=6.9Hz,6H). LCMS(ESI,m / z):439[M+H] + .

[0364] Example 30: Synthesis of Compound 36 [ka] 6-[(4-amino-2,6-dichlorophenyl)methyl]-4-isopropyl-2H-pyridazin-3-one was prepared according to a literature procedure (J. Med. Chem. 2014, 57, 3912-3923) to give a yellow solid (1.9 g, 50%).

[0365] (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)hydrazinylidene)acetyl)carbamate was prepared similarly as described for (2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate to give a yellow solid (659 mg, 86%).

[0366] 2-(4-[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile was prepared similarly as described for 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile to give an off-white solid (1.3 g, 86%).

[0367] 2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid was prepared similarly as described for 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid to give a yellow oil (800 mg, 48%).

[0368] t-Butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate was prepared similarly as described for t-butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate to give a yellow solid (600 mg, 65%).

[0369] 6-Amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]-phenyl]-4H-1,2,4-triazine-3,5-dione was prepared similarly as described for 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H-1,2,4-triazine-3,5-dione to give a white solid (227 mg, 49%). 1 H NMR (300MHz, DMSO-d6) δ 7.76(s,2H),7.30(s,1H),6.52(br,2H),4.24(s,2H),2.98-3.02(m,1H),1.15(d,J=6.9Hz,6H). LCMS(ESI,m / z):423[M+H] + .

[0370] Example 31 Synthesis of Compound 37 [ka] 4-Amino-2-chloro-6-methylphenol was prepared similarly as described in WO2004014382 to give a brown solid (10.8 g, 88%).

[0371] 3-Chloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline was prepared similarly as described for 3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-5-methylaniline to give a brown semi-solid (9.5 g, 68%).

[0372] 6-(4-amino-2-chloro-6-methylphenoxy)-4-isopropyl-2H-pyridazin-3-one was prepared similarly as described for 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one to give a pink solid (6.5 g, 68%).

[0373] Ethyl (2-(2-(3-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-5-methylphenyl)hydrazinylidene)-2-cyanoacetyl)carbamate was prepared similarly as de...

Claims

1. A compound of formula I', (I’)TL-L ａ -CE-HD or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein: i) TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; 【Chemistry 1】 During the ceremony, Q １ , Q ２ , Q ３ , Q ４ , Q ５ , Q ６ , and Q ８ Each of is independently nitrogen or -CR ｂ -, and each R ｂ are independently hydrogen, halogen, or lower alkyl; R １ is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C- or O-carboxy group, -CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of said carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; R ２ is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R ３ is hydrogen or lower alkyl, R ４ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of said carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; R ５ is hydroxy, NH ２ , alkylamino, alkanoylamino, or alkylsulfonylamino; Or, R ４ and R ５ together with the carbon atom to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or Or, R ４ and R ５ together with the carbon atom to which they are attached form a 7- to 11-membered optionally substituted spirocyclic ring or a 7- to 11-membered optionally substituted spiroheterocyclic ring; Alk is hydrogen or optionally substituted alkyl; R １１ is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system; or a bicyclic heterocyclic ring system, ii) CE is a moiety of formula IV, 【Chemistry 2】 During the ceremony, R ６ and R ７ are independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R ８ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Optionally, R ７ and R ８ together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring; Q ７ is nitrogen or -CR ｃ -, wherein R ｃ is hydrogen, halogen, or lower alkyl; (TL) is a moiety of formula IV that is TL-L ａ - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV is attached to -HD; iii) HD is a moiety of formula V or VI, 【Chemistry 3】 During the ceremony, R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -C(R ｄ ) ３ , -(C(R ｄ ) ２ ) ｎ -OR ｄ , -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -S(=O) ｑ R ｄ , -(C(R ｄ ) ２ ) ｎ -CN, -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ , -(C(R ｄ ) ２ ) ｎ -C(=O)-OR ｄ , -(C(R ｄ ) ２ ) ｎ -HeAr, or -(C(R ｄ ) ２ ) ｎ -C(=O)-N(R ｄ ) ２ is selected from Each R ｄ is independently hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1, or 2; each n is independently selected from 0, 1, 2, 3, 4, or 5; HeAr is a 5- or 6-membered heteroaryl; R １０ is hydrogen or -C(R ｅ ) ３ and each R ｅ is independently hydrogen, halogen, or optionally substituted lower alkyl; L ａ are independently a bond, -(C(R ａ ) ２ ) ｚ -, oxygen, sulfur, or -NR ａ -, wherein Each R ａ are independently hydrogen or lower alkyl; z is 0, 1, 2, 3, 4, or 5; however, (1) TL is a moiety of formula IIIa, wherein Q ４ , Q ５ , and Q ６ is -CH-, and R ４ is optionally substituted C １ -C ３ an alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted carbamoyl group; and HD is a moiety of formula V, wherein R ９ is H or -CN, and Q ７ When is -CH-, R ５ cannot be hydroxy, (2) TL is a moiety of formula IIa, wherein Q １ , Q ２ , and Q ３ is -CH-, and R １ But -CH ３ and R ２ is hydrogen and HD is a moiety of formula V, where R ９ is hydrogen, and Q ７ is -CH-, and R ６ is halogen or methyl; R ７ and R ８ together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, R ４ and R ５ cannot be taken together with the carbon atom to which they are attached to form a 5-membered heteroaryl group, (3) TL is a moiety of formula IIIa, wherein Q ４ is nitrogen, and Q ５ and Q. ６ is -CH-, and R ５ is —OH and HD is a moiety of formula V, where R ９ is -CN, and Q ７ is -CH-, and L ａ But -CH ２ -, then R ４ cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene; (4) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen and HD is a moiety of formula V, where R ９ is hydrogen, -CN, or -CO ２ H and Q ７ is -CH-, and R ６ and R ７ is independently halogen or methyl, or R ７ and R ８ together with the carbon atom to which they are attached form a 5-membered non-aromatic carbocyclic ring, R ４ cannot be isopropyl or 2-hydroxy-1-methyl-ethyl, (5) TL is a moiety of formula IIIb, wherein Q ４ -CR ｃ - and Q ５ is nitrogen and HD is a moiety of formula V, ９ is -CN, and Q ７ is -CH-, and L ａ is -O-, (a) R ６ , R ７ , and R ８ None of the atoms can be deuterium. (b) Q ４ cannot be -CD-, where D is deuterium; (c) R ４ is a 3- to 5-membered cycloalkyl ring optionally substituted with one or more halogens; a non-aromatic (carbocyclic) alkyl optionally substituted with methyl or hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxy, or methoxy; phenethyl optionally substituted with halogen; C optionally substituted with 1 to 6 substituents selected from halogen, hydroxyl, and deuterium. １ -C ４ alkyl; (tetrahydro-2H-pyran-4-yl)methyl; or 3- to 5-membered heterocycloalkyl optionally substituted with benzyl; (6) TL is a moiety of formula IIIb; (i) Q ４ and Q. ５ is nitrogen, or (ii) Q ４ and Q. ５ -CR ｂ - or (iii) Q ４ is nitrogen, and Q ５ -CR ｃ -, and HD is a moiety of formula V, where R ９ is -CN, and Q ７ When is -CH-, R ４ HA -CH(CH ３ ) ２ or -CH(CD ３ ) ２ (7) TL is a moiety of formula IIIa, wherein Q ４ is -CH-, and Q ５ and Q. ６ is nitrogen, R ４ is isopropyl and HD is a moiety of formula V, where R ９ is -CN, and Q ７ When is -CH-, R ５ is -NH ２ Or -NHCH ３ It is not possible to be (8) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen, L ａ is -O-, and Q ７ is —CH— and HD is a moiety of formula V, R ９ cannot be methyl, (9) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen, R ４ is isopropyl, L ａ is -O-, and Q ７ is —CH— and HD is a moiety of formula V, R ９ cannot be isopropyl, (10) TL is a moiety of formula IIa, wherein Q １ , Q ２ , and Q ３ is -CH-, and L ａ is -O-, and Q ７ is -CH-, and R ６ and R ７ is independently chlorine or trifluoromethyl, and HD is a moiety of formula V, wherein R ９ is —CN or methyl, R １ is isopropyl, 4-tetrahydropyranyl, or -C(O)NH ２ It is not possible to be (11) TL is a moiety of formula IIa, wherein Q １ and Q. ２ is -CH-, and Q ３ is nitrogen, L ａ is -O-, and Q ７ is -CH-, and R ６ and R ７ is chlorine and HD is a moiety of formula V, where R ９ When is -CN, R １ cannot be isopropyl, (12) TL is a moiety of formula IIb, wherein Q １ , Q ２ , and Q ３ is -CH-, and L ａ is -O-, and Q ７ is -CH-, and R ６ and R ７ is chlorine and HD is a moiety of formula V, where R ９ When is -CN, R １ cannot be isopropyl, (13) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen, L ａ is -O-, and Q ７ is -CH-, and R ６ and R ７ is chlorine and HD is a moiety of formula VI, wherein R １０ is H, Me, Et, isopropyl, -CH ２ CF ３ , or -CH ２ CHF ２ If R ４ is C ２ -C ５ Alkyl or C １ -C ３ cannot be hydroxyalkyl, (14) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen, L ａ is -O-, and Q ７ is -CH-, and R ６ and R ７ is chlorine and HD is a moiety of formula VI, wherein R １０ When is H or Me, R ４ cannot be cyclopropyl, (15) TL is a moiety of formula IIIb, wherein Q ４ is -CH-, and Q ５ is nitrogen, L ａ Ga-CH ２ - and Q ７ is -CH-, and R ６ and R ７ are both chlorine or both methyl, and HD is a moiety of formula VI, where R １０ When is H or Me, R ４ cannot be isopropyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

2. TL is a moiety of formula IIIb, ４ is -CH-, and Q ５ is nitrogen and HD is a moiety of formula V, ９ Ga-CH ２ CN or -C≡CH, and Q ７ is -CH-, and R ６ and R ７ is chlorine, R ４ 2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11,

3. TL is a moiety of formula IIIb; 【Chemistry 4】 HD is a moiety of formula V, 【Chemistry 5】 During the ceremony, R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -OR ｄ , -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -S(=O) ｑ R ｄ , -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ , -(C(R ｄ ) ２ ) ｎ -C(=O)-OR ｄ , -(C(R ｄ ) ２ ) ｎ -HeAr, or -(C(R ｄ ) ２ ) ｎ -C(=O)-N(R ｄ ) ２ is selected from Each R ｄ are independently hydrogen or optionally substituted C １ -C ５ is alkyl, each q is independently 0 or 2; 3. The compound of claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein each n is independently 0 or 1.

4. R ９ is hydrogen, -(CH ２ ) ｎ -OR ｄ , -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -S(=O) ｑ R ｄ , -(CH ２ ) ｎ -C≡C-R ｄ , - (CH ２ ) ｎ -C(=O)-OR ｄ , -(CH ２ ) ｎ -HeAr, or -(CH ２ ) ｎ -C(=O)-N(R ｄ ) ２ 4. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

5. R ９ is hydrogen, -(CH ２ ) -OR ｄ , -(CH ２ )-N(R ｄ ) ２ , -N(R ｄ ) ２ , -(CH ２ ) -S(=O) ｑ R ｄ , -C≡C-R ｄ , -(CH ２ )-C(=O)-OR ｄ , -C(=O)-OR ｄ , -(CH ２ )-HeAr, or -C(=O)-N(R ｄ ) ２ 5. The compound of claim 3 or 4, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

6. R ９ is hydrogen, -NH ２ or -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

7. R ９ But -NH ２ 7. The compound of any one of claims 3 to 6, wherein:

8. R ９ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

9. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

10. TL is a moiety of formula IIIb; 【Chemistry 6】 HD is a moiety of formula VI: 【Chemistry 7】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

11. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

12. Q ４ is -CH-, and Q ５ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

13. 13. The compound of any one of claims 3 to 12, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein Alk is hydrogen.

14. Alk is hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy １ -C ６ 13. The compound of any one of claims 3 to 12, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein R is an alkyl group.

15. R ４ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, or an optionally substituted (heterocycloalkyl)alkyl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

16. R ４ But, C １ -C ６ Alkyl; C ２ -C １０ Alkenyl non-aromatic C ３ -C １２ Carbocycle; C ６ -C １０ an aryl group; a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group, where R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

17. R ４ But, C １ -C ６ Alkyl, C ２ -C １０ Alkenyl, non-aromatic C ３ -C １２ a 3- to 6-membered heterocycloalkyl ring, (carbocyclic)alkyl group, aralkyl group, or (heterocycloalkyl)alkyl group containing 1 to 4 ring heteroatoms independently selected from carbocycle, oxygen, sulfur, or nitrogen; R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

18. R ４ But, C １ -C ６ Alkyl, C ２ -C １０ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)alkyl group, (cyclopentyl)alkyl group, benzyl group, (tetrahydrofuranyl)alkyl group, or (tetrahydropyranyl)alkyl group; R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

19. R ４ But, C １ -C ６ 19. The compound of any one of claims 3 to 18, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein R is an alkyl group.

20. R ４ But, C ６ -C １０ an aryl group or a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

21. R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and C １ -C ６ 1 to 5 R independently selected from the group consisting of haloalkoxy ｇ , or two R ｇ form a ring together with the atoms to which they are attached, or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

22. R ４ Hydroxy, halogen, C １ -C ６ Alkyl, and C １ -C ６ 1 to 5 R independently selected from the group consisting of alkoxy ｇ 19. The compound of any one of claims 3 to 18, wherein R is 1 or 2; or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

23. TL is a moiety of formula IIIa; 【Chemistry 8】 HD is a moiety of formula V; 【Chemistry 9】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

24. R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -CN, or -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ 24. The compound of claim 23, wherein:

25. R ９ is hydrogen, -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -CN, or -(CH ２ ) ｎ -C≡C-R ｄ 25. The compound of claim 23 or 24, which is: or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

26. R ９ is hydrogen, -N(R ｄ ) ２ , -CN, or -C≡C-R ｄ 26. The compound of any one of claims 23 to 25, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

27. R ９ is hydrogen, -NH ２ 27. The compound of any one of claims 23 to 26, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the compound is selected from -C, -CN, or -C≡CH.

28. R ９ But -NH ２ 28. The compound of any one of claims 23 to 27, wherein:

29. R ９ 28. The compound of any one of claims 23 to 27, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein is hydrogen.

30. R ９ is -CN, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

31. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

32. TL is a moiety of formula IIIa; 【Chemistry 10】 HD is a moiety of formula VI: 【Chemistry 11】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

33. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

34. R ４ and R ５ are taken together with the carbon atom to which they are attached to form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

35. R ４ and R ５ together with the carbon atom to which they are attached form a 5- or 6-membered non-aromatic carbocyclic group; ６ -C １０ an aryl group; a 3- to 6-membered heterocycloalkyl ring containing from 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; or a 5- to 10-membered heteroaryl ring containing from 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein said carbocyclic group, said aryl group, said heterocycloalkyl ring, and said heteroaryl ring are each independently selected from hydroxy, halogen, C １ -C ６ Alkyl, C １ -C ６ 1 to 5 R independently selected from alkoxy and oxo ｇ and / or two R ｇ together with the atom to which they are attached form a 3- to 6-membered carbocyclic group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

36. R ４ and R ５ together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, said heterocycloalkyl ring being １ -C ６ 1 to 5 R independently selected from alkyl, and oxo; ｇ and / or two R ｇ together with the atom to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

37. R ４ and R ５ together with the carbon atom to which they are attached, C １ -C ６ 1 to 5 R independently selected from alkyl and oxo ｇ and / or forming a pyrrolidine optionally substituted with two R ｇ together with the atom to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

38. TL is a moiety of formula IIIaa, 【Chemistry 12】 In the formula, each R ｇ But independently, C １ -C ６ alkyl or two R ｇ are taken together with the atom to which they are attached to form a 3- to 6-membered non-aromatic carbocyclic group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

39. The two R ｇ together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

40. TL is a moiety of formula IIIab, 【Chemistry 13】 In the formula, R ｇ But, C １ -C ６ 37. The compound of any one of claims 23 to 36, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

41. R ｇ 41. The compound of claim 40, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein is isopropyl.

42. TL is a moiety of formula IIIac, 【Chemistry 14】 In the formula, R ｇ But, C １ -C ６ 37. The compound of any one of claims 23 to 36, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

43. R ｇ is methyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

44. TL is a moiety of formula IIIad, 【Chemistry 15】 In the formula, each R ｇ are independently hydrogen or C １ -C ６ 37. The compound of any one of claims 23 to 36, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

45. R ４ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted carbamoyl group; R ５ is hydroxy, NH ２ , alkylamino, alkanoylamino, or alkylsulfonylamino, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

46. R ４ But, C １ -C ６ Alkyl, C ２ -C １０ Alkenyl, non-aromatic C ３ -C １２ carbocycle, C ６ -C １０ an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, a (heteroaryl)alkyl group, or -C(O)NR ｍ R ｎ and R ｍ and R ｎ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ６ Alkoxy, C ６ -C １０ independently selected from the group consisting of an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; R ４ Hydroxy, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, and C ６ -C １０ 1 to 5 R independently selected from aralkoxy; ｇ is optionally replaced by R ５ But hydroxy, NH ２ , alkylamino, alkanoylamino, or alkylsulfonylamino, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

47. R ４ But, C １ -C ６ Alkyl, C ２ -C １０ Alkenyl, non-aromatic C ３ -C １２ carbocycle, C ６ -C １０ an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or -C(O)NR ｍ R ｎ and R ｍ and R ｎ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ６ Alkoxy, C ６ -C １０ independently selected from the group consisting of an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; R ４ Hydroxy, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, and C ６ -C １０ 1 to 5 R independently selected from aralkoxy; ｇ is optionally replaced by R ５ is hydroxy, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

48. R ４ C １ -C ３ 48. The compound of any one of claims 23-33 or 45-47, which is alkyl.

49. Q ４ , Q ５ , and Q ６ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

50. Q ４ is -CH-, and Q ５ and Q. ６ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

51. Q ４ is nitrogen, and Q ５ and Q. ６ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

52. TL is a moiety of formula IIId, 【Chemistry 16】 HD is a moiety of formula V; 【Chemistry 17】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

53. R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -CN, or -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ 53. The compound of claim 52, wherein:

54. R ９ is hydrogen, -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -CN, or -(CH ２ ) ｎ -C≡C-R ｄ 54. The compound of claim 52 or 53, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, which is

55. R ９ is hydrogen, -N(R ｄ ) ２ , -CN, or -C≡C-R ｄ 55. The compound of any one of claims 52 to 54, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

56. R ９ is hydrogen, -NH ２ 56. The compound of any one of claims 52 to 55, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the compound is selected from -C, -CN, or -C≡CH.

57. R ９ But -NH ２ 57. The compound of any one of claims 52 to 56, wherein:

58. R ９ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

59. R ９ is -CN, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

60. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

61. TL is a moiety of formula IIId, 【Chemistry 18】 HD is a moiety of formula VI: 【Chemistry 19】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

62. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

63. R １１ But, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Haloalkoxy, halogen, or C ３ -C ９ benzene optionally substituted with cycloalkyl; １ -C ５ 63. The compound of any one of claims 52 to 62, which is pyridine optionally substituted with alkyl; cinnoline; isoquinoline; quinoline; pyrazolo[1,5-a]pyridine; imidazo[1,5-a]pyridine; benzo[b]thiophene; chroman; 1,2,3,4-tetrahydronaphthalene; or naphthalene, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

64. Q ８ is -CH-, and Q ５ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

65. 65. The compound of any one of claims 52 to 64, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein Alk is hydrogen.

66. Alk is hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy １ -C ６ 65. The compound of any one of claims 52 to 64, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

67. TL is a moiety of formula IIa, 【Chemistry 20】 HD is a moiety of formula V; 【Chemistry 21】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

68. R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -CN, or -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ 68. The compound of claim 67, which is: or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

69. R ９ is hydrogen, -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -CN, or -(CH ２ ) ｎ -C≡C-R ｄ 69. The compound of claim 67 or 68, which is: or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

70. R ９ is hydrogen, -N(R ｄ ) ２ , -CN, or -C≡C-R ｄ 70. The compound of any one of claims 67 to 69, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

71. R ９ is hydrogen, -NH ２ 71. The compound of any one of claims 67 to 70, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the compound is selected from -C, -CN, or -C≡CH.

72. R ９ But -NH ２ 72. The compound of any one of claims 67 to 71, wherein:

73. R ９ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

74. R ９ is -CN, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

75. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

76. TL is a moiety of formula IIa, 【Chemical 22】 HD is a moiety of formula VI: 【Chemistry 23】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

77. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

78. R １ is hydrogen, -CN, C １ -C ６ Alkyl, non-aromatic C ３ -C １２ carbocycle, C ６ -C １０ an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, or -C(O)-R ｊ Wherein R ｊ But -NR ｍ R ｎ Or -OR ｍ and R ｍ is hydrogen or C １ -C ６ alkyl, R ｎ But, C １ -C ６ alkyl, or R ｍ and R ｎ form a ring structure together with the nitrogen to which they are attached, R １ are independently selected from phenyl and haloalkyl; ｋ 78. The compound of any one of claims 67 to 77, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, optionally substituted with

79. R １ is hydrogen, -CN, C １ -C ６ alkyl, cyclopentyl, phenyl, (cyclopropyl) alkyl, benzyl, or -C(O)-R ｊ and R ｊ But -NR ｍ R ｎ Or -OR ｍ and R ｍ is hydrogen or C １ -C ６ alkyl, R ｎ But, C １ -C ６ alkyl, or R ｍ and R ｎ together with the nitrogen to which they are attached to form 1,2,3,4-tetrahydroisoquinoline, R １ are independently selected from phenyl and haloalkyl; ｋ 79. The compound of any one of claims 67 to 78, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, optionally substituted with

80. R ２ is hydrogen, halogen, hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from alkoxy １ -C ６ Alkyl, hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 10 substituents independently selected from alkoxy ３ -C ９ 80. The compound of any one of claims 67 to 79, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, which is cycloalkyl, or -CN.

81. R ２ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

82. R ３ 82. The compound of any one of claims 67-81, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein is hydrogen.

83. R ３ But, C １ -C ５ 82. The compound of any one of claims 67 to 81, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

84. Q １ , Q ２ , and Q ３ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

85. Q １ is -CH-, and Q ２ and Q. ３ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

86. Q ２ is -CH-, and Q １ and Q. ３ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

87. Q １ is nitrogen, and Q ２ and Q. ３ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

88. Q ２ is nitrogen, and Q １ and Q. ３ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

89. TL is a moiety of formula IIb, 【Chemistry 24】 HD is a moiety of formula V; 【Chemistry 25】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

90. R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -CN, or -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ 90. The compound of claim 89, wherein:

91. R ９ is hydrogen, -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -CN, or -(CH ２ ) ｎ -C≡C-R ｄ 91. The compound of claim 89 or 90, which is: or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

92. R ９ is hydrogen, -N(R ｄ ) ２ , -CN, or -C≡C-R ｄ 92. The compound of any one of claims 89 to 91, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

93. R ９ is hydrogen, -NH ２ 93. The compound of any one of claims 89 to 92, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the compound is selected from -C, -CN, or -C≡CH.

94. R ９ But -NH ２ 94. The compound of any one of claims 89 to 93, wherein:

95. R ９ 94. The compound of any one of claims 89 to 93, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein is hydrogen.

96. R ９ is -CN, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

97. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

98. TL is a moiety of formula IIb, 【Chemistry 26】 HD is a moiety of formula VI: 【Chemistry 27】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

99. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

100. R １ is hydrogen, -CN, C １ -C ６ Alkyl, non-aromatic C ３ -C １２ carbocycle, C ６ -C １０ an aryl group, a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, or -C(O)-R ｊ Wherein R ｊ But -NR ｍ R ｎ Or -OR ｍ and R ｍ is hydrogen or C １ -C ６ alkyl, R ｎ But, C １ -C ６ alkyl, or R ｍ and R ｎ form a ring structure together with the nitrogen to which they are attached, R １ Hydroxy, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, and C ６ -C １０ 1 to 5 R independently selected from aralkoxy; ｋ 100. The compound of any one of claims 89 to 99, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, optionally substituted with:

101. R １ But, C １ -C ６ 101. The compound of any one of claims 89-100, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

102. R ３ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

103. R ３ But, C １ -C ５ 102. The compound of any one of claims 89-101, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

104. Q １ , Q ２ , and Q ３ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

105. Q １ is -CH-, and Q ２ and Q. ３ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

106. TL is a moiety of formula IIIc; 【Chemistry 28】 HD is a moiety of formula V; 【Chemical Formula 29】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

107. R ９ is hydrogen, -(C(R ｄ ) ２ ) ｎ -N(R ｄ ) ２ , -(C(R ｄ ) ２ ) ｎ -CN, or -(C(R ｄ ) ２ ) ｎ -C≡C-R ｄ 107. The compound of claim 106, wherein:

108. R ９ is hydrogen, -(CH ２ ) ｎ -N(R ｄ ) ２ , -(CH ２ ) ｎ -CN, or -(CH ２ ) ｎ -C≡C-R ｄ 108. The compound of claim 106 or 107, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

109. R ９ is hydrogen, -N(R ｄ ) ２ , -CN, or -C≡C-R ｄ 109. The compound of any one of claims 106 to 108, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, selected from:

110. R ９ is hydrogen, -NH ２ 110. The compound of any one of claims 106 to 109, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the compound is selected from -C≡CH, -CN, or -C≡CH.

111. R ９ But -NH ２ 111. The compound of any one of claims 106 to 110, wherein:

112. R ９ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

113. R ９ is -CN, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

114. R ９ is -C≡CH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

115. TL is a moiety of formula IIIc; 【Chemistry 30】 HD is a moiety of formula VI: 【Chemistry 31】 3. A compound according to claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

116. R １０ is hydrogen, -CHF ２ , -CH ３ or ethyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

117. R １１ But, C １ -C ５ Alkyl, halogen, or C ３ -C ９ 117. The compound of any one of claims 106 to 116, which is benzene optionally substituted with cycloalkyl, or naphthalene, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

118. R ５ But hydroxy, NH ２ , C １ -C ６ Alkylamino, C １ -C ６ Alkanoylamino, or C １ -C ６ 118. The compound of any one of claims 106-117, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, which is alkylsulfonylamino.

119. Q ５ , Q ６ , and Q ８ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

120. Q ８ is -CH-, and Q ５ and Q. ６ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

121. Q ６ is -CH-, and Q ５ and Q. ８ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

122. Q ５ is -CH-, and Q ６ and Q. ８ is nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

123. L ａ is oxygen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

124. L ａ But -CH ２ or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

125. Q ７ is -CH-, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

126. R ６ and R ７ each independently is halogen, or hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from alkoxy １ -C ５ alkyl, R ８ is hydrogen, or R ６ is halogen, or hydroxy, halogen, and C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from alkoxy １ -C ５ alkyl, R ７ and R ８ are taken together with the carbon atom to which they are attached to form a 4-, 5-, or 6-membered carbocyclic ring, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

127. R ６ is Cl, R ７ is Cl, R ８ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

128. R ６ is Cl, R ７ is Cl, R ８ is methyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

129. R ６ is halogen, R ７ and R ８ together with the carbon atom to which they are attached form a four-membered carbocyclic ring, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

130. R １ is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, and an optionally substituted C-carboxy group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

131. 131. The compound of claim 130, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said alkyl is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

132. 132. The compound of claim 131, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein at least one carbon atom of the recited alkyl moiety is perfluorinated.

133. 132. The compound of claim 131, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said alkyl is substituted with cycloalkyl or aryl.

134. 134. The compound of claim 133, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl.

135. 134. The compound of claim 133, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said aryl is an optionally substituted phenyl.

136. 131. The compound of claim 130, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the carbocyclic group is cyclohexane or cyclopentane.

137. 131. The compound of claim 130, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the aryl group is phenyl.

138. 131. The compound of claim 130, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said C-carboxy group is a moiety of the formula -C(=O)-O-R, where R is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

139. R ２ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

140. Q １ , Q ２ , Q ３ , and Q ４ But -CR ｂ -, and each R ｂ is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

141. Q ５ and Q. ６ 140. The compound of any one of claims 1, 2, or 130-139, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

142. TL is a moiety of formula IIIb; R ４ But, C １ -C ６ Alkyl; C ２ -C １０ Alkenyl; non-aromatic C ３ -C １２ Carbocycle; C ６ -C １０ an aryl group; a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group, where R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

143. TL is a moiety of formula IIIb; R ４ But, C １ -C ６ Alkyl, C ２ -C １０ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)alkyl group, (cyclopentyl)alkyl group, benzyl group, (tetrahydrofuranyl)alkyl group, or (tetrahydropyranyl)alkyl group; R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ or two R ｇ are taken together with the atom to which they are attached to form an aromatic or non-aromatic 3-6 membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

144. TL is a moiety of formula IIIb; R ４ But, C １ -C ６ alkyl, (cyclobutyl)alkyl, (cyclopentyl)alkyl, benzyl, (tetrahydrofuranyl)alkyl, or (tetrahydropyranyl)alkyl; R ４ Hydroxy, halogen, CN, C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, and C ６ -C １０ 1 to 5 R independently selected from the group consisting of aralkoxy; ｇ 140. The compound of any one of claims 1, 2, or 130-139, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, optionally substituted with

145. TL is a moiety of formula IIIb; R ４ But, C １ -C ６ 140. The compound of any one of claims 1, 2, or 130-139, a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

146. R ４ is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

147. R ５ is hydroxy, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

148. R ６ and R ７ is independently chlorine, bromine, and iodine, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

149. R ６ and R ７ or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

150. R ６ and R ７ 150. The compound of any one of claims 1, 2, or 130-149, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

151. R ６ and R ７ or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

152. R ８ is hydrogen, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

153. R ｃ is hydrogen or methyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

154. TL is a moiety of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; 【Chemistry 32】 During the ceremony, Q １ , Q ２ , Q ３ , Q ４ , Q ５ , Q ６ , and Q ８ each independently represents nitrogen or -CR ｂ -, and each R ｂ are independently hydrogen, halogen, or lower alkyl; R １ is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C- or O-carboxy group, -CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of said carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; R ２ is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R ３ is hydrogen, R ４ is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, and the nitrogen of the carbamoyl group or carbamoylalkyl group is a heteroatom within the ring structure; R ５ But hydroxy, NH ２ , alkylamino, alkanoylamino, or alkylsulfonylamino; Or, R ４ and R ５ together with the carbon atom to which they are attached form a 5- or 6-membered optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group; or Or, R ４ and R ５ together with the carbon atom to which they are attached form a 7- to 11-membered optionally substituted spiroheterocycle or a 7- to 11-membered optionally substituted spiroheterocycle; Alk is hydrogen or optionally substituted alkyl; CE is a moiety of formula IV, 【Chemical 33】 During the ceremony, R ６ and R ７ each is independently selected from halogen, —CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R ８ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q ７ is nitrogen or -CR ｃ -, wherein R ｃ is hydrogen, halogen, or lower alkyl; (TL) is a moiety of formula IV, TL-L ａ - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV is attached to -HD; HD is a moiety of formula V or VI, 【Chemical Formula 34】 During the ceremony, R ９ But -NH ２ , -CN, -CH ２ -S-CH ３ , or -CH ２ -S(=O) ２ -CH ３ is selected from R １０ But -CH ３ and L ａ is oxygen or -CH ２ 3. The compound of claim 1 or 2, wherein -, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

155. TL is a moiety of formula II, 【Chemistry 35】 During the ceremony, Q １ , Q ２ , and Q ３ each independently represents nitrogen or -CR ｂ -, and each R ｂ are independently hydrogen, halogen, or lower alkyl; R １ is an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C- or O-carboxy group, -CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of said carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; R ２ is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN; R ３ is hydrogen, CE is a moiety of formula IV, 【Chemical 36】 During the ceremony, R ６ and R ７ each is independently selected from halogen, —CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl; R ８ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen; Q ７ is nitrogen or -CR ｃ -, wherein R ｃ is hydrogen, halogen, or lower alkyl; (TL) is a moiety of formula IV, TL-L ａ - indicates the point where it connects to (HD) indicates the point where the moiety of formula IV is attached to -HD; HD is a moiety of formula V, 【Chemical 37】 During the ceremony, R ９ is hydrogen, -CN, -NH ２ , -C(R ｄ ) ２ -S-R ｄ , -C(R ｄ ) ２ -S(=O) ２ R ｄ or -C≡C-R ｄ and each R ｄ is independently hydrogen or lower alkyl; L ａ is oxygen or -CH ２ 2. The compound of claim 1, wherein -, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

156. A compound selected from the group consisting of: 【Chemical Formula 38】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

157. 157. A pharmaceutical composition comprising a compound according to any one of claims 1 to 156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, and at least one pharma- ceutically acceptable excipient.

158. 157. A method of treating a disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 157, wherein the disorder or disease is selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

159. 157. Use of a compound according to any one of claims 1 to 156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, for the manufacture of a medicament for the treatment of a disorder or disease selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

160. 157. The compound of any one of claims 1 to 156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, for use in treating a disorder or disease selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

161. The composition of claim 157 for use in treating a disorder or disease selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

162. 1. A method of treating a thyroid hormone receptor associated disorder in a patient, comprising:

157. A method comprising: identifying a patient in need of treatment for a thyroid hormone receptor associated disorder; and administering to or contacting with the patient a compound of any one of claims 1-156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, or a pharmaceutical composition of claim 157.

163. The method of claim 162, wherein the thyroid hormone receptor-associated disorder is selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

164. 157. A method of selectively modulating the activity of thyroid hormone receptor beta (THR-β), comprising contacting said thyroid hormone receptor with a compound according to any one of claims 1 to 156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

165. 165. The method of claim 164, wherein said contacting is in vitro or ex vivo.

166. 165. The method of claim 164, wherein said contacting is in vivo.

167. 157. A compound according to any one of claims 1 to 156, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, for use in selectively modulating the activity of thyroid hormone receptor beta (THR-β).

168. 158. The composition of claim 157 for use in selectively modulating the activity of thyroid hormone receptor beta (THR-β).

169. 1. A method of treating a disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein the disorder or disease is selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer, and wherein the compound is 【Chemical Formula 39】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

170. 1. A method of selectively modulating the activity of thyroid hormone receptor beta (THR-β), comprising contacting said thyroid hormone receptor with a compound, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof, wherein said compound: 【Chemistry 40】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt, prodrug, amide, or ester thereof.

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