THR-β modifier and method of use

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 of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 005,661 filed on April 6, 2020, U.S. Provisional Patent Application No. 62 / 944,052 filed on December 5, 2019, and U.S. Provisional Patent Application No. 62 / 845,252 filed on May 8, 2019, the full disclosures of each of these are incorporated herein by reference.

[0002] This invention belongs to the field of pharmaceutical compounds, their formulations, and methods of use in the treatment of diseases. Specifically, this invention belongs to the field of THR-β modifiers and their use. [Background technology]

[0003] Alongside the global rise in obesity, non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease and liver transplantation worldwide [1, 2]. NAFLD is thought to affect 30% of the adult population, as well as 70–80% of people with obesity and diabetes. NAFLD is defined as more than 5% excess hepatic fat accumulation induced by causes other than alcohol consumption. NAFLD progresses to hepatitis (non-alcoholic steatohepatitis, NASH) and fibrosis in varying proportions of individuals, and ultimately to liver failure and hepatocellular carcinoma (HCC) in vulnerable 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 needs in patients with NAFLD and NASH are effective therapies to halt the progression of the liver disease, and in some cases reverse fibrosis, which is a major predictor of the evolution of the liver disease.[5, 6]

[0005] Thyroid hormones (TH) are essential for the normal development, growth, and metabolism of 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, TR first binds as a heterodimer or homodimer on the TH response element (TRE) located in the promoter region of the target gene, where the TRE interacts with the core repressor. Upon ligand binding, the TR homodimer dissociates in preference to heterodimerization with the retinoid X receptor (RXR), resulting in the release of the core presser and the recruitment of the coactivator. This new complex attracts numerous proteins involved in RNA polymerase II transcription of the targeted gene.

[0006] Two distinct loci, denoted THRA and THRB, are involved in encoding multiple interrelated TR isoforms with different tissue distributions and biological functions. The two major isoforms with the broadest levels of tissue expression are TRα1 and TRβ1[8]. TRα1 is first expressed during fetal development and is widely expressed in adult tissues, while TRβ1 appears later in development and is most highly expressed in the adult liver, kidneys, and lungs[9]. TRα1 is an important regulator of cardiac output, while TRβ1 plays a role in regulating metabolism in the liver. Importantly, the natural thyroid hormone T3 activates both TRα1 and TRβ1 without significant selectivity.

[0007] The design of small thyroid-mimicking molecules 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 reduction compared to cardiac effects such as heart rate, cardiac hypertrophy, and contractility [10-12].

[0008] Another strategy to avoid TRα activation 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 blood and the heart

[13] . TRα and TRβ agonists are also used for indications other than liver-related diseases, as is known in the art. [Overview of the project]

[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)TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId, and ii)L a They are joined independently;-(C(R a )2) n -; oxygen; sulfur; -NR a -i) CE is part of formula IV, iv) HD is part of formula V or VI, and the substituents are as defined herein, wherein the compound or a pharmaceutically acceptable salt, prodrug, amide or ester thereof is also disclosed. Pharmaceutical compositions comprising the above-mentioned compounds, as well as methods for treating a disease by administering or contacting one or more of the above-mentioned compounds to a patient, are also disclosed. [ka] [Brief explanation of the drawing]

[0010] [Figure 1] The chemical structures of compound 67, as confirmed by X-ray crystallography, are shown. [Figure 2] The chemical structure of compound 67-A, as confirmed by X-ray crystallography, is shown. [Modes for carrying out the invention]

[0011] Disclosed herein are novel compounds that are effective modulators of THR-β activity and can be used to treat a variety of THR-β-related disorders. The compounds and their uses are discussed in detail below. Some of the compounds disclosed herein are agonists of TRα and / or TRβ receptors, and others 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 specific embodiments are not intended to be exhaustive or to limit the scope to a broader range of embodiments discussed herein. An embodiment described in conjunction with a specific embodiment is not necessarily limited to that embodiment and can be implemented in conjunction with any other embodiment.

[0013] Where used herein, “about” is to be understood by those skilled in the art and to some extent depending on the context in which it is used. Where there is a use of a term that is not obvious to those skilled in the art, “about” means up to plus or minus 10% of the particular term, given the context in which it is used.

[0014] In the context describing elements (particularly in the context of the following claims), the use of the terms “a,” “an,” and “the,” and similar references, should be interpreted as encompassing both singular and plural forms, unless otherwise indicated herein or unless the context clearly contradicts it. References to ranges of values ​​herein are intended to function as a simplified way of referring individually to each individual value included in the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were referred to individually. All methods described herein may be carried out in any preferred order, unless otherwise indicated herein or unless the context clearly contradicts it. Any and all examples or exemplary terms provided herein (e.g., “~etc.”) are intended merely to better illustrate embodiments and, unless otherwise stated, do not constitute a limitation of the claims. Nothing in this specification should be interpreted as indicating an essential element not claimed.

[0015] In the definition of chemical substituents, R x and R y Each of these is independently a hydrogen atom, an alkyl group, a carbocyclic ring, a heterocyclic ring, an aryl group, or a heteroaryl group, and all of these, except for hydrogen, can be optionally substituted.

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

[0017] As used herein, “pharmaceutically acceptable salt” means a salt of a compound that does not cause significant irritation to the patient to whom the compound is administered and does not impair the biological activity and properties of the compound. pharmaceutically acceptable salts can be obtained by reaction of the compounds disclosed herein with an acid or a base. Examples of base-forming salts include, but are not limited to, ammonium salts (NH4 +); alkali metal salts, such as, without limitation, sodium or potassium salts, alkaline earth salts, such as, without limitation, calcium or magnesium salts, salts of organic bases, such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; salts with amino acids, such as, without limitation, salts with amino groups such as 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 the patient to whom it is administered. The ester is metabolized in the body to yield the parent compound, e.g., the compound recited in the claims. Thus, the ester does not inactivate the biological activity and properties of the compound. Pharmaceutically esters can be obtained by reacting the compounds disclosed herein with an alcohol. Methyl, ethyl, and isopropyl esters are some of the common esters that are prepared. Other suitable esters are well known to those skilled in the art (e.g., Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, New York, N.Y., 2014 (incorporated herein by reference in its entirety)).

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

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

[0021] Unless otherwise indicated, when a substituent is considered to be "optionally substituted," it means that the substituent can 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-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, O-cyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino groups including mono- and di-substituted amino groups, as well as their protected derivatives. Protecting groups that can form protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as those of Wuts mentioned above.

[0022] As used herein, “carbocyclic” refers to a ring structure in which all atoms in the ring are carbon atoms. If any of the atoms in the ring are not carbon atoms, the ring is a “heterocyclic” ring. Examples of atoms in a ring include sulfur, oxygen, and nitrogen. Carbocyclic or heterocyclic rings may also be polycyclic, e.g., fused ring systems, spirocyclic systems, or bridging ring systems. Examples of these polycyclic rings include adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Additional non-limiting examples include: [ka] These are some examples.

[0023] As used herein, “aryl” refers to a carbon (all carbon) ring having a completely delocalized π-electron system. An “aryl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When an aryl is a fused ring system, the ring connected to the rest of the molecule has a completely delocalized π-electron system. Other rings in the fused ring system may or may not have a completely delocalized π-electron system. Examples of aryl groups include, but are not limited to, the radicals of benzene, naphthalene, and azulene. Additional non-limiting examples include: [ka] These are some examples.

[0024] As used herein, “heteroaryl” refers to a ring having a completely delocalized π-electron system and containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A “heteroaryl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). If the heteroaryl is a fused ring system, the ring connected to the rest of the molecule has a completely delocalized π-electron system. Other rings in the fused ring system may or may not have a completely 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 is replaced by a heteroatom selected from nitrogen, oxygen, and sulfur.

[0026] As used herein, “alkyl” refers to a hydrocarbon group that is linear or branched and completely saturated (without double or triple bonds). The alkyl groups of the compounds disclosed herein may contain 1 to 20 carbon atoms. The alkyl groups herein may also be of medium size, having 1 to 10 carbon atoms. The alkyl groups herein may also be lower alkyl groups, 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 groups of the compounds of this disclosure may be substituted or unsubstituted. If substituted, the substituents may be cycloalkyl, aryl, heteroaryl, heteroarylcyclyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR x R y , and one or more groups independently selected from the protected amino acids.

[0028] As used herein, “alkenyl” refers to an alkyl group containing one or more double bonds in a linear or branched hydrocarbon chain. The alkenyl groups of the compounds disclosed herein may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups disclosed above with respect to alkyl group substitution or any substitution.

[0029] As used herein, “alkenyl” refers to an alkyl group containing one or more triple bonds in a linear or branched hydrocarbon chain. The alkynyl groups of the compounds disclosed herein may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups disclosed above with respect to alkyl group substitution or any substitution.

[0030] As used herein, "acyl" means "R × This refers to the C(=O)- group.

[0031] As used herein, “cycloalkyl” refers to a fully saturated (double-bond-free) hydrocarbon ring. The cycloalkyl groups of the compounds of this disclosure may range from C3 to C8. The cycloalkyl groups may be substituted or unsubstituted. If substituted, the substituents may be selected from those shown above with respect to alkyl group substitution. The “cycloalkyl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). If the cycloalkyl group is a fused ring system, the ring connected to the rest of the molecule is the cycloalkyl group as defined above. The other rings in the fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0032] As used herein, “cycloalkenyl” refers to a cycloalkyl group containing one or more double bonds in the ring, but if there are more than one, they cannot form a completely delocalized π-electron system in the ring (otherwise the group is “aryl” as defined herein). The cycloalkenyl group of the compounds of this disclosure may be unsubstituted or substituted. If substituted, the substituent may be selected from the same groups disclosed above with respect to alkyl group substitution. The “cycloalkenyl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). If the cycloalkenyl is a fused ring system, the ring connected to the rest 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 a two-radical and is bonded to two other parts. Thus, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC:(methyl)ethylene) (-CH2-CH(CH3)-), and isobutylene (IUPAC:2-(methyl)propylene) (-CH2-CH(CH3)-CH2-) are examples of alkylene groups, but are not limited to these. Similarly, the term "cycloalkylene" refers to a cycloalkyl group, as defined herein, which is bonded to two other parts in a similar manner. The terms "alkenylene" and "cycloalkenylene" are used when the alkyl and cycloalkyl groups contain unsaturated carbon atoms.

[0034] As used herein, “heterocycloalkyl,” “heteroarylcyclic,” or “heteroarylcyclyl” refers to a ring having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur in its ring system. The ring may also contain one or more double bonds, provided that they do not form a completely delocalized π-electron system within the ring. The rings as defined herein may be stable 3- to 18-membered rings consisting of a carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroarylcyclyl group of the compounds of this disclosure may be unsubstituted or substituted. If substituted, the substituent may 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 trifluoromethane-sulfonamide. A “heterocyclic alkyl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When a heterocyclic alkyl is a fused ring system, the ring connected to the rest of the molecule is a heterocyclic alkyl as defined above. The other rings in the fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0035] As used herein, "aralkyl" refers to 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 alkylenes substituted with a heterocyclic group. Similarly, “(heterocycloalkyl)alkyl” refers to alkylenes 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-carboxyl" group is "R x This refers to the C(=O)O- group.

[0040] The "C-carboxyl" group refers to the "-C(=O)R" group.

[0041] The "acetyl" group refers to the CH3C(=O)- group.

[0042] The "C-amide" group is "-C(=O)NR x R y It refers to the base.

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

[0044] The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are 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 hydroxyl group can be converted to an ester, and any carboxyl group can be converted to either an amide or an ester (see, for example, Wuts above).

[0046] In any compound of the present disclosure having one or more chiral centers, unless the absolute stereochemistry is explicitly shown, it is understood that each center may independently be R, S, or a mixture thereof. In addition, in any compound of the present disclosure having one or more double bond-forming geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E, Z, or a mixture thereof.

[0047] It is understood that the disclosure of compounds herein inherently includes the disclosure of their tautomers, where applicable. For example, the following disclosures: [ka] Furthermore, the following disclosures, [ka] This includes the reverse, even if only one of the two structures is disclosed.

[0048] Throughout this disclosure, when exemplifying or naming compounds, it should be understood that isotopically enriched analogs of the compounds are also intended. For example, a compound may have deuterium incorporated in place of hydrogen, or carbon-13 in place of carbon which has a natural isotopic distribution. Isotope enrichment may occur at one position on the compound, i.e., when only one hydrogen atom is replaced by deuterium, or at more than one position. This disclosure also includes compounds in which all analogous atoms are replaced by their less common isotopes, e.g., perdeutero compounds in which all hydrogen atoms are replaced by deuterium. Isotopeally enriched compounds are useful when obtaining NMR spectra or when utilizing isotopic effects in controlling the reaction rate of the compound received.

[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 living organisms. Multiple techniques for administering compounds exist in the art, including, but not limited to, oral, injectable, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

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

[0051] The term "diluent" defines a compound that is diluted in water to dissolve a target compound and stabilize its biologically active form. Salts dissolved in buffer solutions are used 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 a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound.

[0052] In certain embodiments, the same substance may act as a carrier, diluent, or excipient, or have two of these roles, or all three roles. Therefore, a single additive to a pharmaceutical composition can have multiple functions.

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

[0054] compound In one embodiment, the compound of formula I is disclosed herein. (I)TL-L a -CE-HD or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, i) TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId, [ka] JPEG0007844578000007.jpg35141- In the formula, - Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b - and each R b- R1 is independently hydrogen, halogen, or lower alkyl, and - R1 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted carbocyclic alkyl group, optionally substituted aralkyl group, optionally substituted heterocyclic alkyl group, optionally substituted heteroarylalkyl group, optionally substituted amino group, optionally substituted C-carboxyl group or O-carboxyl group, -CN, optionally substituted carbamoyl group, or optionally substituted carbamoylalkyl group, and 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 a lower alkyl group. - R4 is an optionally substituted alkyl group, 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 heteroarylalkyl 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 group or carbamoylalkyl group is a heteroatom in the ring structure. - R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino, - Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form an optionally substituted non-aromatic carbocyclic group of 5 or 6 members, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. - Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. - Alk is an alkyl group that is substituted with hydrogen or optionally substituted. ii) CE is part of equation IV, [ka] During the ceremony, - Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. - R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. - Optionally, R7 and R8, together with the carbon atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered carbon ring, heterocycle, aryl, or heteroaryl ring. - Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, -(TL) is where part IV of equation IV is TL-L a - indicates the point to connect, -(HD) indicates the point where the part of equation IV above connects to -HD. iii) HD is part of equation 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 ) Selected from 2, ·Each R d These are independently lower alkyl groups substituted with hydrogen or optionally. 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-membered or 6-membered heteroaryl. - R 10 is hydrogen, -C(R e )3, and each R e These are independently hydrogen, halogens, or optionally substituted lower alkyl groups. - R 11 This is a bicyclic ring system containing an aryl group optionally substituted with a lower alkyl, halogen, or cycloalkyl group; or an aromatic or saturated ring; or a bicyclic heterocycle containing an aromatic or saturated ring. iv)L a They are independent, joined, -(C(R a )2) n -, oxygen, sulfur, -NR a - and in the formula, -Each R a These are independently hydrogen or a lower alkyl group. -n is 0, 1, 2, 3, 4, or 5, and is a compound or a pharmaceutically acceptable salt thereof, prodrug, amide, or ester.

[0055] In some embodiments, R1 is an optionally substituted alkyl group, an optionally substituted carbocyclic group, an optionally substituted aryl group, and an optionally substituted C-carboxyl group or O-carboxyl group. In some of these embodiments, the alkyl group 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-carboxyl group is the -C(=O)-OR part of formula, and the O-carboxyl group is the -OC(=O)-R part of formula, 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 This is 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 hydroxyl.

[0060] In some embodiments, TL is [ka] This is the portion selected from JPEG0007844578000011.jpg44156.

[0061] In some embodiments, TL is [ka] This is the portion selected from JPEG0007844578000013.jpg109153.

[0062] In some embodiments of the compound of formula I, R6 and R7 are independently chlorine, bromine, and iodine, respectively. In other embodiments, R6 and R7 are independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, where the alkyl group of the lower alkyl and lower alkoxy is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl, respectively. In some embodiments, R6 and R7 are identical. In certain embodiments, R6 and R7 are independently chlorine or methyl.

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

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

[0065] In some embodiments, the compound disclosed herein is of formula I, where, -TL is a part of equation 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 These are independently hydrogen, halogen, or lower alkyl, R1 is an optionally substituted alkyl group, 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 heteroarylalkyl group, an optionally substituted amino group, an optionally substituted C-carboxyl group or O-carboxyl 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 a halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN. R3 is hydrogen, R4 is an optionally substituted alkyl group, 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 heteroarylalkyl 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 group or carbamoylalkyl group is a heteroatom in the ring structure. R5 is either hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino, Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alternatively, if Q6 is nitrogen and R5 is hydroxyl, it is a tautomer of the part of formula III. • Alk is an alkyl group that is substituted with hydrogen or optionally substituted. -CE is part of equation IV. [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is where part IV of equation TL-L a - indicates the point to connect, • (HD) indicates the point where part of equation IV connects to -HD. • HD is part of equation V or VI, [ka] During the ceremony, · R9 is -NH2, and R 10 It is -CH3, ·L a It is oxygen.

[0066] In other embodiments, the compound disclosed herein is of formula I, where, TL is part of equation II, [ka] During the ceremony, Q1, Q2, and Q3 are each independently nitrogen or -CR b - and each R bThese are independently hydrogen, halogen, or lower alkyl, R1 is an optionally substituted alkyl group, 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 heteroarylalkyl group, an optionally substituted amino group, an optionally substituted C-carboxyl group or O-carboxyl 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 a halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN. R3 is hydrogen, -CE is part of equation IV. [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is where part IV of equation TL-L a - indicates the point to connect, • (HD) indicates the point where part of equation IV connects to -HD. -HD is part of equation V, [ka] During the ceremony, R9 is hydrogen, -CN, or -C≡CR d And R d is hydrogen or a lower alkyl group, ·L a It is oxygen.

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

[0068] In another embodiment, the compounds of formula I' disclosed herein are (I')TL-L a -CE-HD or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, in which, i) TL is a part 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 These 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-carboxyl group or O-carboxyl 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 a lower alkyl group. R4 is an optionally substituted alkyl group, an optionally substituted alkenyl group, 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 group or carbamoylalkyl group is optionally a heteroatom in the ring structure. Is R5 a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino? Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alk is an alkyl group that is substituted with hydrogen or optionally substituted. R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a bicyclic ring system; or a bicyclic heterocyclic ring system. ii) CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Optionally, R7 and R8, together with the carbon atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered non-aromatic carbon ring, heterocycloalkyl, aryl, or heteroaryl ring. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is the part of equation IV, TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD, iii) HD is part of equation 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≡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) and 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 is independently a bond, -(C(R<00​​​​​​​​​​​​​ (1) If TL is part of formula IIIa, where 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 part of formula V, where R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxyl. (2) If TL is part of formula IIa, where Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is part of formula V, where R9 is hydrogen, Q7 is -CH-, R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are bonded form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are bonded cannot form a 5-membered heteroaryl group. (3) TL is part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is part of formula V, where R9 is -CN, Q7 is -CH-, L a However, if it is -CH2-, R4 cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene. (4) If TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is hydrogen, -CN, or -CO2H, and 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 bonded form a 5-membered non-aromatic carbocyclic ring, then R4 cannot be isopropyl or 2-hydroxy-1-methylethyl. (5) TL is part of equation IIIb, and in the equation Q4 is -CR c -, Q5 is nitrogen, HD is part of formula V, in the formula R9 is -CN, Q7 is -CH-, L a If it 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 hydroxyl; (1H-pyrazole-4-yl)methyl; (3-methylisoxazole-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxyl, or methoxy; phenethyl optionally substituted with halogen; a 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) TL is part of equation IIIb, (i) Q4 and Q5 are nitrogen, or (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -If HD is part 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 part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, HD is part of formula V, where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3, (8) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a If is -O-, Q7 is -CH-, and HD is part of formula V, then R9 cannot be methyl. (9) TL is the part of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, R4 is isopropyl, L a If is -O-, Q7 is -CH-, and HD is part of formula V, then R9 cannot be isopropyl. (10)TL is part of equation IIa, where Q1, Q2, and Q3 are -CH-, L a However, if Q7 is -O-, and Q7 is -CH-, and R6 and R7 are independently chlorine or trifluoromethyl, and HD is part of formula V, where R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl, or -C(O)NH2. (11) TL is part of formula IIa, where Q1 and Q2 are -CH-, Q3 is nitrogen, L a If is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula V, and in the formula R9 is -CN, then R1 cannot be isopropyl. (12) TL is part of equation IIb, where Q1, Q2, and Q3 are -CH-, L a If is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula V, and in the formula R9 is -CN, then R1 cannot be isopropyl. (13) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula VI, where R 10 However, if R4 is H, Me, Et, isopropyl, -CH2CF3, or -CH2CHF2, then R4 cannot be a C2-C5 alkyl or a C1-C3 hydroxyalkyl. (14) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula VI, where R 10 If is H or Me, then R4 cannot be cyclopropyl. (15)TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L aQ7 is -CH2-, R6 and R7 are both chlorine or both are methyl, HD is part of formula VI, where R 10 If R4 is H or Me, then R4 cannot be isopropyl. In some embodiments, if TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is -CH2CN or -C≡CH, Q7 is -CH-, and R6 and R7 are chlorine, then R4 cannot be isopropyl.

[0069] In another embodiment, the compounds of formula I' disclosed herein are (I')TL-L a -CE-HD or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, in which, i) TL is a part 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 These 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-carboxyl group or O-carboxyl 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 a lower alkyl group. R4 is an optionally substituted alkyl group, an optionally substituted alkenyl group, 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 group or carbamoylalkyl group is optionally a heteroatom in the ring structure. Is R5 a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino? Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alk is an alkyl group that is substituted with hydrogen or optionally substituted. R 11 is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a bicyclic ring system; or a bicyclic heterocyclic ring system. ii) CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Optionally, R7 and R8, together with the carbon atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered non-aromatic carbon ring, heterocycloalkyl, aryl, or heteroaryl ring. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD. iii) HD is part of equation 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 ) Selected from 2, Each R d These are independently lower alkyl groups substituted with hydrogen or optionally. 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-membered or 6-membered heteroaryl. R 10 is hydrogen or -C(R e )3, and each R e These are independently hydrogen, halogens, or optionally substituted lower alkyl groups. (iv)L a They are independent, joined, -(C(R a )2) z -, oxygen, sulfur, or -NR a - and in the formula, Each R a These are independently hydrogen or a lower alkyl group. z is 0, 1, 2, 3, 4, or 5. however, (1) If TL is part of formula IIIa, where 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 part of formula V, where R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxyl. (2) If TL is part of formula IIa, where Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is part of formula V, where R9 is hydrogen, Q7 is -CH-, R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are bonded form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are bonded cannot form a 5-membered heteroaryl group. (3) TL is part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is part of formula V, where R9 is -CN, Q7 is -CH-, L a However, if it is -CH2-, R4 cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene. (4) If TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is hydrogen, -CN, or -CO2H, and 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 bonded form a 5-membered non-aromatic carbocyclic ring, then R4 cannot be isopropyl or 2-hydroxy-1-methylethyl. (5) TL is part of equation IIIb, and in the equation Q4 is -CR c -, Q5 is nitrogen, HD is part of formula V, in the formula R9 is -CN, Q7 is -CH-, L a If it 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 hydroxyl; (1H-pyrazole-4-yl)methyl; (3-methylisoxazole-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxyl, or methoxy; phenethyl optionally substituted with halogen; a 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) TL is part of equation IIIb, (i) Q4 and Q5 are nitrogen, or (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -If HD is part 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 part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, HD is part of formula V, where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3, (8) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a If is -O-, Q7 is -CH-, and HD is part of formula V, then R9 cannot be methyl. (9) TL is the part of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, R4 is isopropyl, L a If is -O-, Q7 is -CH-, and HD is part of formula V, then R9 cannot be isopropyl. (10)TL is part of equation IIa, where Q1, Q2, and Q3 are -CH-, L a However, if Q7 is -O-, and Q7 is -CH-, and R6 and R7 are independently chlorine or trifluoromethyl, and HD is part of formula V, where R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl, or -C(O)NH2. (11) TL is part of formula IIa, where Q1 and Q2 are -CH-, Q3 is nitrogen, L a If is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula V, and in the formula R9 is -CN, then R1 cannot be isopropyl. (12) TL is part of equation IIb, where Q1, Q2, and Q3 are -CH-, L a If is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula V, and in the formula R9 is -CN, then R1 cannot be isopropyl. (13) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula VI, where R 10 However, if R4 is H, Me, Et, isopropyl, -CH2CF3, or -CH2CHF2, then R4 cannot be a C2-C5 alkyl or a C1-C3 hydroxyalkyl. (14) TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L a is -O-, Q7 is -CH-, R6 and R7 are chlorine, HD is part of formula VI, where R 10 If is H or Me, then R4 cannot be cyclopropyl. (15)TL is part of equation IIIb, where Q4 is -CH- and Q5 is nitrogen, L aQ7 is -CH2-, R6 and R7 are both chlorine or both are methyl, HD is part of formula VI, where R 10 If is H or Me, then R4 cannot be isopropyl. (16) If TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is -CH2CN or -C≡CH, Q7 is -CH-, and R6 and R7 are chlorine, then R4 cannot be isopropyl.

[0070] In another embodiment, the compounds of formula I' disclosed herein are (I')TL-L a -CE-HD or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, in which, i) TL is a part 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 These 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-carboxyl group or O-carboxyl 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 a lower alkyl group. R4 is an optionally substituted alkyl group, an optionally substituted alkenyl group, 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 group or carbamoylalkyl group is optionally a heteroatom in the ring structure. Is R5 a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino? Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alk is an alkyl group that is substituted with hydrogen or optionally substituted. R 11 This is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and cycloalkyl groups; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring. ii) CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Optionally, R7 and R8, together with the carbon atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered non-aromatic carbon ring, heterocycloalkyl, aryl, or heteroaryl ring. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD. iii) HD is part of equation 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 ) Selected from 2, Each R d These are independently lower alkyl groups substituted with hydrogen or optionally. 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-membered or 6-membered heteroaryl. R 10 is hydrogen or -C(R e )3, and each R e These are independently hydrogen, halogens, or optionally substituted lower alkyl groups. L a They are independent, joined, -(C(R a )2) z -, oxygen, sulfur, or -NR a - and in the formula, Each R a These are independently hydrogen or a lower alkyl group. z is 0, 1, 2, 3, 4, or 5. however, (1) If TL is part of formula IIIa, where 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 part of formula V, where R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxyl. (2) If TL is part of formula IIa, where Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is part of formula V, where R9 is hydrogen, Q7 is -CH-, R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are bonded form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are bonded cannot form a 5-membered heteroaryl group. (3) TL is part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is part of formula V, where R9 is -CN, Q7 is -CH-, L a However, if it is -CH2-, R4 cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene. (4) If TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is hydrogen, -CN, or -CO2H, and 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 bonded form a 5-membered non-aromatic carbocyclic ring, then R4 cannot be isopropyl or 2-hydroxy-1-methylethyl. (5) TL is part of equation IIIb, and in the equation Q4 is -CR c -, Q5 is nitrogen, HD is part of formula V, in the formula R9 is -CN, Q7 is -CH-, L a If it 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 ring optionally substituted with 1 to 6 substituents selected from halogens, hydroxyls, and deuterium; or a 3- to 5-membered heterocycloalkyl ring. (6) TL is part of equation IIIb, (i) Q4 and Q5 are nitrogen, or (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -If HD is part 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 part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is part of formula V, where R9 is -CN and Q7 is -CH-, then R5 cannot be -NH2 or -NHCH3. In some embodiments, if TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen, and HD is part of formula V, where R9 is -CH2CN or -C≡CH, Q7 is -CH-, and R6 and R7 are chlorine, then R4 cannot be isopropyl.

[0071] In another embodiment, the compounds of formula I' disclosed herein are (I')TL-L a -CE-HD or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, in which, i) TL is a part 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 These 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-carboxyl group or O-carboxyl 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 a lower alkyl group. R4 is an optionally substituted alkyl group, an optionally substituted alkenyl group, 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 group or carbamoylalkyl group is optionally a heteroatom in the ring structure. Is R5 a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino? Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alk is an alkyl group that is substituted with hydrogen or optionally substituted. R 11 This is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and cycloalkyl groups; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring. ii) CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Optionally, R7 and R8, together with the carbon atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered non-aromatic carbon ring, heterocycloalkyl, aryl, or heteroaryl ring. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD. iii) HD is part of equation 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 ) Selected from 2, Each R d These are independently lower alkyl groups substituted with hydrogen or optionally. 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-membered or 6-membered heteroaryl. R 10 is hydrogen or -C(R e )3, and each R e These are independently hydrogen, halogens, or optionally substituted lower alkyl groups. (iv)L a They are independent, joined, -(C(R a )2) z -, oxygen, sulfur, or -NR a - and in the formula, Each R a These are independently hydrogen or a lower alkyl group. z is 0, 1, 2, 3, 4, or 5. however, (1) If TL is part of formula IIIa, where 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 part of formula V, where R9 is H or -CN, and Q7 is -CH-, then R5 cannot be hydroxyl. (2) If TL is part of formula IIa, where Q1, Q2, and Q3 are -CH-, R1 is -CH3, R2 is hydrogen, and HD is part of formula V, where R9 is hydrogen, Q7 is -CH-, R6 is halogen or methyl, and R7 and R8 together with the carbon atoms to which they are bonded form a 5-membered non-aromatic carbocyclic ring, then R4 and R5 together with the carbon atoms to which they are bonded cannot form a 5-membered heteroaryl group. (3) TL is part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, R5 is -OH, HD is part of formula V, where R9 is -CN, Q7 is -CH-, L a However, if it is -CH2-, R4 cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene. (4) If TL is part of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, HD is part of formula V, where R9 is hydrogen, -CN, -CH2CN, -C≡CH, or -CO2H, 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 bonded form a 5-membered non-aromatic carbocyclic ring, then R4 cannot be isopropyl or 2-hydroxy-1-methylethyl. (5) TL is part of equation IIIb, and in the equation Q4 is -CR c-, Q5 is nitrogen, HD is part of formula V, in the formula R9 is -CN, Q7 is -CH-, L a If it 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 ring optionally substituted with 1 to 6 substituents selected from halogens, hydroxyls, and deuterium; or a 3- to 5-membered heterocycloalkyl ring. (6) TL is part of equation IIIb, (i) Q4 and Q5 are nitrogen, or (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -If HD is part 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 part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, R4 is isopropyl, and HD is part 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', TL is a part 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 These are independently hydrogen, halogen, or lower alkyl, R1 is an optionally substituted alkyl group, 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-carboxyl group or O-carboxyl 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 a halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, or -CN. R3 is hydrogen, R4 is an optionally substituted alkyl group, 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, wherein the nitrogen of the carbamoyl group or carbamoylalkyl group is a heteroatom in the ring structure. Is R5 a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino? Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form a 5-membered or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form a spirocyclic ring or a spiroheterocyclic ring with any choice of 7- to 11 members. Alk is an alkyl group that is substituted with hydrogen or optionally substituted. CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD. HD is part of expression V or VI, [ka] During the ceremony, R9 is selected from -NH2, -CN, -CH2-S-CH3, or -CH2-S(=O)2-CH3. R 10 However, it is -CH3, L a However, it is either oxygen or -CH2-.

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

[0074] In some embodiments of the compound of formula I', TL is part of equation IIa, [ka] HD is part of formula VI. [ka]

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

[0076] In some embodiments of the compound of formula I', TL is part of equation IIb, [ka] HD is part of formula VI. [ka]

[0077] In some embodiments of the compound of formula I', TL is part of equation IIIa, [ka] HD is part of equation V. [ka]

[0078] In some embodiments of the compound of formula I', TL is part of equation IIIa, [ka] HD is part of formula VI. [ka]

[0079] In some embodiments of the compound of formula I', TL is part of equation IIIb, [ka] HD is part of equation 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 ) Selected from 2, Each R d These are independently hydrogen- or optionally substituted C1-C5 alkyl groups. Each q is independently either 0 or 2. Each n is independently either 0 or 1.

[0080] In some embodiments of the compound of formula I', TL is part of equation IIIb, [ka] HD is part of expression VI. [ka]

[0081] In some embodiments of the compound of formula I', TL is part of equation IIIc, [ka] HD is part of equation V. [ka]

[0082] In some embodiments of the compound of formula I', TL is part of equation IIIc, [ka] HD is part of expression VI. [ka]

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

[0084] In some embodiments of the compound of formula I', TL is part of equation IIId, [ka] HD is part of expression VI. [ka]

[0085] In some embodiments of the compound of formula I', TL is part of equation II. [ka] During the ceremony, Each of Q1, Q2, and Q3 independently contains nitrogen or -CR b - and each R b These are independently hydrogen, halogen, or lower alkyl, R1 is an optionally substituted alkyl group, 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-carboxyl group or O-carboxyl 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 a halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, or -CN. R3 is hydrogen, CE is part of equation IV, [ka] During the ceremony, Each of R6 and R7 is independently selected from halogens, -CN, optionally substituted lower alkyls, optionally substituted lower alkoxys, optionally substituted lower alkenyls, or cyclopropyls. R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen. Q7 is nitrogen or -CR c - and in the formula, R c However, it is hydrogen, halogen, or lower alkyl, (TL) is TL-L a - indicates the point to connect, (HD) indicates that the part of equation IV connects to -HD. HD is part of equation 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 However, independently, they are hydrogen or lower alkyl, L a However, it is either 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 Q1, Q2, and Q3 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 Q4, Q5, and Q6 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 atoms.

[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 Q5, Q6, and Q8 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 the compounds of formula I', R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, and optionally substituted C-carboxyl group. In some embodiments of the compounds 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 the compounds of formula I', at least one carbon atom of the listed alkyl moiety is perfluorinated. In some embodiments of the compounds of formula I', the alkyl is substituted with cycloalkyl or aryl. In some embodiments of the compounds of formula I', the cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl. In some embodiments of the compounds of formula I', the aryl is optionally substituted phenyl. In some embodiments of the compounds of formula I', the carbocyclic group is cyclohexane or cyclopentane. In some embodiments of the compounds of formula I', the aryl group is phenyl. In some embodiments of the compound of formula I', the C-carboxyl group is the -C(=O)-OR portion of the formula, 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 hydrogen, C1-C6 alkyl, non-aromatic C3-C 12 carbocyclic group, C6-C 10 R1 is 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-carboxyl group or an O-carboxyl group, a -CN, or a carbamoyl group, where R1 is hydroxyl, halogen, -CN, amino, oxo, O-carboxyl group, C-carboxyl group, C-amide group, N-amide, C1-C6 alkoxy, C6-C10 A 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroaryl groups independently selected from alkoxy groups, C3-C9 cycloalkyl groups, oxygen, sulfur, or nitrogen, or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroaryl groups independently selected from oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R independently selected from the group consisting of aryls k It is optionally replaced by [this].

[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 compounds of formula I', R1 is an optionally substituted C1-C6 alkyl. In some embodiments of the compounds of formula I', R1 is a hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is a C1-C6 alkyl group optionally substituted by. In some embodiments of the compound of formula I', R1 is C 1- It is a C6 alkyl group.

[0101] In some embodiments of the compounds of formula I', R1 is an optionally substituted non-aromatic carbocyclic group. In some embodiments of the compounds of formula I', R1 is a hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10Aralcoxy, 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 aryls k Non-aromatic C3-C substituted by choice 12 It is a carbocyclic group.

[0102] In some embodiments of the compounds of formula I', R1 is an optionally substituted aryl group. In some embodiments of the compounds of formula I', R1 is a hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amide, N-amide, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k C6-C was optionally replaced. 10 It is an aryl group.

[0103] In some embodiments of the compounds of formula I', R1 is an optionally substituted heterocycloalkyl group. In some embodiments of the compounds of formula I', R1 is a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where the heterocycloalkyl ring is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10Aralcoxy, 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 aryls k It is optionally replaced by [this].

[0104] In some embodiments of the compounds of formula I', R1 is an optionally substituted heteroaryl group. In some embodiments of the compounds of formula I', R1 is a 5- to 10-membered ring heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where the heteroaryl group is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is optionally replaced by [this].

[0105] In some embodiments of the compounds of formula I', R1 is an optionally substituted (carbocyclic) alkyl group. In some embodiments of the 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)C 1- It is a C6 alkyl group, and R1 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, oxo, C 1-C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkyl, C6-C 10 Aralcoxy, 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 aryls k It is optionally replaced by [this].

[0106] In some embodiments of the compounds of formula I', R1 is an optionally substituted aralkyl group. In some embodiments of the compounds of formula I', R1 is a hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k This is a benzyl group optionally substituted by [the specified agent].

[0107] In some embodiments of the compounds of formula I', R1 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of the compounds of formula I', R1 is a hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkyl, C6-C 10 Aralcoxy, 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 aryls k It is a (heterocycloalkyl)alkyl group that has been optionally substituted by [the specified agent].

[0108] In some embodiments of the compounds of formula I', R1 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of the compounds of formula I', R1 is a hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is a (heteroaryl)alkyl group that has been optionally substituted by [the specified agent].

[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, 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, C6-C 10 Aryl, C-carboxy, C-amide, -(SO2)(C 1- C6alkyl), -C(O)O(C1- C6alkyl), -C(O)O(C 1- C6 haloalkyl), -C(O)O(C 3- 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 An amino group optionally substituted with one or two substituents independently selected from the group consisting of aryls. In some embodiments of the compound of formula I', R1 is -NR m R n And in the formula, R m and R n This includes 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, C-carboxy, C-amide, -(SO2)(C 1- C6alkyl), -C(O)O(C 1- C6alkyl), -C(O)O(C 3- 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 Independently selected from the group consisting of aryls; or R m and R n However, together with the nitrogen atoms to which they are bonded, they form a 3- to 18-membered heterocycloalkyl ring, where R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is optionally replaced by [this].

[0110] In some embodiments of the compound of formula I', R1 is an optionally substituted C-carboxyl group. -C(O)(C 1- C6 alkyl), -C(O)(C 3- C9 cycloalkyl), -C(O) (3- to 6-membered heterocycloalkyl), -C(O) (5- to 10-membered heteroaryl), and -C(O)(C6-C 10 It is an aryl compound, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 acrylics k It is optionally replaced by [this].

[0111] In some embodiments of the compound of formula I', R1 is an optionally substituted O-carboxyl 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 It is an aryl compound, and R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is optionally replaced by [this].

[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 And in the formula, R m and R n This includes 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 C6-C 10 Independently selected from a group consisting of aryls; or R m and R n However, together with the nitrogen atoms to which they are bonded, they form a 3- to 18-membered heterocycloalkyl ring, where R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls k It is optionally replaced by [this].

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

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

[0115] In some embodiments of the compound of formula I', R1 is hydrogen;-CN;C1-C6 alkyl;non-aromatic C3-C 12 Carbocycle, C6-C 10 Aryl group; 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; (carbocyclic) alkyl group; aralkyl group; (heterocycloalkyl) alkyl group, or -C(O)-R j And in the formula, R j -NR m R n OR m And; R m R is hydrogen or a C1-C6 alkyl group; n is a C1-C6 alkyl group; or, R m and R n These, together with the nitrogen to which they are bonded, form a ring structure; R1 can be hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C6-C 10 1 to 5 R selected independently from allalkoxy k It is optionally replaced by [this].

[0116] In some embodiments of the compound of formula I', R1 is hydrogen, -CN, C1-C6 alkyl, non-aromatic C3-C 12 It is a carbon ring, C6-C 10 Aryl group; 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; (carboncyclic) alkyl group; aralkyl group; (heterocycloalkyl) alkyl group; or -C(O)-R j And in the formula, R j -NR m R n OR m And; R m R is hydrogen or a C1-C6 alkyl group; n is a C1-C6 alkyl group; or, R m and R n These, together with the nitrogen atoms to which they are bonded, form a ring structure; R1 is one to three R atoms independently selected from phenyl and haloalkyl groups. k It is optionally replaced by [this].

[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 And in the formula, R j -NR m R n OR m And R m R is hydrogen or C1-C6 alkyl, n is a C1-C6 alkyl group, or R m and R n These, together with the nitrogen they bind to, form 1,2,3,4-tetrahydroisoquinoline, where R1 is one to three R molecules independently selected from phenyl and haloalkyl groups. k It will be replaced by an optional choice.

[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 And in the formula, R j -NR m R n OR m And; R m R is hydrogen or a C1-C6 alkyl group; n is a C1-C6 alkyl group, or R m and R n These, together with the nitrogen they bind to, form 1,2,3,4-tetrahydroisoquinoline, where R1 is one to three R molecules independently selected from phenyl and haloalkyl groups. k It is optionally replaced by [this].

[0119] In some embodiments of the compound of formula I', R2 is hydrogen, halogen, C 1- C6 alkyl, C 3- C9 is cycloalkyl, or -CN; R2 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 It is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl compounds.

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

[0121] In some embodiments of the compounds of formula I', R2 is an optionally substituted C1-C6 alkyl. In some embodiments of the compounds of formula I', R2 is a hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, C 3- C8 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 These are C1-C6 alkyl groups that are optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl groups.

[0122] In some embodiments of the compound of formula I', R2 is optionally substituted with a C3-C9 cycloalkyl group. In some embodiments of the compound of formula I', R2 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 3- It is a C8 cycloalkyl. In some embodiments of the compound of formula I', R2 is a C3-C9 cycloalkyl that is 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 compounds of formula I', R2 is hydrogen or an optionally substituted C1-C6 alkyl group. In some embodiments of the compounds 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 the compound of formula I', R2 is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents independently selected from hydrogen, halogens, hydroxyl, halogens, and C1-C6 alkoxys, a C3-C9 cycloalkyl group optionally substituted with 1 to 10 substituents independently selected from hydroxyl, halogens, and C1-C6 alkoxys, or a -CN group.

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

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

[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 10R4 is a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, 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 R4 is hydroxy, CN, C1-C6 alkyl, or C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C 10 1 to 5 R selected systematically from the group consisting of allalkoxy g It is either arbitrarily replaced by or two R g Together with the atoms to which they are bonded, they form a 3- to 6-membered aromatic or non-aromatic bond 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 R4 is a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, 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 R4 is hydroxyl, halogen, C1-C6 alkyl, or C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of allalkoxy g It is either arbitrarily replaced by or two R g These atoms, together with the atoms they bond to, 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 heterocyclic alkyl ring of 3 to 6 members containing 1 to 4 ring heteroatoms independently selected from a carbocyclic ring, oxygen, sulfur, or nitrogen, a (carbocyclic) alkyl group, an aralkyl group, or a (heterocyclic alkyl) alkyl group, where 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 selected independently from allalkoxy g It is either arbitrarily replaced by or two R g Together with the atoms to which they bond, they form aromatic or non-aromatic 3- to 6-membered rings that optionally contain 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 R4 is a 3- to 6-membered heterocyclic alkyl ring containing 1 to 4 cyclic heteroatoms independently selected from a carbocyclic ring, oxygen, sulfur, or nitrogen, a (carbocyclic) alkyl group, an aralkyl group, or a (heterocyclic alkyl)alkyl group, where R4 is hydroxyl, halogen, C1-C6 alkyl, or C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of allalkoxy g It is optionally replaced by [this].

[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, pyridazine-3(2H)-one, phenyl, naphthyl, pyridinyl, sinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)alkyl, (cyclopentyl)alkyl, benzyl group, (tetrahydrofuranyl)alkyl, or (tetrahydropyranyl)alkyl, where R4 is hydroxy, halogen, CN, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloxyalkyl, and C6-C 10 One to five R groups independently selected from the group consisting of allalkoxy. g It is either arbitrarily replaced by or two R g These atoms, together with the atoms to which they bond, form a 3- to 6-membered aromatic or aromatic ring that optionally contains one or two 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, (cyclopentyl)alkyl, benzyl group, (tetrahydrofuranyl)alkyl, or (tetrahydropyranyl)alkyl, where 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 allalkoxy g It is optionally replaced by [this].

[0133] In some embodiments of the compound of formula I', R4 is an optionally substituted alkyl. In some embodiments of the compound of formula I', R4 is an optionally substituted C1-C6 alkyl. In some embodiments of the compound of formula I', R4 is a hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is a C1-C6 alkyl which is optionally substituted with. 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 allalkoxy g It is a C1-C6 alkyl group optionally substituted by . 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- It is a C6 alkyl group. In some embodiments of the compound of formula I', R4 is C 1- It is a C3 alkyl group. In some embodiments of the compound of formula I', R4 is a C5-C6 alkyl group.

[0134] In some embodiments of the compound of formula I', R4 is an optionally substituted alkenyl. In some embodiments of the compound of formula I', R4 is an optionally substituted C2-C 10It is an alkenyl. In some embodiments of the compound of formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g C2-C is arbitrarily substituted. 10 It is an alkenyl. 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 allalkoxy g C2-C replaced by choice 10 It is Alkenil.

[0135] In some embodiments of the compounds of formula I', R4 is an optionally substituted non-aromatic carbocyclic group. 12 It is a carbon ring. In some embodiments of the compound of formula I', R4 is hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, 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 aryls g Non-aromatic C3-C substituted by choice 12 It is a carbocyclic group, or two R groups. g These atoms, together with the atoms to which they are bonded, form a 3- to 6-membered aromatic or non-aromatic ring optionally containing one or two ring heteroatoms independently selected from oxygen, oxygen, sulfur, or nitrogen. In some embodiments of the compounds of formula I', R4 is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g Non-aromatic C3-C substituted by choice 12 It 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 allalkoxy g Non-aromatic C3-C substituted by choice 12 It is a carbocyclic group, or two R groups. gThese, together with the atoms to which they bond, form a 3- to 6-membered aromatic or non-aromatic compound optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compounds 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 allalkoxy g Non-aromatic C3-C substituted by choice 12 It is a carbocyclic group.

[0136] In some embodiments of the compounds of formula I', R4 is an optionally substituted heterocycloalkyl group. In some embodiments of the 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, where the heterocycloalkyl ring is hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, C 3- A 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from C9 cycloalkyl, oxygen, sulfur, or nitrogen, and C6-C 10 1 to 5 R groups independently selected from the group consisting of 5- to 10-membered heteroaryl groups containing 1 to 4 ring heteroaryl groups independently selected from aryl groups g It is either arbitrarily replaced by or two R gHowever, together with the atoms to which they bond, they 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 the compounds of formula I', R4 is an optionally substituted 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is optionally substituted by. In some embodiments of the compound 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, where the heterocycloalkyl ring is hydroxy, halogen, CN, oxo, C1-C6 alkyl, or 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 allalkoxy g It is optionally substituted by. In some embodiments of the compound 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, where the heterocycloalkyl ring 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 allalkoxy gIt is optionally replaced by [this].

[0137] In some embodiments of the compounds of formula I', R4 is an optionally substituted (carbocyclic) alkyl group. In some embodiments of the 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)C 1- It is a C6 alkyl group, and R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 Aralcoxy, 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 aryls g It is either arbitrarily replaced by or two R g These, together with the atoms to which they bond, 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 the 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)C 1- It is a C6 alkyl group, and R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, oxo, C 1-C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is optionally substituted by [another compound]. In some embodiments of the compound of formula I', R4 is (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- It is a C6 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 allalkoxy g It is optionally replaced by [this].

[0138] In some embodiments of the compounds of formula I', R4 is an optionally substituted aralkyl group. In some embodiments of the compounds of formula I', R4 is a hydroxyl, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, 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 aryls g A benzyl group optionally substituted by, or two R g These, together with the atoms to which they bond, form an aromatic or non-aromatic 3- to 6-membered ring containing 1-2 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compounds of formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g The benzyl group is optionally substituted. 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 allalkoxy g It is a benzyl group optionally substituted by . 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 allalkoxy gThis is a benzyl group optionally substituted by [the specified agent].

[0139] In some embodiments of the compounds of formula I', R4 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of the compounds of formula I', R4 is a hydroxy, oxo, halogen, amino, CN, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, 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 selected independently from the aryl g A (heterocycloalkyl)alkyl group optionally substituted by, or two R g Together with the two atoms to which they bond, they 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 the compounds of formula I', R4 is hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls gIt is a (heterocycloalkyl)alkyl group optionally substituted by . 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 allalkoxy g It is a (heterocycloalkyl)alkyl group that has been optionally substituted by [the specified agent].

[0140] In some embodiments of the compounds of formula I', R4 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of the compounds of formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g A (heteroaryl)alkyl group optionally substituted by, or two R g These, together with the atoms they bond to, form a 3- to 6-membered aromatic or non-aromatic ring optionally containing one or two ring heteroatoms independently selected from oxygen or nitrogen. In some embodiments of the compounds of formula I', R4 is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is a (heteroaryl)alkyl group optionally substituted by . 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 allalkoxy g It is a (heteroaryl)alkyl group optionally substituted by . 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 allalkoxy g It is a (heteroaryl)alkyl group that has been optionally substituted by [the specified agent].

[0141] In some embodiments of the compound of formula I', R4 is C6-C 10 A 5- to 10-membered heteroaryl ring containing an aryl group or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where R4 is hydroxyl, halogen, CN, C1-C6 alkyl, or 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 allalkoxy g It is optionally replaced by, or by two R gHowever, together with the bonded atoms, they form a 3- to 6-membered aromatic or non-aromatic ring that optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compounds of formula I', R4 is C6-C 10 A heteroaryl ring with 5 to 10 members containing an aryl group or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where R4 is hydroxyl, halogen, C1-C6 alkyl, or C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R independently selected from the group consisting of allalkoxy g It is optionally replaced by [this].

[0142] In some embodiments of the compound of formula I', R4 is optionally substituted with C6-C 10 It is an aryl group. In some embodiments of the compound of formula I', R4 is hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amide, N-amide, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, 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 aryls g C6-C, which was optionally replaced by 10 It is either an aryl group or two R groups. gThese, together with the atoms to which they bond, 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 the compounds of formula I', R4 is hydroxy, halogen, -CN, O-carboxy, C-carboxy, C-amide, N-amide, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g C6-C, which was optionally replaced by 10 It is an aryl 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 allalkoxy g C6-C, which was optionally replaced by 10 It is either an aryl group or two R groups. g These, together with the atoms to which they bond, form a 3- to 6-membered aromatic or non-aromatic compound optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compounds 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 allalkoxy g C6-C, which was optionally replaced by 10 It is an aryl group.

[0143] In some embodiments of the compound of formula I', R4 is 1 to 5 R independently selected from the group consisting of hydroxy, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. g Either a benzene optionally substituted by, or two R g However, together with the atoms to which they bond, they form a 3- to 6-membered aromatic or non-aromatic ring containing one or two ring heteroatoms, optionally selected independently from oxygen, sulfur, or nitrogen. In some embodiments of the compound of formula I', R4 is one to five R, independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, and C1-C6 alkoxy. g Either a benzene optionally substituted by, or two R g However, these atoms combine with the atoms they bond to to form a ring.

[0144] In some embodiments of the compound of formula I', R4 is 1 to 5 R independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, and C1-C6 alkoxy. g This is naphthalene that has been optionally substituted by [another substance].

[0145] In some embodiments of the compounds of formula I', R4 is an optionally substituted heteroaryl group. In some embodiments of the compounds of formula I', R4 is a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where the heteroaryl ring is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Aralcoxy, 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 groups independently selected from the group consisting of aryl groups g It is either arbitrarily replaced by or two R g However, together with the atoms they bond to, they form a 3- to 6-membered non-aromatic or non-aromatic ring optionally containing one or two ring heteroatoms independently selected from oxygen, oxygen, sulfur, or nitrogen. In some embodiments of the compounds of formula I', R4 is an optionally substituted 5- to 10-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where the heteroaryl ring is hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 A 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from aryl, C1-C6 alkoxy, C6-C10 aralkoxy, 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 C6-C 10 1 to 5 R independently selected from the group consisting of aryls g It is optionally substituted by. In some embodiments of the compound of formula I', R4 is a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, where the heteroaryl ring is hydroxy, halogen, CN, C1-C6 alkyl, or 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 allalkoxy gIt is optionally substituted by. In some embodiments of the compound 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, where the heteroaryl ring 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 allalkoxy g It is optionally replaced by [this].

[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, 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, C6-C 10 Aryl, C-carboxy, C-amide, -(SO2)(C 1- C6alkyl), -C(O)O(C 1- C6alkyl), -C(O)O(C 1- C6 haloalkyl), -C(O)O(C 3- 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 An amino group optionally substituted with one or two substituents independently selected from the group consisting of aryls. In some embodiments of the compound of formula I', R4 is -NR m R n And in the formula, R m and R nThis includes 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, C-carboxy, C-amide, (SO2)(C 1- C6alkyl), -C(O)O(C 1- C6alkyl), C(O)O(C 3- C9 chloroalkyl), -C(O)O (3- to 6-membered heterocycloalkyl), -C(O)O (5- to 10-membered heteroaryl), and -C(O)O(C6-C 10 Independently selected from the group consisting of aryls; or R m and R n However, together with the nitrogen atoms to which they are bonded, they form a 3- to 18-membered heterocycloalkyl ring, where R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is optionally replaced by [this].

[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 And in the formula, 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 Independently selected from a group consisting of aryls; or R m and R n However, together with the nitrogen atoms to which they are bonded, they form a 3- to 18-membered heterocycloalkyl ring, where R1 is hydroxy, halogen, -CN, amino, C 1- C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is optionally replaced by [this].

[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 And in the formula, R m and R n This includes 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 C6-C 10 Independently selected from a group consisting of aryls; or R m and R nHowever, together with the nitrogen they bond to, they form a 3- to 18-membered heterocycloalkyl ring, where R1 is hydroxy, halogen, -CN, amino, C1-C6 alkyl, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 aryls g It is optionally replaced by [this].

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

[0150] In some embodiments of the compound of formula I', R5 is an alkylamino. In some embodiments of the compound of formula I', R5 is -NR u R v And in the formula, R u is hydrogen or C 1- It is a C6 alkyl group, R v These are hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 1- C 12 It is alkyl.

[0151] In some embodiments of the compound of formula I', R5 is an alkanoylamino acid. In some embodiments of the compound of formula I', R5 is -NR u C(O)R v And in the formula, R u R is hydrogen or C1-C6 alkyl, v These are hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 1- C 12 It is alkyl.

[0152] In some embodiments of the compound of formula I', R5 is an alkylsulfonylamino acid. In some embodiments of the compound of formula I', R5 is -NR u SO2R v And R u is hydrogen or C 1- It is a C6 alkyl group, R v These are hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 1- C 12 It is alkyl.

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

[0154] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, are substituted with non-aromatic C3-C 12 Carbon ring, optionally substituted C6-C 10 The compounds form an aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, form a 5-membered or 6-membered non-aromatic C3-C 12 Carbocycle, C6-C 10 A 4- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from an aryl group, oxygen, sulfur, or nitrogen, or a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the carbocyclic, aryl group, heterocycloalkyl group, and heteroaryl group can be hydroxyl, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkyl, C6-C 10 Aralcoxy, 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 It is optionally substituted with 1 to 5 substituents selected from the group consisting of aryl compounds.

[0155] In some embodiments of the compounds of formula I', R4 and R5, together with the carbon atoms to which they are bonded, form a 7- to 11-membered spirocyclic ring or a 7- to 11-membered spiroheterocycle, and the spirocyclic ring and spiroheterocycle are hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkyl, C6-C 10 Aralcoxy, 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 It is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl compounds.

[0156] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, form an optionally substituted non-aromatic carbon ring of five or six members, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group.

[0157] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, form a 5-membered 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 each contain 1 to 5 R groups independently selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, and oxo. g Replaced by choice and / or two R g These atoms, together with the atoms they bond to, form a 3- to 6-membered carbocyclic group.

[0158] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, form a 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heterocycloalkyl ring contains 1 to 5 R atoms independently selected from the group consisting of C1-C6 alkyl and oxo. g Optionally replaced by and / or two R g However, together with the atoms they bond to, they form 3- to 6-membered non-aromatic carbon rings.

[0159] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are bonded, are 1 to 5 R atoms independently selected from C1-C6 alkyl and oxo compounds. g This forms pyrrolidines that are optionally substituted, and / or two R g These atoms, together with the atoms they bond to, form a 3- to 6-membered non-aromatic carbocyclic group.

[0160] In some embodiments of the compound of formula I', TL is the part of formula IIIaa, [ka] In the formula, each R g However, independently, they are either C1-C6 alkyl or two R gHowever, together with the atoms to which they bond, they form alkenes optionally substituted with C1-C6 alkyl groups, or two R g However, together with the atoms they bond to, they form a 3- to 6-membered non-aromatic carbocyclic group. In some embodiments of the compound of formula I', two R g These, together with the atoms to which they are bonded, form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0161] In some embodiments of the compound of formula I', TL is the part of formula IIIaa, [ka] In the formula, each R g However, independently, they are either C1-C6 alkyl or two R g However, together with the atoms they bond to, they form a 3- to 6-membered non-aromatic carbocyclic group. In some embodiments of the compound of formula I', two R g These atoms, together with the atoms they bond to, form a cyclopentyl group or a cyclohexyl group.

[0162] In some embodiments of the compound of formula I', TL is part of formula IIIab, [ka] R g However, it is a C1-C6 alkyl. In some embodiments of the compound of formula I', R g It is isopropyl.

[0163] In some embodiments of the compound of formula I', TL is part of formula IIIac, [ka] R g However, it is a C1-C6 alkyl. In some embodiments of the compound of formula I', R g It is methyl.

[0164] In some embodiments of the compound of formula I', TL is part of formula IIIad, [ka] In the formula, each R g These are independently hydrogen or a C1-C6 alkyl group.

[0165] In some embodiments of the compound of formula I', R4 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocycloalkyl, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, or optionally substituted carbamoyl group, and R5 is a hydroxyl, 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 A 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, 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 10A 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; an alkyl group independently selected from the group consisting of a (carbocyclic) alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; R m and R n These, together with the nitrogen atoms to which they are bonded, form a 3-18 member heterocycloalkyl ring. R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R selected independently from allalkoxy g Replaced by optional means; 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 A 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, 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 10A 3- to 6-membered heterocycloalkyl ring containing 1 to 4 ring heteroatoms independently selected from aryl groups, oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; an alkyl group independently selected from the group consisting of a (carbocyclic) alkyl group, an aralkyl group, a (heterocycloalkyl)alkyl group, a (heteroaryl)alkyl group, or a (heteroaryl)alkyl group; R m and R n These, together with the nitrogen atoms to which they are bonded, form a 3-18 member heterocycloalkyl ring. R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, and C6-C 10 1 to 5 R selected independently from allalkoxy g Replaced by optional means; R5 is hydroxyl.

[0168] In some embodiments of the compounds of formula I', Alk is hydrogen or optionally substituted C1-C6 alkyl. 10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 1- It is a C6 alkyl group. 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-amide, N-amide, C1-C6 alkoxy, C6-C10 Aralcoxy, 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 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl atoms. 1- It is a C6 alkyl group. In some embodiments of the compound of formula I', Alk is a C1-C6 alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, and C1-C6 alkoxy groups.

[0169] In some embodiments, the compound of formula I' is R 11 R is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups; or a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring. In some embodiments of the compound of formula I', R 11 R is an aryl group optionally substituted with 1 to 5 substituents independently selected from lower alkyls, halogens, and C3-C9 cycloalkyls; or a bicyclic ring system containing either an aromatic or saturated ring; or a bicyclic heterocycle containing either an aromatic or saturated ring. In some embodiments of the compound of formula I', R 11 C6-C1 is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups. 10The aryl group is a 5- to 10-membered heteroaryl group containing an aryl group or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups, or is 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 C6-C1 is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and C3-C9 cycloalkyl groups. 10 An aryl group; or a bicyclic ring system of 7 to 12 members containing either an aromatic or saturated ring; or a bicyclic heterocycle of 7 to 12 members containing either an aromatic or saturated ring. In some embodiments of the compound of formula I', R 11 C6-C1 is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups. 10 It is an aryl group. In some embodiments of the compound of formula I', R 11 C6-C1 is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, halogen, and C3-C9 cycloalkyl groups. 10 It is an aryl group. In some embodiments of the compound of formula I', R 11 R is a 5- to 10-membered heteroaryl group containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, and the heteroaryl group is optionally substituted with 1 to 5 substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups. In some embodiments of the compound of formula I', R 11 R 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 11R is 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 R is optionally substituted with benzenes, benzenes, benzenes, benzenes, benzenes, and 11 This refers to 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 the compound of formula I', each of R6 and R7 is a halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and C1-C6 alkoxy, and R8 is hydrogen, or R6 is a halogen or a 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 atoms to which they are bonded form a 4-membered, 5-membered, or 6-membered carbon ring.

[0171] In some embodiments of the compound of formula I’, each of R6 and R7 is independently chlorine, bromine, and iodine. In some embodiments of the compound of formula I’, each of R6 and R7 is independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, and 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 the compound of formula I’, R6 and R7 are the same. In some embodiments of the compound of formula I’, each of R6 and R7 is independently chlorine or methyl. In some embodiments of the compound of formula I’, R6 is Cl, R7 is Cl, and R8 is hydrogen. In some embodiments of the compound of formula I’, R6 is Cl, R7 is Cl, and R8 is methyl. In some embodiments of the compound of formula I’, R6 is halogen, and R7 and R8 together with the carbon atom to which they are attached form a 4-membered carbon 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-amide, N-amide, C1-C6 alkoxy, C 3- Lower alkyl optionally substituted by 1 to 5 substituents selected from the group consisting of C5 cycloalkyl, an oxygen, sulfur, or nitrogen heteroatom-containing 3- to 5-membered heterocycloalkyl group containing 1 heteroatom independently selected therefrom. In some embodiments of the compound of formula I’, R8 is optionally substituted lower alkoxy. In some embodiments of the compound of formula I’, R8 is hydroxy, halogen, amino, -CN, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C 3-It is lower alkoxy optionally substituted by 1 to 5 substituents selected from the group consisting of 3- to 5-membered heterocycloalkyl groups containing 1 heteroatom independently selected from C5 cycloalkyl, oxygen, sulfur, or nitrogen. In some embodiments of the compound of formula I', R8 is cyano. In some embodiments of the compound of formula I', R8 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-C 10 aryl, or a 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≡C-R d d In some embodiments of the compound of formula I', R9 is hydrogen, -(CH2) n -N(R d n -CN, or -(CH2) n -C≡C-R dIn some embodiments of the compound of formula I', R9 is hydrogen, -N(R d )2, -CN, or -C≡CR d R9 is selected from the following. 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 -CN. 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 -HeAr. 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 These are independently hydrogen, or hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 It is a lower alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl compounds. In some embodiments of the compound of formula I', each R d is hydrogen. In some embodiments of the compound of formula I', each R d These are independently hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 It is a lower alkyl group that is optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl compounds.

[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 the compound of formula I', HeAr is a five-membered or six-membered heteroaryl group containing one to three ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0181] In some embodiments, the compound of formula I' is R 10 is hydrogen or -C(R e )3, and each R e These are independently hydrogen, halogen, or hydroxyl, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, 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 It is a lower alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl compounds. In some embodiments of the compound of formula I', R 10 is hydrogen. In some embodiments of the compound of formula I', R 10 is -C(R e )3, and each R e These are independently hydrogen, halogen, or hydroxyl, halogen, -CN, amino, O-carboxy, C-carboxy, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Aralcoxy, C 3-A 3- to 6-membered heterocycloalkyl group containing 1 to 4 ring heteroatoms independently selected from 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 C6-C 10 Lower alkyl optionally substituted by 1 to 5 substituents independently selected from the group consisting of aryl. In some embodiments of the compound of formula I’, R 10 is -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 compound of formula I’, L a is -(C(R a )2) z -. In some embodiments of the compound of formula I’, L a is -CH2-. 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 is -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, the compounds disclosed herein are selected from the group consisting of: [ka] JPEG0007844578000068.jpg213149JPEG0007844578000069.jpg230154JPEG0007844578000070.jpg222156JPEG000 7844578000071.jpg216154JPEG0007844578000072.jpg204157JPEG0007844578000073.jpg236157JPEG00078445780 00074.jpg202157JPEG0007844578000075.jpg222157JPEG0007844578000076.jpg223156JPEG0007844578000077.j pg206155JPEG0007844578000078.jpg206155JPEG0007844578000079.jpg232156JPEG0007844578000080.jpg222157

[0185] Compound synthesis The compounds of this disclosure were synthesized using the general synthetic procedures described in Schemes 1 to 10 below. Performing each of the illustrated steps is within the scope of the skill of a person skilled in the art, who also knows how to modify the synthetic procedures of the following schemes to synthesize the entire range of compounds disclosed herein. The synthetic procedures for individual compounds are provided in the Examples section below.

[0186] As described in Scheme 1, the aromatic amine compound of formula S-II is converted to the aza-uracil compound of formula S-III by first generating the corresponding diazonium salt, then reacting it with an N-(2-cyanoacetyl)-carbamate, and finally cyclizing it to form the compound of formula S-III. Next, the nitrile of formula S-III is hydrolyzed to the carboxylic acid compound of formula S-IV. Then, the compound of formula S-IV is reacted with diphenyl phosphoryl azide (DPPA) to form the compound of formula SV. Finally, the compound of formula SV is deprotected. [ka]

[0187] As described in Scheme 2, the aromatic amine compound of formula S-II can be converted to the boronic acid compound of formula S-VII by first generating a diazonium salt and then reacting it with tetrahydroxydiborane. The corresponding boronic acid is then coupled with a bromo-azauracil compound of formula Int-I that is appropriately protected (by the protecting group "PG"). The resulting bromide compound of formula S-VIII is then further converted by either substitution or transition metal catalytic conversion, as illustrated in the Examples section below. Removal of the protecting group "PG" yields the compound of formula SX. [ka] JPEG0007844578000083.jpg65150

[0188] The synthesis of the aromatic amine compound of formula S-XIV is described in Scheme 3. The compound of formula S-XI is reacted with the compound of formula S-XII (where "X" represents a halogen such as F or Cl), and then protected with the protecting group "PG" to obtain the compound of formula S-XIII. Reduction of the nitro functional group of the compound of formula S-XIII leads to the formation of the aromatic amine compound of formula S-XIV. [ka]

[0189] Scheme 4 describes the synthesis of the compound of formula S-XIX. Following the transmetallation reaction of the compound of formula S-XVI (where "X" in the structure represents a halogen, e.g., Br or I), it is added to the aldehyde of general formula S-XV to obtain the alcohol compound of formula S-XVII, which is then reduced to the compound of formula S-XVIII. Deprotection of PG2 of the compound of formula S-XVIII leads to the formation of the compound of formula S-XIX. [ka] JPEG0007844578000086.jpg72152

[0190] As shown in Scheme 5, compounds of formula S-XX are obtained by coupling a compound of formula S-VII with a bromide compound 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 (whose structure represents a halogen, e.g., Cl, Br, or I) is coupled with a compound of formula S-XXII via a Suzuki coupling to form a compound of formula S-XXIII. The protecting group PG3, e.g., the benzyl moiety, can then be removed to obtain a compound of formula S-XXIV. The resulting phenolic functional group can then be replaced with a triflate group to obtain a compound of general formula S-XXV. The -OTf group can then be replaced with an -NH2 moiety via a transition metal-catalyzed reaction, such as a Buchwald coupling with t-butylcarbamate or benzophenone imine, followed by deprotection to obtain 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 react with an aldehyde of type S-XXVIII to form a compound of formula S-XXIX. Further structural details of formula S-XXIX are shown in Scheme 7. [ka]

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

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

[0194] Scheme 8 describes the 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 acid chlorides and Lewis acids (e.g., InBr3) in a nonpolar aprotic solvent (e.g., dichloroethane). The newly formed ketone group can be partially reduced to an alcohol or completely reduced to the corresponding alkane. Further conversion of the ketone group is obvious 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 procedures from the available literature. [ka]

[0195] Scheme 9 describes the general synthesis of the compound of formula S-XXXIII. 4-Bromo-6-chloropyridazine-3-amine can be converted to the corresponding 4-aryl-6-chloropyridazine-3-amine (S-XXXII) under typical Suzuki-Miyaura conditions, for example, using ArB(OH)2 (e.g., phenylboronic acid) and a palladium catalyst (e.g., PdCl2(PPh3)2). Subsequent transformation of the amino group to Cl via typical Sandmeyer reaction conditions (e.g., CuCl2, t-Bu-ONO, acetonitrile, heat) yields the S-XXXIII type compound. [ka]

[0196] Scheme 10 describes a general synthesis of the compound of formula S-XXXVI. The compound of formula S-XXXIV can be coupled with a base (e.g., K2CO3) and phenol HO-CE-HD at high temperature under a Cu(I)-mediated coupling reaction in DMSO to obtain an intermediate of type S-XXXV. Subsequent hydrolysis of chloropyridazine via acetic acid and its acetate (e.g., NaOAc) yields a product of formula S-XXXVI from which the desired positional isomer can be isolated. In the context of Scheme 10, the group HD may include a general protecting group that can be cleaved at the intermediate S-XXXV stage or at the end of the synthesis to obtain the compound of formula S-XXXVI. [ka]

[0197] The synthesis of compounds of formula S-XXXVII can be carried out using procedures described in the literature. For example, the alkynyl ester can be combined with protected aniline under the conditions described in Org. Lett. 2014, 16, 3568-3571, using a Ru catalyst, to obtain 6-bromoquinolone. Alternatively, compounds 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 the compound of formula S-XXXVII, which can be started from a dihalogenated aminoaryl (S-XXXVII-a). The amine is then protected (e.g., trimethylacetamide) to obtain an 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 obtain the alcohol product S-XXXVI-c, which is oxidized in the next step (via a common oxidizing agent, e.g., Dess-Martin reagent) to obtain the ketone S-XXXVII-d. The ketone undergoes an aldol-type reaction with a protected ester (e.g., t-butyl) to obtain the intermediate S-XXXVII-e. In the final step, intramolecular cyclization occurs to obtain the compound of formula S-XXXVII. [ka]

[0199] Forming the final product by incorporating the compound of formula S-XXXVII can be achieved using similar methods described in schemes 6a and 6b. [ka]

[0200] Several methods exist for accessing the compound 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. Incorporating the compound of formula S-XXXVIII to form the final product can be achieved using similar methods described in schemes 6a and 6b.

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

[0202] Pharmaceutical composition In another embodiment, pharmaceutical compositions comprising, or consisting thereof, the compounds described herein and at least one pharmaceutically acceptable excipient are disclosed herein.

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

[0204] In another embodiment, disclosed herein are pharmaceutical compositions comprising, essentially comprising, or comprising a compound of formula I' described herein and at least one pharmaceutically acceptable excipient.

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

[0206] The pharmaceutical compositions disclosed herein may contain excipients such as lactose and corn starch, flow promoters such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. Sweeteners and / or flavoring agents may be added if desired. Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO3), Cremofer, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), fluids such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, and combinations thereof.

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

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

[0209] Suitable antioxidants for use in this 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., "Tween20" and "Tween80," as well as plutonic agents such as F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, as well as phosphatidylethanolamine), fatty acids and fatty esters, steroids such as cholesterol, as well as chelating agents such as EDTA, zinc, and other suitable cations.

[0211] Furthermore, the compositions disclosed herein may optionally contain one or more acids or bases. Non-limiting examples of usable acids include acids 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 bases 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 a composition will vary depending on the role of the excipient, the dosage requirements of the active ingredient, and the specific needs of the composition. However, generally, excipients are present in a composition in an amount of about 1% to about 99% by weight, 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 a composition of the present disclosure is selected from at least about 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or 95% by weight.

[0213] The pharmaceutical compositions described herein may be administered to human patients themselves, or as part of pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or with suitable carriers or excipients. Techniques for the formulation and administration of the compounds of this application can be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990.

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

[0215] The pharmaceutical compositions disclosed herein may be prepared in known forms, for example, by conventional mixing, dissolution, granulation, sugar coating, wet grinding, emulsification, encapsulation, encapsulation, or tableting processes. These pharmaceutical compositions may then be formulated in conventional methods using one or more known physiologically acceptable carriers, including excipients and / or adjuvants, which facilitates the processing of the active compound into a pharmaceutically usable formulation. Any of the known techniques, carriers, and excipients may be used as is preferred and understood in the art, for example, in Remington's Pharmaceutical Sciences.

[0216] Pharmaceutical compositions suitable for use in the formulations of this disclosure include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. More specifically, therapeutically effective dose means an amount of a compound effective in preventing, alleviating, or improving the symptoms of the disease being treated, or in extending survival time. In some embodiments, therapeutically effective dose means an amount of a compound effective in alleviating or improving the symptoms of the disease being treated, or in extending survival time.

[0217] While precise dosages can be determined for each drug, in most cases several generalizations regarding dosage can be made. A daily dose regimen for adult human patients may be, for example, 0.001 mg to 1000 mg, preferably 0.01 mg to 500 mg, for example, 1 to 200 mg of each component, or each active component of the pharmaceutical compositions disclosed herein, or the oral dose of its pharmaceutically acceptable salt calculated as a free base or free acid, with the compositions administered 1 to 4 times daily or once weekly. Alternatively, the compositions disclosed herein may be administered by continuous release, such as sustained release, delayed release, or continuous release, preferably in doses of up to 500 mg of each component per day. Therefore, the total daily dose by oral administration of each component is typically in the range of 0.1 mg to 2000 mg.

[0218] Treatment method In another embodiment, disclosed herein is a method for treating a thyroid hormone receptor-related disorder in a patient, the method comprising, essentially comprising, or comprising, the steps of: identifying a patient in need of treatment for a thyroid hormone receptor-related disorder; and administering to or bringing into contact with the patient a compound described herein.

[0219] In another embodiment, disclosed herein is a method for treating a thyroid hormone receptor-related disorder in a patient, the method comprising the steps of identifying a patient in need of treatment for a thyroid hormone receptor-related disorder, and administering to or bringing into contact with the patient a compound of formula I described herein. In some embodiments, a method for treating a thyroid hormone receptor-related disorder in a patient essentially comprises or consists of the steps of identifying a patient in need of treatment for a thyroid hormone receptor-related disorder, and administering to or bringing into contact with the patient a compound of formula I described herein.

[0220] In another embodiment, disclosed herein is a method for treating a thyroid hormone receptor-related disorder in a patient, the method comprising, essentially comprising, or comprising the steps of: identifying a patient in need of treatment for a thyroid hormone receptor-related disorder; and administering to or bringing into contact with the patient a compound of formula I' described herein.

[0221] In some embodiments, healthcare professionals such as physicians, physician assistants, and nurses identify individuals requiring treatment for thyroid hormone receptor-related disorders and / or candidates for treatment with the compounds disclosed herein. Identification may be based on medical test results, non-response to other first-line therapies, the specific nature of a particular liver disorder, and the like.

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

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

[0224] In another embodiment, disclosed herein is a method for treating NASH in a subject requiring treatment of NASH, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0225] In another embodiment, disclosed herein is a method for treating obesity in a subject requiring treatment of obesity, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0226] In another embodiment, disclosed herein is a method for treating hyperlipidemia in a subject requiring treatment for hyperlipidemia, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0227] In another embodiment, disclosed herein is a method for treating hypercholesterolemia in a subject requiring treatment for hypercholesterolemia, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0228] In another embodiment, disclosed herein is a method for treating diabetes in a subject requiring treatment, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0229] In another embodiment, disclosed herein is a method for treating hepatic stipe in a subject requiring treatment of hepatic stipe, the method comprising, essentially comprising, or comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

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

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

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

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

[0234] The following are illustrative of aspects of the present invention and do not limit 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] JPEG0007844578000099.jpg162151

[0236] Composition of constituent units Synthesis of 1,3-isopropyl-1H-indole-5-ol [ka] To a stirred mixture of (4-methoxyphenyl)hydrazine (10.00 g, 72.375 mmol, 1.0 equivalent) in 100 mL of AcOH, isovalaraldehyde (6.23 g, 0.072 mmol, 1 equivalent) was added dropwise at 80°C. The resulting mixture was stirred at 120°C for 2 hours. The resulting mixture was concentrated under vacuum. 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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 equivalent) in DCM (100.00 mL), boron tribromide (35.88 g, 143.217 mmol, 3 equivalents) was added dropwise at -78°C for 1 hour. The resulting mixture was stirred at room temperature for a further 3 hours. The reaction was quenched by adding H2O at 0°C. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-isopropyl-1H-indole-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 equivalent) in AcOH (500 mL), isovalaraldehyde (23.03 g, 267.37 mmol, 1.00 equivalent) was added dropwise at 80°C. The resulting mixture was stirred at 120°C for 3 hours. The resulting mixture was concentrated under vacuum. 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-3-isopropyl-1H-indole (28 g, 44%) as a brown solid.

[0239] Synthesis of 2b,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 equivalent), DMAP (20.44 mg, 167.29 μmol, 0.02 equivalents), and DIPEA (2.38 g, 18.40 mmol, 2.2 equivalents) in DCM (60 mL), ToSCl (1.91 g, 10.04 mmol, 1.2 equivalents) was added at 20°C. The resulting mixture was then stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, UV) showed that the starting materials were completely consumed. The mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0-10%) to obtain 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] Synthesis of 2c.5-bromo-3-pentyl-1H-indazole [ka] To a solution of 5-bromo-2-fluoro-benzaldehyde (25 g, 123.15 mmol, 1 equivalent) in THF (100 mL), bromo(pentyl)magnesium (1 M, 184.73 mL, 1.5 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched at 0°C with saturated NH4Cl (50 mL), then diluted with H2O (50 mL), and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to obtain 1-(5-bromo-2-fluoro-phenyl)hexane-1-ol (9.5 g, 34.53 mmol, yield 28%) as a colorless oil.

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

[0242] To a solution of 1-(5-bromo-2-fluorophenyl)hexane-1-one (5 g, 18.31 mmol, 1 equivalent) in NMP (2 mL), hydrazine hydrate (2.16 g, 36.61 mmol, 2.09 mL, 85% purity, 2 equivalents) was added at 20°C. The mixture was stirred at 100°C for 12 hours. The reaction mixture was added to ice water (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to obtain 5-bromo-3-pentyl-1H-indazole (2 g, 7.49 mmol, yield 41%) as a white solid.

[0243] 3. Synthesis of 3-3-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 equivalent) in toluene (50 mL), Bu4NHSO4 (0.43 g, 1.27 mmol, 0.10 equivalent) was gradually added at 0°C. TsCl (2.90 g, 15.26 mmol, 1.2 equivalent) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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 equivalent) in THF, n-BuLi (31.2 ml, 51.0 mmol, 5.0 equivalents, 1.6 M in hexane) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C for 40 minutes under a nitrogen atmosphere. DMF (3.70 g, 0.051 mmol, 5.0 equivalents) was added at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C for 1.5 hours 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (1.1 g, 31%) as a pale yellow oil.

[0245] 4. 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 equivalent) was left in acetic anhydride (50 mL) under reflux (140°C) for 5 hours. After drying the reaction medium, the precipitate was isolated and then recrystallized from ether to obtain 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 equivalents, 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 equivalent) was added dropwise to DMF (150 mL). The reaction medium was stirred at room temperature for 1 hour, then [(chloromethoxy)methyl]benzene (8.54 g, 54.53 mmol, 1.1 equivalents) was added, and stirring was continued at room temperature for 18 hours. After drying and concentration, the resulting residue was dissolved in H2O (200 mL) and extracted with ethyl acetate (EA) (3 × 500 mL). After drying with Na2SO4, the organic phase was evaporated, and the resulting clear oily substance was purified to isolate 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 equivalent). This mixture was heated under reflux for 4 hours and then dried and concentrated. The residue was dissolved in H2O and then extracted with EA. After drying and evaporating 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 equivalent) in ACN (5 mL), BSA (529.8 mg, 2.61 mmol, 2.5 equivalents) was added 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 CH3I (251.4 mg, 1.77 mmol, 1.7 equivalents) was added dropwise at 82°C, and stirring was continued for 20 hours at 82°C. The mixture was cooled to room temperature, concentrated under reduced pressure, then dissolved in DCM, washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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 using 2.5 equivalents of iodoethane instead of 1.7 equivalents of CH3I, similar to the preparation described for 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione.

[0249] 6. Synthesis of 6.5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole [ka] To a stirred solution of 3-isopropyl-1H-indole-5-ol (1.00 g, 5.71 mmol, 1.00 equivalent) in THF, tert-butoxypotassium (0.64 g, 5.70 mmol, 1.0 equivalent) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the resulting mixture was concentrated under vacuum and redissolved in DMF. Second reaction flask: To a stirred solution of 1,2,3-trichloro-5-nitrobenzene (1.29 g, 5.70 mmol, 1.0 equivalent) in DMF, the first reaction flask was added at 0°C. The resulting mixture was stirred at 0°C for 5 minutes, then heated 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 obtain 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-indole-5-ol (5.10 g, 29.10 mmol, 1.0 equivalent) in 50 mL of DMSO, K2CO3 (4.42 g, 32.0 mmol, 1.1 equivalent) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (4.92 g, 29.1 mmol, 1.0 equivalent) were gradually added at room temperature. The resulting mixture was stirred at 100°C for 2 hours. 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 obtain 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (6 g, 64%) as a pale yellow solid.

[0251] 8. Synthesis of 8.5-(2,6-dichloro-4-nitrophenoxy)-1H-indole [ka] To a solution of 5-hydroxyindole (16.0 g, 120.2 mmol, 1.0 equivalent) in acetonitrile (320 mL), tert-butoxide potassium (13.48 g, 120.2 mmol, 1.0 equivalent) was added at 0°C. After 20 minutes, the mixture was concentrated to remove the acetonitrile and dissolved in N,N-dimethylformamide (320 mL). Then, 1,2,3-trichloro-5-nitrobenzene (27.21 g, 120.2 mmol, 1.00 equivalent) was added at 0°C. The resulting solution was stirred overnight at 100°C and then quenched with water (300 mL). The resulting solution was extracted with ethyl acetate (3 × 500 mL), the organic layers were combined and washed with brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain 28 g of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (68% yield) as a yellow solid.

[0252] Synthesis of 9,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]oxyaniline [ka] To a stirred solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.29 g, 3.532 mmol, 1.0 equivalent) in toluene (50.00 mL), TsCl (0.81 g, 4.239 mmol, 1.2 equivalents), KOH (50%) (21.4 mL), and Bu4NHSO4 (0.12 g, 0.353 mmol, 0.1 equivalent) in toluene (10 mL) were added dropwise at 0°C. The resulting mixture was stirred at room temperature for 6 hours. After the reaction was complete, the resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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-methylbenzensulfonyl)indole (1.40 g, 2.73 mmol, 1.0 equivalent) and NH4Cl (1.16 g, 21.62 mmol, 8.0 equivalents) in EtOH (50 mL) and H2O (25 mL), Fe powder (0.75 g, 13.514 mmol, 5.00 equivalent) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2 hours under a nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was washed with EA. The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with EA and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)-indole-5-yl]oxy]aniline (1.11 g, 78%) as a white solid.

[0254] 10. Synthesis of 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-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 equivalent) in 50 mL of toluene, TsCl (3.53 g, 0.018 mmol, 1.2 equivalents), Bu4NHSO4 (0.52 g, 0.002 mmol, 0.1 equivalent), and KOH (50 mL) were added dropwise at 0°C. The mixture was stirred overnight at room temperature 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in hexane to obtain 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 equivalent) in MeOH (70 mL), Pd / C (1.74 g) was gradually added. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was washed with MeOH (1 × 500 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-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-methylbenzenesulfonyl)indole-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 equivalent) in THF (5 mL), MeLi-LiBr (1.7 mL, 1.76 mmol, 2.0 equivalents, 1 M in ether) was added under nitrogen at -78°C. Then, t-BuLi (1.6 mL, 2.64 mmol, 3.00 equivalents, 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 equivalent) 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 sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified to obtain 2,2,2-trifluoro-N-(4-[hydroxy]3-isopropyl-1-(4-methylbenzenesulfonyl)indole-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-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300.0 mg, 0.537 mmol, 1.00 equivalent) in DCM (5 mL) was stirred at 0°C under nitrogen. Then, a solution of Et3SiH (374.7 mg, 3.22 mmol, 6.0 equivalent) in DCM (15 mL) and a solution of TMSOTf (7.16 mg, 0.032 mmol, 0.06 equivalent) in DCM (5 mL) were 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 NaHCO3 solution (20 mL). The resulting solution was extracted with dichloromethane (3 × 50 mL), the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product containing 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)acetamide was isolated as a yellow solid (260 mg, 85% pure, 76% yield).

[0258] To a solution of 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)acetamide (260.0 mg, 0.479 mmol, 1.0 equivalent) in MeOH (10 mL) and H2O (2 mL), stirred at room temperature under nitrogen, NaOH (76.66 mg, 1.917 mmol, 4.0 equivalents) was added. The reaction mixture was stirred overnight at 60°C. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with dichloromethane (3 × 50 mL), the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated as a yellow solid containing 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylaniline (230 mg, 90% pure, 97% yield).

[0259] 12. Synthesis of 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indole-5-yl]oxyaniline [ka] To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (28.0 g, 86.65 mmol, 1.0 equivalent) in toluene (720 mL), tetrabutylammonium bisulfate (2.94 g, 8.665 mmol, 0.10 equivalent) and potassium hydroxide (120.00 g, 2138.8 mmol, 25.0 equivalent) in water (120 mL) were added at 0°C. 4-toluenesulfonyl chloride (19.82 g, 103.98 mmol, 1.20 equivalent) in toluene (720 mL) was added dropwise at 0°C. The reaction mixture 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 organic layers were combined and concentrated under reduced pressure. The residue was purified to obtain 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 equivalent) in ethanol (500 mL) and water (250 mL), iron powder (15.21 g, 272.36 mmol, 5.0 equivalent) and ammonium chloride (23.31 g, 435.78 mmol, 8.0 equivalent) were added. The resulting solution was stirred at 50°C for 2 hours. The resulting mixture was filtered, and the filtered cake was washed with dichloromethane (6 × 100 mL). The filtrate was extracted with dichloromethane (3 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indole-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-pyridazine-3-one [ka] To a solution of 3,6-dichloropyridazine (50.00 g, 335.64 mmol, 1.0 equivalent) in H2O (1.20 L), AgNO3 (57.02 g, 335.64 mmol, 1.0 equivalent) and isobutyric acid (29.57 g, 335.64 mmol, 1.0 equivalent) were gradually added at room temperature under an air atmosphere, and then the mixture was stirred at 50°C under a nitrogen atmosphere. H2SO4 (98.76 g, 1006.9 mmol, 3.0 equivalent) was gradually added at 50°C, and the mixture was stirred at 60°C. Then, (NH4)2S2O8 (229.78 g, 1006.914 mmol, 3.0 equivalent) was added, and the mixture was stirred at 70°C for 30 minutes 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 sodium 2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 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 equivalent) in DMSO (200 mL), phenol, 4-amino-2,6-dichloro-(18.63 g, 104.68 mmol, 1.0 equivalent), K2CO3 (58.16 g, 420.81 mmol, 4.02 equivalents), and CuI (11.96 g, 62.81 mmol, 0.60 equivalents) were gradually added. 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 obtain 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazine-3-yl)oxy]aniline (17 g, 49%) as a green solid.

[0263] To a solution of 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazine-3-yl)oxy]aniline (17.00 g, 51.111 mmol, 1.0 equivalent) in HOAc (200 mL), NaOAc (24.33 g, 178.89 mmol, 3.50 equivalents) was gradually added. The mixture was stirred overnight at 100°C under a nitrogen atmosphere. NaOH (12.27 g, 306.77 mmol, 6.0 equivalents) and MeOH (200 mL) were gradually added to the mixture. 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 Na₂SO₄. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazine-3-one (11 g, 69%) as an off-white solid.

[0264] 13b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]aniline [ka] A mixture of 3,6-dichloro-4-isopropylpyridazine (80.0 g, 419 mmol, 1.00 equivalent), 4-amino-2,6-dichlorophenol (74.5 g, 419 mmol, 1.0 equivalent), K2CO3 (232 g, 1675 mmol, 4.0 equivalent), and CuI (47.9 g, 251 mmol, 0.6 equivalent) in DMSO (800 mL) was stirred overnight at 60°C. 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 a petroleum ether to ethyl acetate ratio (PE:EA) of 5:1) to obtain 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazine-3-yl)oxy]aniline (35.0 g, yield 24%) 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 equivalent) and potassium methoxide (21.1 g, 301 mmol, 10.0 equivalent) in MeOH (50 mL) was stirred at 65°C for 48 hours. 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5:1 PE:EA) to obtain 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-pyridazine-3-yl)oxy]phenylboronic acid [ka] A 1000 mL round-bottom flask was packed with 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (14.13 g, 44.98 mmol, 1.0 eq) in 200 mL of MeOH. HCl (4.10 mL, 112.439 mmol, 3 equivalents) was added dropwise at 0°C. H2O (100 mL) was added at 0°C. The mixture was stirred for 10 minutes, then NaNO2 (3.72 g, 53.971 mmol, 1.20 equivalents) was added, and the mixture was stirred for a further 30 minutes at 0°C. Tetrahydroxydiborane (40.32 g, 449.749 mmol, 10.0 equivalents) was added. The reaction mixture was stirred at 60°C for 1 hour. The resulting solution was quenched with water (50 mL). The obtained solution was extracted with dichloromethane (3 × 400 mL), the organic layer was combined with the organic layer, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. By purification, 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine-3-yl)oxy]phenylboronic acid (6.3 g, 37%) was obtained as a white solid.

[0267] 14b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]phenylboronic acid [ka] To a stirred mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline (5.80 g, 17.7 mmol, 1.00 equivalent) and CuBr2 (7.89 g, 35.3 mmol, 2.00 equivalent) in ACN (40 mL), tert-butylnitrite (4.24 mL, 35.4 mmol, 2.0 equivalent) was added dropwise at 0°C. The resulting mixture was then warmed to room temperature and stirred for a further 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA at a 10:1 ratio) to obtain 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 equivalent), bis(pinacolate)diborone (972 mg, 3.83 mmol, 1.50 equivalent), Pd(dppf)Cl2 (187 mg, 0.256 mmol, 0.10 equivalent), and KOAc (750 mg, 7.64 mmol, 3.00 equivalent) in 1,4-dioxane (10 mL) was stirred at 90°C for 2 hours. After cooling to 25°C, the solid was filtered, and the filtrate 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 minutes) to obtain 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-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)-indole-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)indole-5-yl]oxyaniline (15.00 g, 33.532 mmol, 1.0 equivalent) in water (700 mL), concentrated hydrochloric acid (336 mL), and acetic acid (942 mL), sodium nitrite (4.86 g, 70.418 mmol, 2.1 equivalents) in water (50 mL) was added dropwise at 0°C. After the addition, the reaction mixture was stirred at 0°C for 45 minutes. Then, the reaction mixture was quickly poured at 0°C into a solution of ethyl N-(2-cyanoacetyl)carbamate (7.85 g, 50.30 mmol, 1.5 equivalents) and pyridine (336 mL) in water (600 mL). The resulting mixture was stirred at 0°C for 30 minutes and filtered. The filtered cake was washed with water (100 mL) and petroleum ether (200 mL) and dried under reduced pressure to obtain ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indole-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-indole-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (18.40 g, 29.95 mmol, 1.0 equivalent) in N,N-dimethylacetamide (300 mL), potassium acetate (11.76 g, 119.782 mmol, 4.0 equivalent) was added. The reaction mixture was stirred at 120 °C for 2 hours and quenched with water (100 mL). The mixture was extracted with ethyl acetate (3 × 100 mL), 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 obtain 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indole-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)indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (7.0 g, 12.32 mmol, 1.0 equivalent) and p-toluenesulfonic acid (0.210 g, 1.232 mmol, 0.1 equivalent) in dichloromethane (300 mL), N-iodosuccinimide (4.16 g, 18.47 mmol, 1.5 equivalent) was added at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 6 hours and quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3 × 200 mL), the combined organic layers were washed with saturated sodium thiosulfate solution (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified to obtain 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indole-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 equivalent) in HOAc (43.8 mL, 764.03 mmol) and HCl (15.3 mL, 503.55 mmol), NaNO2 (230.59 mg, 3.34 mmol, 2.1 equivalents) in H2O (33.4 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes 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 equivalents) in pyridine (20 mL) and H2O (40.9 mL) were added at 0°C. The resulting mixture was held at 0°C for 30 minutes. The precipitated solid was collected by filtration and washed with PE and H2O (3 × 300 mL) to obtain N-[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazin-1-ylidene)-carbonyl]-carbamate ethyl. This may also be called (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-hydrazinylidene)acetyl)-carbamate (the name produced by ChemDro) (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]hydrazine-1-ylidene)carbonyl]carbonyl]carbamate (also known 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 equivalent) in DMA (13.36 mL), KOAc (261.01 mg, 2.660 mmol, 2.0 equivalent) was gradually added at room temperature. The mixture was stirred under a nitrogen atmosphere at 120 °C for 3 hours. The reaction products were 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 sodium 2SO4. After filtration, the filtrate was concentrated. This yielded 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 equivalent) in 200 mL of DCM stirred at room temperature, 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (4.37 g, 13.995 mmol, 1.2 equivalents), Cu(OAc)2 (4.24 g, 23.326 mmol, 2 equivalents), and pyridine (1.85 g, 23.326 mmol, 2 equivalents) were added. The reaction mixture was stirred at room temperature under oxygen for 2 days, and then concentrated under reduced pressure to obtain the crude product. Purification yielded 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, yield 28%) as an off-white solid.

[0275] 18. Synthesis of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)phenyl]-N,N-dimethylmethaneimamide [ka] An 8 mL vial was filled with 6-chloro-2-methyl-3-nitropyridine (20.00 g, 115.895 mmol, 1.0 equivalent), phenol, 4-amino-2,6-dichloro-(24.76 g, 139.07 mmol, 1.2 equivalents), K2CO3 (48.05 g, 347.69 mmol, 3.0 equivalents), and DMF (200 mL). The resulting mixture was stirred overnight at 60°C. The reaction mixture was quenched with water (400 mL). The resulting mixture was extracted with EA (3 × 500 mL), the organic layers were combined, washed with brine (2 × 400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with EA:PE (0% to 40% over 30 minutes) to obtain the desired product, 3,5-dichloro-4-[(6-methyl-5-nitropyridine-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-nitropyridine-2-yl)oxy]aniline (36.40 g, 115.88 mmol, 1.0 equivalent) and (dimethoxymethyl)dimethylamine (33.14 g, 278.1 mmol, 2.4 equivalents) in dimethylformamide (400 mL), TEA (11.73 g, 115.9 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at 100 °C for 4 hours. The mixture was cooled to 60 °C and concentrated under reduced pressure to remove half of the DMF. The resulting solution was passed on to the next step without further processing.

[0277] To a solution of (E)-N'-(3,5-dichloro-4-((6-((E)-2-(dimethylamino)vinyl)-5-nitropyridine-2-yl)oxy)phenyl)-N,N-dimethylformimidoamide (49.17 g, 115.89 mmol, 1.0 equivalent) in DMF (200 mL) and MeOH (400 mL), Pd / C (10.0 g, 93.967 mmol, 0.81 equivalents) and NaOAc (9.51 g, 115.89 mmol, 1.0 equivalent) were added under hydrogen. The resulting mixture was stirred overnight at room temperature. The mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with EA:PE (0% to 70% over 30 minutes) to obtain the desired product (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridine-5-yloxy]phenyl)-N,N-dimethylmethaneimidoamide (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]pyridine-5-yloxy]phenyl)-N,N-dimethylmethanimidamide (5.00 g, 14.32 mmol, 1.0 equivalent) and I2 (4.00 g, 15.75 mmol, 1.1 equivalents) in dimethylformamide (50 mL), KOH (3.21 g, 57.27 mmol, 4.0 equivalents) was added. The resulting mixture was stirred overnight at room temperature and quenched with water (80 mL). The resulting mixture was extracted with EA (3 × 100 mL), the organic layers were combined, washed with brine (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was ground with 5:1 PE:EA to obtain the desired product (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)phenyl]-N,N-dimethylmethaneimidoamide (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]pyridine-5-yl]oxy)aniline [ka] To a solution of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide (3.0 g, 6.31 mmol, 1.0 equivalent), K3PO4 (2.01 g, 9.471 mmol, 1.5 equivalents), and 1,1'-bis(di-t-butylphosphino)ferrocene dichloride palladium (0.410 g, 0.631 mmol, 0.10 equivalents) in dioxane (75 mL) and H2O (15 mL), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (4.24 g, 25.26 mmol, 4.0 equivalents) was added under nitrogen. The resulting mixture was stirred overnight at 60°C and quenched with water (100 mL). The resulting mixture was extracted with EA (3 × 150 mL), the organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography and eluted with EA:PE (0% to 50% in 30 minutes) to obtain the desired product (E)-N'-(3,5-dichloro-4-[[3-(propa-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy]phenyl)-N,N-dimethylmethaneimidoamide (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-(propa-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy]phenyl)-N,N-dimethylmethaneimidoamide (400.0 mg, 1.028 mmol, 1.0 equivalent) in MeOH (25 mL), Pd / C (250.0 mg, 2.349 mmol, 2.3 equivalents) was added. The resulting mixture was stirred at room temperature under a hydrogen atmosphere 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 obtain the crude product (E)-N'-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl]-oxy)phenyl]-N,N-dimethylmethanimidamide (380 mg, crude) as a yellow solid. LCMS(ESI,m / z):391[M+H] + .

[0281] Ethylenediamine (262.6 mg, 4.37 mmol, 4.5 equivalents) was added to a solution of (E)-N'-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)phenyl]-N,N-dimethylmethaneimidoamide (380.0 mg, 0.97 mmol, 1.0 equivalent) in ethyl alcohol (25 mL). The resulting mixture was stirred and refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain the crude product 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-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-methoxypyridazine-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione [ka] A mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]phenylboronic acid (400 mg, 1.12 mmol, 1.0 equivalent), 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (398 mg, 1.28 mmol, 1.15 equivalent), PdAmphos(Cl)2 (79.3 mg, 0.112 mmol, 0.1 equivalent), and K3PO4 (713 mg, 3.36 mmol, 3.0 equivalent) in 1,4-dioxane (8 mL) / water (0.8 mL) was stirred at 90°C for 2 hours. After cooling to 25°C, the solid was filtered, and the filtrate cake was washed with EA (3 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with 1:1 PE:EA) to obtain 4-[(benzyl-oxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]-phenyl]-2H-1,2,4-triazine-3,5-dione (190 mg, yield 30%) 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-dimethylbenzene (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-dioxaborolan (1.84 g, 6.87 mmol) in dioxane (10 mL), 8N aqueous KOH solution (858.57 μL, 6.86 mmol) was added, followed by heating under N2 protection at room temperature (approximately 15°C). ℃ ) with Pd[P(t-Bu)3] 2(87.75 mg (171.71 μmol) was added. The mixture was then stirred at 30°C for 18 hours. TLC (PE:EA, 10:1, I2 staining) showed that the bromide was completely consumed and two new spots were formed. 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 under vacuum to obtain the crude product, which was purified by flash silica gel chromatography (eluent of 0-2% ethyl acetate / petroleum ether) to obtain the desired 2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (870 mg, yield 72%) as a white solid.

[0284] 22. Synthesis of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]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 equivalent) and 2-[(4-benzyloxy-2,6-dimethylphenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.79 g, 5.09 mmol, 2 equivalents) in dioxane (30 mL) and H2O (6 mL), dichloropalladium; tris-o-tolylphosphan (299.79 mg, 381.39 μmol, 0.15 equivalents) and K3PO4 (1.62 g, 7.63 mmol, 3 equivalents) were added at 20°C under the protection of N2. The resulting mixture was then stirred at 100°C for 15 hours under an N2 atmosphere. The combined mixture (combined with a 300 mg batch) was diluted with H2O (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0-10%) to obtain 5-[(4-benzyloxy-2,6-dimethylphenyl)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-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.52 mmol, 1 equivalent) in MeOH (20 mL) and THF (10 mL), Pd-C (10%, 1.07 g) was added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under H2 (50 psi) at 35°C for 18 hours. The mixture was filtered, and the filtrate was concentrated and purified by flash silica gel chromatography (0-100% ethyl acetate in petroleum ether) to obtain 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenol (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]pyridine-5-yl]methyl]-3,5-dimethylphenol (1 g, 2.23 mmol, 1 equivalent) and pyridine (440.84 mg, 5.57 mmol, 2.5 equivalents) in 25 mL of DCM at 0°C, Tf2O (754.76 mg, 2.68 mmol, 441.38 μL, 1.2 equivalents) was slowly added dropwise. After the addition, the mixture was stirred at 0°C for 1 hour. The reaction mixture was partitioned between 30 mL of H2O and 30 mL of DCM. The organic phase was separated, washed with brine (10 mL x 3), dried over anhydrous MgSO4, filtered, and concentrated to obtain the crude product, which was purified by flash silica gel chromatography (0-10% ethyl acetate in petroleum ether) to obtain [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo]pyridine-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (1.25 g, 2.15 mmol, yield 97%) as a colorless gum.

[0287] 23. Synthesis of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylaniline: [ka] To a solution of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (300 mg, 516.67 μmol, 1 equivalent) and tert-butylcarbamate (121.05 mg, 1.03 mmol, 2 equivalents) in dioxane (8 mL), Pd2(dba)3 (47.31 mg, 51.67 μmol, 0.1 equivalent), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphan (59.79 mg, 103.33 μmol, 0.2 equivalents), and Cs2CO3 (505.03 mg, 1.55 mmol, 3 equivalents) were added at 20°C under the protection of N2. Next, the resulting mixture was stirred under N2 at 100°C for 15 hours. LC-MS indicated that the reaction was complete. The mixture was diluted with H2O (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 obtain the residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0-10%) to obtain tert-butyl N-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]carbamate (200 mg, 350.19 μmol, 68% yield, 95.9% purity) as a pale yellow solid.

[0288] A solution of tert-butyl N-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]carbamate (170 mg, 310.39 μmol, 1 equivalent) in MeOH (3 mL) was mixed with 4 M HCl gas in MeOH (8 mL) at 20°C. The resulting mixture was then stirred at 20°C for 12 hours. The MeOH was removed under reduced pressure, and the residue was partitioned between EA (50 mL) and H2O (50 mL). The EA phase was washed again with H2O (50 mL). The combined aqueous layer was adjusted to pH 7-8 with saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain 4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylaniline (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 equivalent, 5 g, 20.24 mmol) in anhydrous DCM (150 mL), anhydrous trifluoroacetic acid (2 equivalents, 5.63 mL) was added under N2 at 0°C. The reaction mixture was then stirred at 25°C for 2.5 hours. 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 MgSO4, filtered, and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (DCM) to obtain 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 at 0°C to a mixture of 2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (1 equivalent, 2.40 g, 7 mmol) and 60% NaH (1.5 equivalents, 420 mg) under N2 conditions. The reaction mixture was stirred at 25°C for 1.5 hours, 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 minutes. Anhydrous DMF (5 equivalents, 2.71 mL) was then added, and the reaction mixture was further stirred at -78°C for 1 hour. The reaction mixture was hydrolyzed with saturated NH4Cl aqueous solution (5 mL), poured into DCM (250 mL), and washed four times with brine. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude mixture was recrystallized from high-temperature ethanol to obtain 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (317 mg, 19%) as a yellow solid. The supernatant was recrystallized from high-temperature toluene to obtain a larger amount of 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-indazole-5-yl)methyl)aniline [ka] Anhydrous THF (8.3 mL) was added to a mixture of 5-bromo-3-pentyl-1H-indazole (1 equivalent, 668 mg, 2.5 mmol) and 60% NaH (1.5 equivalents, 150 mg) under N2 at 0°C. The resulting reaction mixture was stirred at 25°C for 1 hour. The mixture was then cooled to -78°C, and n-BuLi (1.5 eq, 2.34 mL) was added dropwise. The reaction mixture was stirred at -78°C for 2 hours. Next, a solution of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (1 equivalent, 613 mg) in anhydrous THF (8.3 mL) was added dropwise to the reaction mixture at -78°C. The reaction mixture was stirred further at this temperature for 1.75 hours, and finally hydrolyzed with saturated NH4Cl aqueous solution (5 mL), poured into DCM (100 mL), and washed three times with water. The organic phase was dried over MgSO4, filtered, and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (20%-40% EA in cyclohexane) to obtain 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazole-5-yl)methyl)-3,5-dimethylphenyl)acetamide (317 mg, 29%) as a white solid.

[0292] A solution of Et3SiH (6 equivalents, 0.71 mL) in anhydrous DCM (20 mL), followed by a solution of TMSOTf (0.075 equivalents, 0.01 mL) in anhydrous DCM (7 mL), was added dropwise to a solution of 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazole-5-yl)methyl)-3,5-dimethylphenyl)acetamide (1 equivalent, 317 mg, 0.73 mmol) in anhydrous DCM (7 mL) under N2 at 0°C. The reaction mixture was stirred at 0°C for 1 hour, at which point the ice bath was removed and the reaction mixture was stirred at 25°C. After 19 hours, additional Et3SiH (6 equivalents, 0.71 mL) and TMSOTf (0.075 equivalents, 0.01 mL) were added, and the reaction mixture was further stirred at 25°C for 5 hours. Next, the reaction product was quenched with saturated NaHCO3 aqueous solution (20 mL), and the aqueous phase was extracted three times with DCM (3 × 50 mL). The combined organic layer was 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 obtain N-(3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (144 mg, 47%) as a white solid.

[0293] NaOH (4 equivalents, 54 mg) was added under N2 conditions to a solution of N-(3,5-di-methyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (1 equivalent, 141 mg, 0.34 mmol) in MeOH (7 mL) and water (1.4 mL). The reaction mixture was stirred at 60°C for 90 hours. The reaction mixture was then quenched with water (30 mL). The resulting solution was extracted with DCM (3 × 20 mL), the combined organic layers were washed with brine (2 × 20 mL), dried over MgSO4, filtered, and evaporated to dry to obtain 3,5-dimethyl-4-((3-pentyl-1H-indazole-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)indole-5-yl]methyl]aniline (1.11 g, 2.277 mmol, 1.00 equivalent) in HCl (21.90 mL), HOAc (62.50 mL), and H2O (47.68 mL), NaNO2 (0.32 g, 4.566 mmol, 2 equivalents) in H2O (4.2 mL) was added dropwise at 0°C for 1 hour. In a second reaction flask, ethyl N-(2-cyanoacetyl)carbamate (0.53 g, 3.424 mmol, 1.5 equivalents) in H2O (58.41 mL) and pyridine (22.35 mL) was left at 0°C for 10 minutes. The above solution was rapidly poured into the second reaction flask at 0°C for 30 minutes. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This yielded N-[(Z)-cyano[2-(3,5-dichloro-4-[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]phenyl)hydrazinylidene]carbonyl]carbamate, which can also be named ethyl(Z)-(2-cyano-(2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indole-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)indole-5-yl]-oxy]phenyl)hydrazinylidene]-carbonyl]carbamate (which can also be called ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indole-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (1.16 g, 1.773 mmol, 1.00 equivalent) in DMA (20.00 mL), KOAc (0.35 g, 3.546 mmol, 2 equivalents) was gradually added at room temperature. The resulting mixture was stirred at 120°C for 2 hours under a nitrogen atmosphere. The reaction product was quenched at room temperature by adding water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The solid was dried overnight at room temperature to obtain 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-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-methylbenzenesulfonyl)indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (521.20 mg, 0.854 mmol, 1.00 equivalent) in THF (20.00 mL), TBAF (20 mL) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65°C for 20 hours under a nitrogen atmosphere. The reaction product was quenched with H2O. The resulting mixture was extracted with EA, washed with brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH 16:1) to obtain the crude product (200 mg). The crude product (200 mg) was purified by preparative HPLC to obtain 2-[3,5-dichloro-4-[(3-isopropyl-1H-indole-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazin-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 nitrogen atmosphere, was filled with 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]-3,5-dimethylaniline (450.00 mg, 1.003 mmol, 1.00 equivalent) in concentrated HCl (9.60 mL), AcOH (27.40 mL), and H2O (20.9 mL). To the stirred solution, NaNO2 (145.35 mg, 2.107 mmol, 2.1 equivalent) in H2O (1.8 mL) was added dropwise and the mixture was incubated at 0°C for 45 minutes. In the second reaction flask, methyl N-(2-cyanoacetyl)carbamate (213.85 mg, 1.505 mmol, 1.50 equivalents) in H2O (25.6 mL) and pyridine (9.80 mL) was left at 0°C for 10 minutes. The above solution was rapidly poured into the second reaction flask at 0°C for 30 minutes. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This yields N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]-3,5-dimethylphenyl)hydrazinylidene]-carbonyl]carbamate, which can also be named ethyl(Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indole-5-yl)oxy)-3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate as a red solid.

[0298] A stirred solution of ethyl N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]-3,5-dimethylphenyl)hydrazine-1-ylidene]-carbonyl]carbamate ((Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indole-5-yl)oxy)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamate (name produced by chemical draw) (560.0 mg, 0.910 mmol, 1.00 equivalent) in DMA (10.00 mL) is mixed with KOAc (178.52 mg, 1.819 mmol (2.0 equivalents) was added gradually at room temperature. The resulting mixture was stirred at 120°C for 2 hours under a nitrogen atmosphere. The reaction product was quenched at room temperature by adding 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-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)-indole-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrile (330.00 mg, 1 equivalent) in THF, 8.00 mL of TBAF (1 M in THF) was added at room temperature. The resulting mixture was stirred at 65°C for 48 hours. 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. Purification yielded 2-[4-[(3-isopropyl-1H-indole-5-yl)oxy]-3,5-dimethylphenyl]-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-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylaniline (480.00 mg, 1.075 mmol, 1.00 equivalent) in concentrated HCl (9.60 mL), HOAc (28.80 mL), and H2O (22.4 mL), stirred under nitrogen at 0°C, NaNO2 (155.72 mg, 2.257 mmol, 2.1 equivalent) in H2O (22.4 mL) was added. The reaction mixture was stirred at 0°C for 45 minutes. The second reaction flask, containing a solution of ethyl N-(2-cyanoacetyl)carbamate (251.72 mg, 1.612 mmol, 1.50 equivalent) in H2O (27.2 mL) and pyridine (9.60 mL), was stirred at 0°C for 10 minutes. The reaction flask from 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 at 520 mg, 80% pure, and 63% yield.

[0301] A solution of ethyl N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)hydrazine-1-ylidene]-carboneyle]carbamate (2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indole-5-yl)methyl)-3,5-dimethylphenyl)hydrazineylidene)carbamate (350.00 mg, 0.570 mmol, 1.0 equivalent) in DMA (8.0 mL) stirred at room temperature, to which KOAc (111.94 mg, 1.141 mmol, 2.0 equivalents were added. The reaction mixture was stirred at 120°C for 3 hours. The reaction mixture 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 obtain 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitride. The desired product was isolated as a dark orange solid at 250 mg, 80% purity, and 62% yield.

[0302] A solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (200.00 mg, 0.352 mmol, 1.00 equivalent) was added to TBAF (10.57 mL, 10.570 mmol, 30.00 equivalent, 1 M in THF) in 5.00 mL of THF stirred under nitrogen at 0°C. The reaction mixture was stirred at 65°C for 3 days. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The sample was purified to obtain 2-(4-((3-isopropyl-1H-indole-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 packed with 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (1.00 g, 1.44 mmol, 1.00 equivalent), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]-palladium(II) (0.11 g, 0.144 mmol, 0.10 equivalent), triethylamine (0.44 g, 4.32 mmol, 3.00 equivalent), and methanol (10 mL). The contents of the autoclave were placed under a carbon monoxide atmosphere (30 atm). The reaction mixture was stirred overnight at 90°C. The catalyst was filtered. The filtrate was concentrated under reduced pressure. The residue was purified to obtain 500 mg (67% yield) of 5-[2,6-dichloro-4-(6-cyano3,5-dioxo-4H-1,2,4-triazine-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)-indole-3-carboxylate as a brown solid.

[0304] A 40 mL vial was filled with methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazine-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)indole-3-carboxylate (400 mg, 0.639 mmol, 1.00 equivalent), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (6.39 mL, 1 M in tetrahydrofuran, 6.39 mmol, 10.0 equivalent). The reaction mixture was stirred overnight at 65°C and quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 × 20 mL), the organic layers were combined and washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain 30.4 mg (15% yield) of methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazine-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-bottomed container was filled with 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (1.00 g, 1.759 mmol, 1.00 equivalent), tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (52.78 mL, 1 M in tetrahydrofuran, 52.78 mmol, 30.00 equivalent). The resulting solution was stirred overnight at 65°C and then quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 × 200 mL), the organic layers were combined and washed with brine (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain 500 mg (69% yield) of 2-[3,5-dichloro-4-(1H-indole-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a yellow solid.

[0306] Cyclopentanone (366 mg, 4.35 mmol, 6.00 equivalents) was added to a solution of 2-[3,5-dichloro-4-(1H-indole-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (300 mg, 0.724 mmol, 1.00 equivalent), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 equivalent), and triethylsilane (337 mg, 2.90 mmol, 4.0 equivalent) in toluene (10 mL) stirred at 100°C under nitrogen. The reaction mixture was stirred overnight at 100°C and concentrated under reduced pressure. Purification yielded 20.2 mg (6% yield) of 2-[3,5-dichloro-4-[(3-cyclopentyl-1H-indole-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-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 packed under nitrogen with 2-[3,5-dichloro-4-(1H-indole-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (300 mg, 0.724 mmol, 1.00 equivalent), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 equivalent), toluene (10.00 mL), and triethylsilane (504.10 mg, 4.35 mmol, 6.00 equivalent). Acetophenone (261 mg, 2.17 mmol, 3.00 equivalent) was added at 100°C. The resulting solution was stirred overnight at 100°C 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. Purified, 63.2 mg (17% yield) of 2-(3,5-dichloro-4-[[3-(1-phenylethyl)-1H-indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile was obtained 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] Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (42.2 mg, 0.0580 mmol, 0.10 equivalent) and potassium carbonate (238.88 mg, 1.728 mmol, 3.00 equivalent) were added to a stirred solution of 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (400 mg, 0.576 mmol, 1.00 equivalent) and phenylboronic acid (91.3 mg, 0.749 mmol, 1.30 equivalent) in dioxane (4 mL) and water (0.8 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at 90°C and concentrated under reduced pressure. The residue was purified to obtain 170 mg (42% yield) of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-phenylindole-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-phenylindole-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (160 mg, 0.248 mmol, 1.00 equivalent) in tetrahydrofuran (4 mL), t-butylammonium fluoride (4.96 mL, 1 M in tetrahydrofuran, 4.96 mmol, 20.00 equivalent) was added at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred overnight at 65°C and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL), the combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification yielded 2-[3,5-dichloro-4-[(3-phenyl-1H-indole-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 equivalent) in HOAc (4.43 mL, 0.074 mmol, 0.16 equivalents), HCl (2.00 mL, 0.055 mmol, 0.12 equivalents) was gradually added at room temperature. The resulting mixture was stirred overnight at 120°C under a nitrogen atmosphere. The crude product (160 mg) was purified to obtain 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine-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 equivalent) in DMSO (5 mL), K2CO3 (190.53 mg, 1.379 mmol, 3.00 equivalent) and H2O2 (2 mL, 30% in water) were gradually added at 0°C. The resulting mixture was stirred at room temperature for 5 hours. The reaction product was quenched with saturated Na2S2O3 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% over 30 minutes) to obtain a crude product (150 mg). This 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 over 9 minutes) to obtain 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] At room temperature, DPPA (375.64 mg, 1.365 mmol, 3.10 equivalents) and Et3N (138.12 mg, 1.365 mmol, 3.10 equivalents) were gradually added 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 equivalent) in t-BuOH (20.00 mL, 210.465 mmol). 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 CH2Cl2 (100 mL) and then washed with NH4Cl (4 × 200 mL), NaHCO3, and brine. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with CH2Cl2:MeOH (50:1) to obtain 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-triazine-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-triazine-6-yl)carbamate (90.0 mg, 1 equivalent) in 4N HCl in 1,4-dioxane (5.00 mL) was stirred overnight at room temperature. 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 over 8 minutes) to obtain 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazin-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 equivalent) and trimethylsilylacetylene (207.96 mg, 2.117 mmol, 3.0 equivalent) in DMF (10 mL), CuI (26.88 mg, 0.141 mmol, 0.20 equivalent), Et3N (214.25 mg, 2.117 mmol, 3.00 equivalent), and Pd(dppf)Cl2 (103.28 mg, 0.141 mmol, 0.20 equivalent) were gradually added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at 80°C 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 sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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 equivalent) in DCM (5 mL), BBr3 (383.84 mg, 1.532 mmol, 4.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours and then quenched with MeOH (5 mL). The resulting mixture was concentrated under reduced pressure to obtain 100 mg (crude) 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 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 equivalent) in MeOH (10 mL), K2CO3 (109.16 mg, 0.790 mmol, 4.00 equivalent) was added and the mixture was stirred at room temperature. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure to obtain the residue. Purification yielded 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 equivalent) and tert-butyl 2-cyanoacetate (208.54 mg, 1.477 mmol, 3.0 equivalents) in DMF (5.00 mg) stirred at room temperature, K2CO3 (272.21 mg, 1.970 mmol, 4.0 equivalents) was added. The reaction mixture was stirred overnight at 90°C. The reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL), the organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain 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-triazine-6-yl]-2-cyanoacetate (190 mg, 58%) as a yellow solid.

[0318] A 50 mL round-bottom flask was filled 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-triazine-6-yl]-2-cyanoacetate (190.00 mg, 0.284 mmol, 1.00 equivalent), TsOH (24.43 mg, 0.142 mmol, 0.5 equivalent), and toluene (5 mL). The resulting solution was stirred at 90°C for 4 hours and then quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL), the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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-triazine-6-yl]acetonitrile (190 mg, yield 82%) 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-triazine-6-yl]acetonitrile (190.00 mg, 0.334 mmol, 1.00 equivalent) in DCM (3 mL) stirred under nitrogen at -78°C, BBr3 (501.57 mg, 2.002 mmol, 6.0 equivalent) was added. 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), the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification yielded 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-triazine-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] 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 equivalent) and diethyl malonate (184.02 mg, 1.149 mmol, 2.00 equivalent) in DMSO (5 mL), stirred at room temperature under nitrogen, was mixed with Cs2CO3 (561.52 mg, 1.723 mmol, 3.0 equivalent). The reaction mixture was stirred at 110°C for 1 hour. The reaction mixture was quenched with water (20 mL). The obtained solution was extracted with dichloromethane (3 × 50 mL), the organic layer was combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (50 mL) and a slurry was prepared using a 100-200 silica gel mesh (2 g). The sample was purified and the desired product was isolated as a yellow oily substance. 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-triazine-6-yl]-propanedioate (250.00 mg, 0.363 mmol, 1.00 equivalent) in DCM (5.00 mL) stirred under nitrogen at 0°C, BBr3 (363.86 mg, 1.452 mmol, 4.00 equivalent) 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), the organic layers were combined, washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. No further purification was performed on this material. The crude product was isolated as a yellow solid at 210 mg, 70% purity, and 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-triazine-6-yl)propanedioate (210.00 mg, 0.369 mmol, 1.00 equivalent) in MeOH (5.00 mL) and H2O (1.00 mL) stirred at room temperature, NaOH (147.78 mg, 3.695 mmol, 10.00 equivalent) was added. The reaction mixture was stirred at 60°C for 4 hours. The pH of the mixture was adjusted to approximately 5-6 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane (3 × 30 mL), the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified to obtain 2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetra-hydro-1,2,4-triazine-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 equivalent) in N-BuOH (5 mL), methylamine (3.3 mL, 6.565 mmol, 10.00 equivalent, 2 M in THF) was added at room temperature. The reaction mixture was stirred overnight at 110 °C. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified to obtain 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 equivalent) in DCM, BBr3 (716.55 mg, 2.860 mmol, 4.00 equivalent) 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 obtain the crude product. Purification yielded 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] 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 equivalent) and dimethylamine (3.3 mL, 6.565 mmol, 10.00 equivalent, 2 M in THF) were added to a 50 mL round-bottom flask at room temperature. The reaction mixture was stirred overnight at 110 °C. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified to obtain 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 packed with 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethyl-amino)-1,2,4-triazine-3,5-dione (160.00 mg, 0.279 mmol, 1.00 equivalent) and DCM (10.00 mL). BBr3 (279.61 mg, 1.116 mmol, 4.00 equivalent) 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 obtain the crude product. Purification yielded 54.3 mg (42% yield) of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine-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] Pd(PPh3)4 (168.46 mg, 0.146 mmol, 0.20 equivalent) was added to a stirred mixture of dioxane (10 mL) and H2O (1 mL) containing 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (250.00 mg, 0.729 mmol, 1.00 equivalent), 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (180.19 mg, 0.875 mmol, 1.20 equivalent), and K2CO3 (201.48 mg, 1.458 mmol, 2.00 equivalent). The mixture was stirred under a nitrogen atmosphere at 90°C overnight. The reaction mixture was quenched with water (15 mL) and extracted with EA (3 × 15 mL). The combined organic layer was washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground with 1:5 EA:PE and MeCN (5 mL) and washed with ether (5 mL) to obtain 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 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, similar to the preparation described for compound 16. 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-indole-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (250.0 mg, 0.604 mmol, 1.00 equivalent) in acetonitrile (4 mL), chlorosulfonyl isocyanate (102.5 mg, 0.724 mmol, 1.2 equivalents) in acetonitrile (0.4 mL) was added dropwise under nitrogen at -45°C. A fine precipitate formed throughout the addition process. The mixture was stirred under nitrogen at -45°C for 10 minutes. Then, N,N-dimethylformamide (4 mL) was slowly added, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding 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 obtain the crude product (160 mg). The crude product (160 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C 18 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 minutes) to obtain 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazine-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] NaNO2 (150.8 mg, 2.19 mmol, 2.1 equivalents) in H2O (12 mL) was added dropwise to a solution of 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)aniline (350.0 mg, 1.04 mmol, 1.0 equivalent) in HCl (5.5 mL, concentrated), AcOH (16 mL), and H2O (12 mL). The mixture was stirred at 0°C for 30 minutes. The reaction mixture was then rapidly poured at 0°C into a solution of ethyl N-(2-cyanoacetyl)carbamate (243.8 mg, 1.56 mmol, 1.5 equivalents) in H2O (16 mL) and pyridine (5.5 mL). The resulting mixture was stirred at 0°C for 30 minutes and filtered. The filtered cake was washed with water (2 × 15 mL) and petroleum ether (2 × 15 mL), and dried under reduced pressure to obtain (350 mg, crude) ethyl N-[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl]oxy)phenyl]hydrazine-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]pyridine-5-yl]oxy)phenyl]hydrazine-1-ylidene])carbonyl]carbamate (350.00 mg, 0.695 mmol, 1.00 equivalent) in DMA (20 mL), KOAc (341.22 mg, 3.477 mmol, 5.00 equivalent) was added. The resulting mixture was stirred overnight at 120°C and quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 40 mL), the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (mobile phase: MeOH / DCM=1:7; Rf=0.4; detection: UV) to obtain the crude product (180 mg). The product was separated by 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: 21 minutes, 10% B to 10% B. Purification yielded the desired product 2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridine-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]-pyridine-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-triazine-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamide (200.00 mg, 0.313 mmol, 1.00 equivalent) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1.25 mL, 1 M in tetrahydrofuran, 1.251 mmol, 4.00 equivalent) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at 65 °C and quenched with water (5 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL), the organic layers were combined, 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 under 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 over 7 minutes), yielding 52 mg (34% yield) of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazine-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 in the same manner as described for compound 21 by reacting it overnight at 80°C using 2 equivalents of isopropylamine instead of 6 equivalents of dimethylamine. 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 in the same manner 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] Chloroformate (126.62 mg, 1.167 mmol, 1.06 equivalents) was added dropwise 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 equivalent) and N,N-diisopropylethylamine (298.77 mg, 2.312 mmol, 2.10 equivalents) in tetrahydrofuran (30 mL) under nitrogen at 0°C. The mixture was stirred at room temperature for 1 hour and then treated dropwise with a solution of sodium borohydride (124.94 mg, 3.302 mmol, 3.00 equivalent) in water (2 mL) at 0°C. The resulting solution was stirred overnight at room temperature, and then slowly quenched with saturated NaHCO3 solution (10 mL). The resulting mixture was extracted with chloroform / isopropanol (3 / 1) (5 × 30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 19%B to 31%B over 8 minutes) to obtain 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, yield 21%) 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 packed 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 equivalent) and acetonitrile (15 mL). Phosphorus tribromide (0.3 mL) was added under nitrogen at 0°C. The resulting solution was stirred at 75°C for 1 hour. The mixture was cooled to room temperature and then quenched with saturated NaHCO3 aqueous solution (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL), the organic layers were combined, washed with brine (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 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 packed with 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazin-3,5-dione (400 mg, 0.795 mmol, 1.00 equivalent), methylamine (1.2 mL, 2 M in tetrahydrofuran, 2.385 mmol, 3.00 equivalent), 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 point, the mixture was acidified by adding 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), extracted with a 3:1 (5 × 30 mL) chloroform:isopropanol mixture, combined with the organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product (300 mg) was purified by preparative HPLC under 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 over 8 minutes. Purification yielded 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, yield 18%) 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 in the same manner as described for compound 24 by using dimethylamine instead of methylamine and reacting it 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 packed 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 equivalent), imidazole (64.95 mg, 0.954 mmol, 1.20 equivalent), potassium carbonate (219.75 mg, 1.590 mmol, 2.00 equivalent), and N,N-dimethylformamide (8 mL). The mixture was stirred at 70°C for 1 hour, then cooled to room temperature and diluted with water (5 mL). At this point, the mixture was acidified by adding 1N 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), extracted with a 3:1 (5 × 30 mL) chloroform:isopropanol mixture, combined with the organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product (150 mg) was purified by preparative HPLC under 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 over 8 minutes. Purification yielded 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(imidazole-1-ylmethyl)-4H-1,2,4-triazine-3,5-dione (14.5 mg, yield 4%) 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] 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 equivalent) and K2CO3 (630 mg, 4.56 mmol, 8.00 equivalent) in DMF (20 mL) was bubbled with difluorochloromethane for 4 hours, and the mixture was stirred at 50°C for 5 hours. The reaction product was quenched by adding 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 (eluting with PE:EA in a 2:1 ratio) to obtain 230 mg (65% yield) of 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-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-methoxypyridazine-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazine-3,5-dione (230 mg, 0.387 mmol, 1.00 equivalent) was added to a hydrogen chloride solution (4 mL, 4 M in 1,4-dioxane) and stirred at 60°C for 2 hours. After cooling to 25°C, the resulting mixture was concentrated under vacuum. 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 minutes); detector: UV 220 / 254 nm). The product was lyophilized to obtain 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 packed under nitrogen 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 equivalent) and N,N-dimethylformamide (8 mL). 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 adding 1N 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 using dichloromethane / methanol (10 / 1) to obtain the crude product (150 mg), which was then purified by preparative HPLC under 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 over 8 minutes. Purification yielded 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, yield 7%) 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 packed under hydrogen 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 equivalent), concentrated hydrochloric acid (2 mL), Pd / C (30.00 mg, 0.282 mmol, 0.41 equivalent), and methanol (30.00 mL, 0.936 mmol, 1.36 equivalent). The resulting solution was stirred overnight at room temperature and then filtered through Celite. The Celite pad was washed with methanol (5 × 30 mL), the filtrate was collected, and concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 solution (10 ml), extracted with chloroform:isopropanol (3:1) (5 × 15 mL), the organic layers were combined, 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 minutes. Purification yielded a white solid, 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, yield 10%). 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] A mixture of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylaniline (70 mg, 156.39 μmol, 1 equivalent) and concentrated HCl (87.97 μL, 6.75 equivalents) was added dropwise to a solution of sodium nitrite (14.84 mg, 215.04 μmol, 1.38 equivalents) in H2O (1 mL) while maintaining the temperature below 0°C. After the addition was complete, the reaction mixture was stirred for 0.5 hours. A mixture of ethyl N-(2-cyanoacetyl)carbamate (27.47 mg, 175.94 μmol, 1.13 equivalents) and NaOAc (43.30 mg, 527.83 μmol, 3.38 equivalents) in EtOH (3 mL) was added dropwise to the resulting diazonium salt solution at below 0°C and stirred for a further 2 hours. The reaction mixture (combined with another 50 mg batch) was diluted with H2O (10 mL), adjusted to pH 7-8 with saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0-35%) to obtain N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo][3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]hydrazono]acetyl]carbamate ethyl (75 mg, yield 31%) as a yellow solid.

[0347] A mixture of ethyl N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]hydrazono]-acetyl]carbamate (55 mg, 89.47 μmol, 1 equivalent) and NaOAc (36.70 mg, 447.36 μmol, 5 equivalents) in AcOH (5 mL) was stirred at 130 °C for 5 hours. The AcOH was removed under reduced pressure, the residue was diluted with H2O (50 mL), the pH was adjusted to 7-8 with saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitride (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]pyridine-5-yl]methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (60 mg, 105.51 μmol, 1 equivalent) in THF (5 mL), TBAF (1 M in THF, 2.53 mL, 24 equivalents) was added all at once at 20 °C. The resulting mixture was then stirred under N2 at 65 °C for 8 hours. LC-MS indicated that the reaction was complete. The mixture was diluted with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated NH4Cl (100 mL x 3) aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC [column: Welch Xtimate C 18 150 × 30 mm, 5 μm; mobile phase: 15% ACN (0.225% FA) in water to 45% ACN (0.225% FA) in water] to obtain 2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)methyl]-3,5-dimethylphenyl]-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 equivalents, 45 mg) in water (6.5 mL) was added to a solution of 3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methylaniline (1 equivalent, 100 mg, 0.31 mmol) in water (6.5 mL) under N2 conditions at 0°C. The reaction mixture was stirred at 0°C for 1 hour. In parallel, a solution of N-(2-cyanoacetyl)carbamate ethyl (1.5 equivalents, 73 mg) in water (7.8 mL) and pyridine (2.7 mL) was stirred at 0°C for 15 minutes. The first reaction mixture was quickly added to the second reaction mixture. The resulting reaction mixture was stirred at 0°C for 2 hours.

[0350] The precipitate was filtered and washed with water and petroleum ether to obtain ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)hydrazinylene)acetyl)carbamate (13 mg) as a yellow solid. The filtrate was extracted with DCM (3 × 50 mL), the combined organic phase was dried over MgSO4, filtered, and evaporated to obtain ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)hydrazinylene)acetyl)carbamate (225 mg) as a yellow solid. The crude substance was used directly in the next step.

[0351] Sodium acetate (4 equivalents, 102 mg) was added to a solution of ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)hydrazinyl-ene)acetyl)carbamate (1 equivalent, 152 mg, 0.31 mmol) in acetic acid (5 mL) under N2. The reaction mixture was heated under reflux for 4 hours, then cooled to 0°C, water (10 mL) was added, and the mixture was stirred for 30 minutes. 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 obtain 40 mg of a red solid, which was further ground in Et2O and iPr2O to obtain 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 packed with 2-[3,5-dichloro-4-[(5-iso-propyl-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 under N2 at 0°C. The resulting solution was stirred at 75°C for 1 hour. 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), the organic layers were combined, washed with brine (1 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 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 packed 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). NaSCH3 (125 mg, 1.79 mmol) was added at 0°C. The mixture was acidified by adding 1 N HCl (5 mL) aqueous solution and extracted with EA (3 × 15 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (1:3) to obtain the crude product (150 mg), which was then purified by preparative HPLC. Purification yielded 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 packed 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 CH3SO2Na (292 mg, 2.86 mmol). The mixture was stirred at 60°C for 1 hour. The mixture was acidified by adding HCl (aqueous solution, 1N, 5 mL) and extracted with EA (3 × 15 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column with DCM:MeOH (10:1) to obtain the crude product, which was then purified by preparative HPLC to obtain 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-bottomed container was packed 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 mixture was stirred at 70°C for 18 hours. The solid was 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 Na₂SO...

Claims

1. A compound selected from the following group: 【Chemistry 1】 【change】 or its stereoisomers or tautomers, or its pharmaceutically acceptable salts.

2. A pharmaceutical composition comprising the compound described in claim 1, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt 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 mellitus, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

4. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a disorder or disease selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes mellitus, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

5. The pharmaceutical composition according to claim 2 for use in treating a disorder or disease selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes mellitus, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

6. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in selectively regulating the activity of thyroid hormone receptor beta (THR-β).

7. The pharmaceutical composition according to claim 2, for use in selectively regulating the activity of the thyroid hormone receptor beta (THR-β).

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