THR-β modulators and their usage

Abstract

This article discloses compound of formula (I): (I)TL-L a -CE-HD or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, wherein i) TL is a part of formula IIIa, IIIb, IIIa, IIIb, IIIc or IIId; ii) CE is a part of formula IV; iii) HD is a part of formula V or VI; wherein substituents are as defined herein. Pharmaceutical compositions comprising the above compounds are also disclosed, as well as methods of treating diseases by administering to or exposing a patient to one or more of the above compounds.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 005,661, filed April 6, 2020, U.S. Provisional Patent Application No. 62 / 944,052, filed December 5, 2019, and U.S. Provisional Patent Application No. 62 / 845,252, filed May 8, 2019, the entire disclosures of each of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present invention is in the field of pharmaceutical compounds and formulations and methods of their use in the treatment of disease. In particular, the present invention is in the field of THR-beta modulators and their use. BACKGROUND

[0004] In parallel with the global increase in obesity, nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and liver transplantation worldwide [1, 2]. It is believed that NAFLD affects 30% of the adult population and 70-80% of obese and diabetic individuals. NAFLD is defined as more than 5% excess liver fat accumulation induced by causes other than alcohol consumption. In a variable proportion of individuals, NAFLD progresses to hepatitis (nonalcoholic steatohepatitis, NASH) and fibrosis, ultimately causing liver failure and hepatocellular carcinoma (HCC) in susceptible individuals [3].

[0005] NASH is the third most common indication for liver transplantation and is becoming the most common in the United States alone [4]. The most important medical need in NAFLD and NASH patients is an effective treatment to stop progression and possibly reverse fibrosis, which is the main predictor of liver disease evolution [5, 6].

[0006] Thyroid hormone (TH) is essential for normal development, growth, and metabolism in all vertebrates. Its action is mediated primarily by triiodothyronine (T3), which acts as a ligand for the TH receptors (TR or THR) β1, β2, and α1 [7]. In the absence of ligand, TRs first bind as heterodimers or homodimers to TH response elements (TREs) located in the promoter regions of target genes, where they interact with a co-repressor. Upon ligand binding, TR homodimers dissociate, favoring the formation of heterodimers with retinoid-X receptor (RXR), releasing the co-repressor and recruiting a co-activator. This new complex attracts a large number of proteins that engage RNA polymerase II in the transcription of the targeted genes.

[0007] Two distinct loci, denoted THRA and THRB, are responsible for encoding multiple related TR isoforms with different tissue distributions and biological functions. The two major isoforms with the most widespread tissue expression levels are TRa1 and TRp1 [8]. TRa1 is expressed first during fetal development and is widely expressed in adult tissues, while TRp1 emerges later in development and exhibits the highest expression in adult liver, kidney, and lung [9]. TRa1 is a key regulator of cardiac output, while TRp1 contributes to control of liver metabolism. Importantly, the natural thyroid hormone T3 activates both TRa1 and TRp1 without any significant selectivity.

[0008] While there is a high degree of structural similarity between the ligand binding domains of TRp and TRa, the design of thyromimetic small molecule agents can identify TR (or THR) agonists with varying degrees of TRp selectivity. The TRp selectivity achieved by some of these compounds improves the lipid lowering therapeutic index relative to cardiac effects, such as heart rate, cardiac hypertrophy, and contractility [10-12].

[0009] Another strategy to avoid TRa activation in cardiac tissue is to design prodrugs of phosphonate-containing TR agonists that are specifically converted to the active agonist in the liver, but remain stable as inactive prodrugs in the blood and extrahepatic tissues, including the heart

[13] . TRa and TRp agonists are also used in indications other than liver-related disorders, as known in the art. SUMMARY

[0010] Disclosed herein are compounds of Formula I:

[0011] (I') TL-L a -CE-HD

[0012] or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) L a is independently a bond; -(C(R a )2) n -; oxygen; sulfur; -NR a -; iii) CE is a moiety of Formula IV; iv) HD is a moiety of Formula V or VI; wherein the substituents are as defined herein. Also disclosed are pharmaceutical compositions comprising the above compounds, and methods of treating a disease by administering or contacting a patient with one or more of the above compounds.

[0013] BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1The chemical structure of compound 67 is depicted as confirmed by x-ray crystallography.

[0015] Figure 2 The chemical structure of compound 67-A is depicted as confirmed by x-ray crystallography. DETAILED DESCRIPTION

[0016] Disclosed herein are novel compounds that are effective modulators of THR-beta activity, which are useful in the treatment of a variety of THR-beta related disorders. The compounds and methods of using the same are discussed in detail below. Certain of the compounds disclosed herein are agonists of the TRa and / or TRP receptors, while others are antagonists of the TRa and / or TRP receptors, and are useful in the treatment of liver related disorders and other indications known in the art to be mediated by the TRa and / or TRP receptors.

[0017] DEFINITIONS

[0018] Various embodiments are described below. It should be noted that the specific embodiments described are not intended as being exhaustive or limiting of the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment.

[0019] As used herein, "about" is as understood by one of ordinary skill in the art and will vary to some degree depending upon the context in which it is used. If a term is used in a manner that would be understood by one of ordinary skill in the art, then "about" will mean up to ± 10% of the particular term from the context in which it is used.

[0020] The use of the terms "a" and "said" and similar referents in the context of describing the application (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate embodiments of the application and does not pose a limitation on the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0021] In the definition of chemical substituents, R x and R y each independently is hydrogen, alkyl, carbocycle, heterocycle, aryl, or heteroaryl, all optionally substituted other than hydrogen.

[0022] Unless otherwise indicated, the abbreviations “TR” and “THR” refer to the thyroid hormone receptor.

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that does not significantly irritate the patient to which it is administered and does not eliminate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with acids or bases. Base-forming salts include (but are not limited to) ammonium salts (NH4+). + Salts of alkali metals, such as, but not limited to, sodium or potassium salts; salts of alkaline earth metals, such as, but not limited to, calcium or magnesium salts; salts of organic bases, such as, but not limited to, dicyclohexylamine, N-methyl-D-reduced glucosamine, and tris(hydroxymethyl)methylamine; and salts having an amino group of an amino acid, such as, but not limited to, arginine and lysine. Applicable acid-based salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, and salicylates.

[0024] As used herein, a “pharmaceutically acceptable ester” is an ester of a compound that does not cause significant irritation to the patient to whom it is administered. Esters are metabolized in the body to produce parent compounds, such as those claimed. Therefore, esters do not eliminate the biological activity and properties of the compound. Pharmaceutically acceptable esters can be obtained by reacting the compounds disclosed herein with alcohols. Methyl, ethyl, and isopropyl esters are some common esters to be prepared. Other esters are well known to those skilled in the art (see, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, New York, NY, 2014, which are incorporated herein by reference in their entirety).

[0025] When the compounds disclosed herein have at least one chiral center, they may exist as racemates or as individual enantiomers. It should be noted that all such isomers and mixtures thereof are included within the scope of this disclosure. Therefore, the representation of a chiral center without specifying R or S indicates that the scope of this disclosure includes R isomers, S isomers, racemic mixtures of isomers, or mixtures in which one isomer exists in greater abundance than another.

[0026] In cases where the methods used to prepare the compounds disclosed herein produce a mixture of stereoisomers, these isomers can be separated by conventional techniques, such as preparative chiral chromatography. The compounds can be prepared in racemic form, or individual enantiomers can be prepared by stereoselective synthesis or by resolution. The compounds can be resolved into their component enantiomers by standard techniques, such as forming diastereomers with optically active acids, for example, (-)-ditolyl-d-tartaric acid and / or (+)-ditolyl-l-tartaric acid, followed by stepwise crystallization and regeneration of the free base. The compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliaries.

[0027] Unless otherwise indicated, when a substituent is considered "optionally substituted," it means that the substituent is a group that can be substituted by one or more individual and independently selected from, but not limited to, the following groups: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclocycloyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-amino(thiocarbamoyl), N-amino(thiocarbamoyl), C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, O-cyanate, thiocyano, isothiocyano, nitro, silyl, trihalomethanesulfonyl, and amino, including monosubstituted and disubstituted amino groups, and 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 the above-mentioned references, such as Wuts.

[0028] As used herein, a “carbocyclic ring” is a ring structure in which all atoms in the ring are carbon atoms. If any atom in the ring is any atom other than a carbon atom, then the ring is a “heterocyclic ring.” Examples of atoms within a ring include sulfur, oxygen, and nitrogen. A carbocyclic or heterocyclic ring can be a polycyclic ring, such as a fused ring system, a spirocyclic system, or a bridged ring system. These polycyclic rings include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, naphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and so on. Additional non-limiting examples include:

[0029]

[0030] As used herein, “aryl” refers to a carbon ring (all-carbon) with a fully delocalized π-electron system. An “aryl” can consist of two or more fused rings (rings sharing two adjacent carbon atoms). When an aryl is a fused-ring system, the rings attached to the remainder of the molecule have a fully delocalized π-electron system. Other rings in a fused-ring system may or may not have a fully delocalized π-electron system. Examples of aryl groups include (but are not limited to) groups of benzene, naphthalene, and chamomile rings. Additional non-limiting examples include:

[0031]

[0032] As used herein, a "heteroaryl" refers to a ring having a fully delocalized π-electron system and containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A "heteroaryl" can consist of two or more fused rings (rings sharing two adjacent carbon atoms). When a heteroaryl is a fused-ring system, the rings attached to the remainder of the molecule have a fully delocalized π-electron system. Other rings in a fused-ring system may or may not have a fully delocalized π-electron system. Examples of heteroaryl rings include (but are not limited to) furans, thiophenes, phthalazins, pyrroles, oxazoles, thiazoles, imidazoles, pyrazoles, isoxazoles, isothiazoles, triazoles, thiadiazoles, pyridines, pyridazines, pyrimidines, pyrazines, and triazines.

[0033] Wherever the word “heterogeneous” is used, it is intended to refer to a specified group, such as an alkyl or aryl group, in which at least one carbon atom is replaced by a heteroatom selected from nitrogen, oxygen, and sulfur.

[0034] As used herein, "alkyl" refers to a straight-chain or branched, fully saturated (without double or triple bonds) hydrocarbon group. The alkyl groups in the compounds disclosed herein may contain 1 to 20 carbon atoms. Alkyl groups as used herein may also have a medium size having 1 to 10 carbon atoms. Alkyl groups as used 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, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

[0035] The alkyl groups in the compounds disclosed in this invention may be substituted or unsubstituted. When substituted, the substituents may be one or more groups independently selected from the following: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-amino(thiocarbamoyl), N-amino(thiocarbamoyl), C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR x R y And the protected amino group.

[0036] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. The alkenyl groups of the compounds disclosed in this invention may be unsubstituted or substituted. When substituted, the substituents may be selected from the same groups disclosed above regarding alkyl substitution or optional substitution.

[0037] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. The alkynyl groups in the compounds disclosed herein may be unsubstituted or substituted. When substituted, the substituents may be selected from the same groups disclosed above regarding alkyl substitution or optional substitution.

[0038] As used in this article, "acyl" refers to "R". x C(=O)-” group.

[0039] As used herein, “cycloalkyl” refers to a fully saturated (without double bonds) hydrocarbon ring. The cycloalkyl groups in the compounds disclosed in this invention can be in the C3 to C8 range. The cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent may be selected from the substituents shown above regarding alkyl substitution. A “cycloalkyl” may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When the cycloalkyl group is a fused ring system, the ring attached to the remainder of the molecule is a cycloalkyl group as defined above. Other rings in a fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl.

[0040] As used herein, “cycloalkenyl” refers to a cycloalkyl group containing one or more double bonds in a ring, but if more than one double bond is present, it cannot form a fully delocalized π-electron system in the ring (otherwise, the group would be “aryl” as defined herein). The cycloalkenyl groups of the compounds disclosed herein may be unsubstituted or substituted. When substituted, the substituent may be selected from the same groups disclosed above regarding alkyl substitution. A “cycloalkenyl” may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When the cycloalkenyl is a fused ring system, the ring attached to the remainder of the molecule is a cycloalkenyl as defined above. Other rings in a fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycloalkenyl.

[0041] The term "alkylene" refers to an alkyl group as defined herein that is a dimer and attached to two other moieties. Therefore, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC: (methyl)ethylene)(-CH2-CH(CH3)-), and isobutylene (IUPAC: 2-(methyl)propyleneene)(-CH2-CH(CH3)-CH2-) are examples of alkylene groups, but are not limited thereto. Similarly, the term "cycloalkylene" refers to a cycloalkyl group as defined herein that is attached to two other moieties in a similar manner. If the alkyl and cycloalkyl groups contain unsaturated carbons, then the terms "alkenylene" and "cycloalkenylene" are used.

[0042] As used herein, “heterocyclic alkyl,” “heterocyclic cycloatom,” or “heterocyclic alkyl group” refers to a ring system having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The ring may also contain one or more double bonds, provided that the double bonds do not form a fully delocalized π-electron system within the ring. The ring as defined herein can be a stable 3- to 18-membered ring consisting of a carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclic alkyl group of the compounds disclosed herein may be unsubstituted or substituted. When substituted, the substituent may be one or more groups independently selected from the group consisting of: halogen, hydroxyl, protected hydroxyl, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxyl, protected carboxyl, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamide, and trifluoromethane-sulfonamide. A “heterocyclic alkyl” may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When the heterocyclic alkyl group is a fused ring system, the ring attached to the remainder of the molecule is a heterocyclic alkyl group as defined above. Other rings in a fused ring system can be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic.

[0043] As used in this article, "aralkyl" refers to an alkylene group that has been substituted with an aryl group.

[0044] As used herein, “carbocycloalkyl” or “(carbocyclo)alkyl” refers to an alkylene group substituted with a carbocyclo group.

[0045] As used herein, “heterocyclic alkyl” or “(heterocyclic)alkyl” refers to an alkylene group substituted with a heterocyclic group. Similarly, “(heterocyclic)alkyl” refers to an alkylene group substituted with a heterocyclic alkyl group.

[0046] As used herein, “heteroarylalkyl” or “(heteroaryl)alkyl” refers to a heteroaryl-substituted alkylene group.

[0047] "O-carboxyl group" refers to "R" x C(=O)O-” group.

[0048] “C-carboxyl group” refers to the “-C(=O)R” group.

[0049] "Acetyl" refers to the CH3C(=O)- group.

[0050] "C-amide group" refers to "-C(=O)NR". x R y "group".

[0051] "N-amide group" refers to "RC(=O)NR". x -" group.

[0052] The term "fully halogenated alkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0053] Using techniques well known to those skilled in the art (see, for example, Wuts above), any unsubstituted or monosubstituted amino group on the compounds herein can be converted into an amide, any hydroxyl group into an ester, and any carboxyl group into an amide or ester.

[0054] It should be understood that in any compound of the present invention having one or more chiral centers, each center may independently be R or S, or a mixture thereof, unless explicitly indicated by absolute stereochemistry. Furthermore, it should be understood that in any compound of the present invention having one or more double bonds that produce geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z, or a mixture thereof.

[0055] It should be understood that disclosure of compounds herein includes disclosure of their tautomers (if applicable). For example, for

[0056] public

[0057] This also includes the

[0058] public

[0059] And vice versa, even if only one of the two structures is disclosed.

[0060] Throughout this disclosure, when demonstrating or naming compounds, it should be understood that isotopically enriched analogs of the compounds are also covered. For example, a compound may incorporate deuterium in place of hydrogen, or carbon-13 in place of carbon having a naturally occurring isotopic distribution. Isotopic enrichment may occur at one position on the compound, i.e., only one hydrogen atom is replaced by deuterium, or at more than one position. This disclosure also covers compounds in which all similar atoms are replaced by their less common isotopic substitutions, such as fully deuterated compounds in which all hydrogen atoms are replaced by deuterium. Isotopically enriched compounds are suitable for utilizing isotopic effects when obtaining NMR spectra or in managing the kinetics of reactions proceeding through the compound.

[0061] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components (e.g., diluents or carriers). Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including (but not limited to) oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting the 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, and salicylic acid.

[0062] The term "carrier" defines a compound that facilitates its incorporation into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for facilitating the absorption of many organic compounds into the cells or tissues of an organism.

[0063] The term "diluent" is defined as a compound diluted in water, which dissolves the compound of interest and stabilizes the biologically active form of the compound. Salts dissolved in buffer solutions are used in the art as diluents. A commonly used buffer solution is a phosphate-buffered saline solution because it mimics the salt conditions of human blood. Because buffer salts control the pH of low-concentration solutions, buffer diluents rarely modulate the biological activity of compounds.

[0064] In some embodiments, the same substance may act as a carrier, diluent, or excipient, or have one of two functions, or all three. Thus, a single additive in a pharmaceutical composition may have multiple functions.

[0065] The term "physiologically acceptable" is defined as a carrier, diluent, or excipient that does not eliminate the biological activity and properties of a compound.

[0066] compound

[0067] In one aspect, this paper discloses compounds of formula I:

[0068] (I)TL-L a -CE-HD

[0069] Or a pharmaceutically acceptable salt, prodrug, amide, or ester thereof, wherein:

[0070] -i)TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId;

[0071]

[0072] -in:

[0073] -Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0074] -R1 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted carbocyclic, optionally substituted aralkyl, optionally substituted heterocyclic, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, optionally substituted amino, optionally substituted C-carboxyl or O-carboxyl, -CN, optionally substituted carbamoyl or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure;

[0075] -R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0076] -R3 is hydrogen or a lower alkyl group;

[0077] -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 aminosulfonyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen atom of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; and

[0078] -R5 is a hydroxyl group, NH2 group, alkylamino group, alkylacylamino group, or alkylsulfonylamino group;

[0079] - Or R4 and R5 together with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group or optionally substituted heteroaryl group.

[0080] -Or R4 and R5, together with the carbon atoms to which they are attached, form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle; and

[0081] -Alk is hydrogen or optionally substituted alkyl;

[0082] ii) CE is part of formula IV

[0083]

[0084] in:

[0085] -R6 and R7 are each independently selected from halogens, -CN, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, optionally substituted lower alkenyl groups, or cyclopropyl groups.

[0086] -R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens;

[0087] -Optionally, R7 and R8 together with the carbon atoms attached thereto form 4, 5 or 6-membered carbon rings, heterocycles, aryl or heteroaryl rings;

[0088] -Q7 represents nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0089] -(TL) indicates that part of expression IV is connected to TL-L a - point; and

[0090] -(HD) indicates that part IV is connected to the point of -HD;

[0091] iii) HD is part of formula V or VI:

[0092]

[0093] in:

[0094] -R9 is selected from hydrogen, -(C(R) d )2) n -C(R d )3、-(C(R d )2) n -OR d 、-(C(R d )2) n -N(R d )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d )2) n -CN、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0095] each R d Independently hydrogen or optionally substituted lower alkyl groups;

[0096] Each q is independently selected from 0, 1, or 2;

[0097] Each n is independently selected from 0, 1, 2, 3, 4, or 5; and

[0098] οHeAr is a 5- or 6-membered heteroaryl group.

[0099] -R 10 For hydrogen, -C(R) e )3, where each R e Independently a lower alkyl group, which is hydrogen, halogenated, or optionally substituted; and

[0100] -R 11 It is an aryl group optionally substituted with a lower alkyl group, halogen, or cycloalkyl group; or a bicyclic system containing an aromatic ring or a saturated ring; or a bicyclic heterocyclic system containing an aromatic ring or a saturated ring.

[0101] iv)L a Independently as a one-key; -(C(R a )2) n -; oxygen; sulfur; -NR a -;in:

[0102] - Each R a Independently hydrogen or a lower alkyl group; and

[0103] -n can be 0, 1, 2, 3, 4 or 5.

[0104] 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 or O-carboxyl group. In some of these embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, the carbocyclic group is cyclohexane or cyclopentane. In various embodiments, the aryl group is phenyl. In some embodiments, the C-carboxyl group is a part of the formula -C(=O)-OR and the O-carboxyl group is a part of the formula -OC(=O)-R, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0105] In some embodiments, R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0106] In some embodiments, Q1, Q2, Q3, and Q4 are -CR b -, where each R b It is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0107] In some embodiments, R4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0108] In some embodiments, R5 is a hydroxyl group.

[0109] In some embodiments, TL is selected from the following:

[0110]

[0111] In some embodiments, TL is selected from the following:

[0112]

[0113]

[0114] In some embodiments of the compound of formula I, R6 and R7 are each independently chlorine, bromine, and iodine. In other embodiments, R6 and R7 are each independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, wherein the alkyl group of the lower alkyl and lower alkoxy is each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are each independently chlorine or methyl.

[0115] In some embodiments of the compound of formula I, R8 is hydrogen.

[0116] In some embodiments, R c It can be hydrogen or methyl.

[0117] In some embodiments, compounds of formula I are disclosed herein, wherein:

[0118] -TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId;

[0119]

[0120] in:

[0121] οQ1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0122] οR1 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 group, an optionally substituted aralkyl group, an optionally substituted heterocyclic 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;

[0123] οR2 is a halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0124] οR3 is hydrogen

[0125] οR4 is optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted carbocyclic, optionally substituted aralkyl, optionally substituted heterocyclic, optionally substituted heteroarylalkyl, optionally substituted amino, optionally substituted aminosulfonyl, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure; and

[0126] οR5 is a hydroxyl group, NH2 group, alkylamino group, alkylacylamino group, or alkylsulfonylamino group;

[0127] ο or R4 and R5 together with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group or optionally substituted heteroaryl group.

[0128] ο or R4 and R5 together with the carbon atoms to which they are attached form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle.

[0129] or, when Q6 is nitrogen and R5 is a hydroxyl group, it is a partial tautomer of formula III; and

[0130] οAlk is hydrogen or optionally substituted alkyl;

[0131] -CE is part of formula IV

[0132]

[0133] in:

[0134] οR6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0135] οR8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens;

[0136] οQ7 represents nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0137] The part of expression IV, ο(TL), is connected to TL-L. a - point; and

[0138] ο(HD) indicates that part of expression IV is connected to the point of -HD;

[0139] -HD is part of formula V or VI:

[0140]

[0141] in

[0142] οR9 is -NH2 and R 10 It is -CH3; and

[0143] οL a It is oxygen.

[0144] In other embodiments, compounds of formula I are disclosed herein, wherein:

[0145] -TL is part of equation II:

[0146]

[0147] in:

[0148] οQ1, Q2, and Q3 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0149] οR1 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 group, an optionally substituted aralkyl group, an optionally substituted heterocyclic 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;

[0150] οR2 is a halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0151] οR3 is hydrogen;

[0152] -CE is part of formula IV

[0153]

[0154] in:

[0155] οR6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0156] οR8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens;

[0157] οQ7 represents nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0158] The part of expression IV, ο(TL), is connected to TL-L. a - point; and

[0159] ο(HD) indicates that part of expression IV is connected to the point of -HD;

[0160] -HD is part of formula V:

[0161]

[0162] in

[0163] οR9 represents hydrogen, -CN, or -C≡CR d , where R d It is hydrogen or a lower alkyl group; and

[0164] οL a It is oxygen.

[0165] In some embodiments, La is a combination of two or more of the following: a key; -(C(R) a )2) n -; oxygen; sulfur; or -NR a -

[0166] In another aspect, this paper discloses compounds of formula I':

[0167] (I')TL-L a -CE-HD

[0168] Or its stereoisomers or tautomers, or pharmaceutically acceptable salts, prodrugs, amides or esters thereof, wherein:

[0169] i) TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

[0170]

[0171] in:

[0172] Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0173] R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted C-carboxyl or O-carboxyl, -CN, optionally substituted carbamoyl or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure;

[0174] R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0175] R3 is hydrogen or a lower alkyl group;

[0176] R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted aminosulfonyl, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure; and

[0177] R5 is a hydroxyl group, NH2 group, alkylamino group, alkylamino group, or alkylsulfonylamino group;

[0178] Or R4 and R5 together with the carbon atoms attached thereto form a five- or six-membered optional substituted non-aromatic carbocyclic group, an optional substituted aryl group, an optional substituted heterocyclic group, or an optional substituted heteroaryl group.

[0179] Or R4 and R5 together with the carbon atoms to which they are attached form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle.

[0180] Alk is hydrogen or optionally substituted alkyl; and

[0181] R 11An aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and cycloalkyl; or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and cycloalkyl; or a bicyclic system; or a bicyclic heterocyclic system;

[0182] ii) CE is part of formula IV

[0183]

[0184] in:

[0185] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0186] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0187] Optionally, R7 and R8, together with the carbon atoms attached thereto, form a 4, 5, or 6-membered non-aromatic carbon ring, heterocyclic alkyl, aryl, or heteroaryl ring.

[0188] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0189] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0190] (HD) indicates that part IV is connected to the point of -HD;

[0191] iii) HD is part of formula V or VI:

[0192]

[0193] in:

[0194] R9 is selected from hydrogen, -(C(R) d )2) n -C(R d )3、-(C(R d )2) n -OR d 、-(C(R d )2) n -N(R d )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d)2) n -CN、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0195] Each R d Independently hydrogen or optionally substituted lower alkyl groups;

[0196] Each q is independently selected from 0, 1, or 2;

[0197] Each n is independently selected from 0, 1, 2, 3, 4, or 5;

[0198] HeAr is a 5- or 6-membered heteroaryl group; and

[0199] R 10 It is hydrogen or -C(R) e )3, where each R e Independently a lower alkyl group, which is hydrogen, halogenated, or optionally substituted; and

[0200] L a Independently as a one-key; -(C(R a )2) z -; oxygen; sulfur; or -NR a -;in:

[0201] Each R a Independently hydrogen or a lower alkyl group; and

[0202] z can be 0, 1, 2, 3, 4 or 5;

[0203] Its limitations are:

[0204] (1) When TL is part of formula IIIa, wherein Q4, Q5 and Q6 are -CH- and R4 is an optionally substituted C1-C3 alkyl, optionally substituted aminosulfonyl or optionally substituted carbamoyl; HD is part of formula V, wherein R9 is H or -CN; and when Q7 is -CH-, R5 cannot be hydroxyl.

[0205] (2) When TL is part of formula IIa, where Q1, Q2 and Q3 are -CH-, R1 is -CH3 and R2 is hydrogen; 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 attached form a 5-membered non-aromatic carbon ring, R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group;

[0206] (3) When TL is a part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, and R5 is -OH; HD is a part of formula V, where R9 is -CN; Q7 is -CH-; L a When R4 is -CH2-, it cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene;

[0207] (4) When TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; HD is part of formula V, where R9 is hydrogen, -CN or -CO2H; Q7 is -CH-; and R6 and R7 are independently halogen or methyl, or R7 and R8 together with the carbon atoms attached to them form a 5-membered non-aromatic carbon ring, R4 cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

[0208] (5) When TL is part of equation IIIb, where Q4 is -CR c - And Q5 is nitrogen; HD is part of formula V, where R9 is -CN; Q7 is -CH-; and L a When it is -O-, then

[0209] (a) None of R6, R7 and R8 can be deuterium;

[0210] (b) Q4 cannot be -CD-, where D is deuterium; and

[0211] (c) R4 may not be a three- to five-membered cycloalkyl ring optionally substituted with one or more halogens; a non-aromatic (carbocyclic) alkyl ring optionally substituted with methyl or hydroxyl groups; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxyl or methoxy groups; phenethyl optionally substituted with halogens; C1-C4 alkyl optionally substituted with one to six substituents selected from halogens, hydroxyl and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or a three- to five-membered heterocyclic alkyl ring optionally substituted with benzyl.

[0212] (6) When TL is a part of formula IIIb, where (i) Q4 and Q5 are nitrogen, and (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c-;HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R4 cannot be -CH(CH3)2 or -CH(CD3)2;

[0213] (7) When TL is part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, and R4 is isopropyl; HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R5 cannot be -NH2 or -NHCH3;

[0214] (8) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a When R9 is -O-; Q7 is -CH-; and HD is a part of formula V, R9 cannot be methyl;

[0215] (9) When TL is a part of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, and R4 is isopropyl; L a When R9 is -O-; Q7 is -CH-; and HD is part of formula V, R9 cannot be isopropyl.

[0216] (10) When TL is a part of formula IIa, where Q1, Q2 and Q3 are -CH-; L a R1 is -O-; Q7 is -CH-; R6 and R7 are independently chloro or trifluoromethyl; and HD is part of formula V, wherein when R9 is -CN or methyl, R1 cannot be isopropyl, 4-tetrahydropyranyl or -C(O)NH2;

[0217] (11) When TL is a part of formula IIa, where Q1 and Q2 are -CH- and Q3 is nitrogen; L a Q7 is -O-; Q8 is -CH-; R6 and R7 are chlorine; and HD is part of formula V, where R1 cannot be isopropyl when R9 is -CN;

[0218] (12) When TL is a part of formula IIb, where Q1, Q2 and Q3 are -CH-; L a Q7 is -O-; Q8 is -CH-; R6 and R7 are chlorine; and HD is part of formula V, where R1 cannot be isopropyl when R9 is -CN;

[0219] (13) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a Q7 is -O-; Q6 is -CH-; R6 and R7 are chlorine; and HD is part of formula VI, where R 10 When R4 is H, Me, Et, isopropyl, -CH2CF3 or -CH2CHF2, R4 cannot be a C2-C5 alkyl or a C1-C3 hydroxyalkyl.

[0220] (14) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a Q7 is -O-; Q6 is -CH-; R6 and R7 are chlorine; and HD is part of formula VI, where R 10 When R4 is H or Me, it cannot be cyclopropyl; and

[0221] (15) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a R6 is -CH2-; Q7 is -CH-; R6 and R7 are both chlorine or both are methyl; and HD is a part of formula VI, wherein R 10 When the R4 is H or Me, it cannot be isopropyl.

[0222] In some embodiments, when TL is a part of formula IIIb, wherein Q4 is -CH- and Q5 is nitrogen; HD is a part of formula V, wherein R9 is -CH2CN or -C≡CH; Q7 is -CH-; and R6 and R7 are chlorine, R4 cannot be isopropyl.

[0223] In another aspect, this paper discloses compounds of formula I':

[0224] (I')TL-L a -CE-HD

[0225] Or its stereoisomers or tautomers, or pharmaceutically acceptable salts, prodrugs, amides or esters thereof, wherein:

[0226] i) TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

[0227]

[0228] in:

[0229] Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0230] R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted C-carboxyl or O-carboxyl, -CN, optionally substituted carbamoyl or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure;

[0231] R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0232] R3 is hydrogen or a lower alkyl group;

[0233] R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted aminosulfonyl, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure; and

[0234] R5 is a hydroxyl group, NH2 group, alkylamino group, alkylamino group, or alkylsulfonylamino group;

[0235] Or R4 and R5 together with the carbon atoms attached thereto form a five- or six-membered optional substituted non-aromatic carbocyclic group, an optional substituted aryl group, an optional substituted heterocyclic group, or an optional substituted heteroaryl group.

[0236] Or R4 and R5 together with the carbon atoms to which they are attached form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle.

[0237] Alk is hydrogen or optionally substituted alkyl; and

[0238] R 11 An aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and cycloalkyl; or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and cycloalkyl; or a bicyclic system; or a bicyclic heterocyclic system;

[0239] ii) CE is part of formula IV

[0240]

[0241] in:

[0242] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0243] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0244] Optionally, R7 and R8, together with the carbon atoms attached thereto, form a 4, 5, or 6-membered non-aromatic carbon ring, heterocyclic alkyl, aryl, or heteroaryl ring.

[0245] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0246] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0247] (HD) indicates that part IV is connected to the point of -HD;

[0248] iii) HD is part of formula V or VI:

[0249]

[0250] in:

[0251] R9 is selected from hydrogen, -(C(R) d )2) n -C(R d )3、-(C(R d )2) n -OR d 、-(C(R d )2) n -N(R d )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d )2) n -CN、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0252] Each R d Independently hydrogen or optionally substituted lower alkyl groups;

[0253] Each q is independently selected from 0, 1, or 2;

[0254] Each n is independently selected from 0, 1, 2, 3, 4, or 5;

[0255] HeAr is a 5- or 6-membered heteroaryl group; and

[0256] R 10 It is hydrogen or -C(R) e )3, where each R e Independently a lower alkyl group, which is hydrogen, halogenated, or optionally substituted; and

[0257] (iv)L a Independently as a one-key; -(C(R a )2) z -; oxygen; sulfur; or -NR a -;in:

[0258] Each R a Independently hydrogen or a lower alkyl group; and

[0259] z can be 0, 1, 2, 3, 4 or 5;

[0260] Its limitations are:

[0261] (1) When TL is part of formula IIIa, wherein Q4, Q5 and Q6 are -CH- and R4 is an optionally substituted C1-C3 alkyl, optionally substituted aminosulfonyl or optionally substituted carbamoyl; HD is part of formula V, wherein R9 is H or -CN; and when Q7 is -CH-, R5 cannot be hydroxyl.

[0262] (2) When TL is part of formula IIa, where Q1, Q2 and Q3 are -CH-, R1 is -CH3 and R2 is hydrogen; 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 attached form a 5-membered non-aromatic carbon ring, R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group;

[0263] (3) When TL is a part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, and R5 is -OH; HD is a part of formula V, where R9 is -CN; Q7 is -CH-; L a When R4 is -CH2-, it cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene;

[0264] (4) When TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; HD is part of formula V, where R9 is hydrogen, -CN or -CO2H; Q7 is -CH-; and R6 and R7 are independently halogen or methyl, or R7 and R8 together with the carbon atoms attached to them form a 5-membered non-aromatic carbon ring, R4 cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

[0265] (5) When TL is part of equation IIIb, where Q4 is -CR c - And Q5 is nitrogen; HD is part of formula V, where R9 is -CN; Q7 is -CH-; and L a When it is -O-, then

[0266] (a) None of R6, R7 and R8 can be deuterium;

[0267] (b) Q4 cannot be -CD-, where D is deuterium; and

[0268] (c) R4 may not be a three- to five-membered cycloalkyl ring optionally substituted with one or more halogens; a non-aromatic (carbocyclic) alkyl ring optionally substituted with methyl or hydroxyl groups; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl optionally substituted with methyl, halogen, hydroxyl or methoxy groups; phenethyl optionally substituted with halogens; C1-C4 alkyl optionally substituted with one to six substituents selected from halogens, hydroxyl and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or a three- to five-membered heterocyclic alkyl ring optionally substituted with benzyl.

[0269] (6) When TL is a part of formula IIIb, where (i) Q4 and Q5 are nitrogen, and (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -;HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R4 cannot be -CH(CH3)2 or -CH(CD3)2;

[0270] (7) When TL is part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, and R4 is isopropyl; HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R5 cannot be -NH2 or -NHCH3;

[0271] (8) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a When R9 is -O-; Q7 is -CH-; and HD is a part of formula V, R9 cannot be methyl;

[0272] (9) When TL is a part of formula IIIb, where Q4 is -CH-, Q5 is nitrogen, and R4 is isopropyl; L a When R9 is -O-; Q7 is -CH-; and HD is part of formula V, R9 cannot be isopropyl.

[0273] (10) When TL is a part of formula IIa, where Q1, Q2 and Q3 are -CH-; L aR1 is -O-; Q7 is -CH-; R6 and R7 are independently chloro or trifluoromethyl; and HD is part of formula V, wherein when R9 is -CN or methyl, R1 cannot be isopropyl, 4-tetrahydropyranyl or -C(O)NH2;

[0274] (11) When TL is a part of formula IIa, where Q1 and Q2 are -CH- and Q3 is nitrogen; L a Q7 is -O-; Q8 is -CH-; R6 and R7 are chlorine; and HD is part of formula V, where R1 cannot be isopropyl when R9 is -CN;

[0275] (12) When TL is a part of formula IIb, where Q1, Q2 and Q3 are -CH-; L a Q7 is -O-; Q8 is -CH-; R6 and R7 are chlorine; and HD is part of formula V, where R1 cannot be isopropyl when R9 is -CN;

[0276] (13) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a Q7 is -O-; Q6 is -CH-; R6 and R7 are chlorine; and HD is part of formula VI, where R 10 When R4 is H, Me, Et, isopropyl, -CH2CF3 or -CH2CHF2, R4 cannot be a C2-C5 alkyl or a C1-C3 hydroxyalkyl.

[0277] (14) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a Q7 is -O-; Q6 is -CH-; R6 and R7 are chlorine; and HD is part of formula VI, where R 10 When the R4 is H or Me, it cannot be cyclopropyl;

[0278] (15) When TL is a part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; L a R6 is -CH2-; Q7 is -CH-; R6 and R7 are both chlorine or both are methyl; and HD is a part of formula VI, wherein R 10 When R4 is H or Me, it cannot be isopropyl; and

[0279] (16) When TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; HD is part of formula V, where R9 is -CH2CN or -C≡CH; Q7 is -CH-; and R6 and R7 are chlorine, R4 cannot be isopropyl.

[0280] In another aspect, this paper discloses compounds of formula I':

[0281] (I')TL-L a -CE-HD

[0282] Or its stereoisomers or tautomers, or pharmaceutically acceptable salts, prodrugs, amides or esters thereof, wherein:

[0283] i) TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

[0284]

[0285] in:

[0286] Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0287] R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted C-carboxyl or O-carboxyl, -CN, optionally substituted carbamoyl or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure;

[0288] R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0289] R3 is hydrogen or a lower alkyl group;

[0290] R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted aminosulfonyl, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure; and

[0291] R5 is a hydroxyl group, NH2 group, alkylamino group, alkylamino group, or alkylsulfonylamino group;

[0292] Or R4 and R5 together with the carbon atoms attached thereto form a five- or six-membered optional substituted non-aromatic carbocyclic group, an optional substituted aryl group, an optional substituted heterocyclic group, or an optional substituted heteroaryl group.

[0293] Or R4 and R5 together with the carbon atoms to which they are attached form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle.

[0294] Alk is hydrogen or optionally substituted alkyl; and

[0295] R 11 It is an aryl group optionally substituted with one to five independent substituents selected from lower alkyl, halogen and cycloalkyl groups; or a bicyclic system containing an aromatic ring or a saturated ring; or a bicyclic heterocycle containing an aromatic ring or a saturated ring system.

[0296] ii) CE is part of formula IV

[0297]

[0298] in:

[0299] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0300] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0301] Optionally, R7 and R8, together with the carbon atoms attached thereto, form a 4, 5, or 6-membered non-aromatic carbon ring, heterocyclic alkyl, aryl, or heteroaryl ring.

[0302] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0303] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0304] (HD) indicates that part IV is connected to the point of -HD;

[0305] iii) HD is part of formula V or VI:

[0306]

[0307] in:

[0308] R9 is selected from hydrogen, -(C(R) d )2) n -C(R d )3、-(C(R d )2) n -OR d 、-(C(R d )2) n -N(Rd )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d )2) n -CN、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0309] Each R d Independently hydrogen or optionally substituted lower alkyl groups;

[0310] Each q is independently selected from 0, 1, or 2;

[0311] Each n is independently selected from 0, 1, 2, 3, 4, or 5;

[0312] HeAr is a 5- or 6-membered heteroaryl group; and

[0313] R 10 It is hydrogen or -C(R) e )3, where each R e Independently a lower alkyl group, which is hydrogen, halogenated, or optionally substituted; and

[0314] L a Independently as a one-key; -(C(R a )2) z -; oxygen; sulfur; or -NR a -;in:

[0315] Each R a Independently hydrogen or a lower alkyl group; and

[0316] z can be 0, 1, 2, 3, 4 or 5;

[0317] Its limitations are:

[0318] (1) When TL is part of formula IIIa, wherein Q4, Q5 and Q6 are -CH- and R4 is an optionally substituted C1-C3 alkyl, optionally substituted aminosulfonyl or optionally substituted carbamoyl; HD is part of formula V, wherein R9 is H or -CN; and when Q7 is -CH-, R5 cannot be hydroxyl.

[0319] (2) When TL is part of formula IIa, where Q1, Q2 and Q3 are -CH-, R1 is -CH3 and R2 is hydrogen; 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 attached form a 5-membered non-aromatic carbon ring, R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group;

[0320] (3) When TL is a part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, and R5 is -OH; HD is a part of formula V, where R9 is -CN; Q7 is -CH-; L a When R4 is -CH2-, it cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene;

[0321] (4) When TL is part of formula IIIb, where Q4 is -CH- and Q5 is nitrogen; HD is part of formula V, where R9 is hydrogen, -CN or -CO2H; Q7 is -CH-; and R6 and R7 are independently halogen or methyl, or R7 and R8 together with the carbon atoms attached to them form a 5-membered non-aromatic carbon ring, R4 cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

[0322] (5) When TL is part of equation IIIb, where Q4 is -CR c - And Q5 is nitrogen; HD is part of formula V, where R9 is -CN; Q7 is -CH-; and L a When it is -O-, then

[0323] (a) None of R6, R7 and R8 can be deuterium;

[0324] (b) Q4 cannot be -CD-, where D is deuterium; and

[0325] (c) R4 may not be a three- to five-membered cycloalkyl ring optionally substituted with one or more halogens; a C1-C4 alkyl ring optionally substituted with one to six substituents selected from halogens, hydroxyl groups and deuterium; or a three- to five-membered heterocycloalkyl ring.

[0326] (6) When TL is a part of formula IIIb, where (i) Q4 and Q5 are nitrogen, and (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -; HD is part of formula V, where R9 is -CN; and when Q7 is -CH-; R4 cannot be -CH(CH3)2 or -CH(CD3)2; and

[0327] (7) When TL is part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, and R4 is isopropyl; HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R5 cannot be -NH2 or -NHCH3.

[0328] In some embodiments, when TL is a part of formula IIIb, wherein Q4 is -CH- and Q5 is nitrogen; HD is a part of formula V, wherein R9 is -CH2CN or -C≡CH; Q7 is -CH-; and R6 and R7 are chlorine, R4 cannot be isopropyl.

[0329] In another aspect, this paper discloses compounds of formula I':

[0330] (I')TL-L a -CE-HD

[0331] Or its stereoisomers or tautomers, or pharmaceutically acceptable salts, prodrugs, amides or esters thereof, wherein:

[0332] i) TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

[0333]

[0334] in:

[0335] Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0336] R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted C-carboxyl or O-carboxyl, -CN, optionally substituted carbamoyl or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure;

[0337] R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -CN;

[0338] R3 is hydrogen or a lower alkyl group;

[0339] R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted amino, optionally substituted aminosulfonyl, optionally substituted carbamoyl, or optionally substituted carbamoylalkyl, wherein the nitrogen of said carbamoyl or carbamoylalkyl is optionally a heteroatom in the ring structure; and

[0340] R5 is a hydroxyl group, NH2 group, alkylamino group, alkylamino group, or alkylsulfonylamino group;

[0341] Or R4 and R5 together with the carbon atoms attached thereto form a five- or six-membered optional substituted non-aromatic carbocyclic group, an optional substituted aryl group, an optional substituted heterocyclic group, or an optional substituted heteroaryl group.

[0342] Or R4 and R5 together with the carbon atoms to which they are attached form a seven- to eleven-membered optionally substituted spirocycle or a seven- to eleven-membered optionally substituted spiroheterocycle.

[0343] Alk is hydrogen or optionally substituted alkyl; and

[0344] R 11 It is an aryl group optionally substituted with one to five independent substituents selected from lower alkyl, halogen and cycloalkyl groups; or a bicyclic system containing an aromatic ring or a saturated ring; or a bicyclic heterocycle containing an aromatic ring or a saturated ring system.

[0345] ii) CE is part of formula IV

[0346]

[0347] in:

[0348] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0349] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0350] Optionally, R7 and R8, together with the carbon atoms attached thereto, form a 4, 5, or 6-membered non-aromatic carbon ring, heterocyclic alkyl, aryl, or heteroaryl ring.

[0351] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0352] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0353] (HD) indicates that part IV is connected to the point of -HD;

[0354] iii) HD is part of formula V or VI:

[0355]

[0356] in:

[0357] R9 is selected from hydrogen, -(C(R) d )2) n -C(R d )3、-(C(R d )2) n -OR d 、-(C(R d )2) n -N(R d )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d )2) n -CN、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0358] Each R d Independently hydrogen or optionally substituted lower alkyl groups;

[0359] Each q is independently selected from 0, 1, or 2;

[0360] Each n is independently selected from 0, 1, 2, 3, 4, or 5;

[0361] HeAr is a 5- or 6-membered heteroaryl group; and

[0362] R 10 It is hydrogen or -C(R) e )3, where each R e Independently a lower alkyl group consisting of hydrogen, halogen, or optionally substituted alkyl groups; and (iv)La Independently as a one-key; -(C(R a )2) z -; oxygen; sulfur; or -NR a -;in:

[0363] Each R a Independently hydrogen or a lower alkyl group; and

[0364] z can be 0, 1, 2, 3, 4 or 5;

[0365] Its limitations are:

[0366] (1) When TL is part of formula IIIa, wherein Q4, Q5 and Q6 are -CH- and R4 is an optionally substituted C1-C3 alkyl, optionally substituted aminosulfonyl or optionally substituted carbamoyl; HD is part of formula V, wherein R9 is H or -CN; and when Q7 is -CH-, R5 cannot be hydroxyl.

[0367] (2) When TL is part of formula IIa, where Q1, Q2 and Q3 are -CH-, R1 is -CH3 and R2 is hydrogen; 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 attached form a 5-membered non-aromatic carbon ring, R4 and R5 together with the carbon atoms to which they are attached cannot form a 5-membered heteroaryl group;

[0368] (3) When TL is a part of formula IIIa, where Q4 is nitrogen, Q5 and Q6 are -CH-, and R5 is -OH; HD is a part of formula V, where R9 is -CN; Q7 is -CH-; L a When R4 is -CH2-, it cannot be cyclohexyl, cycloheptyl, isopropyl, or optionally substituted benzene;

[0369] (4) When TL is part of formula IIIb, where Q4 is -CH- and 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 halogens or methyl groups, or R7 and R8 together with the carbon atoms attached to them form a 5-membered non-aromatic carbon ring, R4 cannot be isopropyl or 2-hydroxy-1-methyl-ethyl.

[0370] (5) When TL is part of equation IIIb, where Q4 is -CR c - And Q5 is nitrogen; HD is part of formula V, where R9 is -CN; Q7 is -CH-; and L a When it is -O-, then

[0371] (a) None of R6, R7 and R8 can be deuterium;

[0372] (b) Q4 cannot be -CD-, where D is deuterium; and

[0373] (c) R4 may not be a three- to five-membered cycloalkyl ring optionally substituted with one or more halogens; a C1-C4 alkyl ring optionally substituted with one to six substituents selected from halogens, hydroxyl groups and deuterium; or a three- to five-membered heterocycloalkyl ring.

[0374] (6) When TL is a part of formula IIIb, where (i) Q4 and Q5 are nitrogen, and (ii) Q4 and Q5 are -CR b - or (iii) Q4 is nitrogen and Q5 is -CR c -; HD is part of formula V, where R9 is -CN; and when Q7 is -CH-; R4 cannot be -CH(CH3)2 or -CH(CD3)2; and

[0375] (7) When TL is part of formula IIIa, where Q4 is -CH-, Q5 and Q6 are nitrogen, and R4 is isopropyl; HD is part of formula V, where R9 is -CN; and Q7 is -CH-; R5 cannot be -NH2 or -NHCH3.

[0376] In some embodiments of the compound of formula I', TL is a part of formula IIa, IIb, IIIa, IIIb, IIIc or IIId;

[0377]

[0378] in:

[0379] Q1, Q2, Q3, Q4, Q5, Q6, and Q8 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0380] R1 is an optionally substituted alkyl group, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocyclic)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxyl group or O-carboxyl group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

[0381] R2 is a halogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or -CN;

[0382] R3 is hydrogen;

[0383] R4 is an optionally substituted alkyl group, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocyclic)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted aminosulfonyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen atom of the carbamoyl group or carbamoylalkyl group is optionally a heteroatom in the ring structure; and

[0384] R5 is a hydroxyl group, NH2 group, alkylamino group, alkylamino group, or alkylsulfonylamino group;

[0385] Alternatively, R4 and R5 together with the carbon atoms attached thereto form a five- or six-membered optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic alkyl group, or optionally substituted heteroaryl group.

[0386] Alternatively, R4 and R5, together with the carbon atoms to which they are attached, may form a seven- to eleven-membered, optionally substituted spirocyclic ring or a seven- to eleven-membered, optionally substituted spiroheterocyclic ring; and

[0387] Alk is hydrogen or an optionally substituted alkyl group;

[0388] CE is part of formula IV

[0389]

[0390] in:

[0391] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0392] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0393] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0394] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0395] (HD) indicates that part IV is connected to the point of -HD;

[0396] HD is a part of formula V or VI:

[0397]

[0398] in:

[0399] R9 is selected from -NH2, -CN, -CH2-S-CH3 or -CH2-S(=O)2-CH3;

[0400] R 10 It is -CH3; and

[0401] L a It is oxygen or -CH2-.

[0402] In some embodiments of the compound of formula I'

[0403] TL is part of equation IIa:

[0404] and

[0405] HD is part of equation V:

[0406]

[0407] In some embodiments of the compound of formula I':

[0408] TL is part of equation IIa:

[0409] and

[0410] HD is part of formula VI:

[0411]

[0412] In some embodiments of the compound of formula I':

[0413] TL is part of equation IIb:

[0414] and

[0415] HD is part of equation V:

[0416]

[0417] In some embodiments of the compound of formula I':

[0418] TL is part of equation IIb:

[0419] and

[0420] HD is part of formula VI:

[0421]

[0422] In some embodiments of the compound of formula I'

[0423] TL is part of equation IIIa:

[0424] and

[0425] HD is part of equation V:

[0426]

[0427] In some embodiments of the compound of formula I'

[0428] TL is part of equation IIIa:

[0429] and

[0430] HD is part of formula VI:

[0431]

[0432] In some embodiments of the compound of formula I'

[0433] TL is part of equation IIIb:

[0434] and

[0435] HD is part of equation V:

[0436]

[0437] in:

[0438] R9 is selected from hydrogen, -(C(R) d )2) n -OR d 、-(C(R d )2) n -N(R d )2、-(C(R d )2) n -S(=O) q R d 、-(C(R d )2) n -C≡CR d 、-(C(R d )2) n -C(=O)-OR d 、-(C(R d )2) n -HeAr or -(C(R) d )2) n -C(=O)-N(R d )2; of which

[0439] Each Rd Independently hydrogen or optionally substituted C1-C5 alkyl;

[0440] Each q is independently 0 or 2; and

[0441] Each n is independently 0 or 1.

[0442] In some embodiments of the compound of formula I'

[0443] TL is part of equation IIIb:

[0444] and

[0445] HD is part of formula VI:

[0446]

[0447] In some embodiments of the compound of formula I'

[0448] TL is part of equation IIIc:

[0449] and

[0450] HD is part of equation V:

[0451]

[0452] In some embodiments of the compound of formula I'

[0453] TL is part of equation IIIc:

[0454] and

[0455] HD is part of formula VI:

[0456]

[0457] In some embodiments of the compound of formula I'

[0458] TL is the part of equation IIId:

[0459] and

[0460] HD is part of equation V:

[0461]

[0462] In some embodiments of the compound of formula I'

[0463] TL is the part of equation IIId:

[0464] and

[0465] HD is part of formula VI:

[0466]

[0467] In some embodiments of the compound of formula I'

[0468] TL is part of Equation II:

[0469]

[0470] in:

[0471] Q1, Q2, and Q3 are each independently nitrogen or -CR b -, where each R b Independently hydrogen, halogen, or lower alkyl;

[0472] R1 is an optionally substituted alkyl group, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocyclic)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxyl group or O-carboxyl group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl group or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

[0473] R2 is a halogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or -CN;

[0474] R3 is hydrogen;

[0475] CE is part of formula IV

[0476]

[0477] in:

[0478] R6 and R7 are each independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl.

[0479] R8 is selected from hydrogen, optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, cyano groups, or halogens.

[0480] Q7 is nitrogen or -CR c -, where R c It is hydrogen, halogen, or a lower alkyl group;

[0481] (TL) indicates that part of expression IV is connected to TL-L. a - point; and

[0482] (HD) indicates that part IV is connected to the point of -HD;

[0483] HD is part of equation V:

[0484]

[0485] in

[0486] R9 represents hydrogen, -CN, -NH2, and -C(R). d )2-SR d -C(R) d )2-S(=O)2R d or -C≡CR d , where each R d Independently hydrogen or a lower alkyl group; and

[0487] L a It is oxygen or -CH2-.

[0488] In some embodiments of the compound of formula I', Q1, Q2, Q3, and Q4 are -CR b -, where each R b The groups are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments of compounds of formula I', Q1, Q2, and Q3 are -CH-.

[0489] 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.

[0490] 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-.

[0491] In some embodiments of the compound of formula I', Q4, Q5, and Q6 are -CR b -, where each R b Independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments of compounds of formula I', Q4, Q5, and Q6 are -CH-.

[0492] 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.

[0493] 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-.

[0494] In some embodiments of the compound of formula I', Q4 is -CH- and Q5 is nitrogen.

[0495] In some embodiments of the compound of formula I', Q5 and Q6 are nitrogen.

[0496] In some embodiments of the compound of formula I', Q5 is nitrogen and Q8 is -CH-.

[0497] In some embodiments of the compound of formula I', Q5, Q6, and Q8 are -CR b -, where each R b Independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments of compounds of formula I', Q5, Q6, and Q8 are -CH-.

[0498] 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.

[0499] In some embodiments of the compound of formula I', R1 is hydrogen, optionally substituted alkyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, and optionally substituted C-carboxyl. In some embodiments of the compound of formula I', the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments of the compound of formula I', at least one carbon atom of the listed alkyl moiety is perfluorinated. In some embodiments of the compound of formula I', the alkyl group is substituted with a cycloalkyl or aryl group. In some embodiments of the compound of formula I', the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl. In some embodiments of the compound of formula I', the aryl group is optionally substituted phenyl. In some embodiments of the compound of formula I', the carbocyclic group is cyclohexane or cyclopentane. In some embodiments of the compound of formula I', the aryl group is phenyl. In some embodiments of the compound of formula I', the C-carboxyl group is part of the formula -C(=O)-OR, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0500] In some embodiments of the compound of formula I', R1 is hydrogen, C 1- C6 alkyl, non-aromatic C3-C 12 carbonyl group, C6-C 10 Aryl, 3- to 6-membered heterocyclic alkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, (carbocyclic)alkyl, aralkyl, (heterocyclic)alkyl, (heteroaryl)alkyl, amino, C-carboxyl or O-carboxyl, -CN or carbamoyl; and R1 optionally comprising one to five independently selected R groups from the group consisting of k Substitution: hydroxyl, halogen, -CN, amino, oxo, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0501] In some embodiments of the compound of formula I', R1 is hydrogen. In some embodiments of the compound of formula I', R1 is -CN.

[0502] In some embodiments of the compound of formula I', R1 is an optionally substituted C 1- C6 alkyl. In some embodiments of compounds of formula I', R1 is optionally selected from one to five independently chosen from the group consisting of the following. k Replacement C1- C6 alkyl: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R1 is C. 1- C6 alkyl.

[0503] 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 optionally derived from one to five independently selected R groups from the group consisting of the following. k Replacement of non-aromatic C3-C 12 Carbocyclic groups: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0504] In some embodiments of compounds of formula I', R1 is an optionally substituted aryl group. In some embodiments of compounds of formula I', R1 is optionally derived from one to five independently selected R groups from the group consisting of... k Replacement C6-C 10 Aryl groups: hydroxyl, halogen, -CN, O-carboxyl, C-carboxyl, C-amide, N-amide, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0505] In some embodiments of the compound of formula I', R1 is an optionally substituted heterocyclic alkyl group. In some embodiments of the compound of formula I', R1 is a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen, wherein the heterocyclic alkyl ring is optionally substituted by one to five independently selected R groups from the group consisting of the group consisting of the group consisting of oxygen, sulfur, or nitrogen. k Substitution: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0506] In some embodiments of the compound of formula I', R1 is an optionally substituted heteroaryl group. In some embodiments of the compound of formula I', R1 is a five- to ten-membered heteroaryl group containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally derived from one to five independently selected R groups from the group consisting of ... k Substitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0507] In some embodiments of the compound of formula I', R1 is an optionally substituted (carbocyclic)alkyl group. In some embodiments of the compound of formula I', R1 is (cyclopentyl)C 1- C6 alkyl, (cyclobutyl)C 1- C6 alkyl, (cyclopentyl)C 1- C6 alkyl, (cyclohexyl)C 1- C6 alkyl, (cycloheptyl)C 1- C6 alkyl, (cyclooctyl)C 1- C6 alkyl or (cyclononyl)C 1- C6 alkyl, and R1 optionally via one to five independently selected R groups from the following groups. kSubstitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0508] 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 optionally derived from one to five independently selected R groups from the group consisting of... k Substituted benzyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0509] In some embodiments of the compounds of formula I', R1 is an optionally substituted (heterocyclic)alkyl group. In some embodiments of the compounds of formula I', R1 is optionally derived from one to five independently selected R groups from the group consisting of... k Substituted (heterocyclic)alkyl groups: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0510] 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 optionally derived from one to five R groups independently selected from the group consisting of... kSubstituted (heteroaryl)alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0511] 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 an amino group optionally substituted with one or two substituents independently selected from the group consisting of: C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, C6-C 10 Aryl, C-carboxyl, C-amide, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -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 (Aryl). In some embodiments of compounds of formula I', R1 is -NR. m R n , where R m and R n Independently select from the following groups: hydrogen, C 1- C6 alkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, C6-C 10 Aryl, C-carboxyl, C-amide, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -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-C10 (aryl); or R m and R n Together with the nitrogen attached thereto, it forms a 3- to 18-membered heterocyclic alkyl ring; and R1 is optionally derived from one to five independently selected R groups from the following groups. k Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0512] In some embodiments of the compound of formula I', R1 is an optionally substituted C-carboxyl group. In some embodiments of the compound of formula I', R1 is -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 (Aryl); and R1 is optionally selected from one to five independently chosen groups of R. k Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0513] 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 (Aryl); and R1 is optionally selected from one to five independently chosen groups of R. k Substitution: hydroxyl, halogen, -CN, amino, C 1-C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0514] In some embodiments of the compound of formula I', R1 is an optionally substituted carbamoyl group. In some embodiments of the compound of formula I', R1 is -C(O)NR. m R n , where R m and R n Independently select from the following groups: hydrogen, C 1- C6 alkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl; or R m and R n Together with the nitrogen attached thereto, it forms a 3- to 18-membered heterocyclic alkyl ring; and R1 is optionally derived from one to five independently selected R groups from the following groups. k Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0515] In some embodiments of compounds of formula I', R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted non-aromatic C3-C6 alkyl, or substituted non-aromatic C3-C6 alkyl. 12 Carbocyclic group, optionally substituted C6-C 10 Aryl and optionally substituted C-carboxyl groups.

[0516] In some embodiments of compounds of formula I', R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted non-aromatic C3-C6 alkyl, or substituted non-aromatic C3-C6 alkyl. 12 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted C-carboxyl, and optionally substituted carbamoyl.

[0517] In some embodiments of compounds of formula I', R1 is hydrogen; -CN; C1-C6 alkyl; non-aromatic C3-C6 alkyl. 12 Carbon ring; C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; or -C(O)-R j ;where R j For -NR m R n or -OR m ;R m It is hydrogen or C1-C6 alkyl; R n It is a C1-C6 alkyl group; or R m and R n Together with the nitrogen to which it is attached, it forms a ring structure; and R1 is optionally passed through one to five independent Rs selected from the following k Substitution: hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0518] In some embodiments of compounds of formula I', R1 is hydrogen, -CN, C1-C6 alkyl; non-aromatic C3-C 12 Carbon ring; C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; or -C(O)-R j ;where R j For -NR m R n or -OR m ;R m It is hydrogen or C1-C6 alkyl; R n It is a C1-C6 alkyl group; or R m and R n Together with the nitrogen attached thereto, it forms a ring structure; and R1 is optionally followed by one to three independent R groups selected from phenyl and haloalkyl groups. k replace.

[0519] In some embodiments of the compound of formula I', R1 is hydrogen, -CN, C1-C6 alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, or -C(O)-R. j ;where R j For -NR m R n or -ORm ;R m It is hydrogen or C1-C6 alkyl; R n It is a C1-C6 alkyl group; or R m and R n Together with the nitrogen attached thereto, it forms 1,2,3,4-tetrahydroisoquinoline; and R1 is optionally denoted by one to three independent R groups selected from phenyl and haloalkyl groups. k replace.

[0520] In some embodiments of the compound of formula I', R1 is hydrogen, -CN, C1-C6 alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, isopropylamino, or -C(O)-R. j ;where R j For -NR m R n or -OR m ;R m It is hydrogen or C1-C6 alkyl; R n It is a C1-C6 alkyl group; or R m and R n Together with the nitrogen attached thereto, it forms 1,2,3,4-tetrahydroisoquinoline; and R1 is optionally denoted by one to three independent R groups selected from phenyl and haloalkyl groups. k replace.

[0521] In some embodiments of the compound of formula I', R2 is hydrogen, halogen, or C. 1- C6 alkyl, C 3- C9 cycloalkyl or -CN; and R2 optionally substituted by one to five independent substituents selected from the group consisting of: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0522] 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.

[0523] In some embodiments of the compound of formula I', R2 is an optionally substituted C1-C6 alkyl group. In some embodiments of the compound of formula I', R2 is a C1-C6 alkyl group optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C... 10 Arylalkoxy, C 3- C8 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0524] In some embodiments of the compound of formula I', R2 is optionally substituted C. 3- C9 cycloalkyl. In some embodiments of compounds of formula I', R2 is a C9 cycloalkyl group optionally substituted with one to five substituents independently selected from the group consisting of the following groups. 3- C8 cycloalkyl groups: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R2 is a C3-C9 cycloalkyl group optionally substituted with one to ten substituents independently selected from the group consisting of: hydroxyl, halogen, and C1-C6 alkoxy.

[0525] In some embodiments of the compound of formula I', R2 is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments of the compound of formula I', R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0526] In some embodiments of the compound of formula I', R2 is hydrogen; halogen; C1-C6 alkyl optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen and C1-C6 alkoxy; C3-C9 cycloalkyl optionally substituted with one to ten substituents independently selected from the group consisting of: hydroxyl, halogen and C1-C6 alkoxy; or -CN.

[0527] 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.

[0528] In some embodiments of the compound of formula I', R4 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, or optionally substituted (heterocyclic)alkyl.

[0529] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group; C2-C 10 Alkenyl; non-aromatic C3-C 12 Carbon ring; C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; or (heterocyclic)alkyl; and R4 optionally comprises one to five independently selected R groups from the group consisting of g Substitution: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which they are attached, they form aromatic or non-aromatic 3- to 6-membered rings that optionally contain one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen.

[0530] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group; C2-C 10 Alkenyl; non-aromatic C3-C 12 Carbon ring; C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; or (heterocyclic)alkyl; and R4 optionally comprises one to five independently selected R groups from the group consisting of g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms attached to it, it forms a ring.

[0531] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group; C2-C 10 Alkenyl; non-aromatic C3-C 12A carbocyclic ring; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl ring; an aralkyl ring; or a (heterocyclic)alkyl ring; and R4 optionally comprising one to five independently selected R atoms from the group consisting of... g Substitution: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which they are attached, they form aromatic or non-aromatic 3- to 6-membered rings that optionally contain one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen.

[0532] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group, C2-C6 alkyl group, or C4-C6 alkyl group. 10 Alkenyl, non-aromatic C3-C 12 A carbocyclic ring, a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, a (carbocyclic)alkyl ring, an aralkyl ring, or a (heterocyclic)alkyl ring; and R4 optionally selected from one to five independently selected R atoms from the group consisting of... g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0533] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group, C2-C6 alkyl group, or C4-C6 alkyl group. 10 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, aziridine-3(2H)-one, phenyl, naphthyl, pyridinyl, cyclopentyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophene, (cyclobutyl)alkyl, (cyclopentyl)alkyl, benzyl, (tetrahydrofuranyl)alkyl or (tetrahydropyranyl)alkyl; and R4 optionally comprises one to five R groups independently selected from the group consisting of the following groups. g Substitution: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which they are attached, they form aromatic or non-aromatic 3- to 6-membered rings that optionally contain one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen.

[0534] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group, C2-C6 alkyl group, or C4-C6 alkyl group. 10Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (cyclobutyl)alkyl, (cyclopentyl)alkyl, benzyl, (tetrahydrofuranyl)alkyl or (tetrahydropyranyl)alkyl; and R4 optionally comprises one to five R groups independently selected from the group consisting of... g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0535] In some embodiments of the compound of formula I', R4 is an optionally substituted alkyl group. In some embodiments of the compound of formula I', R4 is an optionally substituted C1-C6 alkyl group. In some embodiments of the compound of formula I', R4 is optionally derived from one to five independently selected R groups from the group consisting of... g Substituted C1-C6 alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Substituted C1-C6 alkyl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Arylalkoxy. In some embodiments of the compound of formula I', R4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group. In some embodiments of the compound of formula I', R4 is a C1-C3 alkyl group. In some embodiments of the compound of formula I', R4 is a C5-C6 alkyl group.

[0536] In some embodiments of the compound of formula I', R4 is an optionally substituted alkenyl group. In some embodiments of the compound of formula I', R4 is an optionally substituted C2-C group. 10 Alkenyl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen from the group consisting of the following. g Replacement C2-C 10 Alkenyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C6-C 10Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Replacement C2-C 10 Alkenyl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0537] In some embodiments of the compounds of formula I', R4 is an optionally substituted non-aromatic carbocyclic group. In some embodiments of the compounds of formula I', R4 is an optionally substituted non-aromatic C3-C group. 12 Carbocyclic group. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen groups of the following. g Replacement of non-aromatic C3-C 12 Carbocyclic groups: hydroxyl, oxo, halogen, CN, amino, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Replacement of non-aromatic C3-C 12 Carbocyclic groups: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Replacement of non-aromatic C3-C 12 Carbocyclic groups: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Replacement of non-aromatic C3-C 12 Carbocyclic groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0538] In some embodiments of the compound of formula I', R4 is an optionally substituted heterocyclic alkyl group. In some embodiments of the compound of formula I', R4 is a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen; wherein the heterocyclic alkyl ring is optionally substituted by one to five independently selected R groups from the group consisting of the group consisting of the group consisting of oxygen, sulfur, or nitrogen. g Substitution: hydroxyl, oxo, halogen, CN, amino, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R gTogether with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is an optionally substituted 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms selected from oxygen, sulfur, or nitrogen; wherein the heterocyclic alkyl ring is optionally via one to five independently selected R atoms from the group consisting of... g Substitution: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is a 3- to 6-membered heterocyclic alkyl ring containing one to four independently substituted cyclic heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen; wherein the heterocyclic alkyl ring is optionally substituted by one to five independently selected R4s from the group consisting of ... g Substitution: hydroxyl, halogen, CN, oxo group, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 Arylalkoxy. In some embodiments of the compound of formula I', R4 is a 3- to 6-membered heterocyclic alkyl ring containing one to four independently substituted cyclic heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen; wherein the heterocyclic alkyl ring is optionally substituted by one to five independently selected R4s from the group consisting of the group consisting of the group consisting of oxygen, sulfur, or nitrogen. g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0539] In some embodiments of the compound of formula I', R4 is an optionally substituted (carbocyclic)alkyl group. 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-C6 alkyl, and R4 optionally via one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds 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- C6 alkyl, and R4 optionally via one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds 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-C6 alkyl, and R4 optionally via one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0540] In some embodiments of compounds of formula I', R4 is an optionally substituted aralkyl group. In some embodiments of compounds of formula I', R4 is optionally derived from one to five independently selected R groups from the group consisting of... g Substituted benzyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Substituted benzyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Substituted benzyl groups: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10Arylalkoxy. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen from the group consisting of the following. g Substituted benzyl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0541] In some embodiments of the compounds of formula I', R4 is an optionally substituted (heterocyclic)alkyl group. In some embodiments of the compounds of formula I', R4 is optionally derived from one to five independently selected R groups from the group consisting of... g Substituted (heterocyclic)alkyl groups: hydroxyl, oxo, halogen, amino, CN, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Substituted (heterocyclic)alkyl groups: hydroxyl, oxo, halogen, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Substituted (heterocyclic)alkyl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0542] 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 optionally derived from one to five independently selected R groups from the group consisting of... g Substituted (heteroaryl)alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Substituted (heteroaryl)alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Substituted (heteroaryl)alkyl groups: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 Arylalkoxy. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen from the group consisting of the following. g Substituted (heteroaryl)alkyl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0543] In some embodiments of the compound of formula I', R4 is C6-C. 10 The aryl group or a five- to ten-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; and R4 optionally via one to five independently selected R atoms from the group consisting of... g Substitution: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is C6-C. 10 The aryl group or a five- to ten-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; and R4 optionally via one to five independently selected R atoms from the group consisting of... g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0544] In some embodiments of the compound of formula I', R4 is an optionally substituted C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Replacement C6-C 10 Aryl groups: hydroxyl, halogen, -CN, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Replacement C6-C 10Aryl groups: hydroxyl, halogen, -CN, O-carboxyl, C-carboxyl, C-amide, N-amide, amino, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R4 is optionally selected from one to five independently chosen R groups consisting of the following groups. g Replacement C6-C 10 Aryl groups: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10 arylalkoxy, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Replacement C6-C 10 Aryl groups: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0545] In some embodiments of the compound of formula I', R4 is optionally selected from one to five independently chosen groups of the following R... g Substituted benzene: hydroxyl, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of compounds of formula I', R4 is optionally composed of one to five independent R atoms selected from the group consisting of... g Substituted benzene: hydroxyl, halogen, C1-C6 alkyl and C1-C6 alkoxy, or two R g Together with the atoms attached to it, it forms a ring.

[0546] In some embodiments of the compound of formula I', R4 is optionally selected from one to five independently chosen groups of the following R... gSubstituted naphthalenes: hydroxyl, halogen, C1-C6 alkyl and C1-C6 alkoxy.

[0547] In some embodiments of the compound of formula I', R4 is an optionally substituted heteroaryl group. In some embodiments of the compound of formula I', R4 is a five- to ten-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally connected to one to five independently selected R groups from the group consisting of the group consisting of oxygen, sulfur, or nitrogen. g Substitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, 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 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl, or two R g Together with the atoms to which it is attached, it forms an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments of the compound of formula I', R4 is a five- to ten-membered heteroaryl ring containing one to four independent cyclic heteroatoms selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally connected by one to five independent R atoms selected from the group consisting of... g Substitution: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of the compound of formula I', R4 is a five- to ten-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally via one to five independently selected R atoms from the group consisting of ... g Substitution: hydroxyl, halogen, CN, C1-C6 alkyl, C6-C 10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy and C6-C 10Arylalkoxy group. In some embodiments of the compound of formula I', R4 is a five- to ten-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from the group consisting of oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally via one to five independently selected R groups from the group consisting of the following groups. g Substitution: hydroxyl, halogen, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 Araneoxy group.

[0548] 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 an amino group optionally substituted with one or two substituents independently selected from the group consisting of: C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, C6-C 10 Aryl, C-carboxyl, C-amide, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -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 (Aryl). In some embodiments of compounds of formula I', R4 is -NR. m R n , where R m and R n Independently select from the following groups: hydrogen, C 1- C6 alkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, C6-C 10 Aryl, C-carboxyl, C-amide, -(SO2)(C 1- C6 alkyl), -C(O)O(C 1- C6 alkyl), -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 (aryl); or R m and R nTogether with the nitrogen attached thereto, it forms a 3- to 18-membered heterocyclic alkyl ring; and R1 is optionally derived from one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0549] In some embodiments of the compound of formula I', R4 is an optionally substituted aminosulfonyl group. In some embodiments of the compound of formula I', R4 is -SO2NR. m R n , where R m and R n Independently select from the following groups: hydrogen, C 1- C6 alkyl, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl; or R m and R n Together with the nitrogen attached thereto, it forms a 3- to 18-membered heterocyclic alkyl ring; and R1 is optionally derived from one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0550] In some embodiments of the compound of formula I', R4 is an optionally substituted carbamoyl group. In some embodiments of the compound of formula I', R4 is -C(O)NR. m R n , where R m and R n Independently select from the following groups: hydrogen, C 1- C6 alkyl, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl; or R m and R n Together with the nitrogen attached thereto, it forms a 3- to 18-membered heterocyclic alkyl ring; and R1 is optionally derived from one to five independently selected R groups from the following groups. g Substitution: hydroxyl, halogen, -CN, amino, C 1- C6 alkyl, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0551] In some embodiments of the compound of formula I', R5 is a hydroxyl group. In some embodiments of the compound of formula I', R5 is NH2.

[0552] In some embodiments of the compound of formula I', R5 is an alkylamino group. In some embodiments of the compound of formula I', R5 is -NR. u R v , where R u It is hydrogen or C 1- C6 alkyl and R v C is optionally substituted with one to five independently selected substituents from the following group. 1- C 12 Alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocyclic alkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0553] In some embodiments of the compound of formula I', R5 is an alkylamino group. In some embodiments of the compound of formula I', R5 is -NR. u C(O)R v , where R u It is hydrogen or C 1- C6 alkyl and R v C is optionally substituted with one to five independently selected substituents from the following group. 1-C 12 Alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocyclic alkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0554] In some embodiments of the compound of formula I', R5 is an alkylsulfonylamino group. In some embodiments of the compound of formula I', R5 is -NR. u SO2R v , where R u It is hydrogen or C 1- C6 alkyl and R v C is optionally substituted with one to five independently selected substituents from the following group. 1- C 12 Alkyl groups: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C3-C9 cycloalkyl, 3- to 6-membered heterocyclic alkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0555] In some embodiments of the compound of formula I', R5 is a hydroxyl group or NH2. In some embodiments of the compound of formula I', R5 is a hydroxyl group, NH2, C1-C6 alkylamino, C1-C6 alkylacylamino, or C1-C6 alkylsulfonylamino.

[0556] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are attached, form a five- or six-membered, optionally substituted, non-aromatic C3-C group. 12 Carbocyclic group, optionally substituted C6-C 10 Aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl. In some embodiments of compounds of formula I', R4 and R5, together with the carbon atoms to which they are attached, form a five- or six-membered non-aromatic C3-C group. 12 carbonyl group, C6-C 10aryl, 4- to 6-membered heterocyclic alkyl groups containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and 5- to 10-membered heteroaryl groups containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, wherein the carbocyclic, aryl, heterocyclic, and heteroaryl groups are optionally substituted by one to five independently selected substituents from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0557] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are attached, form a seven- to eleven-membered optionally substituted spirocyclic or a seven- to eleven-membered optionally substituted spiroheterocyclic. In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are attached, form a seven- to eleven-membered spirocyclic or a seven- to eleven-membered spiroheterocyclic; and the spirocyclic and spiroheterocyclic are optionally substituted by one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C... 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0558] In some embodiments of the compound of formula I', R4 and R5 together with the carbon atoms to which they are attached form a five- or six-membered optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic alkyl group, or optionally substituted heteroaryl group.

[0559] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are attached, form a five- or six-membered non-aromatic carbocyclic group; C6-C 10Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; or a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; wherein the carbocyclic, aryl, heterocyclic, and heteroaryl rings are optionally derived from one to five independently selected R groups from the group consisting of... g Substitution: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy and oxo groups, and / or optionally two R groups. g Together with the atoms to which they are attached, they form 3 to 6-membered carbon cyclic groups.

[0560] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; and wherein the heterocyclic alkyl ring is optionally pertaining to one to five independently selected R atoms from the group consisting of... g Substitution: C1-C6 alkyl and oxo groups, and / or optionally two R groups. g Together with the atoms attached to it, they form 3 to 6-membered non-aromatic carbon cyclic groups.

[0561] In some embodiments of the compound of formula I', R4 and R5, together with the carbon atoms to which they are attached, form R4 and R5, optionally selected from one to five independent groups of the following groups. g Substituted pyrrolidines: C1-C6 alkyl and oxo groups, and / or optionally two R groups. g Together with the atoms to which they are attached, they form 3 to 6-membered non-aromatic carbon cyclic groups.

[0562] In some embodiments of the compound of formula I', TL is a part of formula IIIaa:

[0563]

[0564] Each R g It is independently a C1-C6 alkyl group; or two R groups. g Together with the atoms to which they are attached, they form an alkene optionally substituted with C1-C6 alkyl groups; or two R groups... g Together with the atoms to which they are attached, they form 3 to 6-membered non-aromatic carbon ring groups. In some embodiments of compounds of formula I', the two R... g Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0565] In some embodiments of the compound of formula I', TL is a part of formula IIIaa:

[0566]

[0567] Each R gIndependently C1-C6 alkyl or two R g Together with the atoms to which they are attached, they form 3 to 6-membered non-aromatic carbon ring groups. In some embodiments of compounds of formula I', the two R... g Together with the atoms to which they are attached, they form cyclopentyl or cyclohexyl groups.

[0568] In some embodiments of the compound of formula I', TL is a part of formula IIIab:

[0569]

[0570] Where R g It is a C1-C6 alkyl group. In some embodiments of compounds of formula I', R... g It is isopropyl.

[0571] In some embodiments of the compound of formula I', TL is a part of formula IIIac:

[0572]

[0573] Where R g It is a C1-C6 alkyl group. In some embodiments of compounds of formula I', R... g It is a methyl group.

[0574] In some embodiments of the compound of formula I', TL is a part of formula IIIad:

[0575]

[0576] Each R g It is independently hydrogen or C1-C6 alkyl.

[0577] In some embodiments of the compound of formula I', R4 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted (carbocyclic)alkyl, optionally substituted aralkyl, optionally substituted (heterocyclic)alkyl, optionally substituted (heteroaryl)alkyl, or optionally substituted carbamoyl; and R5 is a hydroxyl, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino.

[0578] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group; C2-C 10 Alkenyl; non-aromatic C3-C 12 Carbon rings, C6-C 10Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; (heteroaryl)alkyl; or -C(O)NR m R n ;

[0579] R m and R n Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkoxy, C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; or (heteroaryl)alkyl; or R m and R n Together with the nitrogen attached thereto, it forms 3 to 18-membered heterocyclic alkyl rings;

[0580] Furthermore, R4 is optionally selected from one to five independently chosen groups of R. g Substitution: hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 arylalkoxy groups; and

[0581] R5 is a hydroxyl group, NH2, alkylamino group, alkylamino group, or alkylsulfonylamino group.

[0582] In some embodiments of the compound of formula I', R4 is a C1-C6 alkyl group; C2-C 10 Alkenyl; non-aromatic C3-C 12 Carbon rings, C6-C 10 Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; (heteroaryl)alkyl; or -C(O)NR m R n ;

[0583] R m and R n Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkoxy, C6-C 10Aryl; a 3- to 6-membered heterocyclic alkyl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; a 5- to 10-membered heteroaryl ring containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen; (carbocyclic)alkyl; aralkyl; (heterocyclic)alkyl; or (heteroaryl)alkyl; or R m and R n Together with the nitrogen attached thereto, it forms 3 to 18-membered heterocyclic alkyl rings;

[0584] Furthermore, R4 is optionally selected from one to five independently chosen groups of R. g Substitution: hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C1-C6 alkoxy and C6-C 10 arylalkoxy groups; and

[0585] R5 is a hydroxyl group.

[0586] In some embodiments of the compound of formula I', Alk is hydrogen or optionally substituted C. 1- C6 alkyl. In some embodiments of compounds of formula I', Alk is a C1-C6 alkyl group, either hydrogen-based or optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of the compound of formula I', Alk is hydrogen. In some embodiments of the compound of formula I', Alk is a C1-C6 alkyl group optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', Alk is a C1-C6 alkyl group optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, and C1-C6 alkoxy.

[0587] In some embodiments of the compound of formula I', R 11An aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups; or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl groups; or a bicyclic system containing an aromatic ring or a saturated ring; or a bicyclic heterocycle containing an aromatic ring or a saturated ring system. In some embodiments of compounds of formula I', R 11 An aryl group optionally substituted with one to five independently selected substituents chosen from lower alkyl groups, halogens, and C3-C9 cycloalkyl groups; or a bicyclic system containing an aromatic ring or a saturated ring; or a bicyclic heterocycle containing an aromatic ring or a saturated ring system. In some embodiments of compounds of formula I', R 11 C6-C alkyl group optionally substituted with one to five independent substituents selected from lower alkyl, alkoxy, haloalkoxy, halogen and C3-C9 cycloalkyl groups. 10 Aryl; or a five- to ten-membered heteroaryl group containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted by one to five independently selected substituents chosen from lower alkyl, alkoxy, haloalkoxy, halogen, and C3-C9 cycloalkyl groups; or a 7- to 12-membered bicyclic system containing an aromatic ring or a saturated ring; or a 7- to 12-membered bicyclic heterocycle containing an aromatic ring or a saturated ring system. In some embodiments of compounds of formula I', R 11 C6-C alkyl group optionally substituted with one to five independent substituents selected from lower alkyl groups, halogens, and C3-C9 cycloalkyl groups. 10 Aryl; or a 7- to 12-membered bicyclic system containing an aromatic ring or a saturated ring; or a 7- to 12-membered bicyclic heterocycle containing an aromatic ring or a saturated ring system. In some embodiments of compounds of formula I', R 11 C6-C alkyl group optionally substituted with one to five independent substituents selected from lower alkyl, alkoxy, haloalkoxy, halogen and C3-C9 cycloalkyl groups. 10 Aryl. In some embodiments of compounds of formula I', R 11 C6-C alkyl group optionally substituted with one to five independent substituents selected from lower alkyl groups, halogens, and C3-C9 cycloalkyl groups. 10 Aryl. In some embodiments of compounds of formula I', R 11 It is a five- to ten-membered heteroaryl group containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted by one to five independently selected substituents chosen from lower alkyl groups, alkoxy groups, haloalkoxy groups, halogens, and C3-C9 cycloalkyl groups. In some embodiments of compounds of formula I', R 11 It is a 7- to 12-membered bicyclic system containing an aromatic ring or a saturated ring. In some embodiments of compounds of formula I', R 11 It is a 7- to 12-membered bicyclic heterocycle containing an aromatic ring or a saturated ring system. In some embodiments of compounds of formula I', R 11Benzene optionally substituted with one to five substituents independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, halogen, and C3-C9 cycloalkyl; pyridine optionally substituted with C1-C5 alkyl; cycloalkane; isoquinoline; quinoline; pyrazolo[1,5-a]pyridine; imidazo[1,5-a]pyridine; benzo[b]thiophene; chromane; 1,2,3,4-tetrahydronaphthalene; or naphthalene. In some embodiments of compounds of formula I', R 11 Optionally substituted benzene with one to five independent substituents selected from C1-C5 alkyl, halogen and C3-C9 cycloalkyl; 1,2,3,4-tetrahydronaphthalene; or naphthalene.

[0588] In some embodiments of the compound of formula I', R6 and R7 are each independently halogenated or optionally substituted with one to five substituents independently selected from hydroxyl, halogen, and C1-C6 alkoxy; and R8 is hydrogen; or R6 is halogenated or optionally substituted with one to five substituents independently selected from hydroxyl, halogen, and C1-C6 alkoxy; and R7 and R8 together with the carbon atom to which they are attached form a 4, 5, or 6-membered carbon ring.

[0589] In some embodiments of the compound of formula I', R6 and R7 are each independently chlorine, bromine, and iodine. In some embodiments of the compound of formula I', R6 and R7 are each independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, wherein the alkyl group of the lower alkyl and lower alkoxy is each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-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', R6 and R7 are each 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 a halogen, and R7 and R8, together with their attached carbon atoms, form a four-membered carbon ring.

[0590] In some embodiments of the compound of formula I', R8 is hydrogen. In some embodiments of the compound of formula I', R8 is an optionally substituted lower alkyl group. In some embodiments of the compound of formula I', R8 is a lower alkyl group optionally substituted with one to five substituents selected from the group consisting of: hydroxyl, halogen, amino, -CN, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C 3-C5 cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing a heteroatom independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compound of formula I', R8 is an optionally substituted lower alkoxy group. In some embodiments of the compound of formula I', R8 is an optionally substituted lower alkoxy group substituted with one to five substituents selected from the group consisting of: hydroxyl, halogen, amino, -CN, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C 3- C5 cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing a heteroatom independently selected from oxygen, sulfur, or nitrogen. In some embodiments of the compound of formula I', R8 is a cyano group. In some embodiments of the compound of formula I', R8 is a halogen.

[0591] In some embodiments of compounds of formula I', R7 and R8, together with the carbon atoms to which they are attached, form 4, 5, or 6-membered non-aromatic carbon rings, 3 to 5-membered heterocyclic alkyl groups, or C6-C6 carbon rings. 10 Aryl or five to ten heteroaryl rings.

[0592] 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 It is hydrogen. In some embodiments of the compound of formula I', R c It is a halogen. In some embodiments of the compound of formula I', R c It is a lower alkyl group. In some embodiments of compounds of formula I', R... c It can be hydrogen or methyl. In some embodiments of compounds of formula I', Q7 is -CH-.

[0593] In some embodiments of the compound of formula I', R9 is hydrogen, -(C(R) d )2) n -N(R d )2、-(C(R d )2) n -CN or -(C(R) d )2) n -C≡CR d In some embodiments of the compound of formula I', R9 is hydrogen, -(CH2). n -N(R d 2、-(CH2) n -CN or -(CH2) n -C≡CR d In some embodiments of the compound of formula I', R9 is selected from hydrogen, -N(R d 2. -CN or -C≡CR dIn some embodiments of the compound of formula I', R9 is selected from hydrogen, -NH2, -CN, or -C≡CH.

[0594] 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(R d )2.

[0595] In some embodiments of the compound of formula I', each R d A lower alkyl group that is independently hydrogen or optionally substituted by one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3-C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', each R d It is hydrogen. In some embodiments of the compound of formula I', each R... d Independently, a lower alkyl group optionally substituted with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl.

[0596] 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.

[0597] 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.

[0598] In some embodiments of the compound of formula I', HeAr is a 5- or 6-membered heteroaryl group containing one to three cyclic heteroatoms independently selected from oxygen, sulfur, or nitrogen.

[0599] In some embodiments of the compound of formula I', R 10 It is hydrogen or -C(R) e )3, where each R e A lower alkyl group that is independently substituted with hydrogen, halogen, or optionally with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R 10It is hydrogen. In some embodiments of the compound of formula I', R 10 -C(R) e )3, where each R e A lower alkyl group that is independently substituted with hydrogen, halogen, or optionally with one to five substituents independently selected from the group consisting of: hydroxyl, halogen, -CN, amino, O-carboxyl, C-carboxyl, C-amide, N-amide, C1-C6 alkoxy, C6-C 10 Arylalkoxy, C 3- C9 cycloalkyl, 3- to 6-membered heterocycloalkyl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, 5- to 10-membered heteroaryl containing one to four independently selected cyclic heteroatoms chosen from oxygen, sulfur, or nitrogen, and C6-C 10 Aryl. In some embodiments of compounds of formula I', R 10 -C(R) e )3, where each R e Independently hydrogen, halogen, or lower alkyl. In some embodiments of compounds of formula I', R 10 It can be hydrogen, -CHF2, -CH3, or ethyl.

[0600] In some embodiments of the compound of formula I', L a For one key; -(C(R) a )2) z -; oxygen; sulfur; or -NR a -. In some embodiments of the compound of formula I', L a It is a single bond. In some embodiments of the compound of formula I', L a -(C(R) a )2) z -. In some embodiments of the compound of formula I', L a It is -CH2-. In some embodiments of compounds of formula I', L a For oxygen. In some embodiments of compounds of formula I', L a It is sulfur. In some embodiments of the compound of formula I', L a For -NR a -. In some embodiments of the compound of formula I', each R a It is hydrogen. In some embodiments of the compound of formula I', each R... a Independently, it is a lower alkyl group. In some embodiments of compounds of formula I', each R a It is independently hydrogen or a lower alkyl group.

[0601] 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.

[0602] In another aspect, this paper discloses compounds selected from the group consisting of:

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613] Compound Synthesis

[0614] The compounds disclosed herein are synthesized using the general synthetic procedures set forth in Schemes 1-10 below. Those skilled in the art will be able to perform each individual step shown, and will also know how to modify the synthetic procedures below to synthesize the full range of compounds disclosed herein. Synthetic procedures for individual compounds will be provided in the Examples section below.

[0615] As described in Scheme 1, firstly, the corresponding diazonium salt is generated, then reacted with N-(2-cyanoacetyl)-carbamate and finally cyclized to form a compound of formula S-III, thereby converting the aromatic amine compound of formula S-II into the azauracil compound of formula S-III. Next, the nitrile of formula S-III is hydrolyzed to form a carboxylic acid compound of formula S-IV. Then, the compound of formula S-IV is reacted with diphenylphosphoazide (DPPA) to form a compound of formula SV. Finally, the protecting group of the compound of formula SV is removed.

[0616] Option 1

[0617]

[0618] As described in Scheme 2, the aromatic amine compound of formula S-II can be converted into a boric acid compound of formula S-VII by first generating a diazonium salt and then reacting it with tetrahydroxydiborane. The corresponding boric acid is then coupled with a suitable protected (with protecting group 'PG') bromo-azauracil compound of formula Int-I. The resulting bromide of formula S-VIII is then converted by substitution reaction or by transition metal-catalyzed transformation, as illustrated in the Examples section below. Removal of the protecting group 'PG' yields a compound of formula SX.

[0619] Option 2

[0620]

[0621] Scheme 3 describes the synthesis of aromatic amine compounds of formula S-XIV. A compound of formula S-XI is reacted with a compound of formula S-XII ("X" represents a halogen, such as F or Cl), followed by protection with a protecting group 'PG', to produce a compound of formula S-XIII. The nitro group of the compound of formula S-XIII is reduced to form an aromatic amine compound of formula S-XIV.

[0622] Option 3

[0623]

[0624] Scheme 4 describes the synthesis of compounds of formula S-XIX. A compound of formula S-XVI undergoes a transfer metallization reaction (where "X" in the structure represents a halogen, such as Br or I), followed by addition to an aldehyde of general formula S-XV to give an alcohol compound of formula S-XVII, which is then reduced to a compound of formula S-XVIII. The PG2 group of the compound of formula S-XVIII is removed to form a compound of formula S-XIX.

[0625] Option 4

[0626]

[0627] As described in Scheme 5, compounds of formula S-XX are obtained by coupling a compound of formula S-VII with a bromide of formula Int-II.

[0628] Option 5

[0629]

[0630] Scheme 6a describes an alternative synthesis of compounds of general formula S-XIX. A compound of formula S-XXI (where the structure represents a halogen, such as Cl, Br, or I) is coupled with a compound of formula S-XXII via a Suzuki-type coupling to form a compound of formula S-XXIII. The protecting group PG3, for example, the benzyl moiety, can then be removed to produce a compound of formula S-XXIV. The resulting phenolic functional group can then be replaced by a trifluoromethanesulfonate group to produce a compound of general formula S-XXV. This can then be achieved via a transition metal-catalyzed reaction with, for example, tert-butyl carbamate or benzophenone imine, such as Buchwald coupling, where the -OTf group is partially replaced by the -NH2 moiety, followed by deprotection to produce a compound of general formula S-XIX. The method described in Scheme 6a can also be applied when an indazole halide is used instead of S-XXI as the starting material. Alternatively, the indazole halide can undergo lithium-halogen exchange. The resulting aryllithium species can react with aldehydes of type S-XXVIII to form compounds of formula S-XXIX. A further detailed description of the structure of formula S-XXIX is provided in Scheme 7.

[0631] Option 6a

[0632]

[0633] Scheme 6b describes the synthesis of compound S-XXII by reacting a compound of formula S-XXVI with 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)methyl]-1,3,2-dioxaborone-2-yl] via the Suzuki reaction.

[0634] Option 6b

[0635]

[0636] Scheme 7 describes the synthesis of compounds of formula S-XXXI. Compounds of formula S-XXVII undergo a transfer metallization reaction (where "X" in the structure represents a halogen, such as Br or I), followed by addition to an aldehyde of general formula S-XXVIII to give an alcohol compound of formula S-XXIX, which is then reduced to a compound of formula S-XXX. The PG2 group of the compound of formula S-XXX is removed to form a compound of formula S-XXXI.

[0637] Option 7

[0638]

[0639] Scheme 8 describes a general synthesis of compounds of formula S-XXI and their products. When R1 is, for example, hydrogen and Y is hydrogen, R1 can be converted to the corresponding acyl group via an acyl chloride and a Lewis acid (e.g., InBr3) in a nonpolar, aprotic solvent (e.g., dichloroethane). The newly formed ketone group can be partially reduced to an alcohol or completely reduced to the corresponding alkane. Further conversions of the ketone group are apparent to those skilled in the art. In a second example, with R1 being hydrogen and Y being a suitable protecting group (e.g., toluenesulfonyl), R1 can be converted to an iodide group via an iodizing agent (e.g., NIS) using available literature procedures.

[0640] Option 8

[0641]

[0642] Scheme 9 describes the general synthesis of compounds of formula S-XXXIII. Under typical Suzuki-Miyaura conditions, using, for example, ArB(OH)2 (e.g., phenylboronic acid) and a palladium catalyst (e.g., PdCl2(PPh3)2), 4-bromo-6-chloropyridazin-3-amine can be converted to the corresponding 4-aryl-6-chloropyridazin-3-amine (S-XXXII). Subsequently, via typical Sandmeyer reaction conditions (e.g., CuCl2, t-Bu-ONO, acetonitrile, heating), the amino group is converted to Cl to give compounds of type S-XXXIII.

[0643] Option 9

[0644]

[0645] Scheme 10 describes a general synthesis of compounds of formula S-XXXVI. A compound of formula S-XXXIV can be coupled with phenol HO-CE-HD in DMSO with a base (e.g., K₂CO₃) at high temperature via a Cu(I)-mediated coupling reaction to yield an intermediate of type S-XXXV. Subsequently, chloropyridazine is hydrolyzed via acetic acid and an acetate (e.g., NaOAc) to give the product of formula S-XXXVI, wherein the desired regioisomers can be isolated. In the case of Scheme 10, the HD group may contain a general protecting group, which can be cleaved at the S-XXXV stage of the intermediate or at the end of the synthesis to give the compound of formula S-XXXVI.

[0646] Option 10

[0647]

[0648] Compounds of formula S-XXXVII can be synthesized using literature procedures. For example, 6-bromoquinolones can be obtained by combining an alkynyl ester with a protected aniline under the conditions described in Org. Lett. 2014, 16, 3568-3571 using a Ru catalyst. Alternatively, compounds of formula S-XXXVII may be formed by other procedures reported in the literature, including (but not limited to) the following examples: (a) Kadnikov, DV et al.; Journal of Organic Chemistry, 2004, 69, 6772. (b) Manley, PJ et al.; Organic Letters, 2004, 6, 2433. (c) Jia, C.; Piao, D. et al.; Journal of Organic Chemistry, 2000, 65, 7516. (d) Inamoto, K. et al.; J. Organic Chemistry, 2010, 75, 3900. (e) Ferguson, J. et al.; Organic Letters, 2013, 15, 1998. (f) Fan, H.; Organic Letters, 2018, 20, 7929-7932.

[0649]

[0650] Alternatively, Scheme 11 describes the synthesis of compounds of formula S-XXXVII, which can be prepared starting from a dihalogenated aminoaryl group (S-XXXVII-a). The amine is then protected (e.g., trimethylacetamide) to give 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 give an alcohol product S-XXXVI-c, which is subsequently oxidized (via a common oxidizing agent; e.g., a Dess-Martin reagent) to give a ketone S-XXXVII-d. The ketone undergoes an aldol-type reaction with a protected ester (e.g., tert-butyl) to give intermediate S-XXXVII-e. In a final step, intramolecular cyclization can occur to give compounds of formula S-XXXVII.

[0651] Option 11

[0652]

[0653] Compounds of formula S-XXXVII can be incorporated using methods similar to those described in schemes 6a and 6b to form the final product.

[0654]

[0655] Several methods exist for obtaining compounds of formula XXXVIII, including (but not limited to) those found or referenced in the following references: (a) Hajra, S et al.; Organic Letters 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 Infectious Dis. 2016, 2(6), 382-392. Compounds of formula S-XXXVIII can be incorporated into the final product using methods similar to those described in schemes 6a and 6b.

[0656] As described in Scheme 12, a compound of formula S-XXXIX is obtained by coupling a compound of formula S-VII with an azauracil of formula Int-A. The protecting group of the benzyloxymethyl acetal can then be removed using various methods described in the literature.

[0657] Option 12

[0658]

[0659] Pharmaceutical Composition

[0660] In another respect, this document discloses pharmaceutical compositions comprising, substantially consisting of, or consisting of the following: compounds as described herein and at least one pharmaceutically acceptable excipient.

[0661] In another aspect, this document discloses pharmaceutical compositions comprising a compound of Formula I as described herein and a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, this document discloses pharmaceutical compositions comprising, substantially comprising, or consisting of a compound of Formula I as described herein and at least one pharmaceutically acceptable diluent, excipient, or carrier.

[0662] In another respect, this document discloses pharmaceutical compositions comprising, substantially consisting of, or consisting of a compound of formula I' as described herein and at least one pharmaceutically acceptable excipient.

[0663] The pharmaceutical compositions disclosed herein may include pharmaceutically acceptable carriers, such as diluents, disintegrants, sweeteners, lubricants, or flavorings, and may be formulated into oral dosage forms, such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral dosage forms, such as liquids, suspensions, emulsions, gels (ointments, etc.), inhalers, sprays, injections, etc., for external use. These dosage forms may be formulated in various formats, such as for single or multiple administration.

[0664] The pharmaceutical compositions disclosed herein may include excipients such as lactose and corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotensants. Sweeteners and / or flavoring agents may be added if necessary. Exemplary excipients include (but are not limited to) polyethylene glycol (PEG), hydrogenated castor oil (HCO), cetyl alcohol polyoxyethylene ether (cremophor), carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), lubricants such as talc, disintegrants, diluents, buffers, acids, bases, coatings, combinations thereof, etc.

[0665] Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbitol, etc.; disaccharides, such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides, such as raffinose, melitriose, maltodextrin, polydextrose, starch, etc.; and aldose alcohols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucol), pyranosyl sorbitol, inositol, etc.

[0666] Inorganic salts or buffers include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and combinations thereof.

[0667] Antioxidants suitable for use in this disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphite, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0668] Additional exemplary excipients include: surfactants, such as polysorbate, such as “Tween 20” and “Tween 80”; and pluronic, such as F68 and F88 (both available from BASF, Mount Olive, NJ); sorbitol esters; lipids (such as phospholipids, such as lecithin and other phosphatidylcholine and phosphatidylethanolamine); fatty acids and fatty acid esters; steroids, such as cholesterol; and chelating agents, such as EDTA; zinc and other such cationic agents.

[0669] Furthermore, the compositions disclosed herein may optionally comprise one or more acids or bases. Non-limiting examples of acids that may be used include those selected from the group consisting of: hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Non-limiting examples of suitable bases include those selected from the group consisting of: sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumaric acid, and combinations thereof.

[0670] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent component, and the specific needs of the composition. However, generally, the excipient will be present in the 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 the compositions of this disclosure is selected from the following: 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 even 95% by weight.

[0671] The pharmaceutical compositions described herein may be administered to human patients on their own or as a combination therapy, in combination with other active ingredients or suitable carriers or excipients. Techniques for formulating and administering the compounds of this application can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition, 1990.

[0672] Suitable routes of administration may include, for example, oral, transdermal, rectal, transmucosal or enteral administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, and inhalation, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection.

[0673] The pharmaceutical compositions disclosed herein can be manufactured using methods known per se, such as conventional mixing, dissolving, granulation, pelleting, water milling, emulsification, encapsulation, coating, or tableting processes. These pharmaceutical compositions can then be formulated using conventional methods with one or more known physiologically acceptable carriers, said carriers comprising excipients and adjuvants, to facilitate the processing of the active compound into a pharmaceutically usable formulation. Any well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; for example, as described above in Remington Pharmaceutical Sciences.

[0674] Pharmaceutical compositions applicable to formulations disclosed in this invention include compositions containing an amount of active ingredient effective in achieving the intended purpose. More specifically, a therapeutically effective amount means an amount in which the compound effectively prevents, alleviates, or improves disease symptoms or prolongs the survival of a treated subject. In some embodiments, a therapeutically effective amount means an amount in which the compound effectively alleviates or improves disease symptoms or prolongs the survival of a treated subject.

[0675] While the exact dosage will vary depending on the individual drug, some generalizations regarding dosage can be made in most cases. Daily dosing regimens for adult patients may be, for example, oral administration of amounts between 0.001 mg and 1000 mg of each component, preferably between 0.01 mg and 500 mg, for example, 1 to 200 mg of each component, or each active ingredient of the pharmaceutical compositions disclosed herein, calculated as a free base or free acid, or a pharmaceutically acceptable salt thereof, administered 1 to 4 times daily or weekly. Alternatively, the compositions disclosed herein may be administered by continuous, e.g., sustained, delayed, or prolonged release, preferably at a dose of up to 500 mg per component per day. Therefore, the total daily dose of each component administered orally will generally range from 0.1 mg to 2000 mg.

[0676] Treatment

[0677] In another respect, this document discloses a method for treating a patient with thyroid hormone receptor-related disease, the method comprising, substantially comprising, or comprising the following steps: identifying a patient with thyroid hormone receptor-related disease who requires treatment, and administering or exposing the patient to a compound as described herein.

[0678] In another aspect, this document discloses a method for treating a patient with thyroid hormone receptor-related disease, the method comprising the steps of: identifying a patient with thyroid hormone receptor-related disease requiring treatment, and administering or exposing the patient to a compound of formula I as described herein. In some embodiments, the method for treating a patient with thyroid hormone receptor-related disease consists essentially of the steps of: identifying a patient with thyroid hormone receptor-related disease requiring treatment, and administering or exposing the patient to a compound of formula I as described herein.

[0679] In another respect, this article discloses a method for treating a patient with thyroid hormone receptor-related disease, the method comprising, consisting essentially of, or consisting of the following steps: identifying a patient with thyroid hormone receptor-related disease who requires treatment, and administering or exposing the patient to a compound of formula I' as described herein.

[0680] In some embodiments, healthcare professionals such as physicians, physician assistants, and nurse practitioners may identify individuals as candidates for treatment of thyroid hormone receptor-related conditions and / or treatment with the compounds disclosed herein. Identification may be based on medical test results, unresponsiveness to other first-line therapies, specificity of a particular liver condition, etc.

[0681] In some embodiments, thyroid hormone receptor-related conditions are selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0682] In another aspect, this document discloses a method for treating a condition or disease in a subject in need, the method comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of the compound or composition disclosed herein, wherein the condition or disease is selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0683] In another respect, this document discloses a method for treating NASH in a subject in need, the method comprising, substantially comprising, or consisting of the following: administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0684] In another respect, this document discloses a method for treating obesity in a subject in need, the method comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0685] In another respect, this document discloses a method for treating hyperlipidemia in a subject in need, the method comprising, substantially comprising, or consisting of the following: administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0686] In another respect, this document discloses a method for treating hypercholesterolemia in a subject in need, the method comprising, substantially comprising, or consisting of the following: administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0687] In another respect, this document discloses a method for treating diabetes in a subject in need, the method comprising, substantially comprising, or consisting of the following: administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0688] In another respect, this document discloses a method for treating hepatic steatosis in a subject in need, the method comprising, substantially comprising, or consisting of the following: administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.

[0689] In another aspect, this document discloses a method for selectively modulating the activity of thyroid hormone receptor β (THR-β), the method comprising, substantially comprising, or comprising comprising contacting a compound as 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.

[0690] In another aspect, this document discloses a method for selectively modulating the activity of thyroid hormone receptor β (THR-β), the method comprising, substantially comprising, or comprising comprising: contacting a compound of formula I as 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) comprises, substantially comprising, or comprises comprising: contacting a compound of formula I as described herein with a thyroid hormone receptor.

[0691] In another aspect, this document discloses a method for selectively modulating the activity of thyroid hormone receptor β (THR-β), the method comprising, substantially comprising, or comprising comprising contacting a compound of formula I' as 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.

[0692] In another aspect, this document discloses a method for selectively modulating the activity of thyroid hormone receptor β (THR-β), the method comprising, substantially comprising, or comprising comprising: contacting the composition 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.

[0693] Example

[0694] The following examples illustrate aspects of the invention but do not limit its scope. Conditions for preparing several compounds disclosed herein are presented. Procedures for synthesizing common intermediates are provided only once. Chemical names are generated using Marvin 17.28.0 or Chemdraw 18.1.

[0695] Abbreviation list:

[0696] The following abbreviations are used in this disclosure:

[0697]

[0698]

[0699] Synthesis of building blocks

[0700] 1. Synthesis of 3-isopropyl-1H-indole-5-phenol

[0701]

[0702] Isovaleraldehyde (6.23 g, 0.072 mmol, 1 equivalent) was added dropwise to a mixture of (4-methoxyphenyl)hydrazine (10.00 g, 72.375 mmol, 1.0 equivalent) in 100 mL of AcOH under stirring at 80 °C. The resulting mixture was stirred at 120 °C for 2 hours. The mixture was concentrated under vacuum. The 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 give 2.6 g (19%) of 3-isopropyl-5-methoxy-1H-indole as a brown solid.

[0703] Boron tribromide (35.88 g, 143.217 mmol, 3 equivalents) was added dropwise to a solution of 3-isopropyl-5-methoxy-1H-indole (9.03 g, 47.713 mmol, 1.0 equivalent) in DCM (100.00 mL) at -78 °C for 1 hour. The resulting mixture was stirred at room temperature for another 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 give 3-isopropyl-1H-indole-5-phenol (5.86 g, 56%) as a black oil.

[0704] 2a. Synthesis of 5-bromo-3-isopropyl-1H-indole

[0705]

[0706] Isovaleraldehyde (23.03 g, 267.37 mmol, 1.00 equivalent) was added dropwise to a solution of 4-bromophenyl-hydrazine (50.00 g, 267.32 mmol, 1.00 equivalent) in AcOH (500 mL) under stirring at 80 °C. The resulting mixture was stirred at 120 °C for 3 hours. The mixture was concentrated under vacuum. The 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 give 5-bromo-3-isopropyl-1H-indole (28 g, 44%) as a brown solid.

[0707] 2b. Synthesis of 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine:

[0708]

[0709] TosCl (1.91 g, 10.04 mmol, 1.2 equivalent) was added to a 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 equivalent), and DIPEA (2.38 g, 18.40 mmol, 2.2 equivalent) in DCM (60 mL) under stirring at 20 °C. The resulting mixture was then stirred at 20 °C for 12 h. TLC (petroleum ether / ethyl acetate = 5 / 1, UV) showed complete consumption of the starting materials. The mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ethyl acetate in petroleum ether = 0–10%) to give 5-bromo-3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridine as a grayish-white solid (2.6 g, 5.61 mmol, 67.0% yield).

[0710] 2c. Synthesis of 5-bromo-3-pentyl-1H-indazole

[0711]

[0712] Magnesium bromo(pentyl)magnesium (1M, 184.73mL, 1.5 equivalents) was added to a solution of 5-bromo-2-fluorobenzaldehyde (25g, 123.15mmol, 1 equivalent) in THF (100mL) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50mL) at 0°C, followed by dilution with H2O (50mL) and extraction with EA (100mL × 2). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by rapid silica gel chromatography (eluent of 0–30% ethyl acetate / petroleum ether) to give 1-(5-bromo-2-fluoro-phenyl)hex-1-ol (9.5g, 34.53mmol, 28% yield) as a colorless oil.

[0713] To a solution of 1-(5-bromo-2-fluoro-phenyl)hex-1-ol (9.5 g, 34.53 mmol, 1 equivalent) in DCM (100 mL), 10 g of 4A MS and 25.98 g of 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 give a residue, which was purified by rapid silica gel chromatography (eluent of 0–30% ethyl acetate / petroleum ether) to give 1-(5-bromo-2-fluoro-phenyl)hex-1-one (8.2 g, 30.02 mmol, 87% yield) as a pale yellow solid.

[0714] Hydrazine hydrate (2.16 g, 36.61 mmol, 2.09 mL, 85% purity, 2 equivalents) was added to a solution of 1-(5-bromo-2-fluoro-phenyl)hex-1-one (5 g, 18.31 mmol, 1 equivalent) in NMP (2 mL) 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 × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by rapid silica gel chromatography (0–20% ethyl acetate / petroleum ether eluent) to give 5-bromo-3-pentyl-1H-indazole (2 g, 7.49 mmol, 41% yield) as a white solid.

[0715] 3. Synthesis of 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carboxaldehyde

[0716]

[0717] Bu₄NH₄⁻ (0.43 g, 1.27 mmol, 0.10 equivalent) was added dropwise to a stirred solution of 5-bromo-3-isopropyl-1H-indole (3.0 g, 12.6 mmol, 1.00 equivalent) in toluene (50 mL) 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 mixture was concentrated under vacuum. The 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 give 5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4.0 g, 67%) as a pale yellow solid.

[0718] n-BuLi (31.2 mL, 51.0 mmol, 5.0 equivalence, 1.6 M hexane solution) was added dropwise to a solution of 5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4 g, 10.2 mmol, 1.00 equivalence) in THF under a nitrogen atmosphere and stirred at -78 °C. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 40 min. DMF (3.70 g, 0.051 mmol, 5.0 equivalence) was added at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1.5 h. 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 give 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carboxaldehyde (1.1 g, 31%), which was a pale yellow oil.

[0719] 4. Synthesis of 4-[(benzoxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione

[0720]

[0721] 6-Bromo-2,4-dihydro-1,2,4-triazine-3,5-dione (10.00 g, 52.091 mmol, 1.00 equivalent) was placed in acetic anhydride (50 mL) under reflux (140 °C) for 5 hours. After dry concentration of the reaction medium, the precipitate was separated and then recrystallized from diethyl ether to give the desired product. The desired product (11.6 g, 95% purity, 90% yield) was separated as a pale yellow solid.

[0722] NaH (2.19 g, 54.755 mmol, 1.10 equivalent, 60%) was placed in DMF (50 mL) under nitrogen atmosphere. A solution of 2-acetyl-6-bromo-4H-1,2,4-triazine-3,5-dione (11.60 g, 49.571 mmol, 1.0 equivalent) in DMF (150 mL) was added dropwise. The reaction medium was stirred at room temperature for 1 hour, followed by the addition of [(chloromethoxy)methyl]benzene (8.54 g, 54.53 mmol, 1.1 equivalent), and stirring was continued at room temperature for 18 hours. After dry concentration, the 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 purified to obtain a clear oil, and 15 g of crystals were separated. The crystals were placed in 400 mL of EtOH containing TsOH (100.0 mg, 0.581 mmol, 0.01 equivalent). The mixture was refluxed and heated for 4 hours, followed by dry concentration. The residue was dissolved in H₂O and then extracted with EA. After drying and evaporation of the organic phase, the desired product (9.5 g, yellow oil, 90% pure, 61% yield) was obtained as a yellow oil.

[0723] 5a. Synthesis of 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione

[0724]

[0725] BSA (529.8 mg, 2.61 mmol, 2.5 equivalence) was added dropwise 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 equivalence) in 5 mL of ACN at 0 °C under an argon atmosphere. The resulting mixture was stirred at 82 °C under an argon atmosphere for 3 hours, followed by the dropwise addition of CH3I (251.4 mg, 1.77 mmol, 1.7 equivalence) at 82 °C, and stirring was continued at 82 °C for 20 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and then dissolved in DCM, washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (870 mg, 69%) as a yellow solid.

[0726] 5b. Synthesis of 6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione

[0727] 6-Bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione was prepared similarly to 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione, using 2.5 equivalents of iodoethane instead of 1.7 equivalents of CH3I.

[0728] 6. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole

[0729]

[0730] Potassium tert-butoxide (0.64 g, 5.70 mmol, 1.00 equivalent) was added dropwise to a solution of 3-isopropyl-1H-indole-5-phenol (1.00 g, 5.71 mmol, 1.00 equivalent) in THF under stirring at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was concentrated under vacuum and dissolved again in DMF. Second reaction flask: A solution of 1,2,3-trichloro-5-nitrobenzene (1.29 g, 5.70 mmol, 1.0 equivalent) in DMF under stirring was added to the first reaction flask at 0 °C. The resulting mixture was stirred at 0 °C for 5 minutes, and 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 give 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.3 g, 55%) as a yellow solid.

[0731] 7. Synthesis of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole

[0732]

[0733] To a mixture of 50 mL DMSO containing 5.10 g (5.10 g, 29.10 mmol, 1.0 equivalent) of 3-isopropyl-1H-indole-5-phenol (4.42 g, 32.0 mmol, 1.1 equivalent) under stirring, K₂CO₃ and 2-fluoro-1,3-dimethyl-5-nitrobenzene (4.92 g, 29.1 mmol, 1.0 equivalent) were added fractionally. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6 g (64%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole as a pale yellow solid.

[0734] 8. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole

[0735]

[0736] Potassium tert-butoxide (13.48 g, 120.2 mmol, 1.0 equivalent) was added to a solution of 5-hydroxyindole (16.0 g, 120.2 mmol, 1.0 equivalent) in acetonitrile (320 mL) at 0 °C. After 20 minutes, the mixture was concentrated to remove 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, washed with brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 28 g (68% yield) of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole as a yellow solid.

[0737] 9. Synthesis of 5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline

[0738]

[0739] To a 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) under stirring at 0 °C, 10 mL of toluene containing TsCl (0.81 g, 4.239 mmol, 1.2 equivalent), 21.4 mL of KOH (50%), and 0.12 g of Bu₄NHSO₄ (0.12 g, 0.353 mmol, 0.1 equivalent) were added dropwise. The resulting mixture was stirred at room temperature for 6 hours. After the reaction was complete, the 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 give 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (1.40 g, 75%) as a yellow solid.

[0740] Fe powder (0.75 g, 13.514 mmol, 5.00 equivalent) was added fractionally to a stirred solution of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (1.40 g, 2.73 mmol, 1.0 equivalent) and NH4Cl (1.16 g, 21.62 mmol, 8.0 equivalent) in EtOH (50 mL) and H2O (25 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with EA and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]aniline (1.11 g, 78%) as a white solid.

[0741] 10. Synthesis of 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylaniline

[0742]

[0743] TsCl (3.53 g, 0.018 mmol, 1.2 equivalents), Bu4NHSO4 (0.52 g, 0.002 mmol, 0.1 equivalents), and KOH (50 mL) were added dropwise to a mixture of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (5.00 g, 15.414 mmol, 1.00 equivalents) in 50 mL of toluene under stirring 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 in hexane by silica gel column chromatography to give 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (5.8 g, 79%) as a pale yellow solid.

[0744] Pd / C (1.74 g) was added fractionally to a 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). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with MeOH (1 × 500 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-yl]oxy]-3,5-dimethylaniline (3.2 g, 59%) as a pale yellow solid.

[0745] 11. Synthesis of 4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline

[0746]

[0747] MeLi-LiBr (1.7 mL, 1.76 mmol, 2.0 equivalence, 1 M solution in diethyl ether) was added dropwise to a stirred solution of N-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (260.16 mg, 0.879 mmol, 1.0 equivalence) in THF (5 mL) at -78 °C under nitrogen atmosphere. Then, t-BuLi (1.6 mL, 2.64 mmol, 3.00 equivalence, 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-carboxaldehyde (300 mg, 0.879 mmol, 1.0 equivalence) 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified to give 2,2,2-trifluoro-N-(4-[hydroxy[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300 mg, 61%) as a white solid.

[0748] A solution of 2,2,2-trifluoro-N-(4-[hydroxy[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300.0 mg, 0.537 mmol, 1.00 equivalent) in DCM (5 mL) was stirred at 0 °C under nitrogen. Then, solutions of Et3SiH (374.7 mg, 3.22 mmol, 6.0 equivalent) in DCM (15 mL) and 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 then 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), and the organic layers were combined. The mixture was 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 (260 mg, 85% purity, 76% yield) containing 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide, which was a yellow solid, was separated.

[0749] Under nitrogen atmosphere at room temperature, NaOH (76.66 mg, 1.917 mmol, 4.0 equivalent) was added to a stirred solution of 2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (260.0 mg, 0.479 mmol, 1.0 equivalent) in MeOH (10 mL) and H₂O (2 mL). 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), and the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product containing 4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline was isolated as a yellow solid (230 mg, 90% pure, 97% yield).

[0750] 12. Synthesis of 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline

[0751]

[0752] At 0 °C, water (120 mL) containing tetrabutylammonium bisulfate (2.94 g, 8.665 mmol, 0.10 equivalent) and potassium hydroxide (120.00 g, 2138.8 mmol, 25.0 equivalent) in toluene (720 mL) was added 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). Toluene containing 4-toluenesulfonyl chloride (19.82 g, 103.98 mmol, 1.20 equivalent) was added dropwise at 0 °C. The reaction was then stirred at room temperature for 3 hours and quenched with water (200 mL). The mixture was extracted with ethyl acetate (3 × 500 mL), and the organic layers were combined and concentrated under reduced pressure. The residue was purified to give 5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole (34 g, 78% yield) as a yellow solid.

[0753] 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 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). The resulting solution was stirred at 50 °C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (6 × 100 mL). The filtrate was extracted with dichloromethane (3 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline (23 g, 88% yield), which was a pale yellow solid.

[0754] 13a. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one

[0755]

[0756] At room temperature and under air atmosphere, aliquots of AgNO3 (57.02 g, 335.64 mmol, 1.0 equivalent) and isobutyric acid (29.57 g, 335.64 mmol, 1.0 equivalent) were added to a solution of 3,6-dichloropyridazine (50.00 g, 335.64 mmol, 1.0 equivalent) in H2O (1.20 L), followed by stirring at 50 °C under nitrogen atmosphere. Aliquots of H2SO4 (98.76 g, 1006.9 mmol, 3.0 equivalent) were then added at 50 °C and stirred at 60 °C. Next, (NH4)2S2O8 (229.78 g, 1006.914 mmol, 3.0 equivalent) was added and stirred at 70 °C under nitrogen atmosphere for 30 min. 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 Na₂SO₄. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3,6-dichloro-4-isopropylpyridazine (30 g, 47%), which was a pale yellow oil.

[0757] To a solution of 3,6-dichloro-4-isopropylpyridazine (20.00 g, 104.679 mmol, 1.0 equivalent) in DMSO (200 mL), 4-amino-2,6-dichloro-phenol (18.63 g, 104.68 mmol, 1.0 equivalent), K₂CO₃ (58.16 g, 420.81 mmol, 4.02 equivalent), and CuI (11.96 g, 62.81 mmol, 0.60 equivalent) were added fractionally. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The mixture was acidified to pH 8 with concentrated HCl. The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline (17 g, 49%) as a green solid.

[0758] To a solution of 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-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 equivalent) was added fractionally. The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. To the mixture, NaOH (12.27 g, 306.77 mmol, 6.0 equivalent) and MeOH (200 mL) were added fractionally. 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 give 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (11 g, 69%) as a grayish-white solid.

[0759] 13b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]aniline

[0760]

[0761] 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 onto ice water (3 L) and the pH of the mixture was adjusted to 8 with hydrochloric acid (3 N). The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate at a ratio of 5:1, PE:EA) to give 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (35.0 g, 24% yield) as a grayish-white solid. LCMS (ESI, m / z): 332 [M+H] + .

[0762] 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 h. After cooling to 25 °C, the pH of the mixture was adjusted to 6–7 with hydrochloric acid (1 N). The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA 5:1) to give 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline (6.80 g, 65% yield) as a white solid.

[0763] LCMS(ESI,m / z):328[M+H] + .

[0764] 14a. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid

[0765]

[0766] Feed 200 mL of MeOH containing 14.13 g (44.98 mmol, 1.0 equivalent) of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one into a 1000 mL round-bottom flask. Add 4.10 mL (112.439 mmol, 3 equivalent) of HCl dropwise at 0 °C. Add 100 mL of H₂O at 0 °C. Stir the mixture for 10 minutes, then add 3.72 g (53.971 mmol, 1.20 equivalent) of NaNO₂ and stir for another 30 minutes at 0 °C. Add tetrahydroxydiborane (40.32 g, 449.749 mmol, 10.0 equivalent). Stir the reaction at 60 °C for 1 hour. Quench the resulting solution with 50 mL of water. The resulting solution was extracted with dichloromethane (3 × 400 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The purified solution yielded 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (6.3 g, 37%) as a white solid.

[0767] 14b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]phenylboronic acid

[0768]

[0769] tert-butyl nitrite (4.24 mL, 35.4 mmol, 2.0 equivalent) was added dropwise to a mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazine-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) under stirring at 0 °C. The resulting mixture was then heated to room temperature and stirred for another 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA 10:1) to give 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (3.50 g, 48% yield) as a yellow solid.

[0770] LCMS(ESI,m / z):391[M+H] + .

[0771] A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (1.00 g, 2.55 mmol, 1.00 equivalent), bis(pinacol)diboron (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 off and the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (column: C18 silica gel; mobile phase, A: water (containing 0.5% TFA) and B: ACN (20% to 95% within 20 minutes) to give 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]phenylboronic acid (610 mg, 64% yield) as a brown solid.

[0772] LCMS(ESI,m / z):359[M+H] + .

[0773] 15. Synthesis of 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile

[0774]

[0775] At 0 °C, 50 mL of water containing sodium nitrite (4.86 g, 70.418 mmol, 2.1 equivalents) was added dropwise to a solution of 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline (15.00 g, 33.532 mmol, 1.0 equivalents) in water (700 mL), concentrated hydrochloric acid (336 mL), and acetic acid (942 mL). After the addition, the reaction mixture was stirred at 0 °C for 45 min. Then, the reaction mixture was rapidly poured at 0 °C into a solution of N-(2-cyanoacetyl)carbamate (7.85 g, 50.30 mmol, 1.5 equivalents) in water (600 mL) and pyridine (336 mL). The resulting mixture was stirred at 0 °C for 30 min and filtered. The filter cake was washed with water (100 mL) and petroleum ether (200 mL) and dried under reduced pressure to give (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-toluenesulfonyl-1H-indol-5-yl)oxy)phenyl)-hydrazine)-acetyl)carbamate (18.4 g, 80% yield) as a red solid.

[0776] Potassium acetate (11.76 g, 119.782 mmol, 4.0 equivalents) was added to a solution of (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-toluenesulfonyl-1H-indol-5-yl)oxy)phenyl)hydrazine)acetyl)carbamate (18.40 g, 29.95 mmol, 1.0 equivalents) in N,N-dimethylacetamide (300 mL). The reaction was stirred at 120 °C for 2 h and quenched with water (100 mL). The mixture was extracted with ethyl acetate (3 × 100 mL), and the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (14 g, 80% yield) as a brown solid.

[0777] N-iodosuccinimide (4.16 g, 18.47 mmol, 1.5 equivalent) was added to a stirred solution of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (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) under a nitrogen atmosphere at 0 °C. 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), and the combined organic layers were combined, washed with saturated sodium thiosulfate solution (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (5.30 g, 43% yield) as a brown solid.

[0778] 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-triazin-6-carboxynitrile

[0779]

[0780] At 0 °C, 33.4 mL of H₂O containing NaNO₂ (230.59 mg, 1.591 mmol, 1.0 equivalent) was added dropwise 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). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes. The solution was then rapidly poured at 0 °C into a second reaction flask containing pyridine (20 mL) containing N-(2-cyanoacetyl)carbamate (372.75 mg, 2.387 mmol, 1.5 equivalent) and H₂O (40.9 mL). The resulting mixture was incubated at 0 °C for 30 minutes. The precipitated solid was collected by filtration and washed with PE and H2O (3 × 300 mL) to give N-[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazine-1-yl)carbonyl]-carbamate as an orange solid, which can also be named (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)-carbamate (name generated by Chemdraw) (640 mg, 84%).

[0781] At room temperature, ethyl N-[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazine-1-yl)carbonyl]carbamate (which can also be named (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate) (640.00 mg, 1.330 mmol, 1.00 equivalent)) in DMA (13.36 mL) was added fractionally to a solution of KOAc (261.01 mg, 2.660 mmol, 2.00 equivalent). The mixture was stirred at 120 °C under a nitrogen atmosphere for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (4 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated. This produced 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-carboxynitrile (590 mg, 102%) as a deep orange solid.

[0782] 17. Synthesis of 4-[(benzoxy)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

[0783]

[0784] To a stirred 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 DCM (200 ml) at room temperature, 4-[(benzoxy)methyl]-6-bromo-2H-1,2,4-triazin-3,5-dione (4.37 g, 13.995 mmol, 1.2 equivalent), Cu(OAc)₂ (4.24 g, 23.326 mmol, 2 equivalent), and pyridine (1.85 g, 23.326 mmol, 2 equivalent) were added. The reaction mixture was stirred under oxygen at room temperature for 2 days, followed by concentration under reduced pressure to give the crude product. Purification yielded 2.2 g of 4-[(benzoxy)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 (yield 28%), a grayish-white solid.

[0785] 18. Synthesis of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidin

[0786]

[0787] 6-Chloro-2-methyl-3-nitropyridine (20.00 g, 115.895 mmol, 1.0 equivalent), 4-amino-2,6-dichlorophenol (24.76 g, 139.07 mmol, 1.2 equivalent), K₂CO₃ (48.05 g, 347.69 mmol, 3.0 equivalent), and DMF (200 mL) were fed into an 8 mL vial. 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), and the organic layers were combined, washed with brine (2 × 400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography and eluted with EA:PE (0%–40% over 30 minutes) to give the desired product, 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]aniline (36.4 g, 91%), as a yellow solid.

[0788] LCMS(ESI,m / z):314[M+H] + .

[0789] TEA (11.73 g, 115.9 mmol, 1.0 equivalent) was added to a solution of 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]-aniline (36.40 g, 115.88 mmol, 1.0 equivalent) and (dimethoxymethyl)dimethylamine (33.14 g, 278.1 mmol, 2.4 equivalent) in dimethylformamide (400 mL). 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 proceeded to the next step without further treatment.

[0790] Pd / C (10.0 g, 93.967 mmol, 0.81 equivalent) and NaOAc (9.51 g, 115.89 mmol, 1.0 equivalent) were added to a solution of (E)-N'-(3,5-dichloro-4-((6-(((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)oxy)phenyl)-N,N-dimethylformamidin (49.17 g, 115.89 mmol, 1.0 equivalent) in DMF (200 mL) and MeOH (400 mL) under hydrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth mat and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography and eluted with EA:PE (0%–70% over 30 minutes) to give the desired product (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylformamidin (21.5 g, 45%) as a brown solid.

[0791] LCMS(ESI,m / z):349[M+H] + .

[0792] KOH (3.21 g, 57.27 mmol, 4.0 equivalent) was added to a solution of (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylformamidin (5.00 g, 14.32 mmol, 1.0 equivalent) and I2 (4.00 g, 15.75 mmol, 1.1 equivalent) in dimethylformamide (50 mL). 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) and the organic layers were combined, washed with brine (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was wet-milled with PE:EA 5:1 to obtain the desired product (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidin (5.9 g, 78%), which was a yellow solid.

[0793] LCMS(ESI,m / z):475[M+H] + .

[0794] 19. Synthesis of 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline

[0795]

[0796] Under nitrogen atmosphere, 4,4,5,5-tetramethyl-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidinium (3.0 g, 6.31 mmol, 1.0 equivalent), K3PO4 (2.01 g, 9.471 mmol, 1.5 equivalent), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.410 g, 0.631 mmol, 0.10 equivalent) in dioxane (75 mL) and H2O (15 mL) were added to a solution of (E)-N'-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidinium (3.0 g, 6.31 mmol, 1.0 equivalent), K3PO4 (2.01 g, 9.471 mmol, 1.5 equivalent), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.410 g, 0.631 mmol, 0.10 equivalent). 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) and 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%–50% over 30 minutes) to give the desired product (E)-N'-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-N,N-dimethylformamidin (430 mg, 14%) as a yellow solid.

[0797] LCMS(ESI,m / z):389[M+H] + .

[0798] Pd / C (250.0 mg, 2.349 mmol, 2.3 equivalents) was added to a solution of (E)-N'-(3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl)-N,N-dimethylformamidin (400.0 mg, 1.028 mmol, 1.0 equivalent) in MeOH (25 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered through a diatomaceous earth mat and washed with MeOH (20 mL). The combined organic layers were concentrated under reduced pressure to give crude product (E)-N'-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidin (380 mg, crude) as a yellow solid.

[0799] LCMS(ESI,m / z):391[M+H] + .

[0800] 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]pyridin-5-yl]oxy)phenyl]-N,N-dimethylformamidin (380.0 mg, 0.97 mmol, 1.0 equivalent) in ethanol (25 mL). The resulting mixture was refluxed and stirred overnight. The reaction mixture was concentrated under reduced pressure to give crude 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline (350 mg, crude) as a yellow semi-solid.

[0801] LCMS(ESI,m / z):336[M+H] + .

[0802] 20. Synthesis of 4-[(benzoxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazine-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione

[0803]

[0804] A mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronic acid (400 mg, 1.12 mmol, 1.0 equivalent), 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazin-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 off and the filter cake was washed with EA (3 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA 1:1) to give 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, 30% yield) as a pale yellow solid.

[0805] LCMS(ESI,m / z):544[M+H] + .

[0806] 21. Procedure for the synthesis of 2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane:

[0807]

[0808] At room temperature (approximately 15°C), under N2 protection, an aqueous solution of 8N KOH (858.57 μL, 6.86 mmol) was added to a solution of 5-benzoxy-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-dioxaborpentane-2-yl)methyl]-1,3,2-dioxaborpentane (1.84 g, 6.87 mmol) in dioxane (10 mL), followed by the addition of Pd[P(t-Bu)3]2 (87.75 mg, 171.71 μmol). The mixture was then stirred at 30°C for 18 hours. TLC (PE:EA 10:1, stained with I2) showed complete consumption of the bromide and the formation of two new spots. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 × 2 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a crude product, which was purified by rapid silica gel chromatography (eluent of 0–2% ethyl acetate / petroleum ether) to give the desired 2-(4-(benzoxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (870 mg, 72% yield) as a white solid.

[0809] 22. Synthesis of trifluoromethanesulfonic acid [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl] ester

[0810]

[0811] Palladium dichloroisocyanurate (1.0 g, 2.54 mmol, 1 equivalent) and 2-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborone (1.79 g, 5.09 mmol, 2 equivalents) in dioxane (30 mL) and H₂O (6 mL) were added to a solution of 5-bromo-3-isopropyl-1-(p-toluenesulfonyl)pyrrolo[3,2-b]pyridine (1.0 g, 2.54 mmol, 1 equivalent) and H₂O (1.79 g, 5.09 mmol, 2 equivalents). Tri-o-tolylphosphine (299.79 mg, 381.39 μmol, 0.15 equivalents) and K₃PO₄ (1.62 g, 7.63 mmol, 3 equivalents) were then stirred at 100 °C for 15 hours under a nitrogen atmosphere. The combined mixture (combined with a 300 mg batch) was diluted with H2O (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography (ethyl acetate in petroleum ether = 0–10%) to give 5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.44 mmol, 74% yield, 96.5% purity) as a yellow solid.

[0812] Pd-C (10%, 1.07 g) was added to a solution of 5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.52 mmol, 1 equivalent) in MeOH (20 mL) and THF (10 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 35 °C for 18 hours under H2 (50 psi). The mixture was filtered and the filtrate was concentrated and purified by rapid silica gel chromatography (0–100% ethyl acetate in petroleum ether) to give 4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol (1 g, 2.23 mmol, 88% yield) as a white solid.

[0813] Tf₂O (754.76 mg, 2.68 mmol, 441.38 μL, 1.2 equivalent) was slowly added dropwise to a solution of 4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol (1 g, 2.23 mmol, 1 equivalent) and pyridine (440.84 mg, 5.57 mmol, 2.5 equivalent) in DCM (25 mL) at 0 °C. After addition, the mixture was stirred at 0 °C for 1 hour. The reaction mixture was partitioned between H₂O (30 mL) and DCM (30 mL). The organic layer was separated, washed with brine (10 mL × 3), dried over anhydrous MgSO4, filtered and concentrated to obtain the crude product, which was purified by rapid silica gel chromatography (0–10% ethyl acetate in petroleum ether) to give a colorless, gel-like trifluoromethanesulfonic acid [4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl] ester (1.25 g, 2.15 mmol, 97% yield).

[0814] 23. Synthesis of 4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylaniline:

[0815]

[0816] Pd2(dba)3 (47.31 mg, 51.67 μmol, 0.1 equivalent), (5-diphenylphosphine-9,9-dimethyl-oxanthracene-4-yl)-diphenylphosphine (59.79 mg, 103.33 μmol, 0.2 equivalent), and Cs2CO3 (505.03 mg, 1.55 mmol, 3 equivalent) were added to a solution of trifluoromethanesulfonic acid [4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl] ester (300 mg, 516.67 μmol, 1 equivalent) and tert-butyl carbamate (121.05 mg, 1.03 mmol, 2 equivalent) in dioxane (8 mL) under N2 protection at 20 °C. The resulting mixture was then stirred at 100°C under N2 for 15 hours. LCMS showed 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 rapid silica gel chromatography (ethyl acetate in petroleum ether = 0–10%) to give N-[4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]tert-butyl carbamate (200 mg, 350.19 μmol, 68% yield, 95.9% purity) as a pale yellow solid.

[0817] A solution of 4M HCl gas in MeOH (8 mL) was added to a solution of N-[4-[[3-isopropyl-1-(p-toluylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]carbamate tert-butyl (170 mg, 310.39 μmol, 1 equivalent) in MeOH (3 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 then washed with H2O (50 mL). The combined aqueous layers were adjusted to pH 7–8 with a saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4-[[3-isopropyl-1-(p-toluylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylaniline (120 mg, 261.40 μmol, 84% yield, 97.5% purity) as a pale yellow solid.

[0818] 24. Synthesis of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide

[0819]

[0820] Trifluoroacetic anhydride (2 equivalents, 5.63 mL) was added to a solution of 4-iodo-3,5-dimethylaniline (1 equivalent, 5 g, 20.24 mmol) in anhydrous DCM (150 mL) at 0 °C under N2. The reaction mixture was then stirred at 25 °C for 2.5 h. Water (200 mL) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (2 × 150 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude mixture was purified by rapid chromatography on silica gel (DCM) to give 2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (6.35 g, 91%) as a white solid.

[0821] Anhydrous THF (35 mL) was added to a mixture of 2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (1 equivalent, 2.40 g, 7 mmol) and 60% NaH (1.5 equivalent, 420 mg) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1.5 h, then cooled to -78 °C and t-BuLi (2.4 equivalent, 9.88 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 40 min. Then, anhydrous DMF (5 equivalent, 2.71 mL) was added and the reaction mixture was further stirred at -78 °C for 1 h. 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 hot EtOH to give 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (317 mg, 19%) as a yellow solid. The supernatant was recrystallized from hot toluene to give more 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (909 mg, 53%) as a pale yellow solid.

[0822] 25. Synthesis of 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline

[0823]

[0824] 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 equivalent, 150 mg) at 0 °C under N2. 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 equivalent, 2.34 mL) was added dropwise, while 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 was further stirred 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 rapid chromatography on silica gel (20% to 40% EA in cyclohexane) to give 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide (317 mg, 29%) as a white solid.

[0825] A solution of Et3SiH (6 equivalents, 0.71 mL) in anhydrous DCM (20 mL) was added dropwise to a solution of TMSOTf (0.075 equivalents, 0.01 mL) in anhydrous DCM (7 mL) at 0 °C under N2. The reaction mixture was then 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). The reaction 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 stirred further at 25 °C for 5 hours. The reaction was then quenched with saturated NaHCO3 aqueous solution (20 mL), and the aqueous phase was extracted three times with DCM (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude mixture was purified by rapid chromatography on silica gel (0% to 30% EA in cyclohexane) to give N-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (144 mg, 47%) as a white solid.

[0826] NaOH (4 equivalents, 54 mg) was added under N2 atmosphere to a solution of N-(3,5-dimethyl-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), and the combined organic layers were washed with brine (2 × 20 mL), dried over MgSO4, filtered, and evaporated to dryness to give 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.

[0827] Example 1: Synthesis of compound 1

[0828]

[0829] At 0°C, a solution of 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]aniline (1.11 g, 2.277 mmol, 1.00 equivalent) was stirred in HCl (21.90 mL), HOAc (62.50 mL), and H2O (47.68 mL). 4.2 mL of H2O containing NaNO2 (0.32 g, 4.566 mmol, 2 equivalent) was added dropwise over 1 hour. At 0°C, a second reaction flask was added to a solution of N-(2-cyanoacetyl)carbamate (0.53 g, 3.424 mmol, 1.5 equivalent) in 58.41 mL of H2O and pyridine (22.35 mL). The reaction was carried out over 10 minutes. Finally, the solution was rapidly poured into the second reaction flask at 0°C over 30 minutes. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This produced N-[(Z)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]phenyl)hydrazine-1-yl]carbonyl]carbamate as a red solid, which can also be named (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-toluenesulfonyl-1H-indol-5-yl)oxy)phenyl)hydrazine)acetyl)carbamate.

[0830] At room temperature, ethyl N-[(Z)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]-oxy]phenyl)hydrazine-1-yl]carbonyl]carbamate (which can also be named (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-toluenesulfonyl-1H-indol-5-yl)oxy)phenyl)hydrazine)acetyl)carbamate) (1.16 g, 1.773 mmol, 1.00 equivalent)) in DMA (20.00 mL) was added fractionally to KOAc (0.35 g, 3.546 mmol, 2 equivalents). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 hours. The reaction was quenched at room temperature by the addition of water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The solid was dried overnight at room temperature to give 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (521.2 mg, 45%) as a red solid.

[0831] TBAF (20 mL) was added fractionally to a stirred solution of 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (521.20 mg, 0.854 mmol, 1.00 equivalent) in 20.00 mL of THF at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C under a nitrogen atmosphere for 20 hours. The reaction 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 give a crude product (200 mg). The crude product (200 mg) was purified by preparative HPLC to give 2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (11.5 mg, 3%, compound 1) as a yellow solid.

[0832] 1H-NMR: (300MHz, DMSO-d6) δppm: 10.67-10.60 (m, 1H), 7.77 (s, 2H), 7.30 (d, J = 8.7Hz, 1H), 7.07 (s, 1 H), 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).

[0833] Example 2: Synthesis of compound 2

[0834]

[0835] A 100 mL three-necked round-bottom flask, under a nitrogen inert atmosphere, was fed with concentrated HCl (9.60 mL), AcOH (27.40 mL), and H₂O (20.9 mL) containing 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylaniline (450.00 mg, 1.003 mmol, 1.00 equivalent). H₂O (1.8 mL) containing NaNO₂ (145.35 mg, 2.107 mmol, 2.1 equivalent) was added dropwise over 45 minutes. In a second reaction flask at 0°C, 25.6 mL of H₂O containing methyl N-(2-cyanoacetyl)carbamate (213.85 mg, 1.505 mmol, 1.50 equivalent) and 9.80 mL of pyridine were added and allowed to stand for 10 minutes. The solution was then rapidly poured into the second reaction flask at 0°C and allowed to stand for 30 minutes. The precipitated solid was collected by filtration and washed with water and PE. The resulting mixture was concentrated under vacuum. This produces N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazine-1-yl]-carbonyl]carbamate, which is a red solid and can also be named (Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-toluenesulfonyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate.

[0836] At room temperature, ethyl N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazine-1-yl]carbonyl]carbamate (also named (Z)-(2-cyano-2-(2-(4-(((3-isopropyl-1-toluenesulfonyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate) (a name generated by Chemdraw) (560.0 mg, 0.910 mmol, 1.00 equivalent) in DMA (10.00 mL) was added fractionally to a solution of KOAc (178.52 mg, 1.819 mmol, 2.0 equivalent). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 hours. The reaction was quenched at room temperature by the addition of water (10 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (350 mg, 56%) as a red solid.

[0837] To a stirred solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (330.00 mg, 1 equivalent) in THF, 8.00 mL of TBAF (1 M in THF) was added. 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-indol-5-yl)oxy]-3,5-dimethyl-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (132.3 mg, 54%) as a yellow solid.

[0838] 1H-NMR: (300MHz, DMSO-d6) δppm: 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).

[0839] Example 3: Synthesis of compound 3

[0840]

[0841] In the first reaction flask, under nitrogen atmosphere and at 0°C, a solution of 4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline (480.00 mg, 1.075 mmol, 1.00 equivalent) in concentrated HCl (9.60 mL), HOAc (28.80 mL), and H2O (22.4 mL) was added to H2O (22.4 mL). The reaction mixture was stirred at 0°C for 45 minutes. In the second reaction flask, a solution of 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 mixture from the first reaction flask was quickly 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, a yellow solid, was separated, 520 mg, 80% pure, 63% yield.

[0842] KOAc (111.94 mg, 1.141 mmol, 2.0 equivalent) was added to a stirred solution of N-[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)hydrazine-1-yl]carbonyl]carbamate (which can also be named (Z)-(2-cyano-2-(2-(4-(((3-isopropyl-1-toluenesulfonyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate (350.00 mg, 0.570 mmol, 1.0 equivalent) in DMA (8.0 mL) at room temperature. The reaction mixture was stirred at 120 °C for 3 hours. The reaction 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 under vacuum at 60 °C for 2 h to give 2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile. The desired product, 250 mg, 80% pure, 62% yield, was separated as a deep orange solid.

[0843] Under nitrogen atmosphere and at 0°C, TBAF (10.57 mL, 10.570 mmol, 30.00 equivalent, 1 M in THF) was added to a stirred solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (200.00 mg, 0.352 mmol, 1.00 equivalent) in 5.00 mL of THF. The reaction mixture was stirred at 65°C for 3 days. The reaction mixture was then concentrated under reduced pressure to give the crude product. The sample was purified to give 2-(4-((3-isopropyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile (compound 3, 29.7 mg, 99% pure, 20% yield) as a yellow solid.

[0844] 1 H NMR(400MHz,DMSO-d6)δppm:13.00(br,1H),10.63(s,1H),7.19-7.22(m,2H),7.14(s,2H),7.01(d ,J=2.0Hz,1H),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).

[0845] Example 4: Synthesis of compound 4

[0846]

[0847] 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (1.00 g, 1.44 mmol, 1.00 equivalent), dichloro[1,1'-bis(diphenylphosphine)-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) were fed into a 50 mL autoclave. The contents of the autoclave were placed under a carbon monoxide atmosphere (30 atm). The reaction was stirred overnight at 90 °C. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified to give 500 mg (67% yield) of methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzene-sulfonyl)-indole-3-carboxylate as a brown solid.

[0848] Methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)indole-3-carboxylate (400 mg, 0.639 mmol, 1.00 equivalent), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (6.39 mL, 1 M solution in tetrahydrofuran, 6.39 mmol, 10.0 equivalent) were added to a 40 mL vial. The reaction was stirred overnight at 65 °C and quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 × 20 mL), and the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 30.4 mg (15% yield) of methyl 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxylate as a yellow solid.

[0849] 1 ¹H NMR (300MHz, methanol-d⁴) δppm: 7.97 (s, 1H), 7.80 (s, 2H), 7.41–7.44 (m, 2H), 6.88–6.92 (m, 1H), 3.84 (s, 3H).

[0850] Example 5: Synthesis of Compound 5

[0851]

[0852] 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (1.00 g, 1.759 mmol, 1.00 equivalent), tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (52.78 mL, 1 M solution in tetrahydrofuran, 52.78 mmol, 30.00 equivalent) were fed into a 250 mL round-bottom container. 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), and the organic layers were combined, washed with brine (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 500 mg (69% yield) of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile as a yellow solid.

[0853] Cyclopentanone (366 mg, 4.35 mmol, 6.00 equivalent) was added to a stirred solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-carboxynitrile (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) under nitrogen atmosphere at 100 °C. 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-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile as a yellow solid.

[0854] 1 H NMR (300MHz, DMSO-d6) δppm: 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).

[0855] Example 6: Synthesis of Compound 6

[0856]

[0857] Under nitrogen atmosphere, 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (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) were fed into a 50 mL round-bottom flask. 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. Purification yielded 63.2 mg (17% yield) of 2-(3,5-dichloro-4-[[3-(1-phenylethyl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile as a yellow solid.

[0858] 1 H NMR(300MHz,DMSO-d6)δppm: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).

[0859] Example 7: Synthesis of Compound 7

[0860]

[0861] 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)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (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) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 90 °C and concentrated under reduced pressure. The residue was purified to give 170 mg (42% yield) of 2-(3,5-dichloro-4-[[1-(4-methyl-benzene-sulfonyl)-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile as a light brown solid.

[0862] At room temperature under a nitrogen atmosphere, tert-butylammonium fluoride (4.96 mL, 1 M solution in tetrahydrofuran, 4.96 mmol, 20.00 equivalent) was added to a stirred solution of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (160 mg, 0.248 mmol, 1.00 equivalent) in tetrahydrofuran (4 mL). 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), and the combined organic layers were combined, 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-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (compound 7, 39 mg, 32%) as a pale orange solid.

[0863] 1 ¹H NMR (300MHz, methanol-d⁴) δppm: 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).

[0864] Example 8: Synthesis of Compound 8

[0865]

[0866] At room temperature, HCl (2.00 mL, 0.055 mmol, 0.12 equivalents) was added fractionally 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-triazin-6-carboxynitrile (200.00 mg, 0.460 mmol, 1.00 equivalents) in HOAc (4.43 mL, 0.074 mmol, 0.16 equivalents). The resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The crude product (160 mg) was purified to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-carboxylic acid (78.3 mg, 38%) as a grayish-white solid.

[0867] 1 H NMR (400MHz, DMSO-d6): δppm: 13.82 (s, 1H), 12.70 (s, 1H), 12.19 (s, 1H), 7.82 (s, 2H), 7.44 (s, 1H), 3.05 (p, J = 6.8Hz, 1H), 1.20 (d, J = 6.9Hz, 6H).

[0868] Example 9: Synthesis of Compound 9

[0869]

[0870] At 0 °C, K₂CO₃ (190.53 mg, 1.379 mmol, 3.00 equivalent) and H₂O₂ (2 mL, 30% in water) were added fractionally 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-triazin-6-carboxynitrile (200.00 mg, 0.460 mmol, 1.00 equivalent) in DMSO (5 mL). The resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with saturated Na₂S₂O₃ solution at room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18; mobile phase, ACN in water, 10% to 80% gradient over 30 minutes) to give a crude product (150 mg), which was then purified by preparative HPLC (column: XBridge Prep OBD C18 column, mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 33% B over 9 minutes) to give a white solid 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-carboxamide (112.1 mg, 54%).

[0871] 1 H NMR (400MHz, DMSO-d6) δppm: 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).

[0872] Example 10: Synthesis of compound 10

[0873]

[0874] 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 added fractionally 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-triazin-6-carboxylic acid (200.00 mg, 0.440 mmol, 1.00 equivalents) 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, eluting with CH2Cl2:MeOH (50:1) to give N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-tert-butyl carbamate (110 mg, 48%) as a white solid.

[0875] LCMS(ESI,m / z):525[M+H] + .

[0876] A solution of N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate tert-butyl ester (90.0 mg, 1 equivalent) in 5.00 mL of 1,4-dioxane solution in 4N HCl 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 C18, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 40B 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.

[0877] 1H NMR (400MHz, DMSO-d6) δppm: 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).

[0878] Example 11: Synthesis of compound 11

[0879]

[0880] At room temperature under a nitrogen atmosphere, 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 added participle 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-triazin-3,5-dione (430.00 mg, 0.706 mmol, 1.00 equivalent) and trimethylsilylacetylene (207.96 mg, 2.117 mmol, 3.00 equivalent) in DMF (10 mL). 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 Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazin-3,5-dione (260 mg, 52%) as a grayish-white solid.

[0881] BBr3 (383.84 mg, 1.532 mmol, 4.00 equivalent) was added dropwise to a stirred solution of 4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazin-3,5-dione (240.00 mg, 0.383 mmol, 1.00 equivalent) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 4 hours and quenched with MeOH (5 mL). The mixture was concentrated under reduced pressure to give 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-triazin-3,5-dione as a light brown solid.

[0882] 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-triazin-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 stirred at room temperature. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure to give a 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-triazin-3,5-dione) as a white solid.

[0883] 1 H NMR (400MHz, DMSO-d6) δppm: 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)

[0884] Example 12: Synthesis of compound 12

[0885]

[0886] At room temperature, K₂CO₃ (272.21 mg, 1.970 mmol, 4.0 equivalent) was added to a stirred solution of 4-[(benzoxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazin-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 equivalent) in DMF (5.00 mg). 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), and 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 give 190 mg (95% pure) of tert-butyl 2-[4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate as a yellow solid (190 mg, 58%).

[0887] 2-[4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate tert-butyl ester (190.00 mg, 0.284 mmol, 1.00 equivalent), TsOH (24.43 mg, 0.142 mmol, 0.5 equivalent), and toluene (5 mL) were fed into a 50 mL round-bottom flask. The resulting solution was stirred at 90 °C for 4 hours and quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL) and the organic layers were combined. The mixture was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 190 mg of crude (70% pure) 2-[4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile (190 mg, 82% yield) as a yellow oil.

[0888] BBr3 (501.57 mg, 2.002 mmol, 6.0 equivalent) was added to a stirred solution of 2-[4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile (190.00 mg, 0.334 mmol, 1.00 equivalent) in DCM (3 mL) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 × 20 mL), and the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification 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-triazin-6-yl)acetonitrile as a white solid.

[0889] 1 H NMR (400MHz, DMSO-d6) δppm: 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).

[0890] Example 13: Synthesis of compound 13

[0891]

[0892] Under nitrogen atmosphere at room temperature, Cs₂CO₃ (561.52 mg, 1.723 mmol, 3.0 equivalent) was added to a stirred solution of 4-[(benzoxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazin-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). The reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with dichloromethane (3 × 50 mL), and the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (50 mL) and slurried using a 100–200 silica gel sieve (2 g). The sample was purified and the desired product, a yellow oil, was separated. 270 mg, 90% pure, 61% yield.

[0893] BBr3 (363.86 mg, 1.452 mmol, 4.00 equivalents) was added to a stirred solution of 1,3-diethyl 2-[4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-malonic acid (250.00 mg, 0.363 mmol, 1.00 equivalent) in DCM (5.00 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (15 mL). The resulting solution was extracted with dichloromethane (3 × 30 mL), and the organic layers were combined, washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. No further purification was performed on this substance. The crude product, which was a yellow solid, was separated. 210 mg, 70% pure, 71% yield.

[0894] To a stirred solution of 1,3-diethyl 2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)malonic acid (210.00 mg, 0.369 mmol, 1.00 equivalent) in MeOH (5.00 mL) and H₂O (1.00 mL), 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), and the organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified to give 2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)acetic acid. The desired product (54.0 mg, 99.5% pure, 31% yield) was isolated as a white solid.

[0895] 1 H NMR (300MHz, DMSO-d6) δppm: 7.82 (s, 1H), 7.44 (s, 1H), 3.44 (s, 2H), 3.01-3.10 (m, 1H), 1.19-1.24 (m, 6H).

[0896] Example 14: Synthesis of compound 14

[0897]

[0898] Methylamine (3.3 mL, 6.565 mmol, 10.00 equivalent, 2 M THF solution in n-BuOH) was added to a stirred solution of 4-[(benzoxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazin-3,5-dione (400.00 mg, 0.657 mmol, 1.00 equivalent) in n-BuOH (5 mL). The reaction mixture was stirred overnight at 110 °C. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified to give 220 mg (53% yield) of 4-[(benzoxy)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 light-colored solid.

[0899] BBr3 (716.55 mg, 2.860 mmol, 4.00 equivalent) was added to a solution of 4-[(benzoxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-1,2,4-triazin-3,5-dione (400.00 mg, 0.715 mmol, 1.00 equivalent) in DCM under stirring at -78 °C. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a 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-triazin-3,5-dione as a white solid.

[0900] 1 H NMR (300MHz, DMSO-d6) δppm: 12.99 (s, 1H), 12.23 (s, 1H), 8.82 (d, J = 4.8Hz, 1H), 8.16 (s, 2H), 7.42 (s, 1H), 3.03-3.08 (m, 1H), 2.79 (d, J = 4.8Hz, 3H), 1.20 (d, J = 6.9Hz, 6H).

[0901] Example 15: Synthesis of Compound 15

[0902]

[0903] Add 8 mL of n-BuOH containing 4-[(benzoxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazin-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) to a 50 mL round-bottom flask at room temperature. Stir the reaction mixture overnight at 110 °C. Concentrate the reaction mixture under reduced pressure to obtain the residue. The residue was purified to give 170 mg (41% yield) of 4-[(benzoxy)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 light pink solid.

[0904] 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethyl-amino)-1,2,4-triazin-3,5-dione (160.00 mg, 0.279 mmol, 1.00 equivalent) and DCM (10.00 mL) were fed into a 50 mL round-bottom flask. 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 give the crude product. Purification yielded 54.3 mg (42% yield) of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethylamino)-4H-1,2,4-triazin-3,5-dione.

[0905] 1 HNMR (300MHz, DMSO-d6) δppm: 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).

[0906] Example 16: Synthesis of compounds 16 and 23

[0907] Compound 16

[0908]

[0909] Under a nitrogen atmosphere, Pd(PPh3)4 (168.46 mg, 0.146 mmol, 0.20 equivalent) was added to a mixture of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (250.00 mg, 0.729 mmol, 1.00 equivalent), 6-bromo-2-methyl-4H-1,2,4-triazin-3,5-dione (180.19 mg, 0.875 mmol, 1.20 equivalent), K2CO3 (201.48 mg, 1.458 mmol, 2.00 equivalent) in dioxane (10 mL) and H2O (1 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was quenched with water (15 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was wet-milled with EA:PE 1:5 and MeCN (5 mL), washed with diethyl ether (5 mL), to give the desired product 6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-methyl-4H-1,2,4-triazin-3,5-dione (103.8 mg, 34%) as a white solid.

[0910] 1 H NMR (300MHz, DMSO-d6) δppm: 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).

[0911] Compound 23

[0912]

[0913] Compound 23 was prepared similarly to compound 16, using 6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione instead of 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione.

[0914] 1 H 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]+ .

[0915] Example 17: Synthesis of Compound 17

[0916]

[0917] At -45°C under nitrogen, 0.4 mL of acetonitrile containing chlorosulfonyl isocyanate (102.5 mg, 0.724 mmol, 1.2 equivalent) was added dropwise to a solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (250.0 mg, 0.604 mmol, 1.00 equivalent) in acetonitrile (4 mL). A fine precipitate formed during the addition. The mixture was stirred at -45°C under nitrogen for 10 minutes. Then, N,N-dimethylformamide (4 mL) was slowly added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched at 0°C by adding water / ice (10 mL). 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 using dichloromethane:methanol (12:1) to give a crude product (160 mg). The crude product (160 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30 × 150, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B to 50% B over 8 minutes) to give a pale yellow solid 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxynitrile (75.9 mg, 29% yield).

[0918] 1 H NMR(300MHz,DMSO-d6)δ13.30(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).

[0919] Example 18: Synthesis of compounds 18 and 19

[0920]

[0921] Add dropwise 12 mL of H₂O containing NaNO₂ (150.8 mg, 2.19 mmol, 2.1 equivalents) to a solution of 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline (350.0 mg, 1.04 mmol, 1.0 equivalents) in HCl (5.5 mL, concentrated), AcOH (16 mL), and H₂O (12 mL). Stir the mixture at 0 °C for 30 minutes. Then, rapidly pour the reaction mixture at 0 °C into a solution of N-(2-cyanoacetyl)carbamate (243.8 mg, 1.56 mmol, 1.5 equivalents) in H₂O (16 mL) and pyridine (5.5 mL). Stir the resulting mixture at 0 °C for 30 minutes and filter. The filter cake was washed with water (2×15mL) and petroleum ether (2×15mL), and dried under reduced pressure to obtain (350mg, crude) N-[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazine-1-yl])carbonyl]carbamate as a yellow solid.

[0922] LCMS(ESI,m / z):503[M+H] + .

[0923] KOAc (341.22 mg, 3.477 mmol, 5.00 equivalent) was added to a solution of N-[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazine-1-yl])carbonyl]carbamate (350.00 mg, 0.695 mmol, 1.00 equivalent) in DMA (20 mL). 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) and the organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH / DCM = 1:7; Rf = 0.4; detection: UV) to give the crude product (180 mg). The product was separated 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: 10% B to 10% B over 21 minutes. The purified product, 2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (86.3 mg, 26%), was obtained as a yellow solid.

[0924] 1 H NMR(300MHz,DMSO-d6)δ13.25(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).

[0925] LCMS(ESI,m / z):457.0[M+H] + .

[0926] The reaction also produces a byproduct, a yellow solid compound 2-[3,5-dichloro-4-([3-propyl-1H-pyrrolo[3,2-b]-pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylonitrile (20.8 mg, 6%).

[0927] 1 H NMR (300MHz, DMSO-d6) δ13.26(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] + .

[0928] Example 19: Synthesis of compounds 20, 21 and 22

[0929] Compound 21

[0930]

[0931] Feed 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxynitrile (600.00 mg, 0.864 mmol, 1.00 equivalent), dimethylamine (2.59 mL, 2 M solution in tetrahydrofuran, 5.185 mmol, 6.00 equivalent), 1,1'-bis(diphenylphosphine)ferrocene (95.47 mg, 0.173 mmol, 0.20 equivalent), bis(acetonitrile)palladium(II) chloride (22.42 mg, 0.0864 mmol, 0.10 equivalent), triethylamine (262.35 mg, 2.593 mmol, 3.00 equivalent), and toluene (15 mL) into a 20 mL autoclave. The contents of the autoclave were placed under a carbon monoxide atmosphere (20 atm). The reaction was stirred overnight at 100 °C and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL), and the organic layers were combined, washed with brine (3 × 15 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by C18 column chromatography using CH3CN:water (3:2) to give 300 mg (49% yield) of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamide as a light brown solid.

[0932] LCMS(ESI,m / z):637[MH] - .

[0933] Tetrabutylammonium fluoride (1.25 mL, 1 M in tetrahydrofuran, 1 mmol, 4.00 equivalence) was added to a stirred solution of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamide (200.00 mg, 0.313 mmol, 1.00 equivalence) in tetrahydrofuran (10 mL) 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), and 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 RP18 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) to obtain 52 mg (34% yield) of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1H-indole-3-carboxamide as a pale yellow solid.

[0934] 1 ¹H NMR (300MHz, methanol-d⁴) δ 7.76 (s, 1H), 7.68 (s, 2H), 7.41 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.90–6.94 (m, 1H), 3.13 (s, 6H).

[0935] LCMS(ESI,m / z):485[M+H] + .

[0936] Compound 20

[0937]

[0938] Compound 20 was prepared similarly to compound 21, using 2 equivalents of isopropylamine instead of 6 equivalents of dimethylamine and reacting overnight at 80°C.

[0939] 1H NMR (300MHz, methanol-d4) δ7.89 (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).

[0940] LCMS(ESI,m / z):499[M+H] + .

[0941] Compound 22

[0942]

[0943] Compound 22 was prepared similarly to compound 21, using 1.5 equivalents of tetrahydroisoquinoline instead of 6 equivalents of dimethylamine.

[0944] 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.70 (d, J = 8.4 Hz, 3H), 7.45 (d, J = 8.8 Hz, 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 = 6.0 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H).

[0945] LCMS: 573 [M+H] + .

[0946] Example 20: Synthesis of compounds 24, 25 and 26

[0947] Compound 25

[0948]

[0949] Ethyl chloroformate (126.62 mg, 1.167 mmol, 1.06 equivalent) 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-triazin-6-carboxylic acid (500 mg, 1.101 mmol, 1.00 equivalent) and N,N-diisopropylethylamine (298.77 mg, 2.312 mmol, 2.10 equivalent) in tetrahydrofuran (30 mL) under nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature for 1 hour and treated dropwise with a solution of sodium borohydride (124.94 mg, 3.302 mmol, 3.00 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), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product (400 mg) was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 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, producing a white solid 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2,4-triazin-3,5-dione (100.6 mg, 21% yield).

[0950] 1 H NMR(300MHz,DMSO-d6)δ12.48(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).

[0951] LCMS(ESI,m / z):440[M+H] + .

[0952] Compound 24

[0953]

[0954] 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2,4-triazin-3,5-dione (1.60 g, 3.634 mmol, 1.00 equivalent) and acetonitrile (15 mL) were fed into a 50 mL round-bottom flask. Phosphorus tribromide (0.3 mL) was added at 0 °C under nitrogen atmosphere. 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), and the organic layers were combined, washed with brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.1 g (39% yield) of 6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazin-3,5-dione as a yellow solid.

[0955] LCMS(ESI,m / z):502[M+H] + .

[0956] To a 50 mL round-bottom flask, feed 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 solution in tetrahydrofuran, 2.385 mmol, 3.00 equivalent), and N,N-dimethylformamide (8 mL). Stir the mixture at 70 °C for 1 hour. Cool the mixture to room temperature and dilute with water (5 mL). At this point, acidify with 1 N hydrochloric acid (5 mL) and extract with ethyl acetate (3 × 10 mL). Discard the organic layer. The aqueous layer was made alkaline by adding 15 mL of saturated NaHCO3 solution and extracted with a 3:1 mixture of chloroform and isopropanol (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 (300 mg) was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 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-triazin-3,5-dione (64.8 mg, 18% yield) as a white solid. 1H NMR (300MHz, DMSO-d6) δ12.23(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] + .

[0957] Compound 26

[0958]

[0959] Compound 26 was prepared similarly to compound 24, using dimethylamine instead of methylamine and reacting at 60°C for 1 hour. 1 H NMR (300MHz, DMSO-d6) δ12.21(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] + .

[0960] Example 21: Synthesis of compound 27

[0961]

[0962] To a 100 mL round-bottom flask, feed 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 (400.00 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). Stir the mixture at 70 °C for 1 hour, then cool to room temperature and dilute with water (5 mL). At this point, acidify with 1 N hydrochloric acid (5 mL) and extract with ethyl acetate (3 × 10 mL). Discard the organic layer. The aqueous layer was made alkaline by adding saturated NaHCO3 solution (15 mL) and extracted with a chloroform:isopropanol mixture of 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 (150 mg) was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 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 a white solid 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(imidazol-1-ylmethyl)-4H-1,2,4-triazin-3,5-dione (14.5 mg, 4% yield).

[0963] 1 H NMR(300MHz,DMSO-d6)δ12.19(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).

[0964] LCMS(ESI,m / z):490[M+H] + .

[0965] Example 22. Synthesis of compound 28

[0966]

[0967] Dichlorofluoromethane was bubbled into a mixture of 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazin-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) for 4 hours, and the mixture was stirred at 50 °C for 5 hours. The reaction 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 2:1) to give 230 mg (65% yield) of 4-[(benzoxy)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.

[0968] LCMS(ESI,m / z):594[M+H] + .

[0969] A hydrochloric acid solution (4 mL, 4 M in 1,4-dioxane) containing 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazin-3,5-dione (230 mg, 0.387 mmol, 1.00 equivalent) was 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 BBr3 solution (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, and the residue was purified by reversed-phase chromatography (column: C18 silica gel; mobile phase: A: water (containing 10 mM NH4HCO3) and B: ACN (0% to 50% within 15 minutes); detector: UV 220 / 254 nm). The eluent was lyophilized to give 113.4 mg (63% yield) of 6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-4H-1,2,4-triazin-3,5-dione as a white solid.

[0970] 1H NMR(400MHz,DMSO-d6)δppm: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] + .

[0971] Example 23 Synthesis of compound 29

[0972]

[0973] Under nitrogen atmosphere, 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) and N,N-dimethylformamide (8 mL) were fed into a 50 mL round-bottom flask. Sodium methoxide (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 analyzed by chromatographic analysis on a silica gel column using dichloromethane / methanol (10 / 1) to obtain a crude product (150 mg), which was then purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 31% B to 51% B over 8 minutes; purification yielded a white solid 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methoxymethyl)-4H-1,2,4-triazin-3,5-dione (26.2 mg, 7% yield).

[0974] 1 H NMR (300MHz, DMSO-d6) δ12.53(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).

[0975] LCMS(ESI,m / z):454[M+H] + .

[0976] Example 24 Synthesis of compound 30

[0977]

[0978] Under hydrogen atmosphere, 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-carboxynitrile (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) were fed into a 100 mL round-bottom flask. The resulting solution was stirred overnight at room temperature and then filtered through diatomaceous earth. The diatomaceous earth 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) and 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 C18 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. The purified product was a white solid, 6-(aminomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazin-3,5-dione (29.6 mg, 10% yield). 1 H NMR (300MHz, DMSO-d6) δ7.93 (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] + .

[0979] Example 25. Synthesis of compound 31

[0980]

[0981] A mixture of 4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylaniline (70 mg, 156.39 μmol, 1 equivalent) and concentrated HCl (87.97 μL, 6.75 equivalent) in H₂O (1 mL) was added dropwise to a solution of sodium nitrite (14.84 mg, 215.04 μmol, 1.38 equivalent) 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 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 2 hours. The reaction mixture (combined with another 50 mg batch) was diluted with H2O (10 mL), adjusted to pH 7–8 with a saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (ethyl acetate in petroleum ether = 0–35%) to give N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazine]acetyl]carbamate (75 mg, 31% yield) as a yellow solid.

[0982] A mixture of N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazine]-acetyl]carbamate (55 mg, 89.47 μmol, 1 equivalent) and NaOAc (36.70 mg, 447.36 μmol, 5 equivalent) in AcOH (5 mL) was stirred at 130 °C for 5 hours. The AcOH was removed under reduced pressure, and the residue was diluted with H2O (50 mL), adjusted to pH 7–8 with saturated NaHCO3 aqueous solution, and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-[4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxynitrile (65 mg) as a yellow solid, which was used directly in the next step without further purification.

[0983] TBAF (1M solution in THF, 2.53 mL, 24 equivalents) was added in a single batch to a solution of 2-[4-[[3-isopropyl-1-(p-toluylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxynitrile (60 mg, 105.51 μmol, 1 equivalent) in 5 mL of THF. The resulting mixture was then stirred at 65 °C under N2 for 8 hours. LCMS showed that the reaction was complete. The mixture was diluted with 100 mL of H2O and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated NH4Cl aqueous solution (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC [column: Welch Xtimate C18 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]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxynitrile (25 mg, 56% yield, 98.3% purity) as a pale yellow solid.

[0984] 1 H NMR(400MHz,DMSO-d6)δ□13.11-12.66(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).

[0985] Example 26. Synthesis of compound 32

[0986]

[0987] 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)methyl)aniline (1 equivalent, 100 mg, 0.31 mmol) in HCl 37% (106 equivalents, 2.7 mL), acetic acid (8.3 mL), and water (6.5 mL) under N2 conditions at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Simultaneously, a solution of N-(2-cyanoacetyl)carbamate (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 rapidly added to the second reaction mixture. The resulting reaction mixture was stirred at 0 °C for 2 hours.

[0988] The precipitate was filtered and washed with water and petroleum ether to give ethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazole-5-yl)methyl)phenyl)hydrazine)acetyl)carbamate (13 mg) as a yellow solid. The filtrate was extra...

Claims

1. A compound of Formula I’: TL-L a -CE-HD Formula I', or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: i) TL is a moiety of Formula IIIb: Formula IIIb, wherein: Q4 is -CH- and Q5 is nitrogen; R4 is Ci-C6alkyl; Alk is hydrogen; ii) CE is a moiety of Formula IV Formula IV, wherein: R6 and R7 are each chloro; R8 is hydrogen; Q7 is -CH-; (TL) represents the point of attachment of said moiety of formula IV to TL-L a -; and (HD) indicates the point of attachment of the moiety of Formula IV to -HD; iii) HD is a moiety of Formula V: Formula V, wherein: R9 is -NH2-; and L a is oxygen.

2. A compound selected from the group consisting of: , and .

3. A compound selected from the group consisting of: , , and .

4. A compound, or a pharmaceutically acceptable salt thereof, the compound being .

5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a stereoisomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

6. Use of a compound of any one of claims 1-4, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disease selected from the group consisting of obesity, hyperlipidemia, diabetes, liver steatosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

7. Use of a compound of any one of claims 1-4, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disease selected from the group consisting of nonalcoholic steatohepatitis, hypercholesterolemia, and atherosclerosis.

8. Use of a pharmaceutical composition of claim 5 in the manufacture of a medicament for the treatment of a condition or disease selected from the group consisting of obesity, hyperlipidemia, diabetes, liver steatosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

9. Use of a pharmaceutical composition of claim 5 in the manufacture of a medicament for the treatment of a condition or disease selected from the group consisting of nonalcoholic steatohepatitis, hypercholesterolemia, and atherosclerosis.

10. A method of selectively modulating the activity of thyroid hormone receptor beta, the method comprising contacting a compound of any one of claims 1-4, or a stereoisomer or a pharmaceutically acceptable salt thereof, with the thyroid hormone receptor, wherein the contacting is in vitro.

11. Use of a compound of any one of claims 1-4, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for selectively modulating the activity of thyroid hormone receptor beta.

12. Use of a pharmaceutical composition of claim 5 in the manufacture of a medicament for selectively modulating the activity of thyroid hormone receptor beta.

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