EA047363B1 - THR-β MODULATORS AND METHODS OF THEIR APPLICATION - Google Patents

Description

The present invention relates to the field of pharmaceutical compounds and preparations and a method of using them for the treatment of diseases. In particular, the present invention relates to the field of THR-β modulators and their use.

State of the art

In parallel with the global rise in obesity, non-alcoholic fatty liver disease (NAFLD) is emerging as a leading cause of chronic liver disease and liver transplantation worldwide [1, 2]. NAFLD is thought to affect 30% of the adult population and 70-80% of people with obesity and diabetes. NAFLD is defined as excess fat accumulation in the liver of more than 5% caused by causes other than alcohol consumption. NAFLD progresses to liver inflammation (nonalcoholic steatohepatitis, NASH) and fibrosis in varying numbers of individuals, ultimately leading to liver failure and hepatocellular carcinoma (HCC) in susceptible individuals [3].

In the United States alone, NASH is the third most common indication for liver transplantation and is on track to become the most common [4]. The most important medical need in patients with NAFLD and NASH is effective treatment to arrest the progression and possibly reversal of fibrosis, which is a major predictor of the development of liver disease [5, 6]. Thyroid hormone (TH) is essential for normal development, growth and metabolism of all vertebrates. Its effects are 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, TR first binds as a heterodimer or homodimer to TH response elements (TREs) located in the promoter regions of target genes, where it interacts with corepressors. Upon ligand binding, TR homodimers dissociate in favor of forming a heterodimer with the retinoid-X receptor (RXR), resulting in the release of corepressors and recruitment of coactivators. This new complex recruits a large number of proteins that engage RNA polymerase II in the transcription of target genes.

Two distinct genetic loci, designated THRA and THRB, are responsible for encoding multiple interrelated TR isoforms that have distinct tissue distributions and biological functions. The two major isoforms with the broadest tissue expression levels are TRa1 and TRe1 [8]. While TRa1 is first expressed during fetal development and widely expressed in adult tissues, TRe1 appears later in development and exhibits greatest expression in the adult liver, kidney, and lung [9]. TRa1 is a key regulator of cardiac output, while TR[t1 helps control hepatic metabolism. It is important to note that natural thyroid hormone T3 activates both TRa1 and TRe1 without any significant selectivity.

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

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

The essence of the invention

Disclosed herein are compounds of formula (I') (D) TL-Ln-CE-HD or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, wherein:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId);

ii) L _a independently represents a bond; -(C(R _a ) ₂ )n-; oxygen; sulfur; -NR _a -;

iii) CE is a fragment of formula (IV);

iv) HD is a fragment of formula (V) or (VI);

wherein the substituents are as defined herein.

- 1 047363

Also disclosed are pharmaceutical compositions containing the above compounds and methods for treating a disease by administering to or contacting a patient with one or more of the above compounds.

Brief description of graphic materials

In fig. Figure 1 shows the chemical structure of compound 67, confirmed by X-ray crystallography.

In fig. Figure 2 shows the chemical structure of compound 67-A, confirmed by X-ray crystallography.

Detailed Description of Embodiments

Disclosed herein are novel compounds that are effective modulators of THR-β activity that can be used to treat various THRβ-related disorders. The compounds and their uses are discussed in detail below. Certain of the compounds described herein are agonists, while others are antagonists of TRa and/or TRe receptors and are used for the treatment of liver-related diseases and other indications known in the art that are mediated by TRa and/or TRe receptors .

Definitions

Various embodiments are described below. It should be noted that specific embodiments are not intended to be exhaustive or limiting to the broader aspects discussed herein. One aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and may be practiced with any other embodiment(s).

As used herein, about will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If there are uses of a term that are not clear to those skilled in the art, given the context in which it is used, about will mean up to plus or minus 10% of the specific term.

The use of singular terms and similar references in the context of the description of elements (especially in the context of the following claims) should be construed to cover both the singular and plural unless otherwise indicated herein or clearly contrary to the context. The listing of ranges of values in this document is simply intended to be used as a shorthand method for individually referring to each individual value falling within that range unless otherwise stated herein, and each individual value is included in the specification as if it were separately set forth in this document. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly inconsistent with the context. The use of any and all examples or illustrative language (eg, such as) presented herein is intended merely to better illuminate the embodiments and does not constitute a limitation on the scope of the claims unless otherwise indicated. No language in the specification should be construed to indicate any non-stated item is essential.

In the definition of chemical substituents, R _x and R _y are each independently hydrogen, alkyl, carbocyclic ring, heterocyclic ring, aryl or heteroaryl, all of which except hydrogen are optionally substituted. Unless otherwise noted, the abbreviations TR and THR refer to thyroid hormone receptors.

As used herein, a pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to the patient to whom it is administered and does not alter the biological activity and properties of the compound. Pharmaceutical salts can be prepared by reacting a compound described herein with an acid or base. Salts formed by the base include, but are not limited to, ammonium salt (NH ₄ ⁺ ); alkali metals such as, without limitation, sodium or potassium salts; alkaline earth elements such as, without limitation, calcium or magnesium salts; salt or

- 2 047363 ganic bases, such as, without limitation, dicyclohexylamine, N-methyl-O-glucamine, tris(hydroxymethyl)methylamine; and amino acid salts such as, but not limited to, arginine and lysine. Suitable acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.

As used herein, a pharmaceutically acceptable ester refers to an ester of a compound that does not cause significant irritation to the patient to whom it is administered. The ester is metabolized in the body to form the parent compound, such as the claimed compound. Accordingly, the ester does not cancel the biological activity and properties of the compound. Pharmaceutical esters can be prepared by reacting a compound described herein with an alcohol. Methyl, ethyl and isopropyl esters are some of the most common esters to be prepared. Other suitable esters are well known to those skilled in the art (see, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, ^5th ed., John Wiley & Sons, New York, New York, 2014, which is complete is incorporated herein by reference).

If the compounds described herein have at least one chiral center, they may exist as a racemate or individual enantiomers. It should be noted that all such isomers and mixtures thereof are included within the scope of the present disclosure. Thus, the depiction of a chiral center without the designation R or S means that the scope of the disclosure includes the R isomer, the S isomer, a racemic mixture of isomers, or mixtures in which one isomer is present in greater abundance than the others.

If the methods for preparing the compounds disclosed herein result in the formation of mixtures of stereoisomers, such isomers can be separated by conventional methods, such as preparative chiral chromatography. The compounds can be obtained in racemic form or the individual enantiomers can be obtained by stereoselective synthesis or resolution. Compounds can be separated into their constituent enantiomers by standard methods, such as the formation of diastereomeric pairs by salt formation with an optically active acid such as (-)-di-ptoluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-1 -tartaric acid, followed by fractional crystallization and regeneration of the free base. Compounds can also be separated by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

Unless otherwise indicated, when a substituent is considered optionally substituted, it means that the substituent is a group that may be substituted by one or more groups individually and independently selected from, without limitation, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonide, thiocarbonide, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, O-cyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl and amino, including mono- and disubstituted amino groups, and their protected derivatives. Protecting groups that can form protecting derivatives of the above substituents are known to those skilled in the art and can be found in references such as Wuts, supra.

As used herein, a carbocyclic ring means a ring structure in which all atoms in the ring are carbon atoms. If any of the atoms in the ring is not a carbon atom, then the ring is a heterocyclic ring. Examples of atoms found inside the ring include sulfur, oxygen, and nitrogen. The carbocyclic ring or heterocyclic ring may be polycyclic, for example, a fused ring system, a spirocyclic ring system, or a bridged ring system. These polycyclic rings include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Additional non-limiting examples include:

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

- 3 047363

As used herein, heteroaryl refers to a ring that has a fully delocalized pi electron system and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring. A heteroaryl group may consist of two or more fused rings (rings that have two adjacent carbon atoms). When heteroaryl is a fused ring system, then the ring that is bonded to the rest of the molecule has a fully delocalized pi electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pielectron system. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Wherever the term hetero is used, it is intended to denote a specified group, such as alkyl or aryl, in which at least one carbon atom is replaced by a heteroatom selected from nitrogen, oxygen and sulfur.

As used herein, alkyl refers to a fully saturated straight or branched chain hydrocarbon group (no double or triple bonds). The alkyl group of the compounds disclosed herein may contain from 1 to 20 carbon atoms. The alkyl group as used herein may also have an average size of 1 to 10 carbon atoms. An alkyl group as used herein may also be a lower alkyl having 1 to 5 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, m-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. The alkyl group of the compounds disclosed herein may be substituted or unsubstituted. When substituted, the substituent group(s) may be one or more groups independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonide, thiocarbonide, O -carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR _x R _y and protected amino. As used herein, alkenyl refers to an alkyl group that contains one or more double bonds in a straight or branched hydrocarbon chain. The alkenyl group in the compounds disclosed herein may be unsubstituted or substituted. When substituting, the substituent(s) may be selected from the same groups as described above with respect to alkyl group substitution or with respect to optional substitution.

As used herein, alkynyl refers to an alkyl group that contains one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group in the compounds disclosed herein may be unsubstituted or substituted. When substituting, the substituent(s) may be selected from the same groups as described above with respect to alkyl group substitution or with respect to optional substitution.

As used herein, acyl refers to the group R _x C(=O)-.

As used herein, cycloalkyl refers to a fully saturated (no double bonds) hydrocarbon ring. The cycloalkyl groups of the compounds disclosed herein can range from _C3 to C8. The cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those listed above with respect to alkyl group substitution. A cycloalkyl group may consist of two or more fused rings (rings that have two adjacent carbon atoms). When the cycloalkyl is a fused ring system, then the ring that is bonded to the rest of the molecule is a cycloalkyl as defined above. The other ring(s) in the fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclic.

As used herein, cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds on the ring, although if there is more than one they may not form a fully delocalized pi electron system on the ring (otherwise the group would be aryl as defined in this document). The cycloalkenyl group of the compounds disclosed herein may be unsubstituted or substituted. When substituting, the substituent(s) may be selected from the same groups as described above with respect to alkyl group substitution. A cycloalkenyl group may consist of two or more fused rings (rings that have two adjacent carbon atoms). When the cycloalkenyl is a fused ring system, then the ring that is bonded to the rest of the molecule is a cycloalkenyl as defined above. The other ring(s) in the fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclic.

The term alkylene refers to an alkyl group, as defined herein, that is a diradical and is bonded to two other groups. Therefore, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC: (methyl)ethylene) (-CH2-CH(CH ₃ )-) and isobutylene (IUPAC: 2-( methyl)propylene) (-CH ₂ -CH(CH ₃ )-CH ₂ -) are, without limitation, examples of an alkylene group. Likewise, the term cycloalkylene refers to a cycloalkyl group, as defined herein, that similarly binds to two other moieties. When the alkyl and cycloalkyl groups contain unsaturated carbon atoms, the terms alkenylene and cycloalkenylene are used.

As used herein, heterocycloalkyl, heteroalicyclic or heteroalicyclyl refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds, provided that they do not form a completely delocalized pi electron system in the rings. A ring as defined herein may be a stable 3- to 18-membered ring that consists of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heteroalicyclyl groups of the compounds disclosed herein may be unsubstituted or substituted. When substituting, the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido. A heterocycloalkyl group may consist of two or more fused rings (rings that have two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, then the ring that is bonded to the rest of the molecule is a heterocycloalkyl as defined above. The other ring(s) in the fused ring system may be cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclic.

As used herein, aralkyl refers to an alkylene substituted with an aryl group.

As used herein, carbocyclic alkyl or (carbocyclic)alkyl refers to an alkylene substituted with a carbocyclic group. As used herein, heterocyclic alkyl or (heterocyclic)alkyl refers to an alkylene substituted with a heterocyclic group. Likewise, (heterocycloalkyl)alkyl refers to an alkylene substituted with a heterocycloalkyl group.

As used herein, heteroarylalkyl or (heteroaryl)alkyl refers to an alkylene substituted with a heteroaryl group:

The O-carboxy group belongs to the R _x C(=O)O- group,

The C-carboxy group belongs to the -C(=O)R group, the acetyl group belongs to the CH3C(=O)- group,

The C-amido group belongs to the -C(=O)NR _x R _y group,

The N-amido group belongs to the RC(=O)NR _x - group.

The term perhaloalkyl refers to an alkyl group in which all the hydrogen atoms have been replaced by halogen atoms.

Any unsubstituted or monosubstituted amino group in a compound of this invention can be converted to an amide, any hydroxy group can be converted to an ester, and any carboxyl group can be converted to either an amide or an ester using methods well known to those skilled in the art ( see, for example, Wuts, supra).

It is understood that in any compound disclosed herein having one or more chiral centers, unless absolute stereochemistry is explicitly stated, each center may independently have an R or S configuration or a mixture thereof. It is further understood that in any of the compounds disclosed herein having one or more double bonds forming geometric isomers that may be defined as E or Z, each double bond may independently have the E or Z configuration or a mixture thereof.

It will be understood that the disclosure of a compound of this invention essentially includes the disclosure of its tautomer, if applicable. For example, opening ° also includes opening: and vice versa, even if only one of the two structures is revealed.

In the context of the present description, when a compound is illustrated or named, it is understood that isotopically enriched analogues of the compound are also contemplated. For example, a compound may contain deuterium instead of hydrogen or carbon-13 instead of carbon with a natural isotopic distribution. Isotopic enrichment can occur at one junction, i.e. only one hydrogen is replaced by deuterium, or in more than one place. The present disclosure also includes compounds in which all similar atoms are replaced by their less abundant isotope, such as a perdeuterium compound in which all hydrogen atoms are replaced by deuterium. Isotopically enriched compounds are useful when obtaining NMR spectra or using the isotope effect to control the reaction kinetics to which the compound undergoes. The term pharmaceutical composition from

- 5 047363 refers to mixtures of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound into the body. There are many methods in the art for administering a compound, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be prepared by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. P.

The term carrier defines a chemical compound that facilitates the incorporation of the compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a widely used carrier because it promotes the uptake of many organic compounds into the body's cells or tissues.

The term diluent defines chemical compounds diluted in water that dissolve the compound of interest and also stabilize the biologically active form of the compound. Salts dissolved in buffer solutions are used as diluents in the art. One commonly used buffer solution is phosphate buffered saline because it mimics the salt conditions of human blood. Because buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely changes the biological activity of a compound.

In certain embodiments, the same substance may act as a carrier, diluent, or excipient, or perform any of two roles, or perform all three roles. Thus, one additive to a pharmaceutical composition can perform several functions.

The term physiologically acceptable defines a carrier or diluent that does not interfere with the biological activity and properties of the compound.

Connections

In one aspect, disclosed herein are compounds of formula (I) (I) TL-La-CE-HD or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, wherein:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId):

(Pa) (Hb) (41a)

(IIIb) (Hie) (Hid) wherein each of Q1, Q2, _Q3 , _Q4 , Q5, _Q6 and _Q8 is independently nitrogen or -CR _b -, wherein each R _b is independently hydrogen, halogen or lower alkyl;

R1 represents hydrogen, 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 group, an optionally substituted heteroarylalkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R ₂ represents hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R3 is hydrogen or lower alkyl;

R4 represents 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 group, an optionally substituted heteroarylalkyl group, an optionally substituted an amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

- 6 047363

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring; And

Alk represents hydrogen or optionally substituted alkyl;

ii) CE is a fragment of formula (IV)

(IV) ^r 8 wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring;

Q ₇ represents nitrogen or -CR _c -, where R _c represents hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

iii) HD is a fragment of formula (V) or (VI):

where R9 is selected from hydrogen, -(CRdhVCRh, -(C(Rd)2)n-ORd, -(C(Rd)2)n-N(Rd)2, -(C(Rd)2)n-S(=O)qRd , -(C(Rd)2)n-CN, -(C(Rd)2)n-C^C-Rd, -(C(Rd)2)n-C(=O)-ORd, -(C(RdE)n -HeAr or -(C(Rd)2)n-C(=O)-N(Rd)2;

each Rd independently represents hydrogen or optionally substituted lower alkyl;

each q is independently selected from 0, 1 or 2;

each n is independently selected from 0, 1, 2, 3, 4 or 5;

HeAr is a 5- or 6-membered heteroaryl;

R ₁₀ represents hydrogen, -C(Re) ₃ where each Re independently represents hydrogen, halogen or optionally substituted lower alkyl;

R11 represents an aryl group, optionally substituted with lower alkyl, halogen, cycloalkyl; or a bicyclic ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems;

iv) L _a independently represents a bond; -(C(R _a )2) _n -; oxygen; sulfur; -NR _a -; where each R _a is independently hydrogen or lower alkyl and n is 0, 1, 2, 3, 4 or 5.

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-carboxy or O-carboxyl group. In some of these embodiments, alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain embodiments, the carbocyclic group is cyclohexane or cyclopentane. In various embodiments, the aryl group is phenyl. In some embodiments, the C-carboxy group is a moiety of the formula -C(=O)-O-R and an O-carboxy moiety of the formula -O-C(=O)-R, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In some embodiments, wherein R ₂ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In some embodiments, Q1, Q2, Q3, and _Q4 are -CRb-, wherein each Rb is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In some embodiments, wherein R4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl.

- 7 047363

In some embodiments, R5 is hydroxy.

In some embodiments, the TL is a fragment selected from:

In some embodiments, the TL is a fragment selected from:

- 8 047363

In some embodiments of the compound of formula (I), R6 and R7 are each independently chlorine, bromine, and iodine. In other embodiments, R ₆ and R ₇ are each independently -CN, optionally substituted lower alkyl, or optionally substituted lower alkoxy, wherein the lower alkyl and the lower alkoxy alkyl group are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. In some embodiments, R ₆ and R 7 are each H. In certain embodiments, R ₆ and R ₇ are each independently chlorine or methyl.

In some embodiments of the compound of Formula (I), R ₈ is hydrogen.

In some embodiments, R _c is hydrogen or methyl.

In some embodiments, compounds of formula (I) are disclosed herein, wherein TL is a moiety of formula (IIa), (IIb), (IIIa), (PGL), (IIIc) or (IIId):

wherein each of Q1, Q2, _Q3 , _Q4 , Q5, _Q6 and _Q8 is independently nitrogen or -CRb-, wherein each Rb is independently hydrogen, halogen or lower alkyl;

Ri represents 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 group, an optionally substituted heteroarylalkyl group, an optionally substituted an amino group, optionally substituted with a C-carboxy or O-carboxy group, -CN,

- 9 047363 an optionally substituted carbamoyl group or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

R2 represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R3 is hydrogen _R4 is an optionally substituted alkyl group, an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic alkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic group, an optionally substituted a heteroarylalkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring; or when Q ₆ represents nitrogen and R 5 represents hydroxy, then a tautomer of the fragment of formula (III); And

Alk represents hydrogen or optionally substituted alkyl;

CE is a fragment of formula (IV)

(IV) ^R S wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q ₇ represents nitrogen or -CR _c -, where Rc represents hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V) or (VI):

where R ₉ represents -NH2 and R ₁₀ represents -CH3; And

L _a represents oxygen.

In other embodiments, compounds of formula (I) are disclosed herein, wherein TL is a moiety of formula (II)

wherein each of Q1, Q2, and Q3 is independently nitrogen or -CRb-, wherein each Rb is independently hydrogen, halogen, or lower alkyl;

Ri represents 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 group, an optionally substituted heteroarylalkyl group, optional

- 10 047363 optionally substituted amino group, optionally substituted C-carboxy or O-carboxy group, -CN, optionally substituted carbamoyl group or optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

R2 represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R3 represents hydrogen;

CE is a fragment of formula (IV)

wherein each of R ₆ and R 7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl;

R ₈ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q7 is nitrogen or -CR-, where R _c is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V)

where R ₉ represents hydrogen, -CN or -C.=CR _d . where Rd represents hydrogen or lower alkyl; And

L _a represents oxygen.

In some embodiments, L _a is a combination of two or more bonds; -(C(Ra)2)n-; oxygen; sulfur or -NR-.

In another aspect, disclosed herein are compounds of formula (I')(D) TL-La-CE-HD or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide or ester, wherein:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId):

wherein each of Q1, Q2, _Q3 , _Q4 , Q5, _Q6 and _Q8 is independently nitrogen or -CRb-, wherein each _Rb is independently hydrogen, halogen or lower alkyl;

R ₁ is an optionally replaced alkyl, an optionally replaced non -armed carbocyclic group, an optionally replaced arial group, an optionally replaced heterocyclic group, an optionally replaced heteroaric group, an optionally replaced (carbocyclical) alcoholic group, an optionally detected arallit group, not mandatory Alquille) Alkyle group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R ₂ represents hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R ₃ represents hydrogen or lower alkyl;

R ₄ represents optionally substituted alkyl, optionally substituted alkenyl, not

- 11 047363 optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl)alkyl group, optionally substituted (heter oaryl) an alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring;

Alk represents hydrogen or optionally substituted alkyl; And

R11 represents 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 ring system; or a bicyclic heterocyclic ring system;

ii) CE is a fragment of formula (IV)

(IV) ^R e wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R ₈ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl or heteroaryl ring

Q7 is nitrogen or -CR-, where Rc is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

iii) HD is a fragment of formula (V) or (VI):

(V) ^Rc (VI) ^R w where R9 is selected from hydrogen, -(C(Rd)2)nC(Rdk -(C(RdE)n-ORd, -(C(Rd)2)nN(Rd)2, -(C(R _d )2) _n -S(=O) _q R _d , -(C(Rd)2)n-CN, -(C(Rd)2)nC^C-Rd, -(C( Rd)2)nC(=O)-ORd, -(C(Rd£)n-HeAr or -(C(Rd)2)nC(=O)-N(Rd)2;

each Rd independently represents hydrogen or optionally substituted lower alkyl;

each q is independently selected from 0, 1 or 2;

each n is independently selected from 0, 1, 2, 3, 4 or 5;

HeAr is a 5- or 6-membered heteroaryl; And

R ₁₀ represents hydrogen or -C(Re) ₃ where each Re independently represents hydrogen, halogen or optionally substituted lower alkyl; And

L _a independently represents a bond; -(C(R _a ) ₂ ) _z -; oxygen; sulfur; or -NRa-; wherein each Ra is independently hydrogen or lower alkyl; and z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of formula (IIIa) wherein Q ₄ , Q 5 and Q ₆ are -CH and R ₄ is an optionally substituted N-alkyl group, an optionally substituted sulfamoyl group or an optionally substituted carbamoyl group; HD is a fragment of formula (V), where R ₉ represents H or -CN; and Q7 represent -CH-, then

- 12 047363 wherein R5 cannot be hydroxy;

(2) when TL is a moiety of formula (IIa) wherein Q1, _Q2 and Q3 are -CH-, R1 is -CH3 and R2 is hydrogen; HD is a moiety of formula (V) wherein R ₉ is hydrogen; Q7 is -CH-; _R6 is halogen or methyl and R7 and _R8 , taken together with the carbon atoms to which they are attached, form a 5-membered non-aromatic carbocyclic ring, then _R4 and R5, taken together with the carbon atoms to which they are attached, do not can form a five-membered heteroaryl group;

(3) when TL is a moiety of formula (IIIa) wherein Q ₄ is nitrogen, Q5 and Q ₆ are -CH-, and R5 is -OH; HD is a fragment of formula (V), where R ₉ represents -CN; Q7 is -CH-; L _a represents -CH2-, then R4 cannot represent cyclohexyl, cycloheptyl, isopropyl or optionally substituted benzene;

(4) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q5 is nitrogen; HD is a moiety of formula (V) wherein R9 is hydrogen, -CN or -CO ₂ H; Q7 is -CH-; and R ₆ and R 7 independently represent halogen or methyl, or R 7 and R ₈ taken together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R ₄ cannot represent isopropyl or 2-hydroxy- 1-methylethyl;

(5) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CRc- and Q ₅ is nitrogen; HD is a fragment of formula (V), where R ₉ represent -CN; Q7 is -CH-; and L _a represents -O-, then (a) none of R ₆ , R 7 and R ₈ can represent deuterium;

(b) Q4 cannot be -CD- where D is deuterium; and (c) R4 may not be a 3- or 5-membered cycloalkyl ring, optionally substituted with one or more halogen atoms; non-aromatic (carbocyclic)alkyl, optionally substituted with methyl or hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl, optionally substituted with methyl, halogen, hydroxy or methoxy; phenethyl, optionally substituted with halogen; b-^-alkyl, optionally substituted with one to six substituents selected from halogen, hydroxyl and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or 3- or 5-membered heterocycloalkyl, optionally substituted with benzyl;

(6) when TL is a moiety of formula (IIIb) wherein (i) Q ₄ and Q5 are nitrogen, (ii) Q ₄ and Q5 are -CR _b - or (iii) Q ₄ is nitrogen and Q5 is itself -CRc-; HD is a moiety of formula (V) wherein R9 is -CN; and Q7 are -CH-; then R4 cannot be -CH(CH ₃ ) ₂ or -CH(CD ₃ ) ₂ ;

(7) when TL is a moiety of formula (IIIa) wherein Q ₄ is -CH-, Q5 and Q6 are nitrogen and R4 is isopropyl; HD is a moiety of formula (V) wherein R9 is -CN; and Q7 is -CH-; then R5 cannot be -NH2 or -NHCH3;

(8) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q5 is nitrogen; L _a represents -O-; Q7 is -CH-; and HD is a moiety of formula (V), then R ₉ cannot be methyl;

(9) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH-, Q5 is nitrogen and R ₄ is isopropyl; L _a represents -O-; Q ₇ represents -CH- and HD represents a fragment of formula (V), then R ₉ cannot represent isopropyl;

(10) when TL is a moiety of formula (IIa) wherein Q1, Q2 and Q3 are -CH-; L _a represents -O-; Q7 is -CH-; R<5 and R7 are independently chlorine or trifluoromethyl and HD is a moiety of formula (V) where _R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl or -C(O) _NH2 ;

(11) when TL is a moiety of formula (IIa) wherein Q ₁ and Q ₂ are -CH- and Q ₃ is nitrogen; L _a represents -O-; Q ₇ represents -CH-; R ₆ and R ₇ are chlorine and HD is a fragment of formula (V) where R ₉ is -CN, then R ₁ cannot be isopropyl;

(12) when TL is a moiety of formula (IIb) wherein Q1, Q2, and Q3 are -CH-; L _a represents -O-; Q ₇ represents -CH-; R ₆ and R ₇ are chlorine; and HD is a moiety of formula (V) wherein R9 is -CN, then R1 cannot be isopropyl;

(13) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q5 is nitrogen; La represents -O-; Q7 is -CH-; R6 and R7 are chlorine; and HD is a moiety of formula (VI) wherein R ₁₀ is H, Me, Et, isopropyl, -CH2CF3 or -CH2CHF2, then R4 cannot be ^-^-alkyl or C ₁ -^-hydroxyalkyl;

(14) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and

- 13 047363

Q5 represents nitrogen; L _a represents -O-; Q7 is -CH-; _R6 and R7 are chlorine; and HD is a moiety of formula (VI) wherein R ₁₀ is H or Me, then R ₄ cannot be cyclopropyl; and (15) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q5 is nitrogen; L _a represents -CH2-; Q7 is -CH-; R6 and R7 are both chlorine or methyl; and HD is a moiety of formula (VI) wherein R ₁₀ is H or Me, then R ₄ cannot be isopropyl.

In some embodiments, when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represents -CH2CN or -CbC'H; Q7 is -CH- and R6 and R7 are chlorine, then R4 cannot be isopropyl.

In another aspect, disclosed herein are compounds of formula (I') (D) TL-L _a -CE-HD, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester, wherein:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId):

wherein each of Q1, Q2, _Q3 , _Q4 , _Q5 , _Q6 and _Q8 is independently nitrogen or -CR _b -, wherein each R _b is independently hydrogen, halogen or lower alkyl;

R ₁ is an optionally replaced alkyl, an optionally replaced non -armed carbocyclic group, an optionally replaced arial group, an optionally replaced heterocyclic group, an optionally replaced heteroaric group, an optionally replaced (carbocyclical) alcoholic group, an optionally detected arallit group, not mandatory Alquille) Alkyle group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or CN;

R ₃ represents hydrogen or lower alkyl;

R ₄ represents an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl) )an alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring;

Alk represents hydrogen or optionally substituted alkyl; And

R11 represents 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 bicyclic ring

- 14 047363 system; or a bicyclic heterocyclic ring system; ii) CE is a fragment of formula (IV)

(IV) ^r 8 wherein each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl;

R ₈ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R7 and _R8 , taken together with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl or heteroaryl ring Q7 is nitrogen or -CR _c - where R _c is is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

iii) HD is a fragment of formula (V) or (VI):

(V) ^R 9 (VI) where R9 is selected from hydrogen, -(C(Rd)2)nC(Rd)3, -(C(Rd)2)n-ORd, -(C(Rd)2)nN( Rd)2, -(C(Rd)2)nS(=O)qRd, -(C(Rd)2)n-CN, -(C (R ) ). -C CR , -(C(Rd)2) _n -C(=O)-ORd, -(C(Rd) ₂ ).-HeAr or -(C(Rd) ₂ )nC(=O)-N( Rd) ₂ ;

each R _d independently represents hydrogen or optionally substituted lower alkyl;

each q is independently selected from 0, 1 or 2;

each n is independently selected from 0, 1, 2, 3, 4 or 5;

HeAr is a 5- or 6-membered heteroaryl;

R ₁₀ represents hydrogen or -C(Re) ₃ where each R _e independently represents hydrogen, halogen or optionally substituted lower alkyl; and (iv) L _a independently represents a bond; -(C(R _a ) ₂ ) _z -; oxygen; sulfur or -NR _a -;

wherein each R _a is independently hydrogen or lower alkyl and z is 0, 1, 2, 3, 4 or 5; provided that:

(1) when TL is a moiety of formula (IIIa) wherein Q ₄ , Q ₅ and Q ₆ are -CH and R 4 is an optionally substituted C'i-CR alkyl group, an optionally substituted sulfamoyl group or an optionally substituted carbamoyl group; HD is a moiety of formula (V) wherein R9 is H or -CN; and Q7 is -CH-, then _R5 cannot be hydroxy;

(2) when TL is a moiety of formula (IIa) wherein Q ₁ , Q2 and Q3 are -CH-, R ₁ is -CH3 and R2 is hydrogen; HD is a moiety of formula (V) wherein R9 is hydrogen; Q7 is -CH-; _R6 is halogen or methyl and R7 and _R8 , taken together with the carbon atoms to which they are attached, form a 5-membered non-aromatic carbocyclic ring, then _R4 and _R5 , taken together with the carbon atoms to which they are attached, cannot form a five-membered heteroaryl group;

(3) when TL is a moiety of formula (IIIa) wherein Q4 is nitrogen, _Q5 and _Q6 are -CH- and _R5 is -OH; HD is a fragment of formula (V), where R ₉ represents -CN; Q7 is -CH-; L _a represents -CH2-, then R ₄ cannot represent cyclohexyl, cycloheptyl, isopropyl or optionally substituted benzene;

(4) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and _Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represents hydrogen, -CN or -CO2H; Q7 is -CH- and _R6 and R7 are independently halogen or methyl or _R7 and _R8 taken together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then _R4 cannot represent isopropyl or 2-hydroxy-1-methylethyl;

(5) when TL is a moiety of formula (IIIb) wherein Q4 is -CRc- and _Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represent -CN; Q7 is -CH- and L _a is -O-, then:

(a) none of R ₆ , R ₇ and R ₈ may be deuterium;

- 15 047363 (b) Q ₄ cannot represent -CD-, where D represents deuterium; and (c) R ₄ may not be a three- or five-membered cycloalkyl ring, optionally substituted with one or more halogen atoms; non-aromatic (carbocyclic)alkyl, optionally substituted with methyl or hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl; phenyl; benzyl, optionally substituted with methyl, halogen, hydroxy or methoxy; phenethyl, optionally substituted with halogen; C-^-alkyl, optionally substituted with one to six substituents selected from halogen, hydroxyl and deuterium; (tetrahydro-2H-pyran-4-yl)methyl; or 3- or 5-membered heterocycloalkyl, optionally substituted with benzyl;

(6) when TL is a moiety of formula (IIIb) wherein (i) Q ₄ and Q ₅ are nitrogen, (ii) Q ₄ and Q5 are -CR _b - or (iii) Q ₄ is nitrogen and Q5 are -CRc-; HD is a moiety of formula (V) wherein R ₉ is -CN and Q7 is -CH-; then R ₄ cannot be -CH(CH ₃ ) ₂ or -CH(CD ₃ ) ₂ ;

(7) when TL is a moiety of formula (IIIa) wherein Q4 is -CH-, Q5 and _Q6 are nitrogen, and R4 is isopropyl; HD is a fragment of formula (V), where R ₉ represent -CN; and Q ₇ are -CH-; then R ₅ cannot be -NH ₂ or -NHCH ₃ ;

(8) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and Q5 is nitrogen; L _a represents -O-; Q7 is -CH- and HD is a fragment of formula (V), then R ₉ cannot be methyl;

(9) when TL is a moiety of formula (IIIb) wherein Q4 is -CH-, Q5 is nitrogen and _R4 is isopropyl; L _a represents -O-; Q7 is -CH- and HD is a fragment of formula (V), then R ₉ cannot be isopropyl;

(10) when TL is a moiety of formula (IIa) wherein Q ₁ , Q 2 , and Q ₃ are -CH-; L _a represents -O-; Q7 is -CH-; R6 and R7 are independently chlorine or trifluoromethyl and HD is a fragment of formula (V) where _R9 is -CN or methyl, then R1 cannot be isopropyl, 4-tetrahydropyranyl or -C(O) _NH2 ;

(11) when TL is a moiety of formula (IIa) wherein Q ₁ and Q ₂ are -CH- and Q ₃ is nitrogen; L _a represents -O-; Q ₇ represents -CH-; R ₆ and R ₇ are chlorine and HD is a fragment of formula (V) where R ₉ is -CN, then R ₁ cannot be isopropyl;

(12) when TL is a moiety of formula (IIb) wherein Q1, Q2, and _Q3 are -CH-; La represents -O-; Q7 is -CH-; R6 and R7 are chlorine and HD is a moiety of formula (V) where R9 is -CN, then R1 cannot be isopropyl;

(13) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and Q5 is nitrogen; La represents -O-; Q7 is -CH-; R6 and R7 are chlorine and HD is a moiety of formula (VI) where _R10 is H, Me, Et, isopropyl, -CH2CF3 or -CH2CHF2, then R4 cannot be ^-^-alkyl or C ₁ - ^-hydroxyalkyl;

(14) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q ₅ is nitrogen; L _a represents -O-; Q ₇ represents -CH-; R ₆ and R ₇ are chlorine and HD is a moiety of formula (VI) where R10 is H or Me, then R4 cannot be cyclopropyl;

(15) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and Q5 is nitrogen; La represents -CH2-; Q7 is -CH-; R6 and R7 are both chlorine or methyl and HD is a moiety of formula (VI) where R10 is H or Me, then R4 cannot be isopropyl; and (16) when TL is a moiety of formula (IIIb) wherein Q ₄ is -CH- and Q ₅ is nitrogen; HD is a fragment of formula (V), where R ₉ represents -CH2CN or -SUCH; Q7 is -CH- and R6 and R7 are chlorine, then R4 cannot be isopropyl.

In another aspect, disclosed herein are compounds of formula (I') (D) TL-L _a -CE-HD, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, amide, or ester, wherein:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId):

- 16 047363

(Ulb) (111c) (IIId) wherein each of Q1, Q2, _Q3 , Q4, Q5, _Q6 and _Q8 is independently nitrogen or -CRb-, wherein each _Rb is independently hydrogen, halogen or lower alkyl;

R ₁ is an optionally replaced alkyl, an optionally replaced non -armed carbocyclic group, an optionally replaced arial group, an optionally replaced heterocyclic group, an optionally replaced heteroaric group, an optionally replaced (carbocyclical) alcoholic group, an optionally detected arallit group, not mandatory Alquille) Alkyle group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or CN;

R ₃ represents hydrogen or lower alkyl;

R ₄ represents an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl) )an alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring;

Alk represents hydrogen or optionally substituted alkyl;

R ₁₁ represents an aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, halogen and cycloalkyl; or a bicyclic ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems;

ii) CE is a fragment of formula (IV)

(IV) ^r 8 wherein each of R ₆ and R ₇ is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R5 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R ₇ and R ₈ , taken together with the carbon atoms to which they are attached, form a 4-, 5-, or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl or heteroaryl ring Q7 is nitrogen or -CRc-, where Rc is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

- 17 047363 iii) HD is a fragment of formula (V) or (VI):

where R9 is selected from hydrogen, -(C(Rdh)nC(Rd)3, -(C(Rd)2)n-ORd, -(C(Rd)2)nN(Rd)2, -(C(Rdh) nS(=O)qRd, -(C(Rd)2)n-CN, -(C(Rd)2) _n -CC-Rd, -(C(Rd)2) _n -C(=O)-ORd , -(C(Rdh)n-HeAr or -(C(Rd)2)nC(=O)-N(Rd)2;

each Rd independently represents hydrogen or optionally substituted lower alkyl;

each q is independently selected from 0, 1 or 2;

each n is independently selected from 0, 1, 2, 3, 4 or 5;

HeAr is a 5- or 6-membered heteroaryl;

R ₁₀ represents hydrogen or -C(Re) ₃ where each Re independently represents hydrogen, halogen or optionally substituted lower alkyl; And

L _a independently represents a bond; -(C(R _a )2)z-; oxygen; sulfur; or -NRa-; wherein each Ra is independently hydrogen or lower alkyl and z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of formula (IIIa) wherein _Q4 , Q5 and Q6 are -CH and R4 is an optionally substituted C'i-C'3-alkyl group, an optionally substituted sulfamoyl group, or an optionally substituted sulfamoyl group a substituted carbamoyl group; HD is a fragment of formula (V), where R ₉ represents H or -CN; and Q ₇ are -CH-, then R ₅ cannot be hydroxy;

(2) when TL is a moiety of formula (IIa) wherein Q ₁ , Q 2 and Q ₃ are -CH-, R ₁ is -CH ₃ and R 2 is hydrogen; HD is a moiety of formula (V) wherein R ₉ is hydrogen; Q ₇ represents -CH-; R6 is halogen or methyl and _R7 and _R8 , taken together with the carbon atoms to which they are attached, form a 5-membered non-aromatic carbocyclic ring, then R4 and _R5 , taken together with the carbon atoms to which they are attached, do not can form a five-membered heteroaryl group;

(3) when TL is a moiety of formula (IIIa) wherein Q4 is nitrogen, Q5 and Q6 are -CH- and _R5 is -OH; HD is a fragment of formula (V), where R ₉ represents -CN; Q ₇ represents -CH-; La is -CH2-, then _R4 cannot be cyclohexyl, cycloheptyl, isopropyl or optionally substituted benzene;

(4) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and _Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represents hydrogen, -CN or -CO ₂ H; Q ₇ represents -CH- and R6 and R ₇ independently represent halogen or methyl or R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then R4 cannot represent isopropyl or 2-hydroxy-1-methylethyl;

(5) when TL is a moiety of formula (IIIb) wherein Q4 is -CRc- and Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represent -CN; Q ₇ represents -CH-; and L _a represents -O-, then:

(a) none of R ₆ , R ₇ and R ₈ may be deuterium;

(b) Q4 cannot be -CD- where D is deuterium;

(c) R4 may not be a 3-5 membered cycloalkyl ring, optionally substituted with one or more halogens; C ₁ -C ₄ alkyl, optionally substituted with one to six substituents selected from halogen, hydroxyl and deuterium; or 3- or 5-membered heterocycloalkyl;

(6) when TL is a fragment of formula (IIIb) wherein (i) Q4 and Q ₅ are nitrogen, (ii) Q4 and Q ₅ are -CR _b - or (iii) Q4 is nitrogen, and Q ₅ are -CRc-; HD is a fragment of formula (V), where R ₉ represent -CN; and Q ₇ are -CH-; then R4 cannot be -CH(CH ₃ ) ₂ or -CH(CD ₃ ) ₂ ; and (7) when TL is a moiety of formula (IIIa) wherein Q4 is -CH-, _Q5 and Q6 are nitrogen, and R4 is isopropyl; HD is a fragment of formula (V), where R ₉ represent -CN; and Q ₇ are -CH-; then R5 cannot be -NH2 or -NHCH3.

In some embodiments, when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and _Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represents -CH2CN or -CCH; Q ₇ is -CH- and R6 and R ₇ are chlorine, then R ₄ cannot be isopropyl.

In another aspect, this document discloses compounds of formula (I')

- 18 047363 or its stereoisomer, or tautomer, or pharmaceutically acceptable salt, prodrug, amide or ester, where:

i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId):

wherein each of Q1, Q2, _Q3 , _Q4 , Q5, _Q6 and _Q8 is independently nitrogen or -CRb-, wherein each _Rb is independently hydrogen, halogen or lower alkyl;

R1 is a hydrogen that is not necessarily replaced by a non -instrumental carbocyclic group, an optionally replaced arial group, an optionally replaced heterocyclic group, an optionally replaced heteroaric group, an optionally replaced (carbocyclical) alcoholic group, an optionally detected arallit group, which is not mandatory Alquille) Alkyle Group , an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure ;

R ₂ represents hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R ₃ represents hydrogen or lower alkyl;

R ₄ represents an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted (carbocyclic)alkyl group, optionally substituted aralkyl group, optionally substituted (heterocycloalkyl) )an alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring;

Alk represents hydrogen or optionally substituted alkyl;

Rn represents an aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, halogen and cycloalkyl; or a bicyclic ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems;

ii) CE is a fragment of formula (IV)

wherein each of R ₆ and R ₇ is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R ₅ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl or heteroa

- 19 047363 rile ring;

Q7 is nitrogen or -CRc-, where Rc is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

iii) HD is a fragment of formula (V) or (VI):

where R ₉ SELECTED FROM HYDROGEN, -(C(R _d )2) _n -C(R _d )3, -(C(Rdh)n-ORd, -(CXRbVNCRb,

-(C(Rd)2)nS(=O)qRd, -(C(Rd)2)n-CN, -(C(R _d )2)nCC-Rd, -(C(Rd)2)nC( =O)-ORd, -(C(Rd)2)n-HeAr or -(C(Rd)2)nC(=O)-N(Rd)2;

each Rd independently represents hydrogen or optionally substituted lower alkyl; each q is independently selected from 0, 1 or 2;

each n is independently selected from 0, 1, 2, 3, 4 or 5;

HeAr is a 5- or 6-membered heteroaryl;

R ₁₀ represents hydrogen or -C(R _e ) ₃ where each Re independently represents hydrogen, halogen or optionally substituted lower alkyl; and (iv) L _a independently represents a bond; -(C(R _a ) ₂ ) _z -; oxygen; sulfur or -NR _a -; wherein each R _a is independently hydrogen or lower alkyl; and z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a fragment of formula (IIIa) wherein Q ₄ , Q ₅ and Q ₆ represent -CH and R 4 represents an optionally substituted C ₁ -C ₃ -alkyl group, an optionally substituted sulfamoyl group or an optionally substituted carbamoyl group; HD is a fragment of formula (V), where R ₉ represents H or -CN; and Q7 are -CH-, then _R5 cannot be hydroxy;

(2) when TL is a moiety of formula (IIa) wherein Q1, _Q2 and _Q3 are -CH-, _R1 is _-CH3 and _R2 is hydrogen; HD is a moiety of formula (V) wherein R ₉ is hydrogen; Q ₇ represents -CH-; R ₆ represents halogen or methyl; and R7 and _R8 taken together with the carbon atoms to which they are attached form a 5-membered non-aromatic carbocyclic ring, then _R4 and _R5 taken together with the carbon atoms to which they are attached cannot form a five-membered heteroaryl group;

(3) when TL is a moiety of formula (IIIa) wherein Q4 is nitrogen, _Q5 and _Q6 are -CH- and _R5 is -OH; HD is a fragment of formula (V), where R ₉ represents -CN; Q ₇ represents -CH-; L _a represents -CH ₂ - then R ₄ cannot represent cyclohexyl, cycloheptyl, isopropyl or optionally substituted benzene;

(4) when TL is a moiety of formula (IIIb) wherein Q4 is -CH- and _Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represents hydrogen, -CN, -CH2CN, -C+CH or -CO ₂ H; Q7 is -CH- and R6 and R7 are independently halogen or methyl or R7 and _R8 taken together with the carbon atoms to which they are attached form a 5 membered non-aromatic carbocyclic ring then R4 cannot be isopropyl or 2 -hydroxy-1-methylethyl;

(5) when TL is a moiety of formula (IIIb) wherein Q4 is -CRc- and Q5 is nitrogen; HD is a fragment of formula (V), where R ₉ represent -CN; Q7 is -CH- and L _a is -O-, then:

(a) none of R ₆ , R 7 and R ₈ may be deuterium;

(b) Q ₄ cannot be -CD-, where D is deuterium; and (c) R4 may not be a 3-5 membered cycloalkyl ring, optionally substituted with one or more halogens; C ₁ -C ₄ -alkyl, optionally substituted with one to six substituents selected from halogen, hydroxyl and deuterium; or 3- or 5-membered heterocycloalkyl;

(6) when TL is a moiety of formula (IIIb) wherein (i) Q4 and Q5 are nitrogen, (ii) Q4 and _Q5 are -CRb-, or (iii) Q4 is nitrogen and _Q5 are -CRc-; HD is a fragment of formula (V), where R ₉ represent -CN; and Q7 are -CH-; then R4 cannot be -CH(CH ₃ ) ₂ or -CH(CH ₃ ) ₂ ; and (7) when TL is a moiety of formula (IIIa) wherein Q4 is -CH-, _Q5 and _Q6 are nitrogen, and R4 is isopropyl; HD is a fragment of formula (V), where R ₉ represent -CN; and Q7 is -CH-; then R ₅ cannot

- 20 047363 set as -NH2 or -NHCH3.

In some embodiments, a compound of formula (I') TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId);

wherein each of Q1, Q2, _Q3 , Q4, Q5, _Q6 and _Q8 , independently represents nitrogen or -CR _b -, where each R _b independently represents hydrogen, halogen or lower alkyl;

R1 is an optionally replaced alkyl, not necessarily replaced by a non -armed carbocyclic group, an optionally replaced arial group, an optional heterocyloal group, an optionally replaced heteroiric group, an optionally replaced (carbocyclical) alkyl group, an optionally noticeable arallit group, which is not necessarily noticeable (heterocyl ) the alcoholic group, optional a substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R ₂ represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R ₃ represents hydrogen;

R ₄ represents an optionally substituted alkyl group, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R ₅ represents hydroxy, NH ₂ , alkylamino, alkanoylamino or alkylsulfonylamino;

or _R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring; And

Alk represents hydrogen or optionally substituted alkyl;

CE is a fragment of formula (IV)

wherein each of R6 and R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R5 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q7 is nitrogen or -CRc-, where Rc is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V) or (VI):

- 21 047363

where R ₉ is selected from -NH2, -CN, -CH2-S-CH3 or -CH ₂ -S(=O)2-CH ₃ ;

R ₁₀ represents -CH3;

L _a represents oxygen or -CH2-.

In some embodiments, compounds of formula (I'):

TL is a fragment of formula (IIa)

HD is a fragment of formula (V)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIa)

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIb)

HD is a fragment of formula (V)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIb)

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIIa)

- 22 047363

HD is a fragment of formula (V)

In some embodiments, a compound of formula (I'): TL is a fragment of formula (IIIa):

r ₄ '

(Sha) ^R s

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIIb)

HD is a fragment of formula (V)

where R9 is selected from hydrogen, -(C(Rd)2)n-ORd, -(C(Rdh)nN(Rd)2, -(C(Rd)2)„-S(=O)qRd, -(C (Rd)2)„-C C-Rd, -(C(Rd)2)nC(=O)-ORd, -(C(Rd)2)n-HeAr or -(C(R _d )2)„ -C(=O)-N( _Rd )2;

each R _d independently represents hydrogen or optionally substituted C1-C5 alkyl;

each q is independently equal to 0 or 2;

each n is independently 0 or 1.

In some embodiments, compounds of formula (I'):

TL is a fragment of formula (IIIb)

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIIc)

HD is a fragment of formula (V)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIIc)

- 23 047363

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIId)

HD is a fragment of formula (V)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (IIId)

HD is a fragment of formula (VI)

In some embodiments, a compound of formula (I'): TL is a moiety of formula (II)

wherein each of Q1, Q2 and Q3 is independently nitrogen or -CR|,-, wherein each Rb is independently hydrogen, halogen or lower alkyl;

R1 is an optionally replaced alkyl, not necessarily replaced by a non -armed carbocyclic group, an optionally replaced arial group, an optional heterocyloal group, an optionally replaced heteroiric group, an optionally replaced (carbocyclical) alkyl group, an optionally noticeable arallit group, which is not necessarily noticeable (heterocyl ) the alcoholic group, optional a substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R ₂ represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R3 represents hydrogen; CE is a fragment of formula (IV)

- 24 047363

(IV) ^R a where each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl or cyclopropyl;

R ₈ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q ₇ represents nitrogen or -CRc-, where Rc represents hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V)

(V) ^R 9 where R9 is hydrogen, -CN, -NH2, -C(R _d )2-SR _d , -C(R _d ) ₂ -S(=O)2R _d or -C CR _d , where each Rd is independently hydrogen or lower alkyl; And

L _a represents oxygen or -CH2-.

In some embodiments, the compounds of formula (I') Q1, Q2, Q3 and Q4 are -CRb-, wherein each Rb is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In some embodiments, the compounds of formula (I') Q1, Q2 and Q3 are -CH-.

In some embodiments of the compounds of formula (I'), Q ₁ is -CH- and Q ₂ and Q ₃ are nitrogen. In some embodiments of the compounds of formula (I'), Q ₂ is -CH- and Q1 and Q3 are nitrogen. In some embodiments, compounds of formula (I') Q3 are -CH- and Q1 and Q2 are nitrogen.

In some embodiments of the compounds of formula (I'), Q ₁ is nitrogen and Q ₂ and Q3 are -CH-. In some embodiments of the compounds of formula (I'), Q2 is nitrogen and _Q1 and _Q3 are -CH-. In some embodiments of the compounds of formula (I'), Q3 is nitrogen and Q1 and Q2 are -CH-.

In some embodiments, the compounds of formula (I') Q4, Q5 and Q ₆ are -CR _b -, wherein each R _b is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In some embodiments, the compounds of formula (I') Q ₄ , Q ₅ , and Q ₆ are -CH-.

In some embodiments, the compounds of formula (I') Q4 are -CH- and Q5 and _Q6 are nitrogen. In some embodiments, compounds of formula (I') Q ₅ are -CH- and Q4 and Q6 are nitrogen. In some embodiments, compounds of formula (I') Q6 are -CH- and Q4 and Q5 are nitrogen.

In some embodiments of the compounds of formula (I'), Q ₄ is nitrogen and Q ₅ and Q6 are -CH-. In some embodiments of the compounds of formula (I'), Q5 is nitrogen and _Q4 and _Q6 are -CH-. In some embodiments of the compounds of formula (I'), Q6 is nitrogen and Q4 and Q5 are -CH-.

In some embodiments, compounds of formula (I') Q ₄ are -CH- and Q ₅ is nitrogen.

In some embodiments, the compounds of formula (I') Q5 and Q6 are nitrogen.

In some embodiments, compounds of formula (I') Q ₅ is nitrogen and Q ₈ is -CH-.

In some embodiments, the compounds of formula (I') Q5, _Q6 , and _Q8 are -CRb-, wherein each Rb is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In some embodiments, the compounds of formula (I') Q ₅ , Q ₆ and Q ₈ are -CH-.

In some embodiments, compounds of formula (I') Q5 are -CH- and _Q6 and _Q8 are nitrogen. In some embodiments, compounds of formula (I') Q ₆ are -CH, and Q5 and Q8 are nitrogen. In some embodiments, compounds of formula (I') Q ₈ are -CH- and Q ₅ and Q ₆ are nitrogen.

- 25 047363

In some embodiments of a compound of formula (I'), R1 is hydrogen, an optionally substituted alkyl group, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, and an optionally substituted C-carboxyl group. In some embodiments of the compound of formula (I'), the alkyl 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 moieties is perfluorinated. In some embodiments of the compound of formula (I'), the alkyl is substituted with cycloalkyl or aryl. In some embodiments of the compound of formula (I'), the cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl. In some embodiments of the compound of formula (I'), aryl 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 a compound of formula (I'), the C-carboxy group is a moiety of the formula -C(=O)-O-R, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In some embodiments of a compound of formula (I'), R ₁ is hydrogen, a C 1 -C ₆ alkyl, a non-aromatic C ₃ -C ₁₂ carbocyclic group, a C ₆ -C ₁₀ aryl group, a 3-6 membered heterocycloalkyl group, containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5- or 10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a (carbocyclic)alkyl group, an aralkyl group, (heterocycloalkyl)alkyl group, (heteroaryl)alkyl group, amino group, C-carboxy or O-carboxy group, -CN or carbamoyl group; and R1 is optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, halogen, -CN, amino, oxo, O-carboxy, C-carboxy, C-amido, N-amido, C.'iC. '6-alkoxy. WITH.' ₆ -С'| _O -;-1Rilkoxy. C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compounds of formula (I'), R ₁ is hydrogen. In some embodiments of a compound of formula (I'), R ₁ is -CN.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted C1- _C6 alkyl. In some embodiments of the compound of formula (I'), R1 is C1- _C6 alkyl, optionally substituted with one to five _Rk independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C -carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compounds of formula (I'), R1 is C1- _C6 alkyl.

In some embodiments of a compound of formula (I'), R ₁ is an optionally substituted non-aromatic carbocyclic group. In some embodiments of a compound of formula (I'), R1 is a non-aromatic C ₃ -C ₁₂ carbocyclic group, optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, oxo, halogen, amino, O-carboxy , C-carboxy, C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R ₁ is an optionally substituted aryl group. In some embodiments of a compound of formula (I'), R1 is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, halogen, -CN, O-carboxy, C -carboxy, C-amido, N-amido, amino, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted heterocycloalkyl group. In some embodiments of the compound of formula (I'), R1 is a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein the hetero

- 26 047363 the cycloalkyl ring is optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted heteroaryl group. In some embodiments of a compound of formula (I'), R1 is a 5- or 10-membered heteroaryl group containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl group is optionally substituted with one to five R _k , independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C.'iC.'6-alkyl. C ₁ -C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C1 ₀ -aryl.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted (carbocyclic)alkyl group. In some embodiments of the compound of formula (I'), R1 is (cyclopentyl)C1-C ₆ -alkyl, (cyclobutyl)C1-C ₆ -alkyl, (cyclopentyl)C1-C ₆ -alkyl, (cyclohexyl)C1-C ₆ -alkyl, (cycloheptyl)C1-C ₆ -alkyl, (cyclooctyl)C1-C ₆ -alkyl or (cyclononyl)C1-C ₆ -alkyl, and R1 is optionally substituted with one to five R _k independently selected from the group consisting from hydroxy, halogen, -CX amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one up to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C1 ₀ -aryl.

In some embodiments of a compound of Formula (I'), R1 is an optionally substituted aralkyl group. In some embodiments of a compound of formula (I'), Rj is a benzyl group, optionally substituted with one to five _Rk independently selected from the group consisting of hydroxy, halogen, -CX, amino, O-carboxy, C-carboxy, C -amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C1 ₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl a group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -arila.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of a compound of formula (I'), R1 is a (heterocycloalkyl)alkyl group, optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy , C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6- a member heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ - From ₁₀ -arila.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of a compound of formula (I'), R1 is a (heteroaryl)alkyl group, optionally substituted with one to five _Rk independently selected from the group consisting of hydroxy, halogen, -C^ amino, O-carboxy, C- carboxy, C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 -membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -From ₁₀ -arila.

In some embodiments of a compound of formula (I'), R1 is an optionally substituted amino group. In some embodiments of a compound of formula (I'), R1 is an amino group, optionally substituted with one or two substituents independently selected from the group consisting of C1- _C6 alkyl, C1- _C6 haloalkyl, _C3 - _C9 cycloalkyl , a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen ,

- 27 047363

C ₆ -C ₁₀ -aryl, C-carboxy, C-amido, VO ₂ (C1-C ₆ -alkyl), -C(O)O(C1-C ₆ -alkyl), -C(O)O( C1-C ₆ -haloalkyl), -C(O)O(C ₃ -C ₉ -cycloalkyl), -C(O)O(3-6-membered heterocycloalkyl), -C(O)O(5-10- member heteroaryl) and -C(O)O(C ₆ -C ₁₀ -aryl). In some embodiments, compounds of formula (I') R1 are -NR _m R _n , wherein R _m and R _n are independently selected from the group consisting of hydrogen, C.'iC.'6-alkyl. C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, C ₆ -C ₁₀ -aryl, C-carboxy, C-amido, BO ₂ (C1-C ₆ -alkyl), -C(O)O(C1-C ₆ -alkyl), -C(O)O(C ₃ -C ₉ -cycloalkyl), -C(O)O(3-6-membered heterocycloalkyl), -C(O)O(5- or 10-membered heteroaryl) and -C( O)O(C ₆ -C ₁₀ -aryl); or R _m and R _n together with the nitrogen to which they are attached form a 3-18 membered heterocycloalkyl ring; and R1 is optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, halogen, -CN, amino, C1- _C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5- A 10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compounds of formula (I'), R ₁ is an optionally substituted C-carboxy group. In some embodiments of the compound of formula (I'), R1 is -C(O)(C1-C ₆ -alkyl), -C(O)(C ₃ -C ₉ -cycloalkyl), -C(O)(3- 6-membered heterocycloalkyl), -C(O)(5-10-membered heteroaryl) and -C(O)(C ₆ -C ₁₀ -aryl); and R1 is optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, halogen, -CN, amino, C1- _C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5- A 10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R ₁ is an optionally substituted O-carboxy group. In some embodiments of the compound of formula (I'), R1 is -OC(O)(C1-C ₆ -alkyl), -OC(O)(C ₃ -C ₉ -cycloalkyl), -OC(O) (3- 6-membered heterocycloalkyl), -OC(O) (5- or 10-membered heteroaryl) and -OC(O)(C ₆ -C ₁₀ -aryl); and R1 is optionally substituted with one to five R _k independently selected from the group consisting of hydroxy, halogen, -CN, amino, C1- _C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C1 ₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, 5- A 10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C1 ₀ -aryl.

In some embodiments of a compound of formula (I'), R ₁ is an optionally substituted carbamoyl group. In some embodiments, the compounds of formula (I') R ₁ is -C(O)NR _m R _n , where R _m and R _n are independently selected from the group consisting of hydrogen, C 1 -C ₆ -alkyl, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C1 ₀ -aryl; or R _m and R _n together with the nitrogen to which they are attached form a 3-18 membered heterocycloalkyl ring; and R1 is optionally substituted with one to five Rk independently selected from the group consisting of hydroxy, halogen, -CN, amino, C1- _C6 alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1 -C ₆ -alkoxy, C ₆ -C1 ₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 -membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R ₁ is hydrogen, an optionally substituted C 1 -C ₆ -alkyl group, an optionally substituted non-aromatic C ₃ -C ₁₂ -carbocyclic group, an optionally substituted C ₆ -C ₁₀ -aryl group, and an optionally substituted C-carboxy group.

In some embodiments of a compound of formula (I'), R1 is hydrogen, an optionally substituted C1- _C6 alkyl group, an optionally substituted non-aromatic _C3 - _C12 carbocyclic group, an optionally substituted _C6 - _C10 aryl group, an optionally substituted C -carboxyl group and an optionally substituted carbamoyl group.

In some embodiments of the compounds of formula (I'), R1 is hydrogen; -CN; C1-C ₆ -alkyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring; C ₆ -C ₁₀ -aryl group; 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms,

- 28 047363 independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; an aralkyl group; (heterocycloalkyl)alkyl group; or -C(O)-R _j ; where R _j represent -NRmRn or -ORm; Rm represents hydrogen or C1- _C6 -alknl; Rn represents C1- _C6 -alknl; or Rm and Rn, together with the nitrogen to which they are attached, form a ring structure; and R1 is optionally substituted with one to five R _k independently selected from hydroxy, halogen, C1- _C6 -alkyl, C1- _C6 -haloalkyl, C1- _C6 -alkoxy and _C6 - _C10 -arylkoxy.

In some embodiments of the compounds of formula (I'), R1 is hydrogen, -CN, C1- _C6 alkyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring; C ₆ -C ₁₀ -aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; an aralkyl group; (heterocycloalkyl)alkyl group; or -C(O)-Rj; where Rj represent -NRmRn or -ORm; Rm represents hydrogen or C1- _C6 alkyl; Rn represents C1- _C6 -alknl; or Rm and Rn, together with the nitrogen to which they are attached, form a ring structure; and R1 is optionally substituted with one to three R _k independently selected from phenyl or haloalkyl.

In some embodiments of the compounds of formula (I'), R1 is hydrogen, -CN, C1- _C6 -alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, or -C(O)-Rj; where Rj represent -NRmRn or -ORm; Rm represents hydrogen or C1- _C6 -alknl; Rn represents C1- _C6 alkyl; or Rm and Rn together with the nitrogen to which they are attached form 1,2,3,4-tetrahydroisoquinoline; and R1 is optionally substituted with one to three R _k independently selected from phenyl or haloalkyl.

In some embodiments of the compounds of formula (I'), Ri is hydrogen, -CN, C1- _C6 -alknl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, isopropylamino, or -C(O)-Rj; where Rj represent -NRmRn or -ORm; Rm represents hydrogen or C1- _C6 -alknl; Rn represents C1- _C6 -alknl; or Rm and Rn together with the nitrogen to which they are attached form 1,2,3,4-tetrahydroisoquinoline; and R1, optionally substituted with one to three R _k independently selected from phenyl or haloalkyl.

In some embodiments of the compound of formula (I'), R2 is hydrogen, halogen, C1- _C6alkyl , _C3 - _C9cycloalkyl , or -CN; and R2 is optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, C1-C6 _-alknla , O-carboxy, C-carboxy, C-amido, N-amido, C1 -C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 -membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -arnla.

In some embodiments of the compound of formula (I'), R ₂ is hydrogen. In some embodiments of the compound of formula (I'), R2 is halogen. In some embodiments, compounds of formula (I') R2 are -CN.

In some embodiments of the compound of formula (I'), R2 is an optionally substituted C1- _C6 alkyl. In some embodiments of a compound of formula (I'), R2 is a C1- _C6 alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C- carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen , sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R2 is an optionally substituted C ₃ -C ₉ -cycloalkyl. In some embodiments of a compound of formula (I'), R2 is a C ₃ -C 8 -cycloalkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, C 1 -C ₆ -alkyl , O-carboxy, C-carboxy, C-amido, N-amido, C1- _C6 -alkoxy, _C6 - _C10 -arylkoxy, _C3 - _C9 -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), R2 is a C ₃ -C ₉ -cycloalkyl, optionally substituted with one to ten substituents independently selected from the group consisting of hydroxy, halogen and C1-C ₆ -alkyl.

In some embodiments of a compound of formula (I'), R ₂ is hydrogen or an optionally substituted C1 -C ₆ -alknl. In some embodiments, compounds of formula (I')

- 29 047363

R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In some embodiments of the compounds of formula (I'), R2 is hydrogen; halogen; C^C3-alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen and C ₁ -C ₆ -alkoxy; C ₃ -C ₉ -cycloalkyl, optionally substituted with one to ten substituents independently selected from the group consisting of hydroxy, halogen and C ₁ -C ₆ -alkoxy; or -CN.

In some embodiments of the compound of formula (I'), R ₃ is hydrogen. In some embodiments of a compound of formula (I'), R3 is lower alkyl.

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

In some embodiments of the compounds of formula (I'), R ₄ represents C|-C ₆ -alkyl; C2-C10 alkenyl; non-aromatic C ₃ -C12 carbocyclic ring; C ₆ -C ₁₀ -aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ - C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two Rg together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen.

In some embodiments of the compounds of formula (I'), R ₄ represents C ₁ -C ₆ -alkyl; C2-C ₁₀ alkenyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring; C ₆ -C ₁₀ -aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy, or two Rgs, together with the atoms to which they are attached, form a ring.

In some embodiments of the compounds of formula (I'), R4 is C ₁ -C ₆ -alkyl; C ₂ -C ₁₀ -alkenyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R ₄ is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two R _g together with the atoms to which they are attached form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen.

In some embodiments of the compound of formula (I'), R4 is a C ₁ -C ₆ -alkyl, C ₂ -C ₁₀ alkenyl, non-aromatic C ₃ -C ₁₂ -carbocyclic ring, 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a (carbocyclic)alkyl group, an aralkyl group or a (heterocycloalkyl)alkyl group, and _R4 is optionally substituted with one to five _Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of the compound of formula (I'), R4 is C ₁ -C ₆ -alkyl, C 2 -C ₁₀ -alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one , phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)alkyl group, (cyclopentyl)alkyl group, benzyl group, (tetrahydrofuranyl)alkyl group or (tetrahydropyranyl) )alkyl group and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two Rg together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen.

In some embodiments of a compound of formula (I'), R4 is C ₁ -C ₆ -alkyl,

- 30 047363

a C2-C ₁₀ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (cyclobutyl)alkyl group, (cyclopentyl)alkyl group, benzyl group, (tetrahydrofuranyl)alkyl group or (tetrahydropyranyl)alkyl group; and R ₄ is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C.'iC.'6-alkyl. C ₆ -C ₁₀ -aryl, C.'iC.'6-alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R ₄ is optionally substituted alkyl. In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted C1-C ₆ alkyl. In some embodiments of the compound of formula (I'), R ₄ is C1- _C6 alkyl, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C -carboxy, C-amido, N-amido, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C9-cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of a compound of formula (I'), R4 is C1- _C6 alkyl, optionally substituted with one to five _Rg independently selected from the group consisting of hydroxy, halogen, C1- _C6 alkyl, _C6- C ₁₀ -aryl, C1-C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy. 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 C1- _C6 alkyl. In some embodiments of the compound of formula (I'), R4 is C1- _C3 alkyl. In some embodiments of the compound of formula (I'), R4 is C ₅ -C ₆ alkyl.

In some embodiments of the compound of formula (I'), R4 is optionally substituted alkenyl. In some embodiments of the compound of formula (I'), R4 is an optionally substituted C2- _C10 alkenyl. In some embodiments of a compound of formula (I'), R4 is C2- _C10 alkenyl, optionally substituted with one to five _Rg independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C -carboxy, C-amido, N-amido, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group, containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl . In some embodiments of the compound of formula (I'), R ₄ is a C 2 -C ₁₀ -alkenyl, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R4 is an optionally substituted non-aromatic carbocyclic group. In some embodiments of a compound of formula (I'), R4 is an optionally substituted non-aromatic C ₃ -C ₁₂ carbocyclic group. In some embodiments of a compound of formula (I'), R ₄ is a non-aromatic C ₃ -C ₁₂ carbocyclic group, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, oxo, halogen, CN, amino, O -carboxy, C-carboxy, C-amido, N-amido, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ - C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10- member of a heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryls, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic 3-6- a ring member optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of a compound of formula (I'), R ₄ is a non-aromatic C ₃ -C ₁₂ carbocyclic group, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, oxo, halogen, amino, O- carboxy, C-carboxy, C-amido, N-amido, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of a compound of formula (I'), R4 is a non-aromatic C ₃ -C ₁₂ carbocyclic group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ - alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic A 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of a compound of formula (I'), R4 is a non-aromatic C ₃ -C ₁₂ carbocyclic group, optionally

- 31 047363 optionally substituted with one to five Rg, independently selected from the group consisting of hydroxy, halogen, C-C3-alkyl, C ₆ -C ₁₀ -aryl, G-C-C-alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted heterocycloalkyl group. In some embodiments of the compound of formula (I'), R4 is an optionally substituted 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; wherein the heterocycloalkyl ring is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C.'iC. '6-alkyl. E-C-haloalkyl. C ₆ -C ₁₀ -aryl, C.'iC.'6-alkoxy. C-C-haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 -membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl, or two R _g together with the atoms to which they are attached form an aromatic or non-aromatic 3- A 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compounds of formula (I'), R ₄ is an optionally substituted 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; wherein the heterocycloalkyl ring is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkyl , C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one up to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compounds of formula (I'), R ₄ is an optionally substituted 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; wherein the heterocycloalkyl ring is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, CN, oxo, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ - alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy. In some embodiments of the compounds of formula (I'), R ₄ is an optionally substituted 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; wherein the heterocycloalkyl ring is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ - C ₁₀ -arylkoxy.

In some embodiments of a 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 -C ₆ -alkyl, (cyclobutyl)C ₁ -C ₆ -alkyl, (cyclopentyl)C ₁ -C ₆ -alkyl, (cyclohexyl)C ₁ -C ₆ -alkyl, (cycloheptyl)C ₁ -C ₆ -alkyl, (cyclooctyl)C ₁ -C ₆ -alkyl or (cyclononyl)C ₁ -C ₆ -alkyl and R ₄ is optionally substituted with one to five R _g , independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl, or The two R _gs , together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R ₄ is (cyclopropyl)C ₁ -C ₆ -alkyl, (cyclobutyl)C ₁ -C ₆ -alkyl, (cyclopentyl)C ₁ -C ₆ -alkyl, (cyclohexyl) C ₁ -C ₆ -alkyl, (cycloheptyl)C ₁ -C ₆ -alkyl, (cyclooctyl)C ₁ -C ₆ -alkyl or (cyclononyl)C ₁ -C ₆ -alkyl and R ₄ is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ - haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), R4 is (cyclopropyl)C ₁ -C ₆ -alkyl, (cyclobutyl)C ₁ -C ₆ -alkyl, (cyclopentyl)C ₁ -C ₆ -alkyl, (cyclohexyl)C ₁ -C ₆ -alkyl, (cycloheptyl)C ₁ -C ₆ -alkyl, (cyclooctyl)C ₁ -C ₆ -alkyl or (cyclononyl)C ₁ -C ₆ -alkyl and R ₄ is optionally substituted with one to five R _g , independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

- 32 047363

In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted aralkyl group. In some embodiments of the compound of formula (I'), R ₄ is a benzyl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C -amido, N-amido, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C1-C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C9-cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms , independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryls, or two Rg together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms, independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R4 is a benzyl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C- amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl , a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen , and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), R ₄ is a benzyl group, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C1-C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy. In some embodiments of a compound of formula (I'), R4 is a benzyl group, optionally substituted with one to five Rgs independently selected from the group consisting of hydroxy, halogen, C1- _C6 alkyl, _C6 - _C10 aryl, C1-C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R4 is an optionally substituted (heterocycloalkyl)alkyl group. In some embodiments of a compound of formula (I'), R ₄ is a (heterocycloalkyl)alkyl group, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, oxo, halogen, amino, CN, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C1-C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one up to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of a compound of formula (I'), R4 is a (heterocycloalkyl)alkyl group, optionally substituted with one to five _Rg independently selected from the group consisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy , C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of a compound of formula (I'), R4 is a (heterocycloalkyl)alkyl group, optionally substituted with one to five Rgs independently selected from the group consisting of hydroxy, halogen, C1- _C6 alkyl, _C6 - _C10 -aryl, C1-C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R4 is an optionally substituted (heteroaryl)alkyl group. In some embodiments of a compound of formula (I'), R ₄ is a (heteroaryl)alkyl group, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C -carboxy, C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryls, or two Rg together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen , sulfur or nitrogen. In some embodiments of a compound of formula (I'), R4 is a (heteroaryl)alkyl group, optionally substituted with one to five Rgs independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy , C-amido, N-amido, C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, a 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms,

- 33 047363 independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of a compound of formula (I'), R ₄ is a (heteroaryl)alkyl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy. In some embodiments of a compound of formula (I'), R ₄ is a (heteroaryl)alkyl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ alkyl, C ₆ - Clo-aryl, C-C^alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of the compounds of formula (I'), R4 is a C ₆ -Clo-aryl group or a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, X-C^alkyl, _C6 - _C10 -aryl, C-C^alkoxy, Cl- _C6 -haloalkoxy and The C ₆ -C ₁₀ -arylkoxy, or two Rgs, together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments, the compounds of formula (I') R ₄ represents a C ₆ -C ₁₀ -aryl group or a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; and R ₄ is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen,

C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments of a compound of formula (I'), R4 is an optionally substituted C ₆ -C ₁₀ aryl group. In some embodiments of a compound of formula (I'), R ₄ is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, O-carboxy, C -carboxy, C-amido, N-amido, amino, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl, or two Rg together with the atoms to which they are attached, forming an aromatic or non-aromatic 3-6 membered ring , optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of a compound of formula (I'), R4 is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, O-carboxy, C- carboxy, C-amido, N-amido, amino, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₆ -C ₁₀ - arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms , independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of a compound of formula (I'), R ₄ is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ - alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic A 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of a compound of formula (I'), R4 is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkoxy and C ₆ -C ₁₀ -arylkoxy.

In some embodiments, the compounds of formula (I') R ₄ benzyl, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and C ₁ -C ₆ -haloalkoxy, or two Rg together with the atoms to which they are attached, form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R4 is benzyl, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, or two Rgs together with the atoms to which they are attached form a ring.

In some embodiments of the compound of formula (I'), R4 is naphthyl, optionally substituted with one or five Rgs independently selected from the group consisting of hydroxy, halogen, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy.

In some embodiments of a compound of formula (I'), R ₄ is an optional

- 34 047363 strongly substituted heteroaryl group. In some embodiments of the compound of formula (I'), R ₄ is a 5- or 10-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally substituted with one to five Rg , independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C-C^alkoxy, C ₁ -C ₆ -haloalkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -Cl ₀ -aryls, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R ₄ is a 5- or 10-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally substituted with one to five Rg , independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C.'iC.'6-alkyl. C-C^haloalkyl, C ₆ -C ₁₀ -aryl, C.'iC.'6-alkoxy. C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C1o-aryl. In some embodiments of the compound of formula (I'), R ₄ is a 5- or 10-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally substituted with one to five Rg , independently selected from the group consisting of hydroxy, halogen, CN, C1- _C6 -alkyl, _C6 -C10-aryl, C1- _C6 -alkoxy, C1- _C6- haloalkoxy and C6- _C10 -arylkoxy. In some embodiments of a compound of formula (I'), R4 is a 5- or 10-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionally substituted with one to five Rg, independently selected from the group consisting of hydroxy, halogen, C1- _C6 -alkyl, _C6 -C10-aryl, C1- _C6 -alkoxy and _C6 - _C10 -arylkoxy.

In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted amino group. In some embodiments of a 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 -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, C ₆ -C ₁₀ -aryl, C-carboxy, C-amido, -(8O2)(C1-C ₆ -alkyl), -C(O)0(C ₁ -C ₆ -alkyl), -C (O)O(C ₁ -C ₆ -haloalkyl), -C(O)O(C ₃ -C ₉ -cycloalkyl), -C(O)O(3-6-membered heterocycloalkyl), -C(O) O(5-10-membered heteroaryl) and -C(O)O(C ₆ -C ₁₀ -aryl). In some embodiments, compounds of formula (I') R ₄ are -NR _m R _n , wherein R _m and R _n are independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₉ cycloalkyl , a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen , C ₆ -C ₁₀ -aryl, C-carboxy, C-amido, -(8O2)(C1-C ₆ -alkyl), -C(O)O(C ₁ -C ₆ -alkyl), -C(O )O(C ₃ -C ₉ -cycloalkyl), -C(O)O(3-6-membered heterocycloalkyl), -C(O)O(5- or 10-membered heteroaryl) and -C(O)O( C ₆ -C ₁₀ -aryl); or R _m and R _n together with the nitrogen to which they are attached form a 3-18 membered heterocycloalkyl ring; and R ₁ is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, -CN, amino, C ₁ -C ₆ -alkyl, O-carboxy, C-carboxy, C-amido, N-amido , C ₁ -C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, A 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted sulfamoyl group. In some embodiments, the compounds of formula (I') R4 is -SO ₂ NR _m R _n , where R _m and R _n are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₉ - cycloalkyl, a 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl; or R _m and R _n together with the nitrogen to which they are attached form a 3-18 membered heterocycloalkyl ring; and R ₁ is optionally replaced

- 35 047363 from one to five Rg, independently selected from the group consisting of hydroxy, halogen, -CN, amino, C ₁ -C ₆ -alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C1- _C6 alkoxy, C6- _C10 arylkoxy, _C3 - _C9 cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 -membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), R ₄ is an optionally substituted carbamoyl group. In some embodiments, the compounds of formula (I') R ₄ is -C(O)NRmRn, where Rm and Rn are independently selected from the group consisting of hydrogen, C 1 -C ₆ -alkyl, C ₃ -C ₉ -cycloalkyl, 3 -6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl; or Rm and Rn together with the nitrogen to which they are attached form a 3-18 membered heterocycloalkyl ring; and R1 is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, -CN, amino, C.'iC.'6-alkyl. O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one up to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compounds of formula (I'), R ₅ is hydroxy. In some embodiments of the compounds of formula (I'), R5 is NH2.

In some embodiments of the compound of formula (I'), R5 is an alkylamino. In some embodiments, compounds of formula (I') R5 are -NR _u R _v where R _u is hydrogen or C1- _C6 alkyl and R _v is C1- _C12 alkyl optionally substituted from one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1- _C6 -alkoxy, _C6 - _C10 -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compound of formula (I'), R5 is alkanoylamino. In some embodiments, compounds of formula (I') R5 are -NR _u C(O)R _v where Ru is hydrogen or C1- _C6 alkyl and R _v is C1- _C12 alkyl, optionally substituted from one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1- _C6 -alkoxy, _C6 - _C10- arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms , independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compounds of formula (I'), R ₅ is alkylsulfonylamino. In some embodiments, compounds of formula (I') R ₅ are -NRuSO2R _v where Ru is hydrogen or C1-C ₆ alkyl and R _v is C1-C12 alkyl optionally substituted with one to five independently selected substituents from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1- _C6 -alkoxy, C6- _{C10 -} arylkoxy, _C3 - _C9 -cycloalkyl, 3-6 membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of the compounds of formula (I'), R ₅ is hydroxy or NH ₂ . In some embodiments of the compounds of formula (I'), R ₅ is hydroxy, NH2, C1- _C6- alkylamino, C1- _C6- alkanoylamino, or C1- _C6 -alkylsulfonylamino.

In some embodiments, compounds of formula (I') R ₄ and R ₅ , taken together with the carbon atoms to which they are attached, form a 5- or 6-membered, optionally substituted, non-aromatic C ₃ -C ₁₂ -carbocyclic group, optionally substituted A C ₆ -C ₁₀ aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. In some embodiments, the compounds of formula (I') R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered non-aromatic C ₃ -C ₁₂ carbocyclic group, C ₆ -C ₁₀ aryl group , a 4- to 6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5- or 10-membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and the carbocyclic group,

- 36 047363 aryl group, heterocycloalkyl group and heteroaryl group are optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido , ^-^-alkyl, C ₁ -C ₆ -haloalkyl, ^-^-alkoxy, ^-^^ρ^κοκ^, ^^-cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms , independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁ 0-aryl.

In some embodiments, compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a 7 to 11 membered, optionally substituted spirocyclic ring or a 7 to 11 membered, optionally substituted spiroheterocyclic ring . In some embodiments, the compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a seven- to 11-membered spirocyclic ring or a seven- to 11-membered spiroheterocyclic ring; and the spirocyclic ring and the spiroheterocyclic ring are optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C|-C ₆ -;ih<ui, ^-^-haloalkyl, C-Olicoxy. ^-^^ρ^κοκ^, ^^-cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, 5-10-membered heteroaryl group containing from one up to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁ 0-aryl.

In some embodiments, the compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group.

In some embodiments, the compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a 5- or 6-membered non-aromatic carbocyclic group; C ₆ -C ₁ 0-aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; or a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; and wherein the carbocyclic group, aryl group, heterocycloalkyl ring and heteroaryl ring are optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, ^-^-alkyl, ^-^-alkoxy and oxo, and/or optionally two Rgs together with the atom(s) to which they are attached form a 3-6 membered carbocyclic group.

In some embodiments, the compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; and wherein the heterocycloalkyl ring is optionally substituted with one to five Rgs independently selected from the group consisting of C ₁ -C ₆ alkyl and oxo, and/or optionally two Rgs together with the atom(s) to which they are attached form a 3- 6-membered non-aromatic carbocyclic group.

In some embodiments, the compounds of formula (I') R4 and _R5 , taken together with the carbon atoms to which they are attached, form a pyrrolidine, optionally substituted with one to five Rg independently selected from the group consisting of ^^-alkyl and oxo, and/or optionally two Rgs together with the atom(s) to which they are attached form a 3-6 membered non-aromatic carbocyclic group.

In some embodiments, a compound of formula (I') TL is a moiety of formula (IIIaa)

where each Rg independently represents ^-^-alkyl; or two Rg together with the atom to which they are attached form an alkene, optionally substituted with ^-^-alkyl; or two Rgs together with the atom to which they are attached form a 3-6 membered non-aromatic carbocyclic group.

In some embodiments of the compounds of formula (I'), two Rgs together with the atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

In some embodiments, a compound of formula (I') TL is a moiety of formula (IIIaa)

- 37 047363 where each Rg independently represents a C1-C ₆ -alkyl or two Rg together with the atom(s) to which they are attached form a 3-6 membered non-aromatic carbocyclic group.

In some embodiments of the compounds of formula (I'), the two R _gs together with the atom to which they are attached form a cyclopentyl group or a cyclohexyl group.

In some embodiments of a compound of formula (I'), TL is a fragment of formula (IIIab):

where Rg represents C1- _C6 alkyl.

In some embodiments of the compound of formula (I'), Rg is isopropyl.

In some embodiments, a compound of formula (I') TL is a moiety of formula (IIIac)

where Rg represents C1- _C6 alkyl.

In some embodiments of the compound of formula (I'), Rg is methyl.

In some embodiments, a compound of formula (I') TL is a moiety of formula (IIIad)

where each Rg independently represents hydrogen or C1- _C6 alkyl.

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

In some embodiments, compounds of formula (I'):

R4 is C1- _C6 alkyl; C ₂ -C ₁₀ -alkenyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring, C ₆ -C ₁₀ -aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; aralkyl group; (heterocycloalkyl)alkyl group; (heteroaryl)alkyl group or -C(O)NRmRn;

Rm and Rn are independently selected from the group consisting of hydrogen, C1- _C6 alkyl, _C1 - _C6 haloalkyl, _C2 - _C6 alkoxy, _C6 - _C10 aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a fifty-membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; aralkyl group; (heterocycloalkyl)alkyl group; or (heteroaryl)alkyl group; or

Rm and Rn, together with the nitrogen to which they are attached, form a 3-18 membered heterocycloalkyl ring; And

R ₄ is optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, C 1 -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₁₀ -aryl, C 1 -C ₆ - alkoxy and C ₆ -C ₁₀ -arylkoxy;

R ₅ represents hydroxy, NH ₂ , alkylamino, alkanoylamino or alkylsulfonylamino.

In some embodiments, compounds of formula (I'):

R4 is C1- _C6 alkyl; C2-C10 alkenyl; non-aromatic C ₃ -C ₁₂ -carbocyclic ring, C ₆ -C ₁₀ -aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; aralkyl group; (heterocycloalkyl)alkyl group; (heteroaryl)alkyl group or -C(O)NR _m R _n ;

- 38 047363

Rm and Rn are independently selected from the group consisting of hydrogen, C1- _C6 alkyl, C1- _C6 haloalkyl, C2- _C6 alkoxy, _C6 - _C10 aryl group; a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; a 5-10 membered heteroaryl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; (carbocyclic)alkyl group; aralkyl group; (heterocycloalkyl)alkyl group or (heteroaryl)alkyl group; or

Rm and Rn, together with the nitrogen to which they are attached, form a 3-18 membered heterocycloalkyl ring; And

R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C1- _C6 -alkyl, C1-C6 _- haloalkyl, _C6 - _C10 -aryl, C1- _C6 -alkoxy and C ₆ -C ₁₀ -arylkoxy;

R ₅ represents hydroxy.

In some embodiments of the compound of formula (I'), Alk is hydrogen or optionally substituted C1 -C ₆ -alkyl. In some embodiments of a compound of formula (I'), Alk is hydrogen or C1- _C6 alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms , independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), Alk is hydrogen. In some embodiments of a compound of formula (I'), Alk is C1- _C6 alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C- carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), Alk is C1- _C6 alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, and C1- _C6 alkoxy.

In some embodiments of the compound of formula (I'), R ₁₁ represents an aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and C ₃ -C ₉ -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 ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems. In some embodiments of the compound of formula (I'), R11 is an aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, halogen and C ₃ -C ₉ -cycloalkyl; or a bicyclic ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems. In some embodiments of the compound of formula (I'), R11 is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and C ₃ -C ₉ cycloalkyl; or a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein the heteroaryl group is optionally substituted by from one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and C ₃ -C ₉ -cycloalkyl; or a 7-12 membered bicyclic ring system containing aromatic or saturated rings; or a 7-12 membered bicyclic heterocycle containing aromatic or saturated ring systems. In some embodiments of the compound of formula (I'), R11 is a C ₆ -C ₁₀ aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, halogen and C ₃ -C ₉ cycloalkyl; or a 7-12 membered bicyclic ring system containing aromatic or saturated rings; or a 7-12 membered bicyclic heterocycle containing aromatic or saturated ring systems. In some embodiments of the compound of formula (I'), R11 is a C ₆ -C1 ₀ aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen and C3-C9 cycloalkyl. In some embodiments of the compound of formula (I'), Rn is a C ₆ Cio-aryl group, optionally substituted with one to five substituents independently selected from lower alkyl, halogen and C ₃ -C ₉ -cycloalkyl. In some embodiments of a compound of formula (I'), R11 is a 5- or 10-membered heteroaryl group containing one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein the heteroaryl group is optionally substituted with one to five substituents, whatever you are

- 39 047363 branes of lower alkyl, alkoxy, haloalkoxy, halogen and C ₃ -C ₉ -cycloalkyl. In some embodiments of the compounds of formula (I'), Rn is a 7-12 membered bicyclic ring system containing aromatic or saturated rings. In some embodiments of the compound of formula (I'), R11 is a 7-12 membered bicyclic heterocycle containing aromatic or saturated ring systems. In some embodiments of the compound of formula (I'), R ₁₁ is benzyl, optionally substituted with one to five substituents independently selected from C.'iC.'5-alkyl. C.'iC.'5-alkoxy. C.'iC.'5-haloalkoxy. halogen and ^-^-cycloalkyl; pyridine optionally substituted with C.'rC.'5-alkyl;cinnoline;isoquinoline;quinoline;pyrazolo[1,5-a]pyridine;imidazo[1,5-a]pyridine;benzo[b]thiophene;lame;1,2,3,4tetrahydronaphthalene; or naphthalene. In some embodiments of the compound of formula (I'), R11 is benzyl, optionally substituted with one to five substituents independently selected from ^-^-alkyl, halogen and ^-^-cycloalkyl; 1,2,3,4-tetrahydronaphthalene or naphthalene.

In some embodiments of the compounds of formula (I'), R ₆ and R ₇ are each independently halogen or C1 -^-alkyl, optionally substituted with one to five substituents independently selected from hydroxy, halogen, and Cj-Cg-alkoxy; and R ₈ represents hydrogen; or R ₆ is halogen or n-^-alkyl, optionally substituted with one to five substituents independently selected from hydroxy, halogen and n-^-alkoxy; and R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic ring.

In some embodiments of the compounds of formula (I'), R6 and R7 are each independently chlorine, bromine, and iodine. In some embodiments of a compound of formula (I'), _R6 and R7 are each independently -CN, an optionally substituted lower alkyl, or an optionally substituted lower alkoxy, wherein the lower alkyl and the lower alkoxy alkyl group are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. In some embodiments, the compounds of formula (I') R ₆ and R ₇ are the same. In some embodiments of the compounds of formula (I'), R ₆ and R ₇ are each independently chlorine or methyl. In some embodiments of the compounds of formula (I'), R ₆ is Cl, R ₇ is Cl, and R ₈ is hydrogen. In some embodiments of the compounds of formula (I'), R ₆ is Cl, R ₇ is Cl, and R ₈ is methyl. In some embodiments of the compounds of formula (I'), R ₆ is halogen, and R 7 and R 8, taken together with the carbon atoms to which they are attached, form a 4-membered carbocyclic ring.

In some embodiments of the compound of formula (I'), R ₈ is hydrogen. In some embodiments of a compound of formula (I'), R8 is an optionally substituted lower alkyl. In some embodiments of the compound of formula (I'), R8 is lower alkyl, optionally substituted with one to five substituents selected from the group consisting of hydroxy, halogen, amino, -CN, O-carboxy, C-carboxy, C-amido , N-amido, ^-^-alkoxy, ^-^-cycloalkyl, 3-5 membered heterocycloalkyl group containing one heteroatom independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R ₈ is an optionally substituted lower alkoxy. In some embodiments, the compounds of formula (I') R ₈ lower alkoxy, optionally substituted with one to five substituents selected from the group consisting of hydroxy, halogen, amino, -CN, O-carboxy, C-carboxy, C-amido, N-amido, ^-^-alkoxy, C3-C5 cycloalkyl, 3-5 membered heterocycloalkyl group containing one heteroatom independently selected from oxygen, sulfur or nitrogen. In some embodiments of the compound of formula (I'), R8 is cyano. In some embodiments of the compound of formula (I'), R8 is halogen.

In some embodiments, the compounds of formula (I') R7 and R8, taken together with the carbon atoms to which they are attached, form a 4-, 5-, or 6-membered non-aromatic carbocyclic, 3-5-membered heterocycloalkyl, ^-^o-aryl or a 5-10 membered heteroaryl ring.

In some embodiments of the compound of formula (I'), Q7 is nitrogen. In some embodiments of the compound of formula (I'), Q7 is -CRc-. In some embodiments of the compound of formula (I'), Rc is hydrogen. In some embodiments of the compounds of formula (I'), R _c is halogen. In some embodiments of a compound of formula (I'), R _c is lower alkyl. In some embodiments of the compound of formula (I'), Rc is hydrogen or methyl. In some embodiments, compounds of formula (I') Q7 are -CH-.

In some embodiments of the compound of formula (I'), R9 is hydrogen, -(C(R _d ) ₂ )nN(R _d ) ₂ , -(C(Rd) ₂ )n-CN, or -(C(R _d ) ₂ )nC=C-Rd. In some embodiments of the compound of formula (I'), R ₉ is hydrogen, -(CH ₂ )nN(R _d ) ₂ , -(CH2)n-CN, or -(CH2)nC=CR _d . In some embodiments of the compound of formula (I'), R ₉ is selected from hydrogen, -N(R _d )2, -CN, or -C.=CR,|.

- 40 047363

In some embodiments of the compounds of formula (I'), R ₉ is selected from hydrogen, -NH2, -CN or -CCH.

In some embodiments of the compound of formula (I'), R ₉ is hydrogen. In some embodiments of the compound of formula (I'), R ₉ is -(C(R _d )2) _n -C(R _d ) ₃ . In some embodiments of the compound of formula (I'), R ₉ is -(C(R _d )2) _n -OR _d . In some embodiments of the compound of formula (I'), R ₉ is -(C(R _d ) ₂ ) _n -N(R _d ) ₂ . In some embodiments of a compound of formula (I'), R ₉ is -NH ₂ . In some embodiments of the compound of formula (I'), R ₉ is -(C(R _d ) ₂ ) _n -S(=O) _q Rd. In some embodiments of the compound of formula (I'), R ₉ is -(C(R _d ) ₂ ) _n -CN. In some embodiments of a compound of formula (I'), R ₉ is -CN. In some embodiments of the compound of formula (I'), R9 is -(C(Rd) ₂ ) _n -C^C-Rd. In some embodiments of the compound of formula (I'), R ₉ is -C.=C.'H. In some embodiments of the compound of formula (I'), R ₉ is -(C(Rd)2)nC(=O)-ORd. In some embodiments of the compound of formula (I'), R ₉ is -(C(Rd) ₂ ) _n -HeAr. In some embodiments of the compound of formula (I'), R ₉ is -(C(Rd) ₂ ) _n -C(=O)-N(R _d ) ₂ .

In some embodiments of a compound of formula (I'), each Rd is independently hydrogen or lower alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C- carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms, independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compounds of formula (I'), each R _d is hydrogen. In some embodiments of a compound of formula (I'), each Rd is independently lower alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl.

In some embodiments of a compound of formula (I'), q is 0. In some embodiments of a compound of formula (I'), q is 1. In some embodiments of a compound of formula (I'), q is 2.

In some embodiments of a compound of formula (I'), n is 0. In some embodiments of a compound of formula (I'), n is 1. In some embodiments of a compound of formula (I'), n is 2. In some embodiments of a 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.

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

In some embodiments of a compound of formula (I'), R ₁₀ is hydrogen or -C(Re) ₃ , wherein each Re is independently hydrogen, halogen, or lower alkyl, optionally substituted with one to five substituents independently selected from the group consisting of from hydroxy, halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3 -6-membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -C ₁₀ -aryl. In some embodiments of the compound of formula (I'), R ₁₀ is hydrogen. In some embodiments of a compound of formula (I'), R ₁₀ is -C(Re) ₃ , wherein each Re is independently hydrogen, halogen, or lower alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy , halogen, -CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C1-C ₆ -alkoxy, C ₆ -C ₁₀ -arylkoxy, C ₃ -C ₉ -cycloalkyl, 3-6 -membered heterocycloalkyl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, a 5-10 membered heteroaryl group containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen, and C ₆ -From ₁₀ -arila. In some embodiments of a compound of formula (I'), R ₁₀ is -C(Re) ₃ wherein each Re is independently hydrogen, halogen, or lower alkyl. In some embodiments of the compounds of formula (I'), R ₁₀ is hydrogen, -CHF2, -CH3 or ethyl.

- 41 047363

In some embodiments of a compound of formula (I'), L _a is a bond; -(C(R _a )2) _z -; oxygen; sulfur; or -NR _a -. In some embodiments of a compound of formula (I'), L _a is a bond. In some embodiments of the compound of formula (I'), L _a is -(C(R _a ) ₂ ) _z -. In some embodiments of the compounds of formula (I'), L _a is -CH2-. In some embodiments of the compounds of formula (I'), L _a is oxygen. In some embodiments of the compounds of formula (I'), L _a is sulfur. In some embodiments of the compound of formula (I'), L _a is -NH ₂ . In some embodiments of the compounds of formula (I'), each R _a is hydrogen. In some embodiments of the compounds of formula (I'), each R _a is independently lower alkyl. In some embodiments of the compounds of formula (I'), each Ra is independently hydrogen or lower alkyl.

In some embodiments of a compound of formula (I'), z is 0. In some embodiments of a compound of formula (I'), z is 1. In some embodiments of a compound of formula (I'), z is 2. In some embodiments of a 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.

In another aspect disclosed herein, is a compound selected from the group consisting of:

- 42 047363

- 43 047363

- 44 047363

- 45 047363

- 46 047363

- 47 047363

- 48 047363

- 49 047363

- 50 047363

- 51 047363

Synthesis of compounds

The currently disclosed compounds were synthesized using the general synthetic procedures presented in Schemes 1-10 below. The performance of each individual step illustrated is within the skill of one of ordinary skill in the art, who also knows how to modify the synthetic procedures of the following schemes to synthesize the full range of compounds disclosed herein. The synthetic procedure for individual compounds is presented in the Examples section below.

As described in Scheme 1, the aromatic amino compound of formula S-II is converted to the azauracil compound of formula S-III, first by formation of the corresponding diazonium salt, followed by reaction with Na(2-cyanoacetyl)carbamate and finally cyclization resulting in the compound of formula S -III. The nitrile of formula S-III is then hydrolyzed to a carboxylic acid compound of formula S-IV. The compound of formula S-IV is then reacted with diphenylphosphoryl azide (DPPA) to form the compound of formula S-V. Finally, the compound of Formula S-V is deprotected.

Scheme 1

As described in Scheme 2, an aromatic amino compound of formula S-II can be converted to a boronic acid compound of formula S-VII by first forming a diazonium salt and then reacting

- 52 047363 with tetrahydroxy-diborane. The appropriate boronic acid is then coupled to a suitably protected (PG protecting) bromosauracil compound of formula Int-I. The resulting bromide compound of formula S-VIII is then further converted either by a substitution reaction or by transition metal catalyzed reactions, as illustrated in the Examples section below. Removal of the PG protecting group results in a compound of formula S-X.

Scheme 2

The synthesis of the aromatic amino compound of formula S-XIV is described in Scheme 3.

A compound of formula S-XI is reacted with a compound of formula S-XII (X is a halogen like F or Cl) followed by protection with a protecting group PG to produce a compound of formula S-XIII. Reduction of the nitrofunctional group of a compound of formula S-XIII results in the formation of an aromatic amino compound of formula S-XIV.

Scheme 3

Scheme 4 describes the synthesis of the compound of formula S-XIX. The transmetalation reaction of a compound of formula S-XVT (X in the structure is a halogen, such as Br or I) is followed by addition to an aldehyde of the general formula S-XV to produce an alcohol compound of formula S-XVII, which is then reduced to a compound of formula S-XVIII. Deprotection PG2 of a compound of formula S-XVIII results in the formation of a compound of formula S-XIX.

Scheme 4

As described in Scheme 5, a compound of formula S-XX is prepared by cross-coupling a compound of formula S-VII with a bromide compound of formula Int-II.

Scheme 5

Scheme 6a depicts an alternative synthesis of compounds of general formula S-XIX. Compound

- 53 047363 of formula S-XXI (where the structure is a halogen, for example Cl, Br or I) is cross-coupled with a compound of formula S-XXII by a Suzuki-type cross-coupling, resulting in the formation of a compound of formula S-XXIII. The PG3 protecting group, for example a benzyl moiety, can then be removed to give the compound of formula S-XXIV. The resulting phenolic functionality can then be replaced by a triflate group, resulting in a compound of general formula S-XXV. The -OTf group can then be replaced by an -NH2 moiety via a transition metal catalyzed reaction such as a Buchwald coupling with, for example, tert-butylcarbamate or benzophenone imine, followed by deprotection to give a compound of general formula S-XIX. The method described in Scheme 6a can also be applied when indazole halide S-XXI is used as the starting material. Alternatively, indazole halide can undergo lithium-halogen exchange. The resulting aryllithium species can react with an aldehyde of type S-XXVIII to form compounds of formula S-XXIX. Further development of the structures of formula S-XXIX is described in Scheme 7.

Scheme 6a

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

Scheme 6b

Scheme 7 describes the synthesis of the compound of formula S-XXXI. The transmetalation reaction of a compound of formula S-XXVII (X in the structure is a halogen, such as Br or I) is followed by addition to an aldehyde of the general formula S-XXVIII to produce an alcohol compound of formula S-XXIX, which is then reduced to a compound of formula S-XXX. Deprotection PG2 of a compound of formula S-XXX results in the formation of a compound of formula S-XXXI.

Scheme 7

Scheme 8 describes the general synthesis of compounds of formula S-XXI and their products.

When R ₁ is, for example, hydrogen and Y is hydrogen, then R ₁ can

- 54 047363 be converted to the corresponding acyl group via an acid chloride and a Lewis acid (eg InBr ₃ ) in a non-polar aprotic solvent (eg dichloroethane). The newly formed ketone group can be partially reduced to an alcohol or completely reduced to the corresponding alkane. Further transformations of the ketone group are obvious to those skilled in the art. In the second example, where Ri is hydrogen and Y is a suitable protecting group (eg tosyl), then R1 can be converted to iodide by an iodinating agent (eg NIS) using techniques available in the literature.

Scheme 8

Scheme 9 describes the general synthesis of compounds of formula S-XXXIII. 4-Bromo-6-chloropyridazin-3-amine can be converted to the corresponding 4-aryl-6-chloropyridazin-3-amine (S-XXXII) using, for example, ArB(OH)2 (e.g. phenylboronic acid) and palladium catalyst (eg PdCl ₂ (PPh ₃ ) ₂ ) under typical Suzuki-Miyaura reaction conditions. Subsequent conversion of the amino group to Cl under typical Sandmeyer reaction conditions (e.g. CuCl2, tert-Bu-ONO, acetonitrile, heat) produces compounds of type S-XXXIII.

Scheme 9

Scheme 10 describes the general synthesis of compounds of formula S-XXXVI. Compounds of formula S-XXXIV can be cross-coupled with phenol HO-CE-HD via a Cu(I)-mediated cross-coupling reaction in DMSO with a base (eg K ₂ CO ₃ ) at elevated temperature to produce intermediates type S-XXXV. Subsequent hydrolysis of chloropyridazine with acetic acid and an acetate salt (eg NaOAc) gives products of formula S-XXXVI, from which the desired regioisomer can be isolated. In the context of Scheme 10, the HD group may contain a general protecting group, which can be cleaved at the step of intermediates S-XXXV or at the end of the synthesis to obtain a compound of formula S-XXXVI.

Scheme 10

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

Alternatively, Scheme 11 depicts the synthesis of compounds of formula S-XXXVII, which can be prepared starting from dihalogenated aminoaryl (S-XXXVII-a). The amine is then protected (eg, trimethylacetamide) to give the amide intermediate (S-XXXVII-b). Under strongly basic conditions (e.g., n-buLi, TG F), S-XXXVII-b reacts with an aldehyde containing the desired Rg substitution to give the alcohol product S-XXXVI-c, which is oxidized (with a conventional oxidizing agent; e.g., Dess's reagent -Martin) at the subsequent stage to obtain the ketone S-XXXVII-d. The ketone is subjected to an aldol reaction with a protected ester (eg, t-butyl) to yield intermediate S-XXXVII-e. In the final step, intramolecular cyclization may occur to give the compound of formula S-XXXVII.

- 55 047363

Scheme 11

Incorporation of compounds of formula S-XXXVII to form the final products can occur using similar methods as described in Schemes 6a and 6b.

There are several methods for accessing compounds of formula XXXVIII, and these include, but are not limited to, the methods found in or referred to in the following references: (a) Hajra, S.; et al., Org. Lett. 2018, 20, 4540-4544. (b) Zaytsev, S. et al., Journal of Organic Chemistry (2018), 83(15), 86958709. (c) Wu, C.; et al., Organic Letters (2014), 16(7), 1960-1963. (d) Ye, N.; et al., ACS Infect Dis. 2016, 2(6), 382-392. Incorporation of compounds of formula S-XXXVIII to form the final products can occur using similar methods as described in Schemes 6a and 6b.

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

Scheme 12

Pharmaceutical compositions

In another aspect, disclosed herein are pharmaceutical compositions containing, consisting essentially of, or consisting of a compound as described herein and at least one pharmaceutically acceptable excipient.

In another aspect, disclosed herein are pharmaceutical compositions comprising a compound of formula (I) as described herein and a pharmaceutically acceptable diluent, excipient or carrier. In some embodiments, pharmaceutical compositions disclosed herein contain, consist essentially of, or consist of a compound of formula (I) as described herein and at least one pharmaceutically acceptable diluent, excipient, or carrier. In another aspect, disclosed herein are pharmaceutical compositions containing, consisting essentially of, or consisting of a compound of formula (I'), as described herein, and at least one pharmaceutically acceptable excipient. A pharmaceutical composition disclosed herein may include a pharmaceutically acceptable carrier such as diluents, disintegrants, sweeteners, glidants, or flavoring agents, and may be formulated in an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral dosage form such as topical liquids, topical suspensions, topical emulsions, gels (ointments, etc.), inhalants, nebulizers, injections, etc. These dosage forms can be formulated in various forms, for example in a dosage form for single or multiple administration.

The pharmaceutical composition disclosed herein may include excipients such as

- 56 047363 such as lactose, corn starch, etc., glidants such as magnesium stearate, etc., emulsifying agents, suspending agents, stabilizers and isotonic agents, etc. if desired, a sweetening agent and/or flavoring may be added. Examples of excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophores, carbohydrates, starches (eg, corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (eg calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, combinations thereof, and the like. Specific carbohydrate excipients include, for example: monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose and the like; polysaccharides such as raffinose, melecitose, maltodextrins, dextrans, starches and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucite), pyranosyl sorbitol, myoinositol and the like. Inorganic salt or buffers include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monobasic sodium phosphate, dibasic sodium phosphate, and combinations thereof.

Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof. Additional exemplary excipients include surfactants such as polysorbates, such as Tween 20 and Tween 80, and pluronics, such as F68 and F88 (both available from BASF, Mount Olive Township, NJ), sorbitan esters, lipids (eg , phospholipids such as lecithin and other phosphatidylcholines (and phosphatidylethanolamines), fatty acids and fatty acid esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc and other suitable cations.

In addition, the composition disclosed herein may optionally include one or more acids or bases. Non-limiting examples of acids that can be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid and combinations thereof. Non-limiting examples of suitable bases include bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, fumarate potassium and their combinations. 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 components, and the specific needs of the composition. Typically, however, the excipient will be present in the composition in an amount of from about 1 to about 99% by weight, preferably from about 5 to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient. Typically, the amount of excipient present in the composition of the present disclosure is selected from the following: at least about 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or even 95% by weight.

The pharmaceutical compositions described herein can be administered to a human patient alone or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Methods for the preparation and administration of the compounds of the present invention can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 18th ed., 1990.

Suitable routes of administration may, for example, include oral, transdermal, rectal, transmucosal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as inhalation, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections. The pharmaceutical compositions described herein can be manufactured in a known manner, for example, by conventional processes of mixing, dissolving, granulating, pilling, elutriating, emulsifying, encapsulating, entrapping or tabletting. These pharmaceutical compositions can then be formulated in a conventional manner using one or more known physiologically acceptable carriers containing excipients and/or excipients that facilitate processing of the active compounds into pharmaceutically usable preparations. Any of the well known techniques, carriers and excipients may be used as appropriate and as understood in the art; eg Remington's Pharmaceutical Sciences, supra. Pharmaceutical compositions suitable for use in the compositions disclosed herein include compositions in which the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prevent, alleviate, or ameliorate the symptoms of a disease or prolong the survival of a subject being treated. In some embodiments, a therapeutically effective amount means

- 57 047363 an amount of a compound effective to relieve or alleviate the symptoms of a disease or prolong the survival of a subject being treated.

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

Treatment options

In another aspect, disclosed herein are methods of treating a thyroid hormone receptor disorder in a patient, the method comprising, substantially consisting of, or consisting of the steps of identifying a patient in need of treatment for a thyroid hormone receptor disorder and administering to the patient or bringing a patient into contact with a compound described herein.

In another aspect, disclosed herein are methods of treating a thyroid hormone receptor disorder in a patient, the method comprising the steps of identifying a patient in need of treatment for a thyroid hormone receptor disorder and administering or contacting the patient with a compound of formula ( I) as described in this document. In some embodiments, a method of treating a thyroid hormone receptor disorder in a patient, consisting essentially of or consisting of the steps of identifying a patient in need of treatment for a thyroid hormone receptor disorder and administering or bringing the patient into contact with a compound of formula (I) as described herein.

In another aspect, disclosed herein are methods of treating a thyroid hormone receptor disorder in a patient, the method comprising, consisting essentially of, or consisting of the steps of identifying a patient in need of treatment for a thyroid hormone receptor disorder and administering to the patient or providing patient into contact with a compound of formula (I') as described herein.

In some embodiments, a health care professional, such as a physician, physician assistant, nurse practitioner, and the like, identifies an individual in need of treatment for a thyroid hormone receptor disorder and/or a candidate for treatment with a compound described herein. Detection may be based on the results of medical tests, resistance to other first-line drugs, the specific nature of a particular liver disease, etc.

In some embodiments, the thyroid hormone receptor disorder is selected from nonalcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

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

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

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

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

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

- 58 047363

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

In another aspect, methods disclosed herein for selectively modulating the activity of thyroid hormone receptor beta (THR-β) include, consist essentially of, or consist of contacting a compound as described herein with a thyroid hormone receptor. In some embodiments, contacting is carried out in vitro or ex vivo, while in other embodiments, contacting is carried out in vivo.

In another aspect, methods disclosed herein for selectively modulating the activity of thyroid hormone receptor beta (THR-β) include contacting a compound of formula (I) as described herein with a thyroid hormone receptor. In some embodiments, contacting is carried out in vitro or ex vivo, while in other embodiments, contacting is carried out in vivo. In some embodiments, a method of selectively modulating the activity of thyroid hormone receptor beta (THR-β) essentially consists of or consists of contacting a compound of formula (I) as described herein with a thyroid hormone receptor.

In another aspect, methods disclosed herein for selectively modulating the activity of thyroid hormone receptor beta (THR-β) include, essentially consist of, or consist of contacting a compound of formula (I') as described herein with a thyroid hormone receptor. In some embodiments, contacting is carried out in vitro or ex vivo, while in other embodiments, contacting is carried out in vivo.

In another aspect, methods disclosed herein for selectively modulating the activity of thyroid hormone receptor beta (THR-β) include, consist essentially of, or consist of contacting a composition described herein with a thyroid hormone receptor. In some embodiments, contacting is carried out in vitro or ex vivo, while in other embodiments, contacting is carried out in vivo.

Examples

The following examples of aspects of the present invention do not limit its scope. Conditions for the preparation of several compounds disclosed herein are presented. Methods for the synthesis of common intermediates are presented only once. Chemical names were generated using Marvin 17.28.0 or Chemdraw 18.1.

Table of conditional abbreviations.

The following abbreviations are used in this disclosure:

Ace Acetate ACN Acetonitrile anhydrous Anhydrous aq. Water In and Butyl CAN Cerium ammonium nitrate END Concentrated dhm Dichloromethane DIPEA N.N-Diisopropylethylamine DMA N.N-dimstilacstamide DMF N.N-Dimethylformamide DMSO Dimsyl sulfoxide DPPA Diphsiylphosphoryl azide dppf 1,1 '-Bis(diphenylphosphino)ferrocene EA=EtOAc Ethyl acetate

- 59 047363

ECF Ethyl chloroformate Et Ethyl EtOH Ethanol F.A. Formic acid G G ram(s) h Watch) Me Methyl MeOH Methanol MIN Mitta(s) NIS N-iodosuccinimide RE Petroleum ether room pace. Room temperature saturate, Saturated Sclcctfluor™ 1 -X lormethyl-4-fluoro-1,4diazoniumbicyclo| 2.2.2 |octane bis(tetrafluoroborate) TBAF Tetra-n-butylammonium fluoride TBSCL /irs/m-Butyldimmylsilyl chloride TFU Trifluoroacetic acid THF Tetrahydrofuran

Synthesis of building blocks.

1. Synthesis of 3-isopropyl-1H-indol-5-ol

To a stirred mixture of (4-methoxyphenyl)hydrazine (10.00 g, 72.375 mmol, 1.0 eq.) in 100 ml AcOH, isovaleraldehyde (6.23 g, 0.072 mmol, 1 eq.) was added dropwise at 80°C. The resulting mixture was stirred for 2 hours at 120°C. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (1x100 ml), dried over anhydrous. Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-5-methoxy-N-indole (2.6 g, 19%) as a brown solid.

To a solution of 3-isopropyl-5-methoxy-N-indole (9.03 g, 47.713 mmol, 1.0 eq.) in DCM (100.00 mL) was added boron tribromide (35.88 g, 143.217 mmol, 3 eq. .) drop by drop for 1 hour at -78°C. The resulting mixture was stirred for an additional 3 hours at room temperature. pace. The reaction mixture was quenched by adding H2O at 0°C. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-III-indol-5-ol (5.86 g, 56%) as a black oil.

2a. Synthesis of 5-bromo-3-isopropyl-III-indole

Isovaleraldehyde (23.03 g, 267.37 mmol, 1.00 eq) was added to a stirred solution of 4-bromophenylhydrazine (50.00 g, 267.32 mmol, 1.00 eq) in AcOH (500 mL). drop by drop at 80°C. The resulting mixture was stirred for 3 hours at 120°C. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EA (3x500 ml). The combined organic layers were washed with brine (1x300 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-3-isopropyl-III-indole (28 g, 44%) as a brown solid.

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

Ts

To a stirred solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (2.0 g, 8.36 mmol, 1 eq.), DMAP (20.44 mg, 167.29 cmol, 0.02 eq) and DIPEA (2.38 g, 18.40 mmol, 2.2 eq) in DCM (60 ml) was added TosCl (1.91 g, 10.04 mmol, 1.2 eq) at 20°C. The resulting mixture was then stirred at 20°C for 12 hours. TLC (petroleum ether/ethyl acetate = 5/1, UV) showed that the starting material was completely absorbed. The mixture was diluted with H2O (100 ml) and extracted with DCM (3x100 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filter

- 60 047363 was combined and concentrated to obtain a residue. The residue was purified by flash chromatography on silica gel (Ethyl acetate in petroleum ether = 0-10%) to give 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (2.6 g, 5.61 mmol, yield 67.0%) as a white solid with a metallic tint.

2s. Synthesis of 5-bromo-3-pentyl-1 H-indazole

Η

To a solution of 5-bromo-2-fluorobenzaldehyde (25 g, 123.15 mmol, 1 eq.) in THF (100 mL) was added bromine(pentyl)magnesium (1 M, 184.73 mL, 1.5 eq. ) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding sat. aq. NH ₄ Cl (50 ml) at 0°C and then diluted with H2O (50 ml) and extracted with EA (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (Eluent 0-30% ethyl acetate/petroleum ether) to give 1 -(5-bromo-2-fluorophenyl)hexan-1-ol (9.5 g, 34.53 mmol, 28% yield) as a colorless oil.

To a solution of 1-(5-bromo-2-fluorophenyl)hexan-1-ol (9.5 g, 34.53 mmol, 1 eq.) in DCM (100 ml) was added 4A MS (10 g) and PDC (25.98 g, 69.05 mmol, 2 eq.) 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 flash chromatography on silica gel (Eluent 0-30% ethyl acetate/petroleum ether) to give 1-(5-bromo-2 -fluorophenyl)hexan-1-one (8.2 g, 30.02 mmol, 87% yield) as a pale yellow solid. To a solution of 1-(5-bromo-2-fluorophenyl)hexan-1-one (5 g, 18.31 mmol, 1 eq.) in NMP (2 ml) was added hydrazine hydrate (2.16 g, 36. 61 mmol, 2.09 ml, 85% purity, 2 eq.) 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 (2x50 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (Eluent 0-20% ethyl acetate/petroleum ether) to give 5 -bromo-3-pentyl-1H-indazole (2 g, 7.49 mmol, 41% yield) as a white solid.

3. Synthesis of 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde

Ts

To a stirred solution of 5-bromo-3-isopropyl-1H-indole (3.0 g, 12.6 mmol, 1.00 eq.) in toluene (50 ml) was added Bu ₄ NHSO ₄ (0.43 g, 1.00 eq. 27 mmol, 0.10 eq.) portions at 0°C. TsCl (2.90 g, 15.26 mmol, 1.2 eq.) was added dropwise at 0°C. The resulting mixture was stirred overnight at room. pace. The resulting mixture was concentrated in vacuo. The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (1x200 ml), dried over anhydrous Na ₂ SO ₄ . 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-(4methylbenzenesulfonyl)indole (4.0 g, 67%) as a light yellow solid.

To a stirred solution of 5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4 g, 10.2 mmol, 1.00 eq) in THF was added n-BuLi (31.2 mL, 51.0 mmol , 5.0 eq., 1.6 M in hexane) dropwise at -78°C in a nitrogen atmosphere. The resulting mixture was stirred for 40 minutes at -78°C under a nitrogen atmosphere. DMF (3.70 g, 0.051 mmol, 5.0 eq.) was added at -78°C under nitrogen. The resulting mixture was stirred for 1.5 hours at -78°C under a nitrogen atmosphere. The reaction mixture was quenched with water (50 ml). The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (1x200 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (1.1 g, 31%) as a light yellow oil.

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

HN N O U| X BEAM U

Vg

6-Bromo-2,4-dihydro-1,2,4-triazine-3,5-dione (10.00 g, 52.091 mmol, 1.00 eq.) was placed in acetic anhydride (50 ml) under reflux ( 140°C) for 5 hours. After concentrating the reaction medium to dryness, the precipitate is isolated and then recrystallized from ether to obtain the desired product

- 61 047363 ta. The desired product was isolated as a light yellow solid (11.6 g, 95% purity, 90% yield). NaH (2.19 g, 54.755 mmol, 1.10 eq., 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 eq.) in DMF (150 ml) was poured dropwise. The reaction medium was stirred for 1 hour at room. pace. and then [(chloromethoxy)methyl]benzene (8.54 g, 54.53 mmol, 1.1 eq.) was added and stirred, then stirring was continued for 18 hours at room temperature. pace. After concentration to dryness, the resulting residue was treated with H2O (200 ml) and extracted with ethyl acetate (EA) (3x500 ml). After drying over Na ₂ SO ₄ the organic phase is evaporated, the resulting clear oil is purified and 15 g of crystals are isolated. The crystals were placed in EtOH (400 mL) in the presence of TsOH (100.0 mg, 0.581 mmol, 0.01 eq.). This mixture was refluxed for 4 hours and then concentrated to dryness. The residue was transferred to H2O and then extracted with EA. After drying and evaporation of the organic phases, the desired product was obtained as a yellow oil (9.5 g, yellow oil, 90% purity, 61% yield).

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

Br

O

BSA, CH ₃ |, ACN ^Вг d2°С, 20 h n I

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 eq.) in ACN (5 ml) was added BSA (529.8 mg, 2.61 mmol, 2.5 equiv.) dropwise at 0°C under argon. The resulting mixture was stirred for 3 hours at 82°C in an argon atmosphere, and then CH ₃ I (251.4 mg, 1.77 mmol, 1.7 eq.) was added dropwise at 82°C, and continued stirring for 20 hours at 82°C. The mixture was left to cool to room. temp., concentrated under reduced pressure, and then dissolved in DCM, washed with water and brine, dried over anhydrous Na ₂ SO ₄ . 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.

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

6-Bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione was prepared in a manner similar to that described for 6-bromo2-methyl-4H-1,2,4-triazine-3,5 -dione using 2.5 eq. iodoethane instead of 1.7 eq. CH ₃ I.

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

To a stirred solution of 3-isopropyl-1H-indol-5-ol (1.00 g, 5.71 mmol, 1.00 eq) in THF was added potassium tert-butoxide (0.64 g, 5.70 mmol, .0 eq.) drop by drop at 0°C. The resulting mixture was stirred for 30 minutes at room. pace. After completion of the reaction, the resulting mixture was concentrated in vacuo and redissolved in DMF. Second reaction flask: The contents of the first reaction flask were added to a stirred solution of 1,2,3-trichloro-5-nitrobenzene (1.29 g, 5.70 mmol, 1.0 eq.) in DMF at 0°C. The resulting mixture was stirred for 5 minutes at 0°C 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 Na ₂ SO ₄ . The residue was purified by silica gel column chromatography to give 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl1H-indole (1.3 g, 55%) as a yellow solid.

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

To a stirred mixture of 3-isopropyl-III-indol-5-ol (5.10 g, 29.10 mmol, 1.0 eq.) in 50 ml DMSO was added K ₂ CO ₃ (4.42 g, 32.0 mmol , 1.1 eq.) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (4.92 g, 29.1 mmol, 1.0 eq.) in portions at rt. pace. The resulting mixture was stirred for 2 hours at 100°C. The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (3x50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to give 5-(2,6-dimethyl-4nitrophenoxy)-3-isopropyl-N-indole (6 g, 64%) as a light yellow solid.

8. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-III-indole

- 62 047363

To a solution of 5-hydroxyindole (16.0 g, 120.2 mmol, 1.0 eq) in acetonitrile (320 ml) was added potassium tert-butoxide (13.48 g, 120.2 mmol, 1.0 eq) at 0°C. After 20 min, the mixture was concentrated to remove acetonitrile and dissolved in NXdimethylformamide (320 ml). Then 1,2,3-trichloro-5nitrobenzene (27.21 g, 120.2 mmol, 1.00 eq.) was added at 0°C. The resulting solution was stirred at 100°C overnight and then quenched with water (300 ml). The resulting solution was extracted with ethyl acetate (3x500 ml) and the organic layers were combined, washed with brine (2x300 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)-N-indole as a yellow solid.

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

TsCl ( 0.81 g, 4.239 mmol, 1.2 eq.) in toluene (10 ml), KOH (50%) (21.4 ml), Bu ₄ NHSO ₄ (0.12 g, 0.353 mmol, 0.1 eq. .) drop by drop at 0°C. The resulting mixture was stirred for 6 hours at room. pace. After completion of the reaction, the resulting mixture was extracted with EA (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ . 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.

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 eq.) and NH ₄ Cl (1.16 g, 21.62 mmol, 8.0 eq.) in EtOH (50 ml) and H ₂ O (25 ml) was added Fe powder (0.75 g, 13.514 mmol, 5.00 eq.) in portions at room pace. in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 50°C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter-press cake was washed with EA. The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with EA and dried over anhydrous Na ₂ SO ₄ . 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 white solid.

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

ΥΧ

Ts

To a stirred mixture of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (5.00 g, 15.414 mmol, 1.00 eq.) in 50 ml of toluene was added TsCl (3.53 g , 0.018 mmol, 1.2 eq.), Bu4NHSO ₄ (0.52 g, 0.002 mmol, 0.1 eq.), KOH (50 ml) dropwise at 0°C. The mixture was stirred overnight at room. pace. and extinguished with water (50 ml). The resulting mixture was extracted with EA (3x200 ml). The combined organic layers were washed with brine (1x100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in hexane to give 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4methylbenzenesulfonyl)indole (5.8 g, 79%) as a light yellow solid substances. To a stirred mixture of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (5.80 g, 12.120 mmol, 1.0 eq.) in MeOH (70 ml) Pd/C (1.74 g) was added in portions. The resulting mixture was stirred overnight at room. pace. in a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (1x500 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)indol-5-yl]oxy]-3,5-dimethylaniline (3 .2 g, 59%) as a light yellow solid.

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

To a stirred solution of Na(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (260.16 mg, 0.879 mmol, 1.0 eq.) in THF (5 ml) under nitrogen atmosphere was added MeLi-LiBr (1.7 ml, 1.76 mmol, 2.0 equiv., 1 M in ether) at -78°C. Then t-BuLi (1.6 ml, 2.64 mmol, 3.00 eq, 1.6 M in hexane) was added dropwise at -78°C. The mixture was stirred for 20 minutes at -78°C. 3-Isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (300 mg, 0.879 mmol, 1.0 eq.) was added at -78°C. The resulting mixture

- 63 047363 stirred for 1 hour at room. pace. The reaction solution was quenched with water (10 ml) at room. pace. The resulting mixture was extracted with EA (3x50 ml). The combined organic layers were washed with brine (2x100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified to give 2,2,2-trifluoro-X-(4-[hydroxy[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300 mg, 61 %) as a white solid. Solution of 2,2,2-trifluoro-N(4-[hydroxy[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (300.0 mg, 0.537 mmol, 1.00 eq.) in DCM (5 ml) was stirred under nitrogen atmosphere at 0°C. Then a solution of Et ₃ SiH (374.7 mg, 3.22 mmol, 6.0 eq.) in DCM (15 ml) and TMSOTf (7.16 mg, 0.032 mmol, 0.06 eq.) in DCM (5 ml ) was added dropwise to the reaction mixture. The reaction mixture was stirred for 30 minutes at 0°C and 1.5 hours at room. pace. The reaction mixture was quenched with saturated NaHCO ₃ solution (20 ml). The resulting solution was extracted with dichloromethane (3x50 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product containing 2,2,2-trifluoro-N(4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide was isolated as a yellow solid ( 260 mg, purity 85%, yield 76%). To a solution of 2,2,2-trifluoro-N(4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide (260.0 mg, 0.479 mmol, 1.0 eq.) in MeOH (10 ml) and H2O (2 ml) were stirred under nitrogen atmosphere at room. pace. NaOH (76.66 mg, 1.917 mmol, 4.0 eq.) was added. The reaction mixture was stirred at 60°C overnight. The reaction mixture was quenched with water (20 ml). The resulting solution was extracted with dichloromethane (3x50 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was isolated as a yellow solid containing 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline (230 mg, 90% purity, 97% yield ).

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

N

Ts nh ₂

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-N-indole (28.0 g, 86.65 mmol, 1.0 eq.) in toluene (720 ml) was added tetrabutylammonium hydrogen sulfate (2.94 g , 8.665 mmol, 0.10 eq.) and potassium hydroxide (120.00 g, 2138.8 mmol, 25.0 eq.) in water (120 ml) at 0°C. 4-Toluenesulfonyl chloride (19.82 g, 103.98 mmol, 1.20 eq.) in toluene (720 ml) was added dropwise at 0°C. The reaction mixture was then stirred at room. pace. for 3 hours and quenched with water (200 ml). The mixture was extracted with ethyl acetate (3x500 ml) and the organic layers were combined, 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.

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole (26.00 g, 54.47 mmol, 1.0 eq.) in ethanol (500 ml) and water ( 250 ml) iron dust (15.21 g, 272.36 mmol, 5.0 eq) and ammonium chloride (23.31 g, 435.78 mmol, 8.0 eq) were added. The resulting solution was stirred for 2 hours at 50°C. The resulting mixture was filtered and the filter cake was washed with dichloromethane (6x100 ml). The filtrate was extracted with dichloromethane (3x500 ml). The combined organic layers were combined, washed with brine (300 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy] aniline (23 g, 88% yield) as a light yellow solid.

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

F ,Ν O ^Z N Cl

NH ₂

To a solution of 3,6-dichloropyridazine (50.00 g, 335.64 mmol, 1.0 eq.) in H2O (1.20 L) was added AgNO ₃ (57.02 g, 335.64 mmol, 1.0 eq. .), isobutyric acid (29.57 g, 335.64 mmol, 1.0 eq.) in portions at room. pace. in an air atmosphere and then stirred at 50°C in a nitrogen atmosphere. H ₂ SO ₄ (98.76 g, 1006.9 mmol, 3.0 eq.) was added portionwise at 50°C and stirred at 60°C. Then ( _{NH4)2S2O8 ( 229.78} g, 1006.914 mmol, 3.0 eq.) was added and stirred for 30 min at 70°C under nitrogen atmosphere. The mixture was neutralized to pH 9 with NaOH solution. The resulting mixture was extracted with EA (3x1 l). The combined organic layers were washed with saline (2x1 L), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3,6-dichloro-4-isopropylpyridazine (30 g, 47%) as a light yellow oil.

Phenol, 4-amino-2,6-dichloro- (18.63 g, 104.68 mmol, 1.0 eq.), K ₂ CO ₃ (58.16 g,

- 64 047363

420.81 mmol, 4.02 eq.) and CuI (11.96 g, 62.81 mmol, 0.60 eq.). The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. The mixture was acidified to pH 8 conc. HCl. The resulting mixture was extracted with EA (3x500 ml). The combined organic layers were washed with brine (3x300 ml), dried over anhydrous Na ₂ SO ₄ . 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-3yl)oxy]-aniline (17 g, 49%) as a green solid. NaOAc (24 .33 g, 178.89 mmol, 3.50 eq.) portions. The mixture was stirred overnight at 100°C under a nitrogen atmosphere. NaOH (12.27 g, 306.77 mmol, 6.0 eq) and MeOH (200 mL) were added to the mixture in portions. The resulting mixture was stirred overnight at 120°C under a nitrogen atmosphere. The resulting mixture was extracted with EA (3x500 ml). The combined organic layers were washed with brine (2x200 ml), 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)-4isopropyl-2H-pyridazin-3-one (11 g, 69%) as a white metallic solid.

13b. Synthesis of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline I ^C|

About Ν SG ΝΗ ₂

Mixture of 3,6-dichloro-4-isopropylpyridazine (80.0 g, 419 mmol, 1.00 eq), 4-amino-2,6-dichlorophenol (74.5 g, 419 mmol, 1.0 eq) , K ₂ CO ₃ (232 g, 1675 mmol, 4.0 eq.) and CuI (47.9 g, 251 mmol, 0.6 eq.) in DMSO (800 ml) were stirred overnight at 60°C. After cooling to 25°C, the solution was then poured into ice water (3 L) and the pH of the mixture was adjusted to 8 with hydrochloric acid (3N). The resulting mixture was extracted with EA (3x1 l). The combined organic layers were washed with saline (3x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5:1 petroleum ether to ethyl acetate (PE:EA)) to give 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3yl)oxy] aniline (35.0 g, 24% yield) as a white solid with a metallic tint.

LCMS (ESI, m/z): 332 [M+H]+.

A mixture of 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-aniline (10.0 g, 30.1 mmol, 1.00 eq.) and potassium methoxide (21, 1 g, 301 mmol, 10.0 eq.) in MeOH (50 ml) was stirred for 48 h at 65°C. After cooling to 25°C, the pH of the mixture was adjusted to 6-7 using hydrochloric acid (1N). The resulting mixture was extracted with EA (3x500 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , 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-6methoxypyridazin-3-yl)oxy]aniline (6.80 g, 65% yield ) as a white solid.

LCMS (ESI, m/z): 328 [M+H] ⁺ .

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

A 1000 mL round bottom flask was charged with 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2Hpyridazin-3-one (14.13 g, 44.98 mmol, 1.0 eq.) in MeOH (200 ml). HCl (4.10 mL, 112.439 mmol, 3 equiv.) was added dropwise at 0°C. H2O (100 ml) was added at 0°C. The mixture was stirred for 10 minutes, then NaNO ₂ (3.72 g, 53.971 mmol, 1.20 eq.) was added and stirred for an additional 30 minutes at 0°C. Tetrahydroxydiborane (40.32 g, 449.749 mmol, 10.0 eq) was added. The reaction solution was stirred for 1 hour at 60°C. The resulting solution was quenched with water (50 ml). The resulting solution was extracted with dichloromethane (3x400 ml) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification gave 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (6.3 g, 37%) as a white solid.

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

To a stirred mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline (5.80 g, 17.7 mmol, 1.00 eq.) and CuBr ₂ (7 .89 g, 35.3 mmol, 2.00 eq.) to ACN (40 mL), tert-butyl nitrite (4.24 mL, 35.4 mmol, 2.0 eq.) was added dropwise at 0°C. The resulting mixture was then warmed to room temperature and stirred for another 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA

- 65 047363

10:1) to give 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (3.50 g, 48% yield) as a yellow solid.

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

Mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (1.00 g, 2.55 mmol, 1.00 eq.), bis-(pinacolato)diboron (972 mg, 3.83 mmol, 1.50 eq.), Pd(dppf)Cl ₂ (187 mg, 0.256 mmol, 0.10 eq.) and KOAc (750 mg, 7.64 mmol, 3.00 eq.) in 1 ,4-dioxane (10 ml) was stirred for 2 hours at 90°C. After cooling to 25°C, the solids were filtered and the filter cake was washed with EA (3x20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: C18 silica gel; mobile phase, A: water (containing 0.5% TFA) and B: ACN (20 to 95% for 20 min) to give 3,5-dichloro-4-[( 5-isopropyl-6-methoxypyridazin-3yl)oxy]phenylboronic acid (610 mg, 64% yield) as a brown solid.

LCMS (ESI, m/z): 359 [M+H] ⁺ .

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

/Ύ Ί P ⁰ < Ji J XIX

ΝΗ ^Ts γ Ο

CN

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

To a solution of dgyl-CM2-cyano-2-(2-(3,5-di\lor-4-((Gtosyl-111-indol-5-yl)oxy)phenyl)1'idrazinilidene)acetyl)carbamate (18, 40 g, 29.95 mmol, 1.0 eq.) in CA-dimethylanetamide (300 ml) was added potassium acetate (11.76 g, 119.782 mmol, 4.0 eq.). The reaction mixture was stirred at 120°C for 2 hours and quenched with water (100 ml). The mixture was extracted with ethyl acetate (3x100 ml) and the organic layers were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine -6-carbonitrile (14 g, 80% yield) as a brown solid.

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- N-iodosuccinimide (4 .16 g, 18.47 mmol, 1.5 eq.) at 0°C in a nitrogen atmosphere. The reaction mixture was stirred for 6 hours at 0°C and quenched with water (200 ml). The resulting mixture was extracted with dichloromethane (3x200 ml) and the organic layers were combined, washed with saturated sodium thiosulfate solution (2x500 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to give 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2 ,4triazine-6-carbonitrile (5.30 g, 43% yield) as a brown solid.

16. Synthesis of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazine -6-carbonitrile

To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (500 mg, 1.591 mmol, 1.0 eq.) in HOAc (43.8 ml, 764, 03 mmol) and HCl (15.3 ml, 503.55 mmol) added NaNO ₂ (230.59 mg, 3.34 mmol, 2.1 eq.) in H2O (33.4 ml) dropwise at 0°C . The resulting mixture was stirred for 30 minutes at 0°C under a nitrogen atmosphere. The above solution was quickly poured into a second reaction flask into which ethyl 7N-(2-cyanoacetyl)carbamate (372.75 mg, 2.387 mmol, 1.5 eq.) and H2O (40.9 mL) in pyridine (20 mL) were placed at 0°C. The resulting mixture was kept for 30 min at 0°C. The precipitated solid was collected by filtration and washed with PE and H ₂ O (3x300 ml) to give ethyl Na[^)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine -3-yl)oxy]phenyl]hydrazin-1-ylidene)carbonide]carbamate, which can also be called ethyl-^)-(2-cyano-2-(2-(3,5-dichloro-4-(( 5

- 66 047363 isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-hydrazinylidene)acetyl)-carbamate (name generated using Chemdraw) (640 mg, 84%) as an orange solid. To a solution of ethyl-C-[(A)-cyano('2-[3,5-dichloro-4-[('5-isopropyl-6-oxo-1I-pyridazin-3-yl)oxy|phenyl|hydrazine1- ylidene)carbonide]carbamate, which can also be called ethyl-^)-(2-cyano-2-(2-(3,5-dichloro-4((5-isopropyl-6-oxo-1,6-dihydropyridazin- 3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (640.00 mg, 1.330 mmol, 1.00 eq.), in DMA (13.36 ml) was added KOAc (261.01 mg, 2.660 mmol, 2. 00 eq.) in portions at room. pace. The mixture was stirred for 3 hours at 120°C under a nitrogen atmosphere. The reaction mixture was quenched with water. The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (4x100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated. This led to the formation of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Ipyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4I-1,2,4- triazine-6-carbonitrile (590 mg, 102%) as a dark orange solid.

17. Synthesis of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1I-pyridazin-3yl)oxy]phenyl]-1, 2,4-triazine-3,5-dione

Vg

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

18. Synthesis of ('E)-I-[3,5-dichloro-4-('[3-iodo-1I-pyrrolo[3,2-b|pyridin-5-yl|oxy)phenyl|-HC-dimethylmethanimidamide

C.I.

An 8 ml vessel was loaded with 6-chloro-2-methyl-3-nitropyridine (20.00 g, 115.895 mmol, 1.0 eq.), phenol, 4-amino-2,6-dichloro- (24.76 g, 139.07 mmol, 1.2 eq.), K ₂ CO ₃ (48.05 g, 347.69 mmol, 3.0 eq.) and DMF (200 ml). The resulting mixture was stirred overnight at 60°C. The reaction mixture was quenched with water (400 ml). The resulting mixture was extracted with EA (3x500 ml) and the organic layers were combined, washed with brine (2x400 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with EA:PE (0-40% for 30 min) to give the desired product 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy |aniline (36.4 g, 91%) as a yellow solid.

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

To a solution of 3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy|aniline (36.40 g, 115.88 mmol, 1.0 eq.) and (dimethoxymethyl)dimethylamine ( 33.14 g, 278.1 mmol, 2.4 eq.) in dimethylformamide (400 ml) was added TEA (11.73 g, 115.9 mmol, 1.0 eq.). The resulting mixture was stirred for 4 hours at 100°C. The mixture was cooled to 60°C and concentrated under reduced pressure to remove half of the DMF. The resulting solution was allowed to proceed to the next stage without additional processing.

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

LCMS (ESI, m/z): 349 [M+H| ⁺ .

Solution of (E)-N'-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylmethanimidamide (5.00 g, 14, 32 mmol, 1.0 eq.) and I ₂ (4.00 g, 15.75 mmol, 1.1 eq.) in dimethylformamide (50 ml) was added KOH (3.21 g, 57.27 mmol, 4. 0 eq.). The resulting mixture was stirred overnight at room temperature and quenched with water (80 ml). The resulting mixture was extracted with EA (3x100 ml) and organic

- 67 047363 The chemical layers were combined, washed with brine (2x80 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was triturated with PE:EA 5:1 to obtain the desired product (E)-N'-[3,5dichloro-4-(|3-iodo-1H-pyrrolo|3,2-b|pyridin-5-yl| hydroxy)phenyl|-K,K-dimethylmethanimidamide (5.9 g, 78%) as a yellow solid.

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

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

To a solution of (E)-N-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]^^dimethylmethanimidamide (3.0 g, 6.31 mmol, 1.0 eq.), K ₃ PO ₄ (2.01 g, 9.471 mmol, 1.5 eq.) and 1,1'-bis(ditert-butylphosphino)ferrocene palladium dichloride (0.410 g, 0.631 mmol, 0.10 eq.) in dioxane (75 ml) and H2O (15 ml) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1, 3,2-dioxaborolane (4.24 g, 25.26 mmol, 4.0 eq.) under nitrogen. The resulting mixture was stirred overnight at 60°C and quenched with water (100 ml). The resulting mixture was extracted with EA (3x150 ml) and the organic layers were combined, washed with brine (2x100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was column purified and eluted with EA:PE (0-50% for 30 min) to give the desired product (E)-N-(3,5-dichloro-4-[[3-(prop-1-ene-2 -yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-Ni-dimethylmethanimidamide (430 mg, 14%) as a yellow solid.

LCMS (ESI, m/z): 389 [M+H] ⁺ .

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

LCMS (ESI, m/z): 391 [M+H] ⁺ .

To a solution of (E)-Ni-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-Nidimethylmethanimidamide (380, 0 mg, 0.97 mmol, 1.0 eq.) in ethyl alcohol (25 ml) was added ethylenediamine (262.6 mg, 4.37 mmol, 4.5 eq.). The resulting mixture was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure to give the crude product 3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5yl|oxy)aniline (350 mg, crude) as yellow semi-solid substance.

LCMS (ESI, m/z): 336 [M+H] ⁺ .

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

Mixture of 3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronic acid (400 mg, 1.12 mmol, 1.0 eq.), 4-[(benzyloxy)methyl ]-6-bromo-2H-1,2,4-triazine-3,5-dione (398 mg, 1.28 mmol, 1.15 equiv.), PdAmphos(Cl) ₂ (79.3 mg, 0.112 mmol , 0.1 eq.) and K ₃ PO ₄ (713 mg, 3.36 mmol, 3.0 eq.) in 1,4-dioxane (8 ml)/water (0.8 ml) was stirred for 2 h at 90°C. After cooling to 25°C, the solids were filtered and the filter cake was washed with EA (3x15 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-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6methoxypyridazin-3- yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione (190 mg, 30% yield) as a light yellow solid.

LCMS (ESI, m/z): 544 [M+H] ⁺ .

21. Methods for the synthesis of 2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:

To a solution of 5-benzyloxy-2-bromo-1,3-dimethylbenzene (1 g, 3.43 mmol) and 4,4,5,5-tetramethyl-2- 68 047363

[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (1.84 g, 6.87 mmol) in dioxane (10 ml ) added 8n. aq. KOH (858.57 µl, 6.86 mmol) followed by the addition of Pd[P(tert-Bu) ₃ ] ₂ (87.75 mg, 171.71 µmol) at rt. pace. (~15°C) under protection in an N2 atmosphere. The mixture was then stirred at 30°C for 18 hours. TLC (PE:EA 10:1, developed I2) showed that the bromide was completely absorbed and two new spots formed. The mixture was diluted with water (40 ml), extracted with ethyl acetate (50x2 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (Eluent 0-2% ethyl acetate/petroleum ether) to give the desired 2-(4-(benzyloxy)-2 ,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (870 mg, 72% yield) as a white solid.

22. Synthesis of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5dimethylphenyl]trifluoromethanesulfonate

To a solution of 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.0 g, 2.54 mmol, 1 eq.) and 2-[(4-benzyloxy- 2,6-dimethylphenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.79 g, 5.09 mmol, 2 eq.) in dioxane (30 ml) and H2O ( 6 ml) dichloropalladium was added; tris-o-tolylphosphane (299.79 mg, 381.39 µmol, 0.15 eq.) and K ₃ PO ₄ (1.62 g, 7.63 mmol, 3 eq.) at 20°C under atmospheric protection N2. The resulting mixture was then stirred at 100°C for 15 hours under N2 atmosphere. The combined mixture (combined with 300 mg load) was diluted with H2O (100 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (Ethyl acetate in petroleum ether = 0-10%) to give 5 -[(4-benzyloxy-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.36 g, 2.44 mmol, 74% yield , purity 96.5%) as a yellow solid. To a solution of 5-[(4benzyloxy-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-Cpyridine (1.36 g, 2.52 mmol, 1 eq.) Pd-C (10%, 1.07 g) was added to MeOH (20 ml) and THF (10 ml) under N2 atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The reaction mixture was stirred under H ₂ (50 psi) at 35°C for 18 hours. The mixture was filtered and the filtrate was concentrated and purified by flash silica gel chromatography (0-100% ethyl acetate in petroleum ether) to give 4- [[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol (1 g, 2.23 mmol, 88% yield) as a white solid. To a solution of 4-[[3-isopropyl-1-(ptolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol (1 g, 2.23 mmol, 1 eq. .) and pyridine (440.84 mg, 5.57 mmol, 2.5 eq.) in DCM (25 ml) at 0°C, Tf ₂ O (754.76 mg, 2.68 mmol, 441 .38 µl, 1.2 eq.). 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 phase was separated, washed with brine (10 mlx3), dried over anhydrous MgSO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0-10% ethyl acetate in petroleum ether) to give [4-[[ 3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (1.25 g, 2.15 mmol, 97% yield) in the form of a colorless resin.

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

Ts

To a solution of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5dimethylphenyl]trifluoromethanesulfonate (300 mg, 516.67 µmol, 1 eq.) and tert-butylcarbamate (121.05 mg, 1.03 mmol, 2 eq.) in dioxane (8 ml) was added Pd ₂ (dba) ₃ (47.31 mg, 51.67 µmol, 0.1 eq. .), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)diphenylphosphane (59.79 mg, 103.33 µmol, 0.2 eq.) and Cs ₂ CO ₃ (505.03 mg, 1.55 mmol, 3 equiv.) at 20°C under protection in an atmosphere of N2. The resulting mixture was then stirred at 100°C for 15 hours under N2 atmosphere. LCMS indicated that the reaction was complete. The mixture was diluted with H ₂ O (50 ml) and extracted with EA (50x3 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel (Ethyl acetate in petroleum ether = 0-10%) to give tert-butyl-N[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5 -yl]methyl]-3,5-dimethylphenyl]carbamate (200 mg, 350.19 µmol, 68% yield, 95.9% purity) as a light yellow solid. To the solution

- 69 047363 tert-butyl4-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyrrvdin-5-yl]methyl]-3,5-dimethylphenyl]carbamate (170 mg, 310.39 µmol, 1 eq.) in MeOH (3 ml) was added 4 M HCl gas in MeOH (8 ml) at 20°C. The resulting mixture was then stirred at 20°C for 12 hours. MeOH was removed under reduced pressure and the residue was partitioned between EA (50 ml) and H ₂ O (50 ml). The EA phase was washed again with H2O (50 ml). The combined aqueous layers were brought to pH 7-8 sat. aq. NaHCO ₃ then extracted with EA (50x2 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine-5 -yl]methyl]-3,5-dimethyl-aniline (120 mg, 261.40 µmol, 84% yield, 97.5% purity) as a light yellow solid.

24. Synthesis of 2,2,2-trifluoro-M(4-formyl-3,5-dimethylphenyl)acetamide

Trifluoroacetic anhydride (2 eq., 5.63 mL) was added to a solution of 4-iodo-3,5-dimethylaniline (1 eq., 5 g, 20.24 mmol) in anhydrous DCM (150 mL) under N2 at 0°C WITH. The reaction mixture was then stirred at 25°C for 2.5 hours. Water (200 ml) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (2x150 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash silica gel chromatography (DCM) to give 2,2,2-trifluoro4-(4-iodo-3,5-dimethylphenyl)acetamide (6.35 g, 91%) as a white solid.

Anhydrous THF (35 ml) was added to a mixture of 2,2,2-trifluoro-M(4-iodo-3,5-dimethylphenyl)acetamide (1 eq., 2.40 g, 7 mmol) and NaH 60% (1. 5 equiv., 420 mg) in an N2 atmosphere at 0°C. The reaction mixture was stirred at 25°C for 1.5 hours, then cooled to -78°C and t-BuLi (2.4 eq., 9.88 ml) was added dropwise. The reaction mixture was stirred at -78°C for 40 minutes. Anhydrous DMF (5 eq., 2.71 mL) was then added and the reaction mixture was further stirred at -78°C for 1 hour. The reaction mixture was hydrolyzed sat. aq. NH ₄ Cl (5 ml), poured into DCM (250 ml) and washed 4 times with saline. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was recrystallized from hot EtOH to give 2,2,2-trifluoro-M(4-formyl-3,5-dimethylphenyl)acetamide (317 mg, 19%) as a yellow solid. The supernatant was recrystallized from hot toluene to provide more 2,2,2-trifluoro4(4-formyl-3,5-dimethylphenyl)acetamide (909 mg, 53%) as a light yellow solid.

25. Synthesis of 3,5-dimethyl-4-((3-pentyl-III-indazol-5-yl)methyl)aniline

Anhydrous THF (8.3 mL) was added to a mixture of 5-bromo-3-pentyl-III-indazole (1 eq., 668 mg, 2.5 mmol) and NaH 60% (1.5 eq., 150 mg) at 0°C, in N2 atmosphere. The resulting reaction mixture was stirred at 25°C for 1 hour. The mixture was then cooled to -78°C and n-BuLi (1.5 eq., 2.34 ml) was added dropwise and the reaction mixture was stirred at -78°C C for 2 hours. Then a solution of 2,2,2-trifluoro4-(4formyl-3,5-dimethylphenyl)acetamide (1 equiv., 613 mg) in anhydrous THF (8.3 ml) was added dropwise to the reaction mixture at -78°C. The reaction mixture was further stirred at this temperature for 1.75 hours and finally hydrolyzed sat. aq. NH ₄ Cl (5 ml), poured into DCM (100 ml) and washed 3 times with water. The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (20 to 40% EA in cyclohexane) to give 2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-inαzol-5-yl)methyl) -3,5dimethylphenyl)acetamide (317 mg, 29%) as a white solid. A solution of Et ₃ SiH (6 eq. 0.71 mL) in anhydrous DCM (20 mL) followed by a solution of TMSOTf (0.075 eq., 0.01 mL) in anhydrous DCM (7 mL) was added dropwise with a solution of 2.2, 2-Trifluoro4-(4-(hydroxy(3-pentyl-III-indazol-5yl)methyl)-3,5-dimethylphenyl)acetamide (1 eq., 317 mg, 0.73 mmol) in anhydrous DCM (7 mL) at 0°C in an N ₂ atmosphere. The reaction mixture was stirred at 0°C for 1 hour, at which point the ice bath was removed and the reaction mixture was stirred at 25°C. After 19 hours, more Et ₃ SiH (6 equiv., 0.71 ml) and TMSOTf (0.075 equiv., 0.01 ml) were added and the reaction mixture was further stirred at 25°C for 5 hours. The reaction mixture was then quenched with sat. aq. NaHCO3 (20 ml) and the aqueous phase was extracted 3 times with DCM (3x50 ml). The combined organic layers were washed with brine (150 ml), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 30% EA in cyclohexane) to give M(3,5-dimethyl-4-((3-pentyl-III-indazol-5yl)methyl)phenyl)-2,2 ,2-trifluoroacetamide (144 mg, 47%) as a white solid.

NaOH (4 eq., 54 mg) was added to a solution of M(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide (1 eq., 141 mg, 0.34 mmol) in MeOH (7 ml) and water (1.4 ml) in atmosphere

- 70 047363

N ₂ . 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 (3x20 ml) and the organic layers were combined, washed with brine (2x20 ml), dried over MgSO ₄ , 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.

Example 1 Synthesis of Compound 1

To a stirred solution of 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5yl]methyl]aniline (1.11 g, 2.277 mmol, 1.00 eq.) in HCl (21 .90 ml), HOAc (62.50 ml) and H ₂ O (47.68 ml) added NaNO ₂ (0.32 g, 4.566 mmol, 2 eq.) in H ₂ O (4.2 ml) dropwise for 1 hour at 0°C. In the second reaction flask, ethyl M-(2-cyanoacetyl)carbamate (0.53 g, 3.424 mmol, 1.5 eq) was placed in H2O (58.41 ml) and pyridine (22.35 ml) for 10 min. at 0°C. The above solution was quickly poured into the second reaction flask for 30 min at 0°C. The precipitated solids were collected by filtration and washed with water and PE. The resulting mixture was concentrated in vacuo. This led to the formation of ethyl-N-[(2)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]phenyl)hydrazine -1-ylidene]carbonide]carbamate, which may also be called ethyl-(2)-(2-cyano-2(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H- indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, as a red solid. To a stirred solution of ethyl-M-[(2)-cyano[2-(3,5-dichloro-4-[[3isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)hydrazine-1- ylidene]carbonyl]carbamate, which may also be called ethyl-(2)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1Nindol-5- yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (1.16 g, 1.773 mmol, 1.00 eq.) in DMA (20.00 mL) was added KOAc (0.35 g, 3.546 mmol, 2 eq.) in portions at room pace. The resulting mixture was stirred for 2 hours at 120°C under a nitrogen atmosphere. The reaction mixture was quenched by adding water (10 ml) at room temperature. pace.

The precipitated solid was collected by filtration and washed with water (3x10 ml). The solid was dried overnight at room. pace. to give 2-(3,5-dichloro-4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine -6-carbonitrile (521.2 mg, 45%) as a red solid.

To a stirred solution of 2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4- triazine-6-carbonitrile (521.20 mg, 0.854 mmol, 1.00 eq.) in THF (20.00 ml) was added TBAF (20 ml) portionwise at room temperature. pace. in a nitrogen atmosphere. The resulting mixture was stirred for 20 hours at 65°C under a nitrogen atmosphere. The reaction mixture was quenched with H2O. The resulting mixture was extracted with EA, washed with saline, 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 the crude product (200 mg). The crude product (200 mg) was purified by preparative HPLC to give 2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]3,5-dioxo-4H-1, 2,4-triazine-6-carbonitrile (11.5 mg, 3%, compound 1) as a yellow solid.

1H-NMR (300 MHz, DMSO-d;) δ ppm: 10.67-10.60 (m, 1H), 7.77 (s, 2H), 7.30 (d, J=8, 7 Hz, 1H), 7.07 (s, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.67 (dd, J=8.9, 2.5 Hz, 1H) , 2.94 (p, J=7.0 Hz, 1H), 1.18 (d, J=6.8 Hz, 6H).

Example 2 Synthesis of Compound 2

- 71 047363

4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylaniline (450.00 mg, 1.003 mmol, 1.00 eq.) in conc. HCl (9.60 ml), AcOH (27.40 ml) and H2O (20.9 ml). NaNO2 (145.35 mg, 2.107 mmol, 2.1 eq) in H2O (1.8 mL) was added dropwise to the stirred solution over 45 min at 0°C. In the second reaction flask, methyl N-(2-cyanoacetyl)carbamate (213.85 mg, 1.505 mmol, 1.50 eq.) was placed in H2O (25.6 ml) and pyridine (9.80 ml) for 10 min. at 0°C. The above solution was quickly poured into the second reaction flask for 30 min at 0°C. The precipitated solids were collected by filtration and washed with water and PE. The resulting mixture was concentrated in vacuo. This led to the formation of ethyl-N-[(7)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazine- 1-ylidene]carbonide]carbamate, which can also be called ethyl-(7)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-III-indol-5-yl) oxy)-3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate as a red solid. To a stirred solution of ethyl-N-[(7)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazine-1 -ylidene]carbonide]carbamate, which can also be called ethyl-(7)-(2-cyano-2-(2-(4-((3isopropyl-1-tosyl-III-indol-5-yl)oxy)- KOAc (178.52 mg, 1.819 mmol, 2.0 eq.) in portions at room. pace. The resulting mixture was stirred for 2 hours at 120°C under a nitrogen atmosphere. The reaction mixture was quenched by adding water (10 ml) at room temperature. pace. The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (2x100 ml), 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-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)3,5-dioxo-4H- 1,2,4-triazine-6-carbonitrile (350 mg, 56%) as a red solid.

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-carbonitrile (330.00 mg, 1 eq.) in THF was added TBAF (1 M in THF) (8.00 ml) at room. pace. The resulting mixture was stirred for 48 hours at 65°C. The resulting mixture was diluted with water (100 ml). The resulting mixture was extracted with EA (3x100 ml). The combined organic layers were washed with brine (2x100 ml), dried over anhydrous N2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification allowed us to obtain 2-[4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6- carbonitrile (132.3 mg, 54%) as a yellow solid.

^1H -NMR (300 MHz, DMSO^ ₆ ) δ ppm: 10.66 (s, 1H), 7.29-7.20 (m, 3H), 7.04 (d, J=2, 2 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.60 (dd, J=8.8, 2.5 Hz, 1H), 2.94 (p, J= 6.9 Hz, 1H), 2.10 (s, 6H), 1.19 (d, J=6.8 Hz, 6H).

Example 3 Synthesis of Compound 3

In the first reaction flask to a solution of 4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5yl]methyl]-3,5-dimethylaniline (480.00 mg, 1.075 mmol, 1.00 eq.) in concentrated HCl (9.60 ml), HOAc (28.80 ml) and H ₂ O (22.4 ml), stirred under nitrogen at 0° C., NaNO ₂ (155.72 mg, 2.257 mmol, 2.1 eq.) in H ₂ O (22.4 ml). The reaction mixture was stirred for 45 min at 0°C. In the second reaction flask, a solution of ethyl N-(2-cyanoacetyl)carbamate (251.72 mg, 1.612 mmol, 1.50 eq.) in H ₂ O (27.2 ml) and pyridine (9.60 ml) was stirred at 0°C for 10 min. The contents of the first reaction flask were 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 (3x50 ml) and PE (3x50 ml). The resulting mixture was concentrated in vacuo. The crude product was isolated as a yellow solid, 520 mg, 80% purity, 63% yield. To a solution of ethyl-N-[(7)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)hydrazine-1- ylidene]-carbonyl]carbamate, which may also be called ethyl-(7)-(2-cyano-2(2-(4-((3-isopropyl-1-tosyl-III-indol-5-yl)methyl) -3,5-dimethylphenyl)hydrazinylidene)acetyl)carbamate (350.00 mg, 0.570 mmol, 1.0 eq.) in DMA (8.0 ml) was stirred at room. pace. KOAc (111.94 mg, 1.141 mmol, 2.0 eq.) was added.

The reaction mixture was stirred at 120°C for 3 hours. The reaction mixture was quenched by adding water (10 ml) at room temperature. pace. The precipitated solid was collected by filtration and washing.

- 72 047363 add water (3x10 ml). The solid was dried in vacuo for 2 hours at 60°C to give 2-(4-[[3isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5 -dioxo-4H-1,2,4triazine-6-carbonitrile. The desired product was isolated as a dark orange solid, 250 mg, 80% purity, 62% yield. To a solution of 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine- 6-carbonitrile (200.00 mg, 0.352 mmol, 1.00 eq.) in THF (5.00 mL) was stirred under nitrogen at 0° C. TBAF (10.57 mL, 10.570 mmol, 30.00 eq.) was added. , 1 M in THF). The reaction mixture was stirred at 65°C for 3 days. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The sample was purified to give 2-(4-((3-isopropyl-III-indol-5-yl)methyl)-3,5-dimethylphenyl)-3,5dioxo-2,3,4,5-tetrahydro-1,2 ,4-triazine-6-carbonitrile as a yellow solid (compound 3, 29.7 mg, 99% purity, 20% yield).

^1H NMR (400 MHz, DMSO-ph) δ ppm: 13.00 (br, 1H), 10.63 (s, 1H), 7.19-7.22 (m, 2H), 7 .14 (s, 2H), 7.01 (d, J=2.0 Hz, 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).

Example 4 Synthesis of Compound 4

2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2 was loaded into a 50 ml autoclave. 4-triαzine-6-carbonitrile (1.00 g, 1.44 mmol, 1.00 eq.), dichloro[1,1'bis-(diphenylphosphino)ferrocene]palladium(P) (0.11 g, 0.144 mmol , 0.10 eq.), triethylamine (0.44 g, 4.32 mmol, 3.00 eq.), methanol (10 ml).

The contents of the autoclave were placed in an atmosphere of carbon monoxide (30 atm.). The reaction solution 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) methyl 5-[2,6-dichloro-4-(6cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]- 1-(4-methylbenzenesulfonyl)indole-3-carboxylate as a brown solid. A 40 ml vessel was loaded with methyl 5-[2,6-dichloro-4-(6-cyano-3,5dioxo-4H-1,2,4-triαzin-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl )indole-3-carboxylate (400 mg, 0.639 mmol, 1.00 eq.), tetrahydrofuran (5 mL), tetrabutylammonium fluoride (6.39 mL, 1 M in tetrahydrofuran, 6.39 mmol, 10.0 eq.) . The reaction solution was stirred overnight at 65°C and quenched with water (10 ml). The resulting solution was extracted with dichloromethane (3x20 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified to give 30.4 mg (15% yield) 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.

^1H NMR (300 MHz, methanol^) δ ppm: 7.97 (s, 1H), 7.80 (s, 2H), 7.41-7.44 (m, 2H), 6.88 -6.92 (m, 1H), 3.84 (s, 3H).

Example 5 Synthesis of Compound 5

2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine was loaded into a 250 ml round bottom flask -6-carbonitrile (1.00 g, 1.759 mmol, 1.00 eq.), tetrahydrofuran (20 mL), tetrabutylammonium fluoride (52.78 mL, 1 M in tetrahydrofuran, 52.78 mmol, 30.00 eq.) . The resulting solution was stirred overnight at 65°C and then quenched with water (150 ml). The resulting mixture was extracted with ethyl acetate (3x200 ml) and the organic layers were combined, washed with brine (3x200 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-(III-indol-5yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6- carbonitrile as a yellow solid.

To a solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triαzine-6

- 73 047363 carbonitrile (300 mg, 0.724 mmol, 1.00 eq.), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 eq.) and triethylsilane (337 mg, 2.90 mmol, 4.0 eq. .) in toluene (10 ml), stirred under nitrogen at 100° C., cyclopentanone (366 mg, 4.35 mmol, 6.00 eq.) was added. The reaction mixture was stirred overnight at 100°C and concentrated under reduced pressure. Purification resulted in the formation of 20.2 mg (6% yield) of 2-[3,5-dichloro-4-[(3-cyclopentyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H1 ,2,4-triazine-6-carbonitrile as a yellow solid.

^1H NMR (300 MHz, DMSOO δ ppm: 10.77 (s, 1H), 7.81 (s, 2H), 7.30-7.34 (m, 1H), 7.13 (d , J=1.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 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).

Example 6 Synthesis of Compound 6

2-[3,5-dichloro-4-(III-indol-5-yloxy)phenyl]-3,5-dioxo4H-1,2,4-triazine-6-carbonitrile (300 mg) was loaded into a 50-ml round-bottom flask , 0.724 mmol, 1.00 eq.), trichloroacetic acid (355 mg, 2.17 mmol, 3.00 eq.), toluene (10.00 ml), triethylsilane (504.10 mg, 4.35 mmol, 6 .00 eq.) in a nitrogen atmosphere. Acetophenone (261 mg, 2.17 mmol, 3.00 eq.) 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 (3x50 ml). The organic layers were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification gave 63.2 mg (17% yield) 2-(3,5-dichloro-4-[[3-(1-phenylethyl)-III-indol5-yl]oxy]phenyl)-3,5-dioxo-4H -1,2,4-triazine-6-carbonitrile as a yellow solid.

1H NMR (300 MHz, DMSOO δ ppm: 10.88 (s, 1H), 7.75 (s, 2H), 7.21-7.29 (m, 2H), 7.13-7, 21 (m, 4H), 7.06-7.11 (m, 1H), 6.63-6.67 (m, 1H), 6.38-6.39 (m, 1H), 4.11- 4.18 (m, 1H), 1.56-1.59 (m, 3H).

Example 7 Synthesis of Compound 7

To a stirred solution of 2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4- triazine-6-carbonitrile (400 mg, 0.576 mmol, 1.00 eq.) and phenylboronic acid (91.3 mg, 0.749 mmol, 1.30 eq.) in dioxane (4 ml) and water (0.8 ml) added dichloro[1,G-bis-(diphenylphosphino)-ferrocene]palladium(P) (42.2 mg, 0.0580 mmol, 0.10 eq.) and potassium carbonate (238.88 mg, 1.728 mmol, 3. 00 eq.) at room. pace. in 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) 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-phenylindol-5yl]oxy]phenyl)-3,5-dioxo-4H -1,2,4-triazine-6-carbonitrile as a light brown solid. To a stirred solution of 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfon-yl)-3-phenylindol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4 -triazine-6-carbonitrile (160 mg, 0.248 mmol, 1.00 eq.) in tetrahydrofuran (4 ml) was added tert-butylammonium fluoride (4.96 ml, 1 M in tetrahydrofuran, 4.96 mmol, 20.00 eq. .) at room pace. in a nitrogen atmosphere. The reaction mixture was then stirred overnight at 65°C and quenched with water (10 ml). The resulting mixture was extracted with ethyl acetate (3x10 ml) and the organic layers were combined, washed with brine (3x20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification gave 2-[3,5-dichloro-4-[(3-phenyl-Shindol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile ( compound 7, 39 mg, 32%) as a light orange solid.

1H NMR (300 MHz, methanol-f) δ ppm: 7.78 (s, 2H), 7.50-7.56 (m, 2H), 7.49 (s, 1H), 7.35 -7.41 (m, 3H), 7.18-7.23 (m, 2H), 681-6.84 (m, 1H).

Example 8 Synthesis of Compound 8

- 74 047363

To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazin- 6-carbonitrile (200.00 mg, 0.460 mmol, 1.00 eq.) to HOAc (4.43 mL, 0.074 mmol, 0.16 eq.) was added HCl (2.00 mL, 0.055 mmol, 0.12 eq. .) in portions at room. pace. 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-triazine-6carboxylic acid (78.3 mg, 38%) as a white solid with a metallic tint.

^1H NMR (400 MHz, DMSO-06): δ ppm: 13.82 (s, 1H), 12.70 (s, 1H), 12.19 (s, 1H), 7.82 (s , 2H), 7.44 (s, 1H), 3.05 (p, J=6.8 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).

Example 9 Synthesis of Compound 9

To a solution of 2-[3,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazin- 6-carbonitrile (200.00 mg, 0.460 mmol, 1.00 eq.) in DMSO (5 ml) was added K2CO3 (190.53 mg, 1.379 mmol, 3.00 eq.) and H ₂ O ₂ (2 ml, 30% in water) in portions at 0°C. The resulting mixture was stirred for 5 hours at room. pace. The reaction mixture was quenched with a saturated solution of Na ₂ S ₂ O ₃ at room temperature. pace. And concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18; mobile phase, ACN in water, gradient from 10 to 80% over 30 min) to give the crude product (150 mg), which was then purified by preparative HPLC (Column : XBridge Prep OBD C18 column, mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 20 to 33% B in 9 min) to obtain 2-[3 ,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo4H-1,2,4-triazine-6-carboxamide (112, 1 mg, 54%) as a white solid.

^1H NMR (400 MHz, DMSO-06) δ ppm: 12.76 (s, 1H), 12.20 (s, 1H), 8.14 (br, 1H), 7.85-7 .90 (m, 3H), 7.44 (s, 1H), 3.05 (p, J=6.8 Hz, 1H), 1.20 (d, J=6.8 Hz, 6H).

Example 10 Synthesis of Compound 10

To a solution of 2-[3,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazin- 6-carboxylic acid (200.00 mg, 0.440 mmol, 1.00 eq.) in t-BuOH (20.00 mL, 210.465 mmol), DPPA (375.64 mg, 1.365 mmol, 3.10 eq.) was added and Et ₃ N (138.12 mg, 1.365 mmol, 3.10 eq.) in portions at rt. pace. The resulting mixture was stirred for 24 hours at 85°C under a nitrogen atmosphere. The resulting mixture was concentrated. The residue was dissolved in CH ₂ Cl ₂ (100 ml) and then washed with NH ₄ Cl (4x200 ml), NaHCO ₃ and brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ : MeOH (50:1), to obtain tert-butyl-N-(2-[3,5-dichloro-4[(5-isonropyl-6-oxo- 1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate (110 mg, 48%) as a white solid.

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

A solution of tert-butyl-N-(2-[3,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5dioxo-4H-1, 2,4-triazin-6-yl)carbamate (90.0 mg, 1 eq.) in 4N. HCl in 1,4-dioxane (5.00 ml) was stirred overnight at room temperature. pace. 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 NH ₄ HCO ₃ +0.1% NH3-H2O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 10 to 40 V in 8 min) to obtain 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl )oxy]phenyl]4H-1,2,4-triazine-3,5-dione (18.8 mg, 26%) as a white solid.

1H NMR (400 MHz, DMSO-06) δ ppm: 12.26 (s, 1H), 12.18 (s, 1H), 7.85 (s, 2H), 7.41 (s, 1H ), 6.45 (s, 2H), 2.95-3.10 (m, 1H), 1.19 (d, J=6.9 Hz, 6H).

- 75 047363

Example 11 Synthesis of Compound 11

To a stirred solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo1H-pyridazin-3-yl)oxy]phenyl]-1, 2,4-triazine-3,5-di-one (430.00 mg, 0.706 mmol, 1.00 eq.) and trimethylsilylacetylene (207.96 mg, 2.117 mmol, 3.0 eq.) in DMF (10 ml ) CuI (26.88 mg, 0.141 mmol, 0.20 eq.), Et ₃ N (214.25 mg, 2.117 mmol, 3.00 eq.) and Pd(dppf)Cl ₂ (103.28 mg, 0.141 mmol, 0.20 eq.) in portions at room room. pace. in a nitrogen atmosphere. The reaction mixture was stirred overnight at 80°C and quenched with water (10 ml). The resulting mixture was extracted with EA (3x40 ml). The combined organic layers were washed with water (1x100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy]phenyl ]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione (260 mg, 52%) as a white metallic solid.

To a stirred solution of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-Spyridazin-3-yl)oxy]phenyl]-6-[2-( trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione (240.00 mg, 0.383 mmol, 1.00 eq.) in DCM (5 ml) was added BBr ₃ (383.84 mg, 1.532 mmol , 4.00 eq.) dropwise at 0°C in a nitrogen atmosphere. The reaction solution was stirred for 4 hours at room. pace. and quenched with MeOH (5 ml). The resulting mixture was concentrated under reduced pressure to obtain 100 mg (crude) 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-N-pyridazin-3-yl)oxy]phenyl]-6-[ 2-(trimethylsilyl)ethynyl]-4H-1,2,4-triαzine-3,5-dione as a light brown solid. To a solution of 2-[3,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridαzin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-4H1,2 ,4-triazine-3,5-dione (100.00 mg, 0.197 mmol, 1.00 eq.) in MeOH (10 ml) was added K ₂ CO ₃ (109.16 mg, 0.790 mmol, 4.00 eq. ) stirred at room. pace. The reaction mixture was stirred overnight at room. pace. and concentrated under reduced pressure to obtain a residue. Purification gave 19.4 mg (22% yield) 2-[3,5-dichloro-4-[(5-isonropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-ethynyl-4H1 ,2,4-triazine-3,5-dione as a white solid.

^1H NMR (400 MHz, DMSOO δ ppm: 12.75 (s, 1H), 12.23 (s, 1H), 7.77 (s, 2H), 7.44 (s, 1H), 4.70 (s, 1H), 3.03-3.10 (m, 1H), 1.20 (d, J=6.8 Hz, 6H).

Example 12 Synthesis of Compound 12

To a solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3yl)oxy]phenyl]-1,2 ,4-triazine-3,5-dione (300.00 mg, 0.492 mmol, 1.00 eq.) and tert-butyl-2-cyanoacetate (208.54 mg, 1.477 mmol, 3.0 eq.) in DMF (5.00 mg), stirred at room. temp., K2CO3 (272.21 mg, 1.970 mmol, 4.0 eq.) was added. The reaction mixture was stirred overnight at 90°C. The reaction mixture was quenched with water (30 ml). The resulting mixture was extracted with dichloromethane (3x50 ml) and the organic layers were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified to give 190 mg (95% purity) tert-butyl-2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxoIII-pyridazin- 3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate (190 mg, 58%) as a yellow solid.

Tert-butyl-2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl) was loaded into a 50-ml round-bottom flask. oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate (190.00 mg, 0.284 mmol, 1.00 eq.), TsOH (24.43 mg, 0.142 mmol, 0.5 eq.) and toluene (5 ml). The resulting solution was stirred for 4 hours at 90°C and quenched with water (10 ml). The resulting mixture was extracted with dichloromethane (3x50 ml) and the organic layers were combined, washed with brine (2x30 ml),

- 76 047363 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 190 mg of crude (purity 70%) 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[( 5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile (190 mg, 82% yield) as a yellow oil .

To a solution of 2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-3,5- dioxo-1,2,4-triazin-6-yl]acetonitrile (190.00 mg, 0.334 mmol, 1.00 eq.) in DCM (3 ml), stirred under nitrogen at -78°C, added BBr ₃ (501.57 mg, 2.002 mmol, 6.0 eq.). The reaction mixture was stirred at room. pace. for 4 hours. The reaction mixture was quenched with water (10 ml). The resulting solution was extracted with dichloromethane (3x20 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Purification gave 24.9 mg (16% yield) 2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3, 5-dioxo-4H1,2,4-triazin-6-yl)acetonitrile as a white solid.

^1H NMR (400 MHz, _DMSOD6 ) δ ppm: 12.71 (s, 1H), 12.20 (s, 1H), 7.81 (s, 2H), 7.46 (s, 1H ), 4.05 (s, 2H), 3.03-3.07 (m, 1H), 1.11-1.31 (m, 6H).

Example 13 Synthesis of Compound 13

To a solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-1,2 ,4-triazine-3,5-dione (350.00 mg, 0.574 mmol, 1.00 eq.) and diethyl malonate (184.02 mg, 1.149 mmol, 2.00 eq.) in DMSO (5 ml), stirring in a nitrogen atmosphere at room. temp., Cs ₂ CO ₃ (561.52 mg, 1.723 mmol, 3.0 eq.) was added. The reaction mixture was stirred at 110°C for 1 hour. The reaction mixture was quenched with water (20 ml). The resulting solution was extracted with dichloromethane (3x50 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (50 ml) to give a suspension with 100-200 mesh silica gel (2 g). The sample was purified and the desired product was isolated as a yellow oil, 270 mg, 90% purity, 61% yield.

To a solution of 1,3-diethyl-2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]phenyl ]-3,5-dioxo-1,2,4-triazin-6-yl]propanedioate (250.00 mg, 0.363 mmol, 1.00 eq.) in DCM (5.00 ml) was stirred under nitrogen at 0 °C BBr3 (363.86 mg, 1.452 mmol, 4.00 eq.) was added. The reaction mixture was stirred at room. pace. for 3 hours. The reaction mixture was quenched with water (15 ml). The resulting solution was extracted with dichloromethane (3x30 ml) and the organic layers were combined, washed with brine (2x15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This material was not further purified. The crude product was isolated as a yellow solid, 210 mg, 70% purity, 71% yield.

To a solution of 1,3-diethyl-2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]3,5-dioxo- 4H-1,2,4-triazin-6-yl)propanedioate (210.00 mg, 0.369 mmol, 1.00 eq.) in MeOH (5.00 mL) and H2O (1.00 mL) stirring at room temperature . temp., NaOH (147.78 mg, 3.695 mmol, 10.00 eq.) was added. The reaction mixture was stirred at 60°C for 4 hours. The pH of the mixture was adjusted to ~5-6 using hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane (3x30 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified to give 2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2, 3,4,5-tetrahydro-1,2,4-1riazin-6-yl)acetic acid. The desired product was isolated as a white solid (54.0 mg, 99.5% purity, 31% yield).

1H NMR (300 MHz, DMSOO δ ppm: 7.82 (s, 1H), 7.44 (s, 1H), 3.44 (s, 2H), 3.01-3.10 (m, 1H), 1.191.24 (m, 6H).

- 77 047363

Example 14 Synthesis of Compound 14

C.I.

To a stirred solution of 4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo1H-pyridazin-3-yl)oxy]phenyl]-1, 2,4-triazine-3,5-di-one (400.00 mg, 0.657 mmol, 1.00 eq.) in n-BuOH (5 ml) was added methylamine (3.3 ml, 6.565 mmol, 10.00 eq., 2 M in THF) at room. pace. The reaction mixture was stirred overnight at 110°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified to give 220 mg (53% yield) 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy ]phenyl]-6-(dimethylamino)-1,2,4triazine-3,5-dione as a light solid.

To a stirred solution of 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-Spiridazin-3-yl)oxy]phenyl]-6-(methylamino)- 1,2,4-triazine-3,5-dione (400.00 mg, 0.715 mmol, 1.00 eq.) in DCM was added BBgs (716.55 mg, 2.860 mmol, 4.00 eq.) at -78 °C. The resulting solution was stirred for 4 hours at room. pace. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Purification gave 86.9 mg (54% yield) 2-[3,5-dichloro-4-[(5-isopropyl-6oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-4H -1,2,4-triazine-3,5-dione as a white solid.

¹ H NMR (300 MHz, DMSO-0 ₆ ) δ ppm: 12.99 (s, 1H), 12.23 (s, 1H), 8.82 (d, J=4.8 Hz, 1H ), 8.16 (s, 2H), 7.42 (s, 1H), 3.03-3.08 (m, 1H), 2.79 (d, J=4.8 Hz, 3H), 1 .20 (d, J=6.9 Hz, 6H).

Example 15 Synthesis of Compound 15

4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy]phenyl was added to a 50 ml round bottom flask. ]-1,2,4-triazine-3,5-dione (400.00 mg, 0.657 mmol, 1.00 eq.) in n-BuOH (8 ml) and dimethylamine (3.3 ml, 6.565 mmol, 10 .00 eq., 2 M in THF) at room. pace. The reaction mixture was stirred overnight at 110°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified to give 170 mg (41% yield) 4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)- oxy]phenyl]-6(dimethylamino)-1,2,4-triazine-3,5-dione as a light pink solid.

4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6oxo-III-pyridazin-3-yl)oxy]phenyl]-6- was loaded into a 50-ml round-bottom flask. (dimethyl-amino)-1,2,4-triazine-3,5-dione (160.00 mg, 0.279 mmol, 1.00 eq.), DCM (10.00 ml). BBgz (279.61 mg, 1.116 mmol, 4.00 eq.) was added at -78°C. The resulting solution was stirred for 4 hours at room. pace. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Purification gave 54.3 mg (42% yield) 2-[3,5-dichloro-4-[(5isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethylamino)-4H -1,2,4-triazine-3,5-dione.

¹ H NMR (300 MHz, DMSO-a ₆ ) δ ppm: 7.91 (s, 2H), 7.43 (s, 1H), 3.03-3.10 (m, 1H), 2 .99 (d, J=8.1 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).

Example 16. Synthesis of compounds 16 and 23.

Connection 16 o

- 78 047363

To a stirred mixture of 3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronic acid (250.00 mg, 0.729 mmol, 1.00 eq.), 6 -bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (180.19 mg, 0.875 mmol, 1.20 eq.), K ₂ CO ₃ (201.48 mg, 1.458 mmol , 2.00 eq.) in dioxane (10 ml) and H2O (1 ml) was added Pd(PPh ₃ ) ₄ (168.46 mg, 0.146 mmol, 0.20 eq.) under nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. The reaction solution was quenched with water (15 ml) and extracted with EA (3x15 ml). The combined organic layers were washed with brine (2x15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with EA:PE 1:5 and MeCN (5 ml), washed with ether (5 ml) to obtain the desired product 6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H- pyridazin-3-yl)oxy]phenyl]-2methyl-4H-1,2,4-triαzine-3,5-dione (103.8 mg, 34%) as a white solid.

^1H NMR (300 MHz, DMSOA) δ ppm: 12.45 (br, 1H), 12.21 (s, 1H), 8.10 (s, 2H), 7.43 (s, 1H ), 3.58 (s, 3H), 3.11-2.97 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

Connection 23

I ^C| g ,N Ya. Jk Jk SG γ ΝΗ ^H nL AN^O 23

Compound 23 was prepared similarly to that described for compound 16, using 6-bromo2-ethyl-4H-1,2,4-triazine-3,5-dione instead of 6-bromo-2-methyl-4H-1,2. 4-triazine-3,5-dione.

1H NMR (300 MHz, DMSOO δ ppm: 12.39 (s, 1H), 12.18 (s, 1H), 8.09 (s, 2H), 7.40-7.41 (m, 1H), 3.954.03 (m, 2H), 3.00-3.07 (m, 1H), 1.28 (t, J=7.0 Hz, 3H), 1.28 (t, J=6 .9 Hz, 6H).

LCMS (ESI, m/z): 438 [M+H]+.

Example 17 Synthesis of Compound 17

To a solution of 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carbonitrile (250.0 mg, 0.604 mmol , 1.00 eq.) in acetonitrile (4 ml) was added dropwise chlorosulfonyl isocyanate (102.5 mg, 0.724 mmol, 1.2 eq.) in acetonitrile (0.4 ml) at -45°C under nitrogen atmosphere. During the addition, a fine precipitate formed. The mixture was stirred at -45°C under nitrogen for 10 min, NN-dimethylformamide (4 ml) was then added slowly, the mixture was allowed to warm to room. pace. and stirred for 2 hours. The reaction mixture was quenched by adding water/ice (10 ml) at 0°C. The resulting mixture was extracted with ethyl acetate (3x15 ml). The combined organic layers were washed with water (3x10 ml), saturated NaHCO ₃ and brine, dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC with dichloromethane:methanol (12:1) to give the crude product (160 mg). The crude product (160 mg) was purified by preparative HPLC under the following conditions: (Column: Kinetex EVO C18 column, 30x150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 50 to 50% B over 8 min) to give 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H1,2,4-triazine-2- yl)phenoxy]-1H-indole-3-carbonitrile (75.9 mg, 29% yield) as a light yellow solid.

1H NMR (300 MHz, DMSOA) δ ppm: 13.30 (s, 1H), 12.28 (s, 1H), 8.28 (d, J=3.0 Hz, 1H), 7, 84 (s, 2H), 7.58 (d, J=9.0 Hz, 1H), 6.97-7.01 (m, 1H), 6.86 (d, J=2.4 Hz, 1H ).

Example 18 Synthesis of compounds 18 and 19

0°C,30min

WITH! .CI

HCAe, OMA _N

120°С, during the night < ΛΑ α ΑΑν''f XAy ciADchch' and А'й'* ⁴ ' V сА 18

NaNO ₂ (150.8 mg, 2.19 mmol, 2.1 eq.) in H ₂ O (12 ml) was added dropwise to a solution of 3,5-dichloro-4([3-isopropyl-1H-pyrrolo[3 ,2-b]pyridin-5-yl]oxy)aniline (350.0 mg, 1.04 mmol, 1.0 eq.) in HCl (5.5 mL, conc.), AcOH (16 mL) and H ₂ O (12 ml). The mixture was stirred for 30 minutes at 0°C. Then react

- 79 047363 tion mixture was quickly poured into a solution of ethyl N-(2-cyanoacetyl)carbamate (243.8 mg, 1.56 mmol, 1.5 eq.) in H2O (16 ml) and pyridine (5.5 ml) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes and filtered. The filter cake was washed with water (2x15 ml) and petroleum ether (2x15 ml) and dried under reduced pressure to give (350 mg, crude) ethyl-N-[(E)-cyano([2[3,5-dichloro-4 -([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazin-1-ylidene])carbonide]carbamate as a yellow solid.

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

To a solution of ethyl-N-[(E)-cyano([2-[3,5-dichloro-4-([3-isonropyl-1H-pyrrolo[3,2-b]pyridin-5yl]oxy)phenyl]hydrazine -1-ylidene])carbonide]carbamate (350.00 mg, 0.695 mmol, 1.00 eq.) in DMA (20 ml) was added KOAc (341.22 mg, 3.477 mmol, 5.00 eq.). The resulting mixture was stirred overnight at 120°C and quenched with water (30 ml). The resulting mixture was extracted with EA (3x40 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (Mobile phase: MeOH/DCM = 1:7; Rf = 0.4; detection: UV) to obtain the crude product (180 mg). The product was separated on a preparative chiral HPLC column: CHIRALPAK IE, 2x25 cm, 5 µm; mobile phase A: Hex (0.1% FA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 ml/min; gradient: from 10 to 10% B in 21 min. Purification gave the desired product 2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H1, 2,4-triazine-6-carbonitrile (86.3 mg, 26%) as a yellow solid.

¹ H NMR (300 MHz, DMSOO δ ppm: 13.25 (br, 1H), 11.00 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7 .76 (s, 2H), 7.28 (d, J=2.4 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 2.78-2.95 (m, 1H), 1.13 (d, J=6.6 Hz, 6H).

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

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

1H NMR (300 MHz, DMSOO δ ppm: 13.26 (br, 1H), 11.03 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7, 76 (s, 2H), 7.33 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 2.42 (t, J=7.5 Hz, 2H), 1.45-1.58 (m, 2H), 0.77 (t, J=7.5 Hz, 3H).

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

Example 19. Synthesis of compounds 20, 21 and 22.

Connection 21

2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2 was loaded into a 20 ml autoclave. 4-triazine-6-carbonitrile (600.00 mg, 0.864 mmol, 1.00 eq.), dimethylamine (2.59 ml, 2 M in tetrahydrofuran, 5.185 mmol, 6.00 eq.), 1,1'- bis-(diphenylphosphino)ferrocene (95.47 mg, 0.173 mmol, 0.20 eq.), bis-(acetonitrile) palladium(I) chloride (22.42 mg, 0.0864 mmol, 0.10 eq.), triethylamine (262.35 mg, 2.593 mmol, 3.00 eq.), toluene (15 ml). The contents of the autoclave were placed in an atmosphere of carbon monoxide (20 atm.). The reaction solution was stirred overnight at 100°C and quenched with water (10 ml). The resulting mixture was extracted with ethyl acetate (3x15 ml) and the organic layers were combined, washed with brine (3x15 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was chromatographed on a C18 column chromatography with _CH3 ,CH: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.

LCMS (ESI, m/z): 637 [M-H] ^- .

To a stirred solution of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2yl)phenoxy]-N,Ndimethyl-1-(4- methylbenzenesulfonyl)indole-3-carboxamide (200.00 mg, 0.313 mmol, 1.00 eq.) in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1.25 ml, 1 M in tetrahydrofuran, 1.251 mmol, 4.00 eq. ) at room temperature in 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 (3x20 ml) and the organic layers were combined, washed with brine (5x10 ml) and hydrochloric acid (1 M), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated

- 80 047363 at reduced pressure. The crude product (150 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 ml/ min; gradient: from 27 to 47% B in 7 min) to obtain 52 mg (34% yield) 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2 ,4-triazin-2yl)phenoxy]-K,K-dimethyl-III-indole-3-carboxamide as a light yellow solid.

¹ H NMR (300 MHz, methanol^) δ ppm: 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).

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

Connection 20

Compound 20 is similar to that described for compound 21 using 2 eq. isopropylamine instead of 6 eq. dimethylamine and reacting overnight at 80°C.

1H NMR (300 MHz, methanol^) δ ppm: 7.89 (s, 1H), 7.77 (s, 2H), 7.50 (d, J=2.4 Hz, 1H), 7 .38 (d, J=9.3 Hz, 1H), 6.87-6.91 (m, 1H), 4.12-4.16 (m, 1H), 1.21 (d, J=6 ,6 Hz, 6H).

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

Connection 22

Compound 22 was prepared similarly to that described for compound 21 using 1.5 eq. tetrahydroisoquinoline instead of 6 eq. dimethylamine.

1H NMR (400 MHz, methanol^) δ ppm: 7.70 (d, J=8.4 Hz, 3H), 7.45 (d, J=8.8 Hz, 1H), 7.15 -7.17 (m, 3H), 7.07 (lat, 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).

LCMS: 573 [M+H]+.

Example 20. Synthesis of compounds 24, 25 and 26.

Connection 25

To a solution of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazine -6-carboxylic acid (500 mg, 1.101 mmol, 1.00 eq.) and K,K-diisopropylethylamine (298.77 mg, 2.312 mmol, 2.10 eq.) in tetrahydrofuran (30 ml) at 0°C in under nitrogen atmosphere, ethyl chloroformate (126.62 mg, 1.167 mmol, 1.06 eq.) was added dropwise. The mixture was stirred for 1 hour at room temperature and treated dropwise with a solution of sodium borohydride (124.94 mg, 3.302 mmol, 3.00 eq.) in water (2 ml) at 0°C. The resulting solution was stirred overnight at room temperature and then slowly quenched with saturated NaHCO ₃ solution (10 ml). The resulting mixture was extracted with chloroform/isopropanol (3/1) (5x30 ml) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product (400 mg) was purified by preparative HPLC using the following gradient conditions: Column: XSelect CSH Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3-H2O), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 19 to 31% B in 8 min), resulting in 2-[3,5-dichloro-4[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6 -(hydroxymethyl)-4H-1,2,4-triazine-3,5-dione (100.6 mg, 21% yield) as a white solid.

1H NMR (300 MHz, DMSOO δ ppm: 12.48 (br, 1H), 12.22 (br, 1H), 7.86 (s, 2H), 7.44 (s, 1H) , 5.30 (t, J=6.0 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 3.02-3.11 (m, 1H), 1.20 ( d, J=6.9 Hz, 6H).

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

- 81 047363

Connection 24

I

2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2 was loaded into a 50-ml round-bottom flask ,4-triazine-3,5-dione (1.60 g, 3.634 mmol, 1.00 eq.), acetonitrile (15 ml). Phosphorus tribromide (0.3 ml) was added at 0°C under nitrogen atmosphere. The resulting solution was stirred for 1 hour at 75°C. The mixture was cooled to room temperature and then quenched with saturated aqueous NaHCO ₃ (10 ml). The resulting mixture was extracted with ethyl acetate (3x15 ml) and the organic layers were combined, washed with brine (1x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.1 g (39% yield) 6(bromomethyl)-2 -[3,5-dichloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine3,5-dione as a yellow solid substances.

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

6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]phenyl]-4H-1,2 was loaded into a 50-ml round-bottom flask ,4-triazine-3,5-dione (400 mg, 0.795 mmol, 1.00 eq.), methylamine (1.2 mL, 2 M in tetrahydrofuran, 2.385 mmol, 3.00 eq.) and NN-dimethylformamide ( 8 ml). The mixture was stirred for 1 hour at 70°C. The mixture was cooled to room temperature and diluted with water (5 ml). At this time, acidified by adding 1N. hydrochloric acid (5 ml) and extracted with ethyl acetate (3x10 ml). The organic layer was discarded. The aqueous layer was made basic by adding saturated NaHCO ₃ solution (15 ml) and extracted with a chloroform:isopropanol 3:1 solution (5x30 ml) and 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, 30x150 mm 5 µm; mobile phase A: water (10 mM NH ₄ HCO ₃ + 0.1% NH3-H2O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 17 to 35% B in 8 minutes. Purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[(methylamino)methyl]-4H-1,2 ,4triazine-3,5-dione (64.8 mg, 18% yield) as a white solid.

1H NMR (300 MHz, _DMSOD6 ) δ ppm: 12.23 (br, 1H), 7.88 (s, 2H), 7.43 (s, 1H), 3.83 (s, 2H ), 3.013.19 (m, 1H), 2.51 (s, 3H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 453 [M+H] ⁺ .

Connection 26

Compound 26 was prepared similarly to that described for compound 24, using dimethyl lamine instead of methylamine and reacting at 60°C for 1 hour.

1H NMR (300 MHz, DMSO-06) δ ppm: 12.21 (br, 1H), 7.80 (s, 2H), 7.45 (s, 1H), 3.37 (br. , 2H), 3.033.08 (m, 1H), 2.25 (s, 6H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 467 [M+H] ⁺ .

Example 21 Synthesis of compound 27

6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]phenyl]-4H-1,2 was loaded into a 100 ml round bottom flask. 4-triazine-3,5-dione (400.00 mg, 0.795 mmol, 1.00 eq.), imidazole (64.95 mg, 0.954 mmol, 1.20 eq.), potassium carbonate (219.75 mg, 1.590 mmol, 2.00 eq.) and N,N-dimethylformamide (8 ml). The mixture was stirred for 1 hour at 70°C and subsequently cooled

- 82 047363 brought to room temperature and diluted with water (5 ml). At this time, acidified by adding 1N. hydrochloric acid (5 ml) and extracted with ethyl acetate (3x10 ml). The organic layer was discarded. The aqueous layer was made basic by adding saturated NaHCO3 solution (15 ml) and extracted with chloroform:isopropanol 3:1 (5x30 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 (150 mg) was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C18 column, 30x150 mm, 5 µm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3-H2O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 19 to 37% B in 8 minutes; purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-6-(imidazol-1-ylmethyl)-4H-1,2, 4-triazine-3,5-dione (14.5 mg, 4% yield) as a white solid.

^1H NMR (300 MHz, DMSO^) δ ppm: 12.19 (s, 1H), 7.74 (s, 2H), 7.69 (s, 1H), 7.43 (s, 1H ), 7.21 (s, 1H), 6.90 (s, 1H), 5.15 (s, 2H), 3.02-3.09 (m, 1H), 1.19 (d, J= 6.9 Hz, 6H).

LCMS (ESI, m/z): 490 [M+H] ⁺ .

Example 22 Synthesis of compound 28

F^F

Into the stirred mixture 4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazine- 3,5-Dione (310 mg, 0.569 mmol, 1.00 eq.) and K2CO3 (630 mg, 4.56 mmol, 8.00 eq.) in DMF (20 mL) were bubbled with difluorochloromethane for 4 h, and the mixture stirred for 5 hours at 50°C. The reaction mixture was quenched by adding water (50 ml). The resulting mixture was extracted with EA (3x30 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-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl -6-methoxypyridazin-3-yl)oxy]phenyl]-2(difluoromethyl)-1,2,4-triazine-3,5-dione as a light yellow solid.

LCMS (ESI, m/z): 594 [M+H] ⁺ .

4-[(Benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]phenyl]-2(difluoromethyl)-1,2, 4-triazine-3,5-dione (230 mg, 0.387 mmol, 1.00 eq.) into a solution of hydrogen chloride (4 ml, 4 M in 1,4-dioxane) was stirred for 2 hours at 60°C. After cooling to 25°C, the resulting mixture was concentrated under vacuum. The residue was then diluted with DCM (5 ml) and a solution of BBr3 (1.5 ml, 1M in DCM) was added dropwise at 25°C. The final reaction mixture was stirred for 45 minutes at 25°C. The reaction mixture was quenched by adding water (1 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: Silica gel C18; mobile phase, A: water (containing 10 mM NH4HCO3) and B: ACN (0 to 50% in 15 min); detector: UV 220/254 nm). Product fractions were lyophilized to yield 113.4 mg (63% yield) 6-[3,5dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-( difluoromethyl)-4H-1,2,4-triazine-3,5dione as a white solid.

1H NMR (400 MHz, DMSO^) δ ppm: 12.78 (br s, 1H), 12.22 (br s, 1H), 7.99 (s, 2H), 7.83 ( t, J=57.2 Hz, 1H), 7.45 (s, 1H), 3.13-2.98 (m, 1H), 1.20 (d, J=7.2 Hz, 6H).

LCMS (ESI, m/z): 460 [M+H] ⁺ .

Example 23 Synthesis of Compound 29

6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]phenyl]-4H-1,2 was loaded into a 50-ml round-bottom flask ,4-triazine-3,5-dione (400 mg, 0.795 mmol, 1.00 eq.), HNdimethylformamide (8 ml) under nitrogen atmosphere. Sodium methoxide (0.50 ml, 30% w/w, in methanol) was added at 0°C. The mixture was stirred for 1 hour at 0°C. The mixture was acidified by adding 1N. hydrochloric acid (5 ml) and extracted with ethyl acetate (3x15 ml). The organic layer was washed with brine (2x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated at

- 83 047363 low pressure. The residue was chromatographed on a silica gel column with dichloromethane/methanol (10/1) to give the crude product (150 mg) and then purified by preparative HPLC using the following gradient conditions: Column: XSelect CSH Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 ml/min; gradient: from 31 to 51% B in 8 minutes; purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-Spiridazin-3-yl)oxy]phenyl]-6-(methoxymethyl)-4H-1,2,4-mriazin- 3,5-dione (26.2 mg, 7% yield) as a white solid.

^1H NMR (300 MHz, DMSO^) δ ppm: 12.53 (s, 1H), 12.22 (s, 1H), 7.80 (s, 2H), 7.45 (s, 1H ), 4.32 (s, 2H), 3.03-3.07 (m, 1H), 2.48 (s, 3H), 1.0 (d, J=6.9 Hz, 6H).

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

Example 24 Synthesis of Compound 30

2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-3,5-dioxo-4H-1,2 was loaded into a 100-ml round bottom flask ,4-triazine-6-carbonitrile (300.00 mg, 0.689 mmol, 1.00 eq.), concentrated hydrochloric acid (2 ml), Pd/C (30.00 mg, 0.282 mmol, 0.41 eq.) , methanol (30.00 mL, 0.936 mmol, 1.36 eq.) under hydrogen atmosphere. The resulting solution was stirred overnight at room temperature and then filtered through celite. The celite layer was washed with methanol (5x30 ml), the filtrate was collected and concentrated under reduced pressure. The residue was diluted with saturated NaHCO ₃ solution (10 ml) and extracted with chloroform:isopropanol (3:1) (5x15 ml) and 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, 30x150 mm, 5 µm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3-H2O), mobile phase B: ACN; flow rate: 25 ml/min; gradient: from 5 to 30% B in 9 minutes. Purification gave 6-(aminomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine- 3,5-dione (29.6 mg, 10% yield) white solid.

1H NMR (300 MHz, DMSO-d;) δ ppm: 7.93 (s, 2H), 7.42 (s, 1H), 3.84 (br, 2H), 3.02-3 .07 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 439 [M+H] ⁺ .

Example 25 Synthesis of Compound 31

To a mixture of 4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylaniline (70 mg, 156.39 µmol, 1 equiv .), conc. HCl (87.97 µl, 6.75 eq.) in H2O (1 ml) was added dropwise to sodium nitrite (14.84 mg, 215.04 µmol, 1.38 eq.) in H2O (1 ml), maintaining the temperature below 0°C. After addition was complete, the reaction mixture was stirred for 0.5 h. A mixture of ethyl K-(2-cyanoacetyl)carbamate (27.47 mg, 175.94 µmol, 1.13 eq.) and NaOAc (43.30 mg, 527 .83 µmol, 3.38 eq.) in EtOH (3 ml) was added dropwise to the resulting diazonium solution at below 0°C and stirred for another 2 hours. The reaction mixture (combined with another 50 mg batch) was diluted with H2O (10 ml), adjusted to pH 7-8 sat. aq. NaHCO ₃ then extracted with EA (3x50 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (Ethyl acetate in petroleum ether = 0-35%) to give ethyl-K-[ (2E)-2-cyano-2-[[4-[[3-isopropyl-1-(ptolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]hydrazono] acetyl]carbamate (75 mg, 31% yield) as a yellow solid.

A mixture of ethyl-N-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5yl]methyl]-3, 5-dimethylphenyl]hydrazono]acetyl]carbamate (55 mg, 89.47 µmol, 1 eq.) and NaOAc (36.70 mg, 447.36 µmol, 5 eq.) in AcOH (5 ml) were stirred at 130°C for 5 hours. AcOH was removed under reduced pressure, the residue was diluted with H2O (50 ml), adjusted to pH 7~8 sat. aq. NaHCO ₃ then extracted with EA (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2 -b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazin-6-carbonitrile (65 mg) as a yellow solid, which is

- 84 047363 was used directly in the next step without additional purification.

To a solution of 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5dimethylphenyl]-3,5-dioxo-1, 2,4-triazine-6-carbonitrile (60 mg, 105.51 µmol, 1 eq.) in THF (5 ml) was added with TBAF (1M in THF, 2.53 ml, 24 eq.) in one portion at 20°C . The resulting mixture was then stirred at 65°C for 8 hours under N2 atmosphere. LCMS indicated that the reaction was complete. The mixture was diluted with H2O (100 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with sat. aq. NH4Cl (3x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product, which was purified by Rev. HPLC [Column: Welch Xtimate C18 150x30 mm, 5 µm; mobile phase: 15% ACN in water (0.225% FA) to 45% ACN in water (0.225% FA)] to give 2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridine -5-yl)methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazin-6-carbonitrile (25 mg, 56% yield, 98.3% purity) as a light yellow solid substances.

^1H NMR (400 MHz, D\1CO-s16) δ ppm: 13.11-12.66 (m, 1H), 10.83 (br s, 1H), 7.57 (d, J =8.4 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.15 (s, 2H), 6.70 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 3.20 (td, J=6.8, 13.7 Hz, 1H), 2.39 (s, 6H), 1.33 (d, J=6.9 Hz , 6H).

Example 26. Synthesis of compound 32 ⁿ aOC0l a

P I I

CN

A solution of NaNO ₂ (2.1 eq., 45 mg) in water (6.5 ml) was added to a solution of 3,5-dimethyl-4-((3-pentyl-Shindazol-5-yl)methyl)aniline (1 eq. ., 100 mg, 0.31 mmol) in HCl 37% (106 eq., 2.7 ml), acetic acid (8.3 ml) and water (6.5 ml) at 0°C in an atmosphere of N ₂ . The reaction mixture was stirred at 0°C for 1 hour. In parallel, a solution of ethyl N-(2-cyanoacetyl)carbamate (1.5 eq., 73 mg) in water (7.8 ml) and pyridine (2.7 ml) was stirred at 0°C for 15 minutes. The first reaction mixture was quickly added to the second. The resulting reaction mixture was stirred at 0°C for 2 hours.

The precipitate was filtered and washed with water and petroleum ether to give ethyl (2-cyano-2-(2(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)hydrazinylidene) acetyl)carbamate (13 mg) as a yellow solid. The filtrate was extracted with DCM (3x50 ml) and the combined organic phases were dried over MgSO ₄ , filtered and evaporated to dryness to give ethyl (2-cyano-2-(2-(3,5dimethyl-4-((3-pentyl-III-indazole -5-yl)methyl)phenyl)hydrazinylidene)acetyl)carbamate (225 mg) as a yellow solid. The crude material was used as such in the next step.

Sodium acetate (4 eq., 102 mg) was added to the solution of ethyl (2-cyano-2-(2-(3,5-dimethyl-4-((3-pentylIII-indazol-5-yl)methyl)phenyl) hydrazinylidene)acetyl)carbamate (1 eq., 152 mg, 0.31 mmol) in acetic acid (5 ml) under N ₂ atmosphere. The reaction mixture was heated to boiling for 4 hours and then cooled to 0°C, water (10 ml) was added and the mixture was stirred for 30 minutes. The precipitate was then filtered, washed with water and petroleum ether and purified by flash silica gel chromatography (0 to 10% MeOH in DCM) to give 40 mg of a red solid, which was further triturated in Et ₂ O and iPr ₂ O to give compound 32 ( 20 mg, 15%) as an orange solid.

¹ H-NMR (DMSO, 400 MHz) δ ppm: 0.83 (t, J=2.5 Hz, 3H); 1.27 (lat, s, 4H); 1.63-1.70 (quint., J=7.7 Hz, 2H); 2.28 (s, 6H); 2.80 (t, J=7.2 Hz, 2H); 4.15 (s, 2H); 7.00 (d, J=8.8 Hz, 1H); 7.18 (s, 2H); 7.27 (s, 1H); 7.35 (d, J=8.8 Hz, 1H); 12.51 (s, 1H); 12.99 (s, 1H).

Example 27 Synthesis of compound 33

2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-N-pyridazin-3yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2 was loaded into a 50-ml round-bottom flask ,4-triazine-3,5-dione (1.60 g, 3.63 mmol), CH ₃ CN (15 ml). PBr ₃ (0.3 ml) was added at 0°C under N ₂ atmosphere. The resulting solution was stirred for 1 hour at 75°C. The mixture was cooled to room. temp., and then quenched with NaHCO ₃ (saturated aq., 10 ml). The resulting mixture was extracted with EA (3x15 ml) and the organic layers were combined, washed with brine (1x30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-(bromomethyl)-2-[3,5- dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4triazine-3,5-dione as a yellow solid (1.1 g , 39%).

6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-III) was loaded into a 50-ml round bottom flask

- 85 047363 pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (300 mg, 0.60 mmol), DMF (8 ml). NaSCH ₃ (125 mg, 1.79 mmol) was added at 0°C. The mixture was acidified by adding 1N. aq. HCl (5 ml) and extracted with EA (3x15 ml). The organic layers were combined, washed with brine (2x50 ml), dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (1:3) to give the crude product (150 mg) and then purified by preparative HPLC. Purification gave 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3yl)oxy]phenyl]-6-[(methylsulfanyl)methyl]-4H-1,2,4 -triazine-3,5-dione as a white solid with a metallic tint (32.9 mg, 12%).

^1H NMR (300 MHz, DMSO-dg) δ ppm: 12.55 (br, 1H), 12.21 (s, 1H), 7.81 (s, 2H), 7.45 (s , 1H), 3.54 (s, 2H), 3.01-3.10 (m, 1H), 2.11 (s, 3H), 1.20 (d, J=6.6 Hz, 6H) .

LCMS (ESI, m/z): 470 [M+H]+.

Example 28 Synthesis of Compound 34

I ^C1

A^y°yS °

O^N^CI^^^N^NH ^{n 34} o'

6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]phenyl]-4H-1,2 was loaded into a 50-ml round-bottom flask ,4-triazine-3,5-dione (480 mg, 0.954 mmol), DMF (8 ml), CH ₃ SO ₂ Na (292 mg, 2.86 mmol). The mixture was stirred for 1 hour at 60°C. The mixture was acidified by adding HCl (aq, 1.5 ml) and extracted with EA (3x15 ml). The organic layers were combined, washed with brine (2x50 ml), dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with DCM:MeOH (10:1) to give the crude product and then purified by preparative HPLC to give 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo1H-pyridazin- 3-yl)oxy]phenyl]-6-(methanesulfonylmethyl)-4H-1,2,4-triazine-3,5-dione as a white solid (70.8 mg, 15%).

¹ NMR (300 MHz, DMSO-dg) δ ppm: 12.74 (br, 1H), 12.22 (s, 1H), 7.84 (s, 2H), 7.45 (s, 1H), 4.48 (s, 2H), 3.01-3.11 (m, 4H), 1.20 (d, J=6.9 Hz, 6H).

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

Example 29 Synthesis of compound 35

A 500 ml round bottom flask was charged with 3-methyl-4-nitrophenol (4.50 g, 29.4 mmol), benzyltrimethylammonium tetrachloriodate (24.6 g, 58.8 mmol), AcOH (600 ml). The reaction mixture was stirred for 18 hours at 70°C. Solids were removed by filtration and washed with AcOH (300 ml). The organic layers were concentrated under reduced pressure. The residue was dissolved in EA:water (500 ml:250 ml). The organic layer was separated, washed with brine (2x200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column with EA:PE (4:94) to give 2,6-dichloro-3-methyl-4-nitrophenol as a brown solid (4.9 g, 64%).

A 250 ml vessel was loaded with 2,6-dichloro-3-methyl-4-nitrophenol (5.00 g, 22.5 mmol), Fe powder (6.29 g, 113 mmol), NH4C1 (9.64 g, 180 mmol), EtOH (50 ml) and water (25 ml). The reaction solution was stirred overnight at 50°C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel with EA:PE (2:5) to give 4-amino-2,6dichloro-3-methylphenol as a light brown solid (3.45 g, 59%).

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

6-(4-Amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2H-pyridazin-3-one was prepared in the same manner as described for 6-(4-amino-2,6-dichlorophenoxy) -4-isopropyl-2H-pyridazin-3-one from 4-amino-2,6-dichloro-3-methylphenol to give a metallic white solid (2.5 g, 56%). Ethyl-(E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3yl)oxy)phenyl)hydrazinylidene)acetyl )carbamate was prepared in a similar manner as described for ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1H-pyrrolo[3,2-b ]pyridin-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate to give an orange solid (140 mg, 72%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H- 86 047363

1,2,4-triazine-6-carbonitrile (compound 35-A) was prepared in a manner similar to that described for 2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b ]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-3,5dioxo-1,2,4-triazin-6-carbonitrile to give a brown solid (2.1 g, 64%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H1,2,4-triazine -6-Carboxylic acid was prepared in a manner similar to that described for 2-[3,5-dichloro-4[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5 -dioxo-4H-1,2,4-triazine-6-carboxylic acid to give a brown solid (1.0 g, 52%).

tert-Butyl-No(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5dioxo-4H-1 ,2,4-triazin-6-yl)carbamate was prepared in a manner similar to that described for tert-butyl N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazine -3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin6-yl)-carbamate to give a brown solid (600 mg, 71%).

A 100 ml round bottom flask was loaded with tert-butyl-N(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1Hpyridazin-3-yl)oxy]-2-methylphenyl]-3,5 -dioxo-4H-1,2,4-triazin-6-yl)carbamate (600 mg, 1.11 mmol), DCM (15.0 ml). TFA (5 ml) was added dropwise at 0°C. The reaction solution was stirred overnight at room. pace. and concentrated under reduced pressure. The residue was dissolved with EA (50 ml). The solution was adjusted to pH 8 with NaHCO ₃ (sat. aq.), then extracted with EA (3 x 20 ml), the organic layers were combined, washed with brine (2 x 10 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H-1, 2,4-triazine-3,5-dione (compound 35) as a white solid (105 mg, 39%).

1H NMR (300 MHz, DMSOMb) δ ppm: 12.18 (br, 2H), 7.72 (s, 1H), 7.45 (s, 1H), 6.39 (br, 2H) , 3.013.10 (m, 1H), 2.20 (s, 3H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 439 [M+H]+.

Example 30 Synthesis of compound 36

6-[(4-Amino-2,6-dichlorophenyl)methyl]-4-isopropyl-2H-pyridazin-3-one was prepared according to the literature method (J. Med. Chem. 2014, 57, 3912-3923) to obtain yellow solid (1.9 g, 50%).

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

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4triazin-6- carbonitrile was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1 ,2,4-triazine-6carbonitrile to give a white metallic solid (1.3 g, 86%).

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

tert-Butyl-No(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo4H-1,2, 4-triazin-6-yl)carbamate was prepared in a manner similar to that described for tert-butyl-E-('2-|3,5dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3- yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate to give a yellow solid (600 mg, 65%).

6-Amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-4H-1,2,4-triazine3,5- The dione was prepared in a manner similar to that described for 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H- 1,2,4-triazine-3,5-dione to give a white solid (227 mg, 49%).

1H NMR (300 MHz, DMSO-06) δ ppm: 7.76 (s, 2H), 7.30 (s, 1H), 6.52 (br, 2H), 4.24 (s, 2H), 2.98-3.02 (m, 1H), 1.15 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 423 [M+H]+.

- 87 047363

Example 31 Synthesis of compound 37

4-Amino-2-chloro-6-methylphenol was prepared similarly to that described in WO 2004/014382 to give a brown solid (10.8 g, 88%).

3-Chloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-5-methylaniline was prepared in the same manner as described for 3,5-dichloro-4-[(6-chloro-5- isopropylpyridazin-3-yl)oxy]aniline to give a brown semi-solid (9.5 g, 68%).

6-(4-Amino-2-chloro-6-methylphenoxy)-4-isopropyl-2H-pyridαzin-3-one was prepared in a manner similar to that described for 6-(4-amino-2,6-dichlorophenoxy)-4 -isopropyl-2H-pyridazin-3-one to give a pink solid (6.5 g, 68%).

Ethyl (2-(2-(3-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-5-methylphenyl)hydrazinylidene)-2-cyanoacetyl)carbamate was prepared in a similar manner as described for ethyl-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl )hydrαzinylidene)acetyl)carbamate to give a yellow solid (4.56 g, 75%).

2-[3-Chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5-dioxo-4H-1,2,4triazin-6 -carbonitrile was prepared in a manner similar to that described for 2-[3,5-dichloro-4-[(5-isopropyl6-oxo-III-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H- 1,2,4-triazine-6-carbonitrile to give a light yellow solid (2.3 g, 53%).

2-[3-Chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5-dioxo-4H-1,2,4triazin-6 -carboxylic acid was prepared in a manner similar to that described for 2-[3,5-dichloro-4-[(5isopropyl-6-oxo-1H-pyridαzin-3-yl)oxy]phenyl]-3,5-dioxo-4H -1,2,4-triαzine-6-carboxylic acid to give a white solid (880 mg, 75%).

tert-Butyl-U-(2-[3-chloro-4-[(5-isopropyl-6-oxo-III-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5dioxo-4H-1, 2,4-triazin-6-yl)carbamate was prepared in a manner similar to that described for tert-butyl-N(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridαzin- 3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triαzin-6yl)-carbamate to give a white solid (790 mg, 70%).

6-Amino-2-[3-chloro-4-[(5 -isopropyl-6-oxo-1 H-pyridazin-3 -yl)oxy]-5-methylphenyl]-4H-1,2,4triazine-3, 5-dione was prepared in a manner similar to that described for 6-amino-2-[3,5-dichloro-4-[(5isopropyl-6-oxo-N-pyridazin-3-yl)oxy]-2-methylphenyl]- 4H-1,2,4-triazine-3,5-dione to give a white solid (100 mg, 50%).

1H NMR (400 MHz, DMSO-dQ δ ppm: 12.18 (br, 1H), 12.10 (s, 1H), 7.58-7.61 (m, 1H), 7.51 -7.48 (m, 1H), 7.34-7.37 (m, 1H), 6.41 (s, 2H), 3.08-2.99 (m, 1H), 2.18 (s , 3H), 1.19 (d, J=6.8 Hz, 6H).

LCMS (ESI, m/z): 405.0 [M+H]+.

Example 32 Synthesis of compound 38

6-Amino-2-[4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-3,5-dimethylphenyl]-4H-1,2,4-triazine3,5- The dione was prepared in a manner similar to that described for 6-amino-2-(3,5-dichloro-4-((5-isopropyl-6oxo-1,6-dihydropyridαzin-3-yl)oxy)phenyl)-1,2 ,4-triazine-3,5(2H,4H)-dione to give a white solid (238 mg, 54%).

^1H NMR (300 MHz, DUSO-sb,) δ ppm: 12.10 (br, 1H), 12.00 (br, 1H), 7.30 (s, 1H), 7.25 (s, 2H), 6.32 (lat, 2H), 3.01-3.09 (m, 1H), 2.10 (s, 6H), 1.20 (d, J=6.6 Hz , 6H).

LCMS (ESI, m/z): 385 [M+H]+.

Example 33. Synthesis of compounds 39-A and 39-B

3,6-Dichloro-4-(sec-butyl)pyridazine was prepared in a manner similar to that described for 3,6-dichloro4-isopropylpyridazine (see also Samaritoni, J.G. Homolytic alkylation of 3,6-dichloropyridazine. Org. Prep. Proceded Int. 1988, 20, 117-121) to obtain a yellow oil (23.3 g, 79%).

To a mixture of 3,6-dichloro-4-(sec-butyl)pyridazine (7.00 g, 34.1 mmol) and 4-amino-2,6-dichlorophenol

- 88 047363 (6.68 g, 37.6 mmol) K2CO ₃ (14.2 g, 103 mmol) and CuI (1.95 g, 10.2 mmol) were added to DMSO (70 ml). The resulting mixture was stirred overnight at 90°C under N ₂ atmosphere. Solids were removed by filtration and the filtrate was quenched with NH ₄ Cl (sat. aq., 150 ml). The resulting mixture was extracted with EA (3x200 ml) and the organic layers were combined, washed with brine (2x150 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the crude product. The sample was purified by column chromatography on silica gel, eluted with EA:PE (0-40% for 20 min). Fractions were collected, combined and concentrated under reduced pressure to give 3,5-dichloro-4-[[6-chloro-5-(sec-butyl)pyridazin-3-yl]oxy]aniline as a brown semi-solid (10 g, 72%).

A mixture of 3,5-dichloro-4-[[6-chloro-5-(sec-butyl)pyridazin-3-yl]oxy]aniline (10 g, 28.9 mmol) and NaOAc (8.28 g, 101 mmol ) in AcOH (100 ml) was stirred overnight at 100°C. The mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (100 ml) and the pH was adjusted to 8 with NaOH (aq, 1 M). The mixture was extracted with EA (3x150 ml) and the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml) and NaOH (100 ml, 1 M aq.) and the resulting mixture was stirred overnight at 100°C. The mixture was concentrated under reduced pressure to remove MeOH. The resulting mixture was extracted with EA (3x150 ml) and the organic layers were combined, washed with brine (2x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The sample was purified by column chromatography on silica gel (EA:PE = 0-70% for 20 min). The fractions were collected, combined and concentrated under reduced pressure to give 6-(4-amino-2,6-dichlorophenoxy)-4-(sec-butyl)-2H-pyridazin-3-one as a light yellow solid (5. 95 g, 60%).

Ethyl-(2-(2-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)hydrazinylidene)-2-cyanoacetyl )carbamate, a yellow solid (4.63 g, 77%), was prepared similarly to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl -1H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate.

A mixture of ethyl-(2-(2-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)hydrazinylidene)-2- Cyanoacetyl)carbamate (4.40 g, 8.88 mmol) and NaOAc (3.64 g, 44.4 mmol) in AcOH (50 ml) were stirred for 2 h at 120°C. The mixture was poured into water (100 ml) and the crude product was obtained by filtration. The sample was purified by column chromatography (CH ₃ OH:DCM = 0-15% for 20 min). Fractions were collected, combined and concentrated under reduced pressure to give 2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3 ,5-dioxo-4H-1,2,4-triazine-6carbonitrile as a yellow solid (2.27 g, 52%).

A mixture of 2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H1,2,4 -triazine-6-carbonitrile (1.00 g, 2.23 mmol) in conc. HCl (5 ml) and AcOH (10 ml) were stirred for 2 hours at 120°C. The mixture was poured into water (20 ml), and the desired product was 2-(3,5-dichloro-4-[[6-oxo-5(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3 ,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid was obtained by filtration as a white solid (860 mg, 78%).

To a mixture of 2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H1,2, 4-triazine-6-carboxylic acid (860 mg, 1.84 mmol) in tBuOH (15.0 ml) was added with DPPA (1.52 g, 5.52 mmol) and NEt ₃ (743 mg, 7.35 mmol) . The resulting mixture was stirred overnight at 85°C under N2, then concentrated under reduced pressure. The residue was diluted with DCM (50 ml), washed with brine (30 ml), dried over anhydrous. Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography and eluted with MeOH:DCM (0-7% for 20 min). Fractions were concentrated under reduced pressure to give racemic tert-butyl-N-[2-(3,5dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl) -3,5-dioxo-4H-1,2,4-triazin-6yl]carbamate as a white solid (700 mg, 67%).

tert-Butyl-N-[2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo4H -1,2,4-triazin-6-yl]carbamate (500 mg, 0.927 mmol) was further purified by preparative SFC-HPLC (Column: Reg-AD, 30x250 mm, 5 µm; mobile phase A: CO2, mobile phase B: EtOH (8 mmol/l NH ₃ ·MeOH)-HPLC; flow rate: 50 ml/min; gradient: 220 nm; injection volume: 4 ml; number of runs: 11).

Purification provided enantiomer 1 as a white solid (130 mg, 26%, Rt: 5.79 min), and enantiomer 2 as a white solid (Rt: 6.97 min, 190 mg, 37%).

The boc groups were deprotected from each enantiomer separately in DCM (10 ml) and TFA (3 ml). The resulting mixtures were stirred for 4 hours at room. pace. and concentrated under reduced pressure. The solvent was removed under reduced pressure, the mixtures were diluted with EA (30 ml), washed with NaHCO ₃ (sat. aq., 20 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to obtain the crude product.

Compound 39-A (corresponding to enantiomer 1) was purified by preparative HPLC (Column: co

- 89 047363 Xselect CSH OBD 30x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ + 0.1% NH ₃ -H2O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 23 to 43 V in 7 minutes; 220 nm; RT: 5.32 min) to give a white solid (49.6 mg, 46%).

¹ H NMR (300 MHz, DMSO-06) δ ppm: 11.95-12.52 (m, 2H), 7.86 (s, 2H), 7.42 (s, 1H), 6, 52 (s, 2H), 2.862.94 (m, 1H), 1.64-1.74 (m, 1H), 1.45-1.56 (m, 1H), 1.17 (d, J= 6.9 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H).

LCMS (ESI, m/z): 439.0 [M+H] ⁺ .

Compound 39-B (corresponding to enantiomer 2) was triturated with EA:MeOH (5 mL:1 mL) to obtain the desired product as a white metallic solid (67.5 mg, 42%).

¹ H NMR (300 MHz, DMSOL6) δ ppm: 12.19-12.28 (m, 2H), 7.86 (s, 2H), 7.42 (s, 1H), 6.53 ( s, 2H), 2.832.94 (m, 1H), 1.61-1.77 (m, 1H), 1.43-1.58 (m, 1H), 1.18 (d, J=6, 9 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).

LCMS (ESI, m/z): 439.0 [M+H] ⁺ .

SFC analysis on compounds 39-A and 39-B:

Column name: Enantiocel C3-3, 4.6x100 mm, 3 µm.

Co-solvent: 20% EtOH (0.1% DEA).

Flow rate (ml/min): 4.

Temperature: 35°C.

Detector: 220 nm.

39-A: Rt=2.947 min.

39-B: Rt=3.269 min.

Example 34. Synthesis of compounds 40-A and 40:

3,6-Dichloro-4-cyclobutylpyridazine was prepared similarly to that described for 3,6-dichloro4-isopropylpyridazine to give a colorless oil (12 g, 38%).

3,5-Dichloro-4-[(6-chloro-5-cyclobutylpyridazin-3-yl)oxy]aniline was prepared in the same manner as described for 3,5-dichloro-4-[[6-chloro-5-( sec-butyl)pyridazin-3-yl]oxy]aniline to give a yellow solid (3.07 g, 34%).

Stirred mixture of 3,5-dichloro-4-[(6-chloro-5-cyclobutylpyridazin-3-yl)oxy]aniline (2.52 g, 7.31 mmol), NaOAc (2.10 g, 25.6 mmol ) in AcOH (25 ml) was stirred overnight at 100°C. The resulting mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (30 ml) and the pH was adjusted to 8 with NaOH (aq, 1 M). The mixture was extracted with EA (3x60 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (25 ml) and NaOH solution (25 ml, 1 M aq.) and the resulting mixture was stirred overnight at 120°C. The mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3x60 ml), the organic layers were combined, washed with saline (2x40 ml), dried over anhydrous. Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 6-(4-amino-2,6-dichlorophenoxy)-4-cyclobutyl-2H-pyridazin-3-one (2.27 g, crude) as brown solid matter.

Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (2.61 g, crude yellow solid) was prepared in a manner similar to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-III-indol- 5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate. To a stirred mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl) carbamate (2.50 g, 5.07 mmol) in DMA (25 ml) was added KOAc (1.99 g, 20.3 mmol) in portions at room temperature. pace. The resulting mixture was stirred for 5 hours at 120°C under N ₂ atmosphere. The reaction solution was quenched with water (200 ml) and extracted with EA (3x150 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with DCM:MeOH (9:1) to give 2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-N-pyridazin-3-yl)oxy] phenyl]3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a brown solid (compound 40-A, 2.1 g, 84%).

1H NMR (300 MHz, DMSO-06) δ ppm: 13.27 (br, 1H), 12.19 (s, 1H), 7.79 (s, 2H), 7.49-7, 51 (m, 1H), 3.50-3.62 (m, 1H), 1.93-2.34 (m, 5H), 1.75-1.88 (m, 1H).

To a stirred mixture of 2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]3,5-dioxo-4H-1,2,4- triazine-6-carbonitrile (1.30 g, 2.91 mmol) in AcOH (12 ml) was added dropwise with HCl (6 ml) at room temperature. pace. The resulting mixture was stirred for 2 hours at 120°C. The resulting mixture was concentrated under reduced pressure to remove AcOH. The pH of the mixture was adjusted to 8 with

- 90 047363 Na2CO ₃ (saturated aq.). The resulting mixture was extracted with EA (3x50 ml). The pH of the mixture was adjusted to 5 with HCl (1 M). The resulting mixture was extracted with EA (3x50 ml) and the organic layers were combined, dried over anhydrous Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo -III-pyridazin-3yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (1.0 g, crude) as a yellow solid. The crude product was used in the next step without further purification.

To a stirred solution of 2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-III-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4 -triazine-6-carboxylic acid (800 mg, 1.72 mmol) in tert-BuOH (30 ml) was added with DPPA (1.42 g, 5.15 mmol) and NEt ₃ (694 mg, 6.86 mmol) at drops at room pace. The resulting mixture was stirred overnight at 85°C and concentrated under reduced pressure. The residue was diluted with EA (50 ml) and washed with saline (40 ml). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography PE:EA (4:1) to give tert-butyl-N(2-[3,5-dichloro-4-[(5cyclobutyl-6-oxo-1H-niridazin-3-yl) oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate as a yellow solid (518 mg, 53%). To a stirred solution of tert-butyl-^(2-[3,5-dichloro-4[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H- 1,2,4-triazin-6-yl)carbamate (450 mg, 0.837 mmol) in DCM (5 ml) was added dropwise with TFA (2.50 ml) at 0°C. The resulting mixture was stirred for 3 hours at room. pace. and concentrated under reduced pressure. The residue was diluted with DCM (30 ml), washed with NaHCO ₃ (sat. aq., 40 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-amino-2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4 -triazine-3,5-dione as a white solid (89.4 mg, 24%).

^1H NMR (300 MHz, DMSO-a6) δ ppm: 12.27 (s, 1H), 12.15 (s, 1H), 7.85 (s, 2H), 7.46-7, 47 (m, 1H), 6.52 (s, 2H), 3.50-3.62 (m, 1H), 1.96-2.34 (m, 5H), 1.80-1.87 ( m, 1H).

LCMS (ESI, m/z): 459 [M+Na]+.

Example 35 Synthesis of compound 41

2-[3,5-Dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carboxylic acid was prepared similar to that described for 2-[3,5-dichloro-4-[(5-isopropyl-6oxo-1H-πpyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2 ,4-triazine-6-carboxylic acid, except that the mixture was stirred for 2 hours at 100°C to obtain a brown solid (200 mg, crude).

tert-Butyl-N-(2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4triazine -6-yl)carbamate was obtained from 2-(3,5-dichloro-4-((3-isopropyl-III-indol-5-yl)oxy)phenyl)-3,5dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carboxylic acid as described for tert-butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H -πpyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H1,2,4-triazin-6-yl)-carbamate (from 2-(3,5-dichloro-4-((5-isopropyl -6-oxo-1,6-dihydropyridazin-3yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid) to give yellow solid (117 mg, crude).

6-Amino-2-[3,5-dichloro-4-[(3-isopropyl-III-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione ( compound 41) was prepared in the same way as described for 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6oxo-III-pyridazin-3-yl)oxy]-2-methylphenyl]- 4H-1,2,4-triazine-3,5-dione to give a white solid (13 mg, 17%).

1H NMR (300 MHz, MeOH-d ₄ ) δ ppm: 7.88 (s, 2H), 7.25-7.29 (m, 1H), 7.01 (s, 1H), 6, 85-6.86 (m, 1H), 6.73-6.77 (m, 1H), 2.98-3.08 (m, 1H), 1.28-1.36 (m, 6H).

Example 36 Synthesis of compound 42

6-Amino-2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazine-3,5( 2H,4H)-dione was prepared in a manner similar to that described for 6-amino-2-(3,5-dichloro-4-((5cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl )-1,2,4-triazine-3,5(2H,4H)-dione to give a white solid (101 mg, 51%).

- 91 047363 ^1H NMR (300 MHz, DMSO-06) δ ppm: 12.21 (br, 1H), 12.17 (br, 1H), 7.85 (s, 2H), 7 .44 (s, 1H), 6.52 (broad, 2H), 3.03-3.33 (m, 1H), 1.90-1.98 (m, 2H), 1.50-1, 78 (m, 6H).

LCMS (ESI, m/z): 451 [M+H]+.

Example 3 7. Synthesis of compound 43

6-(4-Amino-2,6-dimethylbenzyl)-2-phenylpyridin-3-ol was prepared in a similar manner as described in WO 2010/122980 and JP 2012106996.

6-Amino-2-[4-[(5-hydroxy-6-phenylpyridin-2-yl)methyl]-3,5-dimethylphenyl]-4H-1,2,4-triazine-3,5dione was prepared from 6- (4-amino-2,6-dimethylbenzyl)-2-phenylpyridin-3-ol similar to that described in the conversion of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one to give 6-amino-2(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3 ,5(2H,4H)dione to give a white solid (43.8 mg, 49%).

¹ H NMR (300 MHz, DMSO-06) δ ppm: 9.32-9.89 (m, 2H), 7.99 (d, J=7.2 Hz, 2H), 7.31- 7.43 (m, 3H), 7.197.24 (m, 3H), 6.76 (d, J=8.1 Hz, 1H), 6.21 (s, 2H), 4.09 (s, 2H ), 2.11 (s, 6H).

LCMS (ESI, m/z): 416 [M+H]+.

Example 38 Synthesis of Compound 44

5-[2,6-Dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N-methyl-1-(4-methylbenzenesulfonyl) indole-3-carboxamide was prepared in a manner similar to that described for 5-[2,6-dichloro-4-(6cyano-3,5-dioxo-4H-1,2,4-triαzin-2-yl)phenoxy]- N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3carboxamide to give a light brown solid (200 mg, 50%).

Subsequent deprotection of the tosyl group was carried out similarly to that described for the formation of 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy ]-N,N-dimethyl-1Hindole-3-carboxamide to give 5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2yl)phenoxy ]-N-methyl-1H-indole-3-carboxamide as a yellow solid (21.5 mg, 14%).

¹ HNMR (300 MHz, MeOH-d ₄ ) δ ppm: 7.85 (s, 1H), 7.78 (s, 2H), 7.52 (d, J=2.4 Hz, 1H) , 7.41 (d, J=8.7 Hz, 1H), 6.91-6.94 (m, 1H), 2.87 (s, 3H).

LCMS (ESI, m/z): 471 [M+H]+.

Example 39 Synthesis of compound 45

flask

5-(2,6-dichloro-4-nitrophenoxy)-1-(4 methylbenzenesulfonyl)indole (1.00 g, 2.10 mmol), NIS (0.71 g, 3.14 mmol) was loaded into a 50-ml round bottom ), p-toluenesulfonic acid (0.05 g, 0.314 mmol), DCM (30 ml). The reaction mixture was stirred for 5 hours at room. temp., and then extinguished with water (150 ml). The resulting mixture was extracted with DCM (3x200 ml) and the organic layers were combined, washed with brine (1x200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with EA:PE (1:4) to give 5-(2,6-dichloro-4-nitrophenoxy)-3-iodo-1-(4-methylbenzenesulfonyl)indole as a yellow solid (580 mg, 41%).

A 50 mL round bottom flask was charged with 5-(2,6-dichloro-4-nitrophenoxy)-3-iodo-1-(4methylbenzenesulfonyl)indole (350 mg, 0.580 mmol), 4,4,6-trimethyl-2-( 3,3,3-trifluoroprop-1-en-2-yl)1,3,2-dioxaborinan (155 mg, 0.696 mmol), PdCl ₂ (dppf) (42.5 mg, 0.058 mmol), K ₂ CO ₃ (241 mg, 1.74 mmol), ethylene glycol dimethyl ether (10 ml) and water (2 ml). The resulting solution was stirred overnight under N2 at 80°C and quenched with water (10 ml), then extracted with EA (3x30 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with EA:PE (1:4) to give 5-(2,6-dichloro-4-nitrophenoxy)-1-(4methylbenzenesulfonyl)-3-(3,3,3-trifluoroprop-1- en-2-yl)indole as a white solid (220 mg, 53%).

- 92 047363

5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-3-(3,3,3-trifluoroprop-1-en-2-yl)indole (210) was loaded into a 100 ml round bottom flask mg, 0.368 mmol), Pd/C (200 mg) and EA (20 ml) in a hydrogen atmosphere. The mixture was stirred for 3 hours at room. pace. The reaction mixture was diluted with EA (60 ml) and filtered through celite, the celite layer was washed with EA (2x10 ml), the filtrate was concentrated under reduced pressure to give 3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-( 1,1,1trifluoropropan-2-yl)indol-5-yl]oxy]aniline as a yellow solid (155 mg, crude).

Ethyl-(2-cyano-2-(2-(3,5 -dichloro-4-(( 1 -tosyl-3 -(1,1,1 -trifluoropropan-2-yl)-1 H-indol-5- yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, orange solid (110 mg, 54%) was prepared as described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4 -((1-tosyl-III-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate. 2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3 -(1,1,1-trifluoropropan-2-yl)indol-5-yl]oxy]phenyl)-3,5 -Dioxo-4H-1,2,4-triαzine-6-carbonitrile, yellow solid (80 mg, 54%) was prepared as described for 2-(4-[[3-isopropyl-1-(4methylbenzenesulfonyl )indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triαzine-6-carbonitrile, except that the reaction time was 5 hours.

Subsequent deprotection of the tosyl group from TBAF to yield 2-(3,5-dichloro-4-[[3-(1,1,1trifluoropropan-2-yl)-1 H-indol-5-yl]oxy]phenyl)- 3,5-Dioxo-4H-1,2,4-triazine-6-carbonitrile as a light yellow solid (18.9 mg, 26%) was carried out in the same manner as described for 2-[4-[( 3-isopropyl-1H-pyrrolo[3-^pyridinA-i^methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazine6-carbonitrile.

^1H NMR (300 MHz, DMSO-dQ δ ppm: 11.20 (br, 1H), 7.81 (s, 2H), 7.34-7.42 (m, 2H), 7. 04 (s, 1H), 6.69-6.72 (m, 1H), 3.92-3.97 (m, 1H), 1.46 (d, J=7.2 Hz, 3H).

LCMS (IER, m/z): 508[M-N] ^- .

Example 40 Synthesis of Compound 46

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-N-indole (3.00 g, 9.29 mmol) in DCM (25 mL) was added diethylaluminum chloride (15 mL, 0.9 M in toluene, 13 .5 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, then benzoyl chloride (1.96 g, 13.9 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 3 hours and quenched with water (25 ml). The resulting mixture was extracted with DCM (3x20 ml). The organic layers were combined, washed with saline (3x20 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (4:1) to give 3-benzoyl-5-(2,6dichloro-4-nitrophenoxy)-III-indole as a light brown solid (1.3 g, 26 %). To a solution of 3-benzoyl-5-(2,6-dichloro-4-nitrophenoxy)-III-indole (1.3 g, 3.04 mmol) in THF (30 ml) was added LiAlH4 (462 mg, 12.2 mmol ) at 0°C in an N2 atmosphere. The reaction mixture was stirred overnight at 60°C and quenched with water (30 ml) at 0°C. NaOH (1N, 30 ml) was added to the resulting solution, followed by the addition of water (30 ml). Solids were removed by filtration and the filter cake was washed with water (3x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC with PE:EA (1:1) to give 4-[(3-benzyl-III-indol-5-yl)oxy]-3,5-dichloroaniline as a light yellow solid (250 mg, 21 %).

Ethyl (2-(2-(4-((3-benzyl-III-indol-5-yl)oxy)-3,5-dichlorophenyl)-hydrazinylidene)-2-cyanoacetyl)carbamate (300 mg, 52%) was prepared in a similar manner as described for ethyl (2-cyano-2-(2-(3,5dichloro-4-((1-tosyl-III-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate .

2-[4-[(3-Benzyl-1H-indol-5-yl)oxy]-3,5-dichlorophenyl]-3,5-dioxo-4H-1,2,4-triazin-6carbonitrile, light a brown solid was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo -4H1,2,4-triazine-6-carbonitrile except that the reaction time was 5 hours instead of 2 hours (13.3 mg, 7%).

1H NMR (300 MHz, MeOH-d ₄ ) δ ppm: 7.72 (s, 2H), 7.28 (d, J=9.0 Hz, 1H), 7.10-7.23 ( m, 5H), 7.03 (s, 1H), 6.77-6.80 (m, 1H), 6.54 (d, J=2.4 Hz, 1H), 3.98 (s, 2H ).

LCMS (ESI, m/z): 502 [MH] ^- .

Example 41 Synthesis of compound 47

- 93 047363

2-[3,5-Dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile, yellow solid (120 mg, 32%).

1H NMR (300 MHz, MeOH-d ₄ ) δ ppm: 7.77 (s, 2H), 7.33-7.37 (m, 1H), 7.24 (d, J=3.0 Hz, 1H), 6.80-6.84 (m, 2H), 6.35-6.36 (m, 1H).

LCMS (ESI, m/z): 412 [M-H]’.

Example 42 Synthesis of compound 48

A 50 mL round bottom flask was charged with 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (2.00 g, 6.19 mmol), DCM (10.0 mL). SnCl ₄ (1.93 g, 7.42 mmol) was added at 0°C. The reaction mixture was stirred at room. pace. within 30 min. Propanoyl chloride (1.14 g, 12.3 mmol) was added followed by CH3NO2 (15 ml). The reaction mixture was stirred overnight at room. pace. and quenched with water (10 ml). The resulting mixture was extracted with EA (3x200 ml) and the organic layers were combined, washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with EA:PE (9:1) to give 1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one as yellow solids (1.6 g, 68.17%).

A 50 mL round bottom flask was charged with 1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan1-one (1.90 g, 5.01 mmol), THF (20 ml). NaH (0.802 g, 20.0 mmol, 60% in mineral oil) was added at 0°C. 4-Toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added at 0°C. The resulting solution was stirred at room. pace. for 2 hours and quenched with NaHCO ₃ (saturated aq., 30 ml). The resulting mixture was extracted with EA (3x80 ml) and the organic layers were combined, washed with brine (2x40 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified on a silica gel column with EA:PE (1:5) to give 1-[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indol-3-yl]propan- 1-one as a yellow solid (1.1 g, 41%).

NBH4 (0.78 g, 20.6 mmol) was added to TFA (10 ml) at 0°C under N ₂ atmosphere. Then a solution of 1-[5(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indol-3-yl]propan-1-one (1.10 g, 2.06 mmol) in DCM ( 30 ml) was added to the mixture. The reaction mixture was stirred overnight at room. pace. and quenched with water (50 ml), then extracted with DCM (3x150 ml) and the organic layers were combined, washed with brine (1x100 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 1- [5-(2,6-dichloro-4nitrophenoxy)-1H-indol-3-yl]propan-1-one as a yellow solid (1.1 g, 99%).

3,5-Dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-propylindol-5-yl]oxy]aniline, yellow solid (870 mg, 74%) was prepared as described for 3. 5-dichloro-4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl]oxy]aniline, except that the reaction mixture was stirred overnight at 50°C. Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-propyl-1-tosyl-1H-indol-5yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, orange solid (850 mg, 48%) was prepared similarly to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5yl)oxy) phenyl)-hydrazinylidene)acetyl)carbamate.

2-(3,5-Dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-propylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H1,2,4-triazine-6- Carbonitrile, a white solid (400 mg, 48%), was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3. 5-dimethylphenyl)-3,5dioxo-4H-1,2,4-triazine-6-carbonitrile, except that the reaction time was 5 hours instead of 2 hours.

Subsequent deprotection of the tosyl group from TBAF to yield 2-[3,5-dichloro-4-[(3-propyl1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4 -triazine-6-carbonitrile as an orange solid (51.7 mg, 20%) was carried out in a manner similar to that described for 2-[4-[(3-isopropyl-1Hpyrrolo[3,2-b]pyridine-5 -yl)methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile.

1H NMR (400 MHz, DUSSH) δ ppm: 10.79 (s, 1H), 7.80 (s, 2H), 7.30 (d, J=8.8 Hz, 1H), 7, 14 (s, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65-6.68 (m, 1H), 2.52-2.57 (m, 2H), 1 .54-1.64 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

LCMS (ESI, m/z): 454 [M-N] ^- .

- 94 047363

Example 43 Synthesis of compound 49

InBr ₃ (0.22 g, 0.619 mmol) and isobutyryl chloride (0.99 g, 9.28 mmol) at 0°C in an N2 atmosphere. The reaction mixture was stirred for 2 hours at 85°C, then quenched with water (20 ml). The solution was extracted with EA (3x200 ml) and the organic layers were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (3:1) to give 1-[5-(2,6-dichloro-4-nitrophenoxy)-III-indol-3-yl]-2-methylpropan-1-one as a light brown solid (1.5 g, 56%).

1-[5-(2,6-Dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indol-3-yl]-2-methylpropan-1-one, light yellow solid (1.3 g, 70%), was obtained in a manner similar to that described for 1 -[5-(2,6-dichloro-4-nitrophenoxy)-1 -(4-methylbenzenesulfonyl)indol-3 -yl]propan-1 -one.

5-(2,6-Dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-3-(2-methylpropyl)indole, light brown solid (1.2 g, 85%), was prepared in the same manner as described for 1-[5-(2,6-dichloro-4-nitrophenoxy)-III-indol-3-yl]propan-1-one, except that after quenching with water, the reaction mixture was neutralized by adding NaOH solution at 0° WITH.

3,5-Dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-(2-methylpropyl)indol-5-yl]oxy]aniline as a light yellow solid (1.2 g, 95%) was prepared in a similar manner as described for 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline.

Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-isobutyl-1-tosyl-1 H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, a red solid (860 mg, 48%) was prepared in a manner similar to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-III-indol- 5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate.

2-(3,5 -Dichloro-4-[ [ 1 -(4-methylbenzenesulfonyl)-3 -(2-methylpropyl)indol-5 -yl]oxy]phenyl)-3,5 dioxo-4H-1,2, 4-Triazine-6-carbonyl, red solid (600 mg, 56%) was prepared as described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl] oxy]-3,5dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

The tosyl group was removed to give 2-(3,5-dichloro-4-[[3-(2-methylpropyl)-III-indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4 -triazine-6-carbonylyl as an orange solid (51.2 mg, 22%), which was prepared in the same manner as described for 2-[3,5-dichloro-4-(III-indol-5yloxy)phenyl] -3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

H NMR (300 MHz, MeOH-d4) δ ppm: 7.78 (s, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 6.73-6.83 (m, 2H), 2.51 (d, J=7.2 Hz, 2H), 1.83-1.92 (m, 1H), 0.90-1.00 ( m, 6H).

LC-MS (ESI, m/z): 468 [M-H] ^- .

Example 44 Synthesis of Compound 50

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-N-indole (2.00 g, 6.19 mmol) in DCM (50 ml) was added SnCl ₄ (1.93 g, 7.43 mmol) at 0°C. The solution was heated to room. pace. and stirred for 30 min, then cyclopropanecarbonyl chloride (0.78 g, 7.43 mmol) was added in small portions by syringe to the suspension, followed by the addition of nitromethane (40 ml). The reaction mixture was stirred at room. pace. for 2 hours, after which ice water (40 ml) was slowly added. Solids were removed by filtration and the filtrate was extracted with EA (3x50 ml), the organic layers were combined, dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with hexane:EA (3:1) to give 3-cyclopropanecarbonyl-5-(2,6-dichloro-4-nitrophenoxy)-N-indole as a yellow solid (1.3 g, 48 %).

3-Cyclopropanecarbonyl-5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole, light brown solid (1.8 g, 70%) was prepared as described for 1 -[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indol-3-yl]propan-1-one.

3-(Cyclopropylmethyl)-5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole, light brown solid (1.6 g, 77%) was prepared as described for 1 -[5-(2,6-dichloro-4-nitrophenoxy)-III-indol-3-yl]propan-1-one, except that after quenching

- 95 047363 water, the reaction mixture was neutralized by adding NaOH solution at 0°C.

3,5-Dichloro-4-[[3-(cyclopropylmethyl)-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline, light yellow solid (1.3 g, 78%) was prepared similarly , as described for 3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline.

Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-(cyclopropylmethyl)-1-tosyl-1H-indol-5yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, red solid (1.18 g, 62%) was prepared in a manner similar to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-III-indol- 5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate.

2-(3,5-Dichloro-4-[[3-(cyclopropylmethyl)-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5dioxo-4H-1,2,4-triαzine -6-carbonitrile, light brown solid (732 mg, 62%), purified by reverse phase chromatography using a C18 column, was prepared as described for 2-(4-[[3-isopropyl-1 -(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-carbonitrile.

The tosyl group was removed to obtain 2-(3,5-dichloro-4-[[3-(cyclopropylmethyl)-III-indol-5yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triαzine -6-carbonitrile as an orange solid (121 mg, 22%) was prepared in a manner similar to that described for 2-[3,5-dichloro-4-(III-indol-5yloxy)phenyl]-3,5-dioxo -4H- 1,2,4-triazine-6-carbonitrile.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ ppm: 7.79 (s, 2H), 7.28-7.31 (m, 1H), 7.11 (s, 1H), 6 .77-6.85 (m, 2H), 2.57 (d, J=6.6 Hz, 2H), 0.95-1.02 (m, 1H), 0.47-0.50 (m , 2H), 0.13-0.16 (m, 2H).

LCMS (ESI, m/z): 466 [M-N] ^- .

Example 45 Synthesis of Compound 51

CN

To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (14.0 g, 70.7 mmol), Cs ₂ CO ₃ (34.7 g, 106 mmol) in DMF (200 ml) was added [2-(chloromethoxy)ethyl]trimethylsilane (17.7 g, 106 mmol) dropwise at 0°C. The mixture was stirred for 2 hours at room. pace. and extinguished with water (400 ml). The mixture was extracted with EA (3x500 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (18:1) to give 2-bromo-5-[[2-(trimethylsilylCtox^methyl^irroloRD-^pyrazine as a yellow solid (21 g, 86%).

To a stirred solution of 2-bromo-5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazine (20.0 g, 60.9 mmol) and 4-amino-2,6-dichlorophenol (16.3 g, 91.4 mmol) in DMSO (200 ml) was added K ₂ CO ₃ (25.3 g, 183 mmol) and CuI (4.64 g, 24.4 mmol) at room. pace. The mixture was stirred overnight at 90°C under N ₂ atmosphere. The reaction mixture was quenched with sat. NH ₄ Cl (aq) and extracted with EA (3x800 ml). The organic layers were combined, washed with saline (2x600 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure.

The residue was purified by reverse phase column chromatography using a C18 column (ACN:H ₂ O = 10-60% in 50 min) to give 3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy ]methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]aniline as a yellow solid (2.2 g, 8%).

To a stirred solution of 3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3b]pyrazin-2-yl)oxy]aniline (2.20 g, 5.17 mmol) in CH3CN (30 ml) was added dropwise (dimethoxymethyl)dimethylamine (1.54 g, 12.9 mmol) at room temperature. pace. The mixture was stirred overnight at 80°C, quenched with water (50 ml), then extracted with EA (3x50 ml) and the organic layers were combined, washed with brine (2x40 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (1:1) to obtain ^^^-dichloro^-^-^-CrimethylsilylCtox^methyl^irrolo-RD-^pyrazin^yl)oxy]phenyl]-Ni-X- dimethylmethanimidamide as a brown oil (1.875 g, 72%). To a stirred solution of N-[3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-b]pyrazin-2yl)oxy]phenyl]-NaX- dimethylmethanimidamide (1.83 g, 3.81 mmol) in DCM (20 ml) was added portionwise with NIS (1.11 g, 4.95 mmol) and p-toluenesulfonic acid (0.20 g, 1.16 mmol) at 0 °C. The reaction mixture was stirred for 4 hours at room. pace. and extinguished with water (50 ml). The mixture was extracted with DCM (3x50 ml) and the organic layers were combined, washed with brine (2x40 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (4:1) to obtain ^^^-dichloro^-1-iodine^-^-CrimethylsilylCtox^methyl^irroloRD-^pyrazin^-yl^x^phenyl]X^ dimethylmethanimidamide as a brown oil (1.33 g, 55%).

To a stirred mixture of Na[3,5-dichloro-4-[(7-iodo-5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3^pyrazin^-yl^x^phenylEX^dimethylmethanimidamide (980 mg, 1.62 mmol), PdCl ₂ (dppf) (106 mg,

- 96 047363

0.162 mmol) and K ₂ PO ₃ (515 mg, 2.42 mmol) in dioxane (33 ml) and water (6 ml) was added 4,4,5,5-tetramethyl2-(prop-1-en-2-yl )-1,3,2-dioxaborolane (1.09 g, 6.47 mmol) at room. pace. The mixture was stirred overnight at 55°C under N2, then quenched with water (60 ml). The mixture was extracted with EA (3x60 ml) and the organic layers were combined, washed with brine (3x50 ml), dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (7:1) to give N(3,5-dichloro-4-[[7-(prop-1-en-2-yl)-5-[[2( trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazin-2-yl]oxy]phenyl)-N,N-dimethylmethanimidamide as a yellow solid (688 mg, 81%). To a stirred mixture of 2-(3,5-dichloro-4-[[3-(prop-1-en2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-3 ,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (688 mg, 1.51 mmol) in EA (24.0 ml) was added Pd/C (90.0 mg, 0.846 mmol) at room . pace. in an N2 atmosphere. The mixture was stirred for 1 hour at room. pace. under H ₂ atmosphere, solids were removed by filtration through celite, and the filtrate was concentrated under reduced pressure to give 2-[3,5-dichloro-4-([3isopropyl-1H-pyrrolo[3,2-b]pyridine-5 - yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a yellow oil (670 mg, 93%). The crude product was used in the next step without further purification. To a stirred solution of (E)-N-[3,5-dichloro-4-[(7-isopropyl-5-[[2(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazin-2-yl) oxy]phenyl]-N,N-dimethylmethanimidamide (670 mg, 1.28 mmol) in ethyl alcohol (15 ml) was added ethylenediamine (347 mg, 5.77 mmol) dropwise at room temperature. pace. The mixture was stirred overnight at 80°C, then concentrated under reduced pressure. The mixture was diluted with EA (40 ml), washed with brine (2x30 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 3,5-dichloro-4-[(7-isopropyl- 5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3^pyrazin^-yl^x^aniline as a brown solid (700 mg, crude).

Ethyl-(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2 ,3-b]pyrazin-2-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, red solid (800 mg, crude) was prepared as described for ethyl-(2-cyano-2-(2- (3,5-dichloro4-((1-tosyl-III-indol-5-yl)oxy)phenyl)-hydrazinyl-idene)acetyl) carbamate.

2-[3,5-Dichloro-4-[(7-isopropyl-5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]phenyl]-3 ,5-dioxo-4H-1,2,4-triazine-6-carbonitrile, a brown solid (186 mg, 21%) was prepared as described for 2-(4-[[3-isopropyl-1- (4-methylbenzenesulfonyl)indol5 -yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-carbonitrile.

The tosyl group was removed to give 2-[3,5-dichloro-4-([7-isopropyl-5H-pyrrolo[2,3b]pyrazin-2-yl]oxy)phenyl]-3,5-dioxo-4H-1 ,2,4-triazine-6-carbonitrile as a white solid (25.5 mg, 17%) was prepared as described for 2-[3,5-dichloro-4-(III-indol-5yloxy) phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

^1H NMR (300 MHz, DMSO-a _b ) δ ppm: 12.45 (br, 1H), 12.21 (s, 1H), 8.10 (s, 2H), 7.43 ( s, 1H), 3.58 (s, 3H), 3.11-2.97 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 456 [M-H] ⁺ .

Example 46 Synthesis of compound 52

To a stirred solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (4.00 g, 26.1 mmol) and NEt ₃ (3.96 g, 39.2 mmol) in DCM (50 ml) was added [2-(chloromethoxy)ethyl]trimethylsilane (13.02 g, 78.4 mmol) dropwise at 0°C. The mixture was stirred overnight at room. pace. and quenched with water (100 ml), then extracted with DCM (3x150 ml). The combined organic layers were washed with brine (2x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA (10:1) to give 3-chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazine as a yellow solid. (3.50 g, 47%).

To a stirred solution of 3-chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3c]pyridazine (3.20 g, 11.3 mmol) and (E)-N-(3,5- dichloro-4-hydroxyphenyl)-X^-dimethylformimidamide (2.63 g, 11.3 mmol) in THF (40 ml) was added Pd ₂ (dba) ₃ -chloroform adduct (1.17 g, 1.13 mmol), JosiPhos (625 mg, 1.13 mmol) and Cs ₂ CO ₃ (7.35 g, 22.5 mmol) at room. pace. The mixture was stirred for 48 h at 95°C under N2 and quenched with water (50 ml). The mixture was extracted with EA (3x60 ml). The combined organic layers were washed with brine (2x50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA (1:2) to give (E)-X'-(3,5-dichloro-4-((7-((2-(trimethylsilyl)ethoxy)methyl) -7H-pyrrolo[2,3-c]pyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamide as a yellow solid (2.2 g, crude).

- 97 047363

To the stirred mixture (E)-N-[3,5-dichloro-4-[(7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3c]11iridazin-3-yl)o1<ci]phenyl ]-\,\-dimethylmethanimidamide (1.12 g, 2.33 mmol) in DCM (12 ml) was added NIS (0.68 g, 3.02 mmol) and p-toluenesulfonic acid (0.12 g, 0.699 mmol ) in portions at 0°C. The mixture was stirred for 4 hours at room. pace. and quenched with water (30 ml) at room. pace. The mixture was extracted with DCM (3x40 ml). The combined organic layers were washed with brine (2x30 ml), dried over anhydrous Na ₂ SO _4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (4:1) to give (E)-N-[3,5-dichloro-4-[(5-iodo-7-[[2-(trimethylsilyl)ethoxy ]methyl]pyrrolo[2,3c]pyridazin-3-yl)oxy]phenyl]-N^-dimethylmethanimidamide as a brown solid (600 mg, crude). To the stirred mixture (E)-N-[3,5-dichloro-4-[(5-iodo-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl )oxy]phenyl]-N,N-dimethylmethanimidamide (650 mg,

1.07 mmol), 1,1'-bis-(di-tert-butylphosphino)ferrocene palladium dichlorides (69.9 mg, 0.107 mmol) and K2PO3 (341 mg, 1.61 mmol) in 1,4-dioxane (10 ml) and water (2 ml) was added 4,4,5,5-tetramethyl-2-(prop-1en-2-yl)-1,3,2-dioxaborolane (721 mg, 4.29 mmol) at room. pace. The mixture was stirred for 4 hours at 50°C under N2 and quenched with water (50 ml) at room. temp., then extracted with EA (3x50 ml). The combined organic layers were washed with brine (2x40 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (3:1) to give (E)-N-(3,5-dichloro-4-[[5-(prop-1-en-2-yl)- 7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin3-yl]oxy]phenyl)-N4N-dimethylmethanimidamide as a brown solid (675 mg, crude).

To the stirred mixture of (E)-N-(3,5-dichloro-4-[[5-(prop-1-en-2-yl)-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo [2 ,3-c]pyridazin-3-yl]oxy]phenyl)-HX-dimethylmethanimidamide (800 mg,

1.54 mmol) in EA (10 ml) was added Pd:C (300 mg) at room. pace. in a hydrogen atmosphere. The mixture was stirred for 1 hour at room. temp., then filtered and the filter cake was washed with EA (3x20 ml). The combined organic layers were concentrated under reduced pressure to give (E)-N-[3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c ]pyridazin-3yl)oxy]phenyl]-N^N-dimethylmethanimidamide as a yellow oil (1 g, crude).

To a stirred solution of (E)-N-[3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl )oxy]phenyl]-HX-dimethylmethanimidamide (1.00 g, 1.92 mmol) in EtOH (9 ml) was added NaOH (9 ml, 9.00 µmol, 1 M) dropwise at room temperature. pace. The mixture was stirred for 3 hours at 80°C, then diluted with water (30 ml) and extracted with EA (3x40 ml). The combined organic layers were washed with brine (2x30 ml), filtered and concentrated under reduced pressure to give 3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2. 3-c]pyridazin-3-yl)oxy]aniline as a brown oil (900 mg, crude). Ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2.3 c] pyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, red solid (920 mg) was prepared similarly to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro- 4-((1-tosyl-1H-indol-5yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate, except that the reaction mixture was stirred for 10 minutes at 0°C. The crude product was used in the next step without further purification.

2-[3,5-Dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3yl)oxy]phenyl]-3,5 -Dioxo-4H-1,2,4-triazine-6-carbonitrile as a brown solid (690 mg, 69%) was prepared as described for 2-(4-[[3-isopropyl-1-( 4methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazin-6carbonitrile.

The tosyl group was removed to give 2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1 ,2,4-triazine-6-carbonitrile as a yellow solid (24.8 mg, 31%), which was prepared in a manner similar to that described for 2-[3,5-dichloro-4-(1Nindol-5- yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

1H NMR (400 MHz, DMSO-dg) δ ppm: 13.28 (s, 1H), 12.03-12.05 (m, 1H), 7.83 (s, 1H), 7.79 ( s, 2H), 7.737.75 (m, 1H), 3.12-3.19 (m, 1H), 1.32 (d, J=6.8 Hz, 6H).

LCMS (ESI, m/z): 458[M+H]+.

Example 47 Synthesis of compound 53

⁵³ nh ₂

The conversion of compound 52 to 53 is similar to the method for the preparation of 6-amino-2-[3,5-dichloro-4-[(5isopropyl-6-oxo-1 H-pyridazin-3 -yl)oxy]phenyl]-4H-1,2 ,4-triazine-3,5-dione gave 2-[3,5-dichloro-4

- 98 047363 ([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carboxylic acid in the form yellow solid (190 mg). The crude product was used in the next step without further purification. To a stirred solution of 2-[3,5-dichloro-4-([5isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2 ,4-triazine-6-carboxylic acid (150 mg, 0.314 mmol) and DPPA (260 mg, 0.943 mmol) in tBuOH (3 ml) was added dropwise NEt ₃ (127 mg, 1.26 mmol) at room temperature. pace. The resulting mixture was stirred overnight at 85°C, then quenched with water (30 ml) at room. pace. and extracted with EA (3x30 ml). The combined organic layers were washed with brine (2x20 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA (3:1) to give tert-butyl-N[2-[3,5-dichloro-4-([5isopropyl-7H-pyrrolo[2,3-c] pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate as a yellow solid (130 mg, crude).

To a stirred solution of tert-butyl-N-[2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3c]pyridazin-3-yl]oxy)phenyl]-3,5- Dioxo-4H-1,2,4-triazin-6-yl]carbamate (120 mg) in DCM (1 ml) was added dropwise with TFA (2 ml) at room temperature. pace. The resulting mixture was stirred for 2 hours at room. pace. and concentrated under reduced pressure. The reaction mixture was quenched with sat. aq. Na ₂ CO ₃ (20 ml) at room. pace. The resulting mixture was extracted with DCM (3x30 ml). The combined organic layers were washed with brine (2x20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-amino-2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-4H1 ,2,4-triazine-3,5-dione as a white solid (44.8 mg).

^1H NMR (300 MHz, DMSO-dg) δ ppm: 11.41-12.07 (br, 2H), 7.85-7.92 (m, 2H), 7.68-7, 79 (m, 2H), 6.41 (s, 2H), 3.10-3.20 (m, 1H), 1.36-1.21 (m, 6H).

LCMS (ESI, m/z): 448 [M+n] ⁺ .

Example 48 Synthesis of Compound 54

To a mixture of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (50 mg, 86.1 µmol ), 2H-1,2,4-triazine-3,5-dione (29.2 mg, 258 µmol), di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4 ,6-triisopropylphenyl)phenyl]phosphane (8.28 mg, 17.2 µmol) and K2CO3 (35.7 mg, 258 µmol) in tert-BuOH (3 ml) was added Pd ₂ (dba) ₃ (7.89 mg , 8.61 µmol) under protection in an N ₂ atmosphere. The mixture was stirred at 110°C for 90 minutes under irradiation in a microwave reactor. The reaction mixture was diluted with H2O (5 ml) and extracted with EA (3x5 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated to give a residue, which was purified by chromatography on silica gel (0-50% EA in PE) to give 2-[4 -[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione in as a yellow solid (60 mg, 98%, 37% purity). Deprotection of the tosyl group was performed similarly to that described for 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin- 6-carbonitrile to give 2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethylphenyl]-1,2,4-triazin- 3.5dione as a white solid (5.88 mg, 15%).

^1H NMR (400 MHz, DMSO-dg) δ ppm: 10.81 (br s, 1H), 8.23 (br s, 1H), 7.59 (s, 1H), 7. 56 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.16 (s, 2H), 6.69 (d, J=8.4 Hz, 1H), 4, 23 (s, 2H), 3.20 (td, J=6.8, 13.6 Hz, 1H), 2.38 (s, 6H), 1.33 (d, J=6.9 Hz, 6H ).

LCMS (ESI, m/z): 390.3 [M+H]+.

Example 49 Synthesis of compound 55

5-[(4-Benzyloxy-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2b]pyridine, p-tolylsulfonyl)pyrrolo[3,2-b]pyridine, a yellow solid (1.36 g, 73%) was prepared in a manner similar to that described for 5-[(4-benzyloxy-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(ptolylsulfonyl)pyrrolo[3, 2-b]pyridine.

4-[[3-Isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol, white solid (1 g, 88%) was prepared in a similar manner as described for 4-[[3-isopropyl-1-(ptolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenol.

- 99 047363

Mixture of [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (600 mg, 1.03 mmol) , bis-(pinacolato)diboron (525 mg, 2.07 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (84.4 mg, 103 μmol), KOAc (304 mg, 3.10 mmol) in DMSO (10 ml) was degassed and purged with N2. The mixture was stirred at 130°C for 16 hours under N2 atmosphere. The reaction mixture was partitioned between H2O (30 ml) and EA (50 ml). The organic phase was separated, washed with brine (30 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to leave a residue. The residue was purified by silica gel chromatography (0-10% EA in PE) to give 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl]-methyl]-3isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine as a yellow solid (340 mg, 59%).

To a solution of 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3isopropyl-1-(p-tolylsulfonyl )pyrrolo[3,2-b]pyridine (290 mg, 519 µmol) in acetone (12 ml) and H2O (6 ml) added NaIO ₄ (1.11 g, 5.19 mmol, 287.71 µl) and NH ₄ OAc (400 mg, 5.19 mmol) at 25°C. After addition, the mixture was stirred at 25°C for 16 hours. The reaction mixture was extracted with EA (3x10 ml). The organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure, then purified by preparative TLC (SiO ₂ , PE:EA = 1:1) to give [4-[ [3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]boronic acid as a white solid (190 mg, 76%).

A mixture of 6-amino-4-(benzyloxymethyl)-2H-1,2,4-triazine-3,5-dione (252 mg, 1.02 mmol), [4-[[3-isopropyl-1-(p- tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]boronic acid (440 mg, 923 µmol), pyridine (146 mg, 1.85 mmol, 149 µl), 4A molecular sieves (5 g) and Cu(OAc) ₂ (83.9 mg, 462 µmol) in DMF (15 ml) were degassed and purged with O ₂ , then the mixture was stirred at 60°C for 16 hours in an O2 atmosphere (through a balloon ). The reaction mixture was cooled to 25°C and diluted with EA (30 ml), then the solid was removed by filtration. The filtrate was washed with H ₂ O (3x10 ml), brine (20 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-30% EA in PE) to give 6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl1-(p-tolylsulfonyl)-pyrrolo[3,2-b ]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione as a yellow resin (140 mg, 20%).

A solution of 6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolyl-sulfonyl)pyrrolo[3,2b]pyridin-5-yl]methyl]-3,5- dimethylphenyl]-1,2,4-triazine-3,5-dione (140 mg, 206 µmol) in TFA (5 ml) was stirred at 80°C for 16 hours. The reaction mixture was diluted with EA (10 ml) and pH brought to 7 NaHCO ₃ (sat. aq.). The organic layer was separated and aq. the layer was extracted with EA (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO ₂ , PE:EA = 1:2) to give 6-amino-2-[4-[[3-isopropyl1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-1,2,4 -triazine-3,5-dione as a white solid (45 mg, 39%).

The tosyl group was removed to obtain 6-amino-2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin5-yl)methyl]-3,5-dimethylphenyl]-1,2,4- triazin-3,5-dione, a white solid (11.3 mg, 35%), which was prepared in a manner similar to that described for 2-[3,5-dichloro-4-(1H-indol-5-yloxy) phenyl]-3,5dioxo-4H-1,2,4-triazine-6-carbonitrile.

1H NMR (400 MHz, DMSO-06) δ ppm: 12.07 (br s, 1H), 10.80 (br s, 1H), 7.55 (d, J=8.4 Hz , 1H), 7.29 (s, 1H), 7.19 (s, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.29 (s, 2H), 4.21 (s, 2H), 3.25-3.19 (m, 1H), 2.34 (s, 6H), 1.34 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 405.6 [M+H]+.

Example 50 Synthesis of Compound 56

2-(2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-7-isopropyl-5-tosyl-5Hpyrrolo[2,3 -b]pyrazine, yellow solid (520 mg, 73%), was prepared similarly to that described for 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine, except that the reaction mixture was heated for 12 hours.

(4-((7-Isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-3,5-dimethylphenyl)boronic acid, yellow solid (670 mg, crude) was prepared in a similar manner as described for [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]boronic acid.

- 100 047363

4-((Benzyloxy)methyl)-2-(4-((7-isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-3,5dimethylphenyl)-1, 2,4-triazine-3,5(2H,4H)-dione, light yellow solid (110 mg, 11%), was prepared similarly to that described for 6-amino-4-(benzyloxymethyl)-2- [4-[[3-isopropyl-1-(ptolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5- diona.

The tosyl group was removed to obtain 2-(4-((7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3, 5(2H,4H)-dione, a white solid (20 mg, 80%), which was prepared in a manner similar to that described for 2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl ]3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

^X H NMR (400 MHz, DMSO-sc) δ ppm: 12.48 (br s, 1H), 11.54 (br s, 1H), 7.93 (s, 1H), 7. 58 (s, 1H), 7.51 (s, 1H), 7.16 (s, 2H), 4.26 (s, 2H), 3.09-3.17 (m, 1H), 2.40 (s, 6H), 1.31 (d, J=6.8 Hz, 6H).

LCMS (ESI, m/z): 391.6 [M+H] ⁺ .

Example 51 Synthesis of Compound 57

2,2,2-Trifluoro-M-(4-(hydroxy(3-isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide, white solid (294 mg, 36%), was prepared similarly to that described for 2,2,2-trifluoroX-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide, except that tert-butyllithium (2.2 eq.) was used. 2,2,2-Trifluoro-M-(4-((3-isopropyl-1H-indazol-5-yl)methyl)3,5-dimethylphenyl)acetamide (209 mg, 81%), white solid, prepared similarly as described for 2,2,2-trifluoro-M-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5dimethylphenyl)acetamide.

Deprotection of trifluoroacetamide to obtain 4-((3-isopropyl-1H-indazol-5-yl)methyl)-3,5dimethylaniline (141 mg, 96%) was carried out in a manner similar to that described for 3,5-dimethyl-4- ((3pentyl-1H-indazol-5-yl)methyl)aniline. 2-(4-((3-Isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4 -triazine-6-carbonitrile, orange solid (10 mg, 8%), was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)in dol-5-yl ]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

'H NMR (DMSO-c1 _b 400 MHz): 1.31 (d, J=6.8 Hz, 6H); 2.28 (s, 6H); 3.22-3.27 (m, 1H); 4.15 (s, 2H), 6.96 (d, J=8.3 Hz, 1H); 7.18 (s, 2H); 7.35 (d, J=8.3 Hz, 1H); 7.38 (s, 1H); 12.47 (s, 1H); 12.99 (s, 1H).

Example 52 Synthesis of Compound 58

6-Amino-2-[3,5-dichloro-4-[(5-cyclohexyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4triazine-3,5- The dione was prepared in a manner similar to that described for 6-amino-2-(3,5-dichloro-4-((5cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2 ,4-triazine-3,5(2H,4H)-dione to give a white solid (101.1 mg, 40%).

^XH NMR (400 MHz, DMSO- _s16 ) 12.18 (br, 2H), 7.83 (s, 2H), 7.35-7.36 (m, 1H), 6.47 (s, 2H), 2.68-2.72 (m, 1H), 1.21-1.84 (m, JN).

LCMS (ESI, m/z): 465 [M+H] ⁺ .

Example 53 Synthesis of Compound 59

3,6-Dichloro-4-(tetrahydro-2H-ruran-4-yl)pyridazine was prepared in a manner similar to that described for 3,6-dichloro-4-isopropylpyridazine (see also Samaritoni, J.G. Homolytic alkylation of 3,6 -dichloropyridazine. Prep. Int. 1988, 20, 117-121) as a white solid (5.3 g, 68%).

Ethyl (2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazinylidene)acetyl)carbamate, brown solid (42 g, crude) was prepared in a manner similar to that described for ethyl-(2 -cyano2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazinyl-idene)acetyl)carbamate, except that the reaction mixture was stirred for 10 minutes at 0°C.

To the stirred mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazinylidene)

- 101 047363 acetyl)carbamate (41.0 g, 119 mmol) in DMA (400 ml) was added KOAc (46.6 g, 475 mmol) in portions at room temperature. pace. The resulting mixture was stirred for 2 hours at 110°C and quenched with water (400 ml). The resulting mixture was extracted with EA (3x600 ml) and the organic layers were combined, washed with brine (3x400 ml), dried over anhydrous Na ₂ SO ₄ the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM:MeOH (19:1) to give 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triαzine-6carbonitrile in as a yellow solid (24.3 g, 62%).

To a stirred solution of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triαzine-6carbonitrile (20 g, 66.9 mmol) in AcOH (200 ml) was added HCl (100 ml) at room. pace. The resulting mixture was stirred for 5 hours at 110°C and concentrated under reduced pressure. The residue was adjusted to pH 9 with NaOH (1 M). The resulting mixture was extracted with EA (2x80 ml). The mixture was adjusted to pH 5 with HCl (1 M), then extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (2x60 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 2-( 3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6carboxylic acid as a yellow solid (19 g, crude). To a stirred solution of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (13.8 g, 43.4 mmol) in tBuOH (150 ml) DPPA (29.9 g, 108 mmol) and NEt ₃ (17.7 g, 174 mmol) were added at room. pace. The mixture was stirred overnight at 85°C and concentrated under reduced pressure, diluted with water (100 ml) and extracted with EA (3x120 ml). The combined organic layers were washed with brine (2 x 80 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM:MeOH (40:1) to give tert-butyl-N-(2-[3,5-dichloro-4-[(diphenoxyphosphoryl)oxy]phenyl]-3,5- dioxo-4H-1,2,4triazin-6-yl)carbamate as a yellow solid (16.0 g, 53%).

To a stirred mixture of tert-butyl-N(2-[3,5-dichloro-4-[(diphenoxyphosphoryl)oxy]phenyl]-3,5dioxo-4H-1,2,4-triazin-6-yl)carbamate (11 .0 g, 17.7 mmol) to tert-BuOH (200 ml) was added NaOH (25 ml, 2 M) dropwise at room temperature. pace. The resulting mixture was stirred for 4 hours at room. pace. and concentrated under reduced pressure. The mixture was diluted with water (50 ml), acidified to pH 6 with HCl (1 M) and extracted with EA (3x100 ml). The organic layers were combined, washed with brine (2x70 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (1:1) to give tert-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2 ,4triazin-6-yl]carbamate as a yellow solid (6.0 g, 78%).

To a stirred mixture of 3,6-dichloro-4-(oxan-4-yl)pyridazine (300 mg, 1.29 mmol) and tert-butylN-[2-(3,5-dichloro-4-hydroxyphenyl)-3, 5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (501 mg, 1.29 mmol) in DMSO (10 ml) was added K ₂ CO ₃ (534 mg, 3.86 mmol) and CuI (123 mg, 0.644 mmol) at room. pace. The mixture was stirred for 16 hours at 110°C in an atmosphere of N ₂ and quenched with water (30 ml) at room. pace. The mixture was extracted with EA (3x40 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous. Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography DCM:MeOH (3:1) to give 6-amino-2-(3,5-dichloro-4-[[6chloro-5-(oxan-4-yl)pyridazin-3-yl ]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione as a brown solid (280 mg, 36%).

To a stirred mixture of 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxan-4-yl)-pyridazin-3yl]oxy]phenyl)-4H-1,2,4 -triazine-3,5-dione (250 mg, 0.515 mmol) in AcOH (4 ml) was added NaOAc (169 mg, 2.06 mmol) at room. pace. The mixture was stirred overnight at 100°C, then quenched with water (30 ml). The mixture was extracted with EA (3x30 ml), the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous. Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM:MeOH (20:1) to give the crude product, which was purified by preparative HPLC to give 6-amino-2-(3,5-dichloro-4-[[5-(oxane-4 -yl)-6-oxo-1 H-pyridazin-3 -yl]oxy]phenyl)-4N-1,2,4triazine-3,5-dione as a white solid (23.3 mg, 10%).

1H NMR (300 MHz, DMSO^ ₆ ) 12.26-12.28 (m, 2H), 7.86 (s, 2H), 7.44-7.46 (m, 1H), 6.54 (s , 2H), 3.933.99 (m, 2H), 3.41-3.49 (m, 2H), 2.95-3.05 (m, 1H), 1.58-1.78 (m, 4H ).

LCMS (ESI, m/z): 467 [M+H]+.

Example 54. Synthesis of compounds 60 and 60-A:

To a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (10.0 g, 48.4 mmol) in THF (100 ml) was added

- 102 047363

NaOCH ₃ (9.57 g, 53.1 mmol, 30% in MeOH) dropwise at 0°C. The mixture was stirred for 0.5 h at 0°C, then quenched with NH ₄ Cl (sat. aq., 150 ml). The mixture was extracted with EA (3x150 ml), the organic layers were combined, washed with brine (2x150 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The sample was purified by column chromatography (EA:PE = 0-30% for 30 min) to obtain methyl 6-chloro-3-methoxypyridazine-4-carboxylate as a yellow solid (7.3 g, 60%). A mixture of methyl 6-chloro-3methoxypyridazine-4-carboxylate (9.00 g, 44.4 mmol) in THF (100 ml) was added dropwise with CH ₃ MgBr (59.2 ml, 178 mmol, 3 M in Et ₂ O ) at -50°C. The mixture was stirred for 2 hours at -50 to 0°C, then quenched with sat. aq. NH ₄ Cl (150 ml) and extracted with EA (3x150 ml). The organic layers were combined, washed with saline (2x150 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (EA:PE = 0-30% for 20 min) to give 2-(6-chloro-3 -methoxypyridazin-4-yl)propan-2-ol as a white metallic solid (2.35 g, 25%).

To a mixture of 2-(6-chloro-3-methoxypyridazin-4-yl)propan-2-ol (2.90 g, 14.3 mmol), (E)-N'-(3,5-dichloro-4hydroxyphenyl) -^Ndimethylmethanimidamide (3.67 g, 15.7 mmol), Cs ₂ CO ₃ (9.33 g, 28.6 mmol) and JosiPhos (0.85 g, 1.43 mmol) in THF (30 ml) Pd ₂ (dba) ₃ -CHCl ₃ (1.48 g, 1.43 mmol) was added. The mixture was stirred for 48 hours at 95°C under N2, then quenched with water (50 ml). The mixture was extracted with EA (3x80 ml) and the organic layers were combined, washed with brine (2x50 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The sample was purified by column chromatography and eluted with EA:PE to give (E)-H'-(3,5-dichloro-4-[[5-(2hydroxypropan-2-yl)-6-methoxypyridazin-3-yl]oxy]phenyl )-H,Ni-dimethylmethanimidamide as a yellow solid (690 mg, 11%).

To a mixture of (E)-H'-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-methoxypyridazin-3-yl]oxy]phenyl)NN-dimethylmethanimidamide (690 mg , 1.73 mmol) and KI (861 mg, 5.18 mmol) in DCM (10 ml) was added TMSCl (563 mg, 5.18 mmol) at 0°C. The mixture was stirred overnight at room. pace. and extinguished with water (20 ml). The mixture was extracted with DCM (3x30 ml) and the organic layers were combined, washed with brine (2x20 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give (E)-N'-(3, 5-dichloro-4-[[5-(2-hydroxypropan-2yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-H,Ndimethylmethanimidamide as a yellow solid (670 mg, crude) .

Mixture of (E)-N'-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)CH-dimethylmethanimidamide (670 mg, 1.74 mmol) in ethanol (10 ml) and NaOH (10 ml, 1 M). The mixture was stirred overnight at 70°C, then concentrated under reduced pressure, diluted with water (50 ml) and extracted with EA (3x50 ml).

The organic layers were combined, washed with saline (2x30 ml), dried over anhydrous. Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 6-(4-amino-2,6-dichlorophenoxy)-4-(2-hydroxypropan-2-yl)-2H-pyridazin-3-one as yellow solids (560 mg, 83%).

Ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazin-3yl)oxy)phenyl )hydrazinylidene)acetyl)carbamate, yellow solid (500 mg, 55%), was prepared similarly to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1 -tosyl-1H-indol-5yl)oxy)phenyl)-hydrazinylidene)acetyl)carbamate.

2-(3,5-Dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo4H-1, 2,4-triazine-6-carbonitrile as a yellow solid (380 mg, 80%) was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5 -yl]oxy]-3,5dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Further steps in the synthesis of compound 60 yielded 6-amino-2-(3,5-dichloro-4-[[5-(2hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl) -4H-1,2,4-triazine-3,5-dione as a white solid (63.9 mg, 35%).

1H NMR (300 MHz, DMSO- _d6 ) δ ppm: 12.2-12.4 (m, 2H), 7.87 (s, 2H), 7.53 (s, 1H), 6, 53 (s, 2H), 5.50 (s, 1H), 1.51 (s, 6H).

LCMS (ESI, m/z): 441 [M+H]+.

Compound 60-A, 6-Amino-2-(3,5-dichloro-4-[[6-oxo-5-(prop-1-en-2-yl)-1H-pyridazin-3yl]oxy]phenyl) -4H-1,2,4-triazine-3,5-dione was obtained as a white solid (13.8 mg, 8%).

1H NMR (300 MHz, DMSOO δ ppm: 12.0-12.5 (m, 2H), 7.87 (s, 2H), 7.54 (s, 1H), 6.49 (s, 3H), 5.57 (s, 1H), 2.12 (s, 3H).

LCMS (ESI, m/z): 423 [M+H]+.

- 103 047363

Example 55 Synthesis of compound 61

To a solution of diisopropylamine (5.18 g, 51.2 mmol) in THF (60 ml) was added n-buLi (19.5 ml, 2.5 M in hexane, 48.7 mmol) dropwise at -78°C in atmosphere N2. The solution was stirred at -78 to about -50° C. for 0.5 hours. Methyl 2-(3,3-difluorocyclobutyl) acetate (prepared according to the procedures detailed in WO 2015/005901 and WO 2015/ 0023913), (4 g, 24.4 mmol) in THF (10 ml) was added dropwise at -78°C. The solution was stirred at -78°C for 0.5 h CH ₃ I (4.50 g, 31.7 mmol) was added at -78°C. The reaction mixture was slowly warmed to room. pace. for 3 h, then quenched with water (30 ml) and extracted with EA (3x50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give methyl 2-(3,3-difluorocyclobutyl)propanoate as a yellow oil (3.9 g, crude).

To a solution of methyl 2-(3,3-difluorocyclobutyl)propanoate (3.8 g, 21.3 mmol) in THF (40 ml) and MeOH (10 ml) was added a solution of NaOH (10N, 20 ml). The solution was stirred overnight at room. pace. The pH was adjusted to 5 with HCl (1N). The mixture was extracted with EA (3x50 ml). The organic phases were combined, washed with brine, dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 2-(3,3-difluorocyclobutyl)propanoic acid as a yellow oil (1.5 g, crude).

3,6-Dichloro-4-[1-(3,3-difluorocyclobutyl)ethyl]pyridazine was prepared in a manner similar to that described for 3,6-dichloro-4-isopropylpyridazine (see also Samaritoni, J.G. Homolytic alkylation of 3, 6-dichloropyridazine. Org. Proced. 1988, 20, 117-121) to obtain a yellow oil (390 mg, 21%).

6-Amino-2-[3,5-dichloro-4-([6-chloro-5-[1-(3,3-difluorocyclobutyl)-ethyl]pyridazin-3-yl]oxy)-phenyl]4H-1 ,2,4-triazine-3,5-dione, yellow oil (280 mg, 33%) was prepared as described for 6-amino-2-(3,5-dichloro-4-[[6-chloro -5-(oxan-4-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazin-3,5dione.

To a solution of 6-amino-2-[3,5-dichloro-4-([6-chloro-5-[1-(3,3-difluorocyclobutyl)ethyl]pyridazin-3yl]oxy)phenyl]-4H- 1,2,4-triazine-3,5-dione (280 mg, 0.539 mmol) in AcOH (8 ml) was added NaOAc (221 mg, 2.69 mmol). The mixture was stirred overnight at 100°C. The reaction mixture was cooled to room. pace. and extinguished with water (50 ml).

The reaction mixture was stirred for 10 min, the solid was filtered and washed with water (2x10 ml) and PE (2x5 ml), then dried under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-amino-2-[3, 5-dichloro-4-([5-[1-(3,3difluorocyclobutyl)ethyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3, 5-dione as a white solid (34.2 mg, 13%).

LCMS (ESI, m/z): 523 [M+Na]+.

Enantiomers were separated by preparative prechiral HPLC using the following gradient conditions: Column: CHIRALPAK IA, 3x25 cm, 5 µm; mobile phase A:Hex:DCM=3:1 (10 mM KH ₃ -CH ₃ OH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 40 ml/min; gradient: from 10 V to 10 V in 50 minutes; 220/254 nm; injected volume: 1 ml; number of runs: 14. Purification gave (RT 1: 35.6 min) (compound 61-A (RT 1=35.6 min, 43.9 mg) as a white solid with a metallic tint, and compound 61-B (RT 2=42.1 min, 41.8 mg).

61-A: ^1H NMR (300 MHz, DMSO-dg) δ ppm: 12.28 (br, 2H), 7.86 (s, 2H), 7.52 (s, 1H), 6 .54 (broad, 2H), 2.99-3.04 (m, 1H), 2.73 (broad, 1H), 2.51-2.60 (m, 1H), 2.44-2 .50 (m, 2H), 2.12-2.24 (m, 1H), 1.15 (d, J=6.9 Hz, 3H). LCMS (ESI, m/z): 501 [M+H]+. [α] ^22.1 D=+18° (MeOH, C=1 mg/ml).

(RT 2: 42.1 min (compound 61-B), 41.8 mg). ^1H NMR (300 MHz, DMSO-06) δ ppm: 12.27 (br, 2H), 7.85 (s, 2H), 7.52 (s, 1H), 6.53 (br ., 2H), 2.98-3.03 (m, 1H), 2.69-2.74 (m, 1H), 2.52-2.54 (m, 1H), 2.44-2, 50 (m, 2H), 2.12-2.24 (m, 1H), 1.15 (d, J=6.9 Hz, 3H). LCMS (ESI, m/z): 501 [M+H]+. [α] ^22.1 D=-14° (MeOH, C=1 mg/ml).

Example 56 Synthesis of compound 62

Silver nitrate was added to a solution of 3,6-dichloropyridazine (5.00 g, 33.6 mmol) in water (100 ml).

- 104 047363 (2.85 g, 16.8 mmol) and oxolane-3-carboxylic acid (3.90 g, 33.6 mmol) in portions at room. temp., and then stirred at 50°C. To this mixture was added sulfuric acid (9.88 g, 101 mmol) in portions at 50°C and stirred at 60°C. Ammonium persulfate (23 g, 101 mmol) in water (50 ml) was then added and stirred for 1 hour at 70°C. The mixture was neutralized to pH 9 with NaOH solution (2N). The mixture was extracted with EA (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (10:1) to give 3,6-dichloro-4-(oxolan-3yl)pyridazine as a light yellow oil (2.8 g, 36%).

To a solution of 3,6-dichloro-4-(oxolan-3-yl)pyridazine (330 mg, 1.51 mmol) and tert-butyl-N-[2-(3,5dichloro-4-hydroxyphenyl)-3,5 -dioxo-4H-1,2,4-triazin-6-yl]-carbamate (586 mg, 1.51 mmol) in DMSO (10 ml) was added K ₂ CO ₃ (625 mg, 4.52 mmol) and CuI (28.7 mg, 0.15 mmol). The reaction mixture was stirred at 110°C for 16 hours under N ₂ atmosphere, then quenched with water (50 ml). The mixture was extracted with EA (3x50 ml), washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with MeOH:DCM (1:20) to give tert-butyl-N-[2-(3,5-dichloro-4-[[6-chloro-5-(oxolan-3-yl) pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate as a brown solid (600 mg, 49%). To a solution of 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxolan-3-yl)-pyridazin-3-yl]oxy]phenyl)-4H1,2,4- triazine-3,5-dione (420 mg, 0.89 mmol) in AcOH (10 ml) was added NaOAc (292 mg, 3.56 mmol). The reaction solution was stirred overnight at 100°C. The reaction solution was poured into water (100 ml) and filtered. The precipitate was purified by preparative HPLC to obtain 6-amino-2-(3,5-dichloro-4[[6-hydroxy-5-(oxolan-3-yl)pyridazin-3-yl]oxy]phenyl)-4H-1, 2,4-triazine-3,5-dione as a white solid (72.8 mg, 18%).

¹ H NMR (300 MHz, DMSO-06) δ ppm: 12.28-12.30 (m, 2H), 7.86 (s, 2H), 7.50 (s, 1H), 6, 54 (s, 2H), 3.804.01 (m, 2H), 3.75-3.78 (m, 1H), 3.63-3.68 (m, 1H), 3.42-3.54 ( m, 1H), 2.18-2.29 (m, 1H), 1.98-2.10 (m, 1H).

LCMS (ESI, m/z): 453 [m+H] ⁺ .

Example 57. Synthesis of compound 63 ,N (T N Cl Η

ST Ν Η

To a solution of 3,6-dichloropyridazine (5.00 g, 33.6 mmol) and phenylboronic acid (8.18 g, 67.1 mmol) in water (180 ml) and 1,2-dichloroethane (180 ml) Selectfluor™ (23.8 g, 67.1 mmol) and TFA (3.83 g, 33.6 mmol) were added. The reaction mixture was stirred at room. pace. for 2 min and add AgNO ₃ (1.14 g, 6.71 mmol) in water (20 ml). The reaction mixture was then stirred at 50°C for 16 hours. The solution was extracted with DCM (2x200 ml). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (25:1) to give 3,6-dichloro-4phenylpyridazine as a yellow solid (950 mg, 12%).

To a solution of 3,6-dichloro-4-phenylpyridazine (338 mg, 1.50 mmol) and tert-butyl-N[2-(3,5-dichloro-4hydroxyphenyl)-3,5-dioxo-4H-1,2 ,4-triazin-6-yl]carbamate (585 mg, 1.50 mmol) in DMSO (15 ml) was added K2CO3 (623 mg, 4.50 mmol) and CuI (143 mg, 0.75 mmol). The reaction mixture was stirred at 110°C for 16 hours under N ₂ atmosphere, then quenched with water (100 ml). The mixture was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a silica gel column with PE:EA (2:3) to give tert-butyl-N-(2-[3,5-dichloro-4-[(6-chloro-5-phenylpyridazin-3yl)oxy]phenyl ]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate as a brown solid (350 mg, 32%).

To a solution of 6-amino-2-[3,5-dichloro-4-[(6-chloro-5-phenylpyridazin-3-yl)oxy]phenyl]-4H-1,2,4triazin-3,5-dione ( 350 mg, 0.733 mmol) and NaOAc (240 mg, 2.93 mmol) was added to AcOH (10 ml). The reaction solution was stirred overnight at 100°C and cooled to room. pace. The reaction solution was poured into water (100 ml) and filtered. The residue was purified by preparative HPLC to give 6-amino-2-[3,5-dichloro-4-[(6-hydroxy-5-phenylpyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazin- 3,5-Dione as a white solid (30.4 mg, 9%).

1H NMR (300 MHz, DMSO) δ ppm: 12.48 (s, 1H), 12.29 (s, 1H), 7.95-7.98 (m, 2H), 7.88 (s , 3H), 7.497.52 (m, 3H), 6.55 (s, 2H).

LCMS (ESI, m/z): 459 [M+H] ⁺ .

- 105 047363

63-Α Η

The regioisomeric product 6-amino-2-(3,5-dichloro-4-((6-oxo-4-phenyl-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine was isolated -3,5(2H,4H)-dione (63-A).

Ή NMR (300 MHz, DMSO-de) δ ppm: 12.40 (s, 1H), 12.28 (s, 1H), 7.87 (s, 1H), 7.79-7.82 (m, 2H), 7.557.59 (m, 3H), 7.13 (s, 1H), 6.53 (s, 2H).

Example 58 Synthesis of Compound 64

INI 12

A 250 ml round bottom flask was charged with Na ₂ CO ₃ (6.00 g, 56.6 mmol), dioxane (45.0 ml), water (15 ml) under N2 atmosphere. The mixture was stirred for 10 minutes at room. pace. Add 4-bromo-6chloropyridazin-3-amine (5.90 g, 28.3 mmol), 2-fluoro-3-methylphenylboronic acid (4.79 g, 31.1 mmol), PdCl ₂ (dppf)-DCM complex (2.31 g, 2.83 mmol). The reaction solution was stirred overnight at 110°C under N2 atmosphere. Solids were removed by filtration. The organic layers were separated with 400 ml EA:saline (1:1). The organic layer was dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with EA:PE (40:60) to give 6-chloro-4-(2-fluoro-3-methylphenyl)pyridazin-3amine as a brown solid (3 g, 37%).

A 100 mL round bottom flask was charged with tert-butyl nitrite (3.38 g, 32.8 mmol), copper(II) chloride (1.77 g, 13.1 mmol) in ACN (30.0 mL). 6-Chloro-4-(2-fluoro-3-methylphenyl)pyridazin-3-amine (2.60 g, 10.9 mmol) was added dropwise at 0°C. The reaction solution was stirred overnight at 60°C and quenched with water (20 ml). The mixture was extracted with EA (3x50 ml), washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel with EA:PE (15:85) to give 3,6-dichloro-4-(2-fluoro-3-methylphenyl)pyridazine as a white metallic solid (1.1 g, 37%) .

A 40 ml vessel was loaded with 3,6-dichloro-4-(2-fluoro-3-methylphenyl)-pyridazine (1.10 g, 4.28 mmol), 4-amino-2,6-dichlorophenyloxidanyl (0.98 g , 5.56 mmol), K ₂ CO ₃ (1.77 g, 12.8 mmol), CuI (0.33 g, 1.71 mmol), DMSO (10 ml) under N2 atmosphere. The reaction solution was stirred for 16 hours at 90°C and quenched with water (20 ml). The mixture was extracted with EA (3x50 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel with EA:PE (1:5) to give 3,5-dichloro-4-[[6-chloro-5-(2-fluoro-3-methylphenyl)pyridazin-3-yl]oxy]aniline in as a brown solid (1.4 g, 78%).

A 40 ml vessel was loaded with 3,5-dichloro-4-[[6-chloro-5-(2-fluoro-3-methylphenyl)pyridazin-3yl]oxy]aniline (1.40 g, 3.51 mmol), NaOAc (1.73 g, 21.1 mmol), AcOH (14 ml) under N2. The reaction solution was stirred overnight at 100°C. The reaction solution was quenched with water (20 ml), extracted with EA (3x50 ml) and the organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. NaOH (1.40 g, 35.1 mmol)), MeOH (7 ml) and water (7 ml) were added. The reaction solution was stirred overnight at 120°C. The reaction mixture was extracted with EA (3x50 ml) and the organic layers were combined, washed with brine (50 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with EA:PE (3:7) to give 6-(4-amino-2,6-dichlorophenoxy)-4-(2-fluoro-3-methylphenyl)-2Hpyridazin-3-one as brown semi-solid (950 mg, 57%).

Ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((5-(2-fluoro-3-methylphenyl)-6-oxo-1,6-dihydropyridazin-3yl)oxy)phenyl )hydrazinylidene)acetyl)carbamate, a brown solid (800 mg, 55%) was prepared similarly to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1- tosyl-III-indol-5yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate. 2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1, 2,4-triazine-6-carbonitrile, brown solid (400 mg, 64%) was prepared as described for 2-(4-[[3-isopropyl-1-(4methylbenzenesulfonyl)indol-5-yl] oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6carbonitrile.

A 100 ml round bottom flask was loaded with 2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-Spiridazin-3-yl]oxy]phenyl)-3,5- dioxo-4H-1,2,4-triazine-6-carbonitrile (250 mg, 0.499 mmol), HCl

- 106 047363 (2 ml), AcOH (10 ml). The reaction solution was stirred for 2 hours at 120°C and concentrated under reduced pressure. The residue was diluted with sat. NaHCO ₃ solution (20 ml), the mixture was extracted with EA (3x30 ml) and the organic layers were discarded. pH aq. layer was adjusted to 5~6 using conc. HCl. The solution was extracted with CHC1 ₃ :isopropanol = 3:1) (3x40 ml), the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 2-(3,5-dichloro-4 -[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid as a white solid with a metallic tint (110 mg, 41%). A 25 ml round bottom flask was loaded with 2-(3,5-dichloro-4-[[5-(2fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5- dioxo-4H-1,2,4-triazine-6-carboxylic acid (110 mg, 0.211 mmol), diphenylphosphoryl azide (174 mg, 0.634 mmol), NEt ₃ (85.6 mg, 0.846 mmol), tBuOH (5 ml) in an N2 atmosphere. The reaction solution was stirred overnight at 85°C and quenched with water (10 ml). The mixture was extracted with EA (3x30 ml), washed with brine (20 ml), dried over anhydrous Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC EA:PE (4:1) to obtain tert-butyl-N-[2-(3,5dichloro-4-[ [ 5 -(2-fluoro-3-methylphenyl)-6-oxo-1H -pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4triazin-6-yl]carbamate as a white metallic solid (80 mg, 46%).

A 50-ml round-bottom flask was loaded with tert-butyl-U-[2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6oxo-1H-pyridazin-3-yl]oxy ]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (130 mg, 0.220 mmol), DCM (5 ml), TFA (1 ml). The reaction solution was stirred overnight at room. pace. and concentrated under reduced pressure. The pH of the residue was adjusted to 8 with NaHCO3 (sat. aq.). The solution was extracted with EA (3x30 ml) and the organic layers were combined, washed with brine (30 ml), dried over anhydrous Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-amino-2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy] phenyl)-4H-1,2,4triazine-3,5-dione as a white solid (10.3 mg, 9%).

^1H NMR (300 MHz, DMSO-dg) δ ppm: 12.52 (s, 0.3H), 12.29 (s, 0.3H), 7.90 (s, 2H), 7 .78 (s, 1H), 7.427.44 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 6.48-6.55 (m, 2H), 2.31 ( s, 3H).

LCMS (ESI, m/z): 491 [M+H]+.

Example 59 Synthesis of compound 65

C.I.

4-Benzyl-3,6-dichloro-pyridazine, yellow oil (270 mg, 27%) was prepared analogously to 3,6-dichloro-4-isopropylpyridazine.

To a solution of 4-benzyl-3,6-dichloropyridazine (270 mg, 1.13 mmol) and tert-butyl-N-[2-(3,5-dichloro-4hydroxyphenyl)-3,5-dioxo-4H-1, 2,4-triazin-6-yl]carbamate (483 mg, 1.24 mmol) in DMSO (10 ml) was added K2CO3 (468 mg, 3.39 mmol) and CuI (215 mg, 1.13 mmol). The reaction mixture was stirred at 110°C for 16 h under N2 atmosphere and quenched with water (100 ml). The mixture was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with MeOH:DCM (4:96) to give tert-butyl-N-(2-[4-[(5-benzyl6-chloropyridazin-3-yl)oxy]-3,5-dichlorophenyl] -3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate as a brown solid (400 mg, 36%).

To a solution of 6-amino-2-[4-[(5-benzyl-6-chloropyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4triazin-3,5-dione (240 mg, 0.49 mmol) NaOAc (160 mg, 1.95 mmol) was added to AcOH (6 ml). The reaction solution was stirred overnight at 100°C and cooled to room. pace. The reaction solution was poured into water (100 ml) and filtered.

The residue was purified by preparative HPLC to give 6-amino-2-[4-[(5-benzyl-6hydroxypyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5 -dione as a white solid (56.6 mg, 24%).

1H NMR (300 MHz, DMSO-dg) δ ppm: 12.27-12.30 (m, 2H), 7.85 (s, 2H), 7.24-7.37 (m, 6H) , 6.53 (s, 2H), 3.87 (s, 2H).

LCMS (ESI, m/z): 495 [M+Na]+.

Example 60 Synthesis of Compound 66

- 107 047363

2-[(4-Benzyloxy-2,6-dimethylphenyl)methyl]-7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3b]pyrazine as a yellow solid (770 mg, 70%) was prepared similarly , as described for 5-[(4-benzyloxy-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2b]pyridine. A mixture of 2-[(4-benzyloxy-2,6-dimethylphenyl)methyl]-7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (610 mg, 1.13 mmol) in DCM ( 20 ml) and BBr3 (1.42 g, 5.65 mmol, 544.54 µl) was added. The reaction mixture was degassed and purged with N2 3 times and then the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding NaHCO ₃ (15 ml) at 0°C and then diluted with H2O (25 ml) and extracted with DCM (3x45 ml). The combined organic layers were dried over MgSO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (EA:PE = 0-10%) to give 4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo-[2,3-b]pyrazin-2-yl] methyl]-3,5-dimethylphenol as a yellow solid (400 mg, 79%).

[4-[[7-Isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate, white solid (430 mg, 83% ) was prepared in a manner similar to that described for [4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate.

Mixture of [4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethylphenyl]trifluoromethanesulfonate (280 mg, 481 µmol), tert -butylcarbamate (226 mg, 1.93 mmol), XantPhos (68.9 mg, 144 µmol), Pd(OAc) ₂ (10.8 mg, 48.1 µmol) and Cs ₂ CO ₃ (627 mg, 1. 93 mmol) in dioxane (10 ml) was degassed and purged with N2, then the mixture was stirred at 100°C for 4 hours under N2. The reaction mixture was concentrated under reduced pressure, then the residue was diluted with H ₂ O (20 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EA:PE = 0-15%) to give tert-butyl- H-[4-[[7-isopropyl-5-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5dimethylphenyl]carbamate as a yellow resin (290 mg, 76 %).

To a solution of tert-butyl-H-[4-[[7-isopropyl-5-(p-tolylsulfonyl)-pyrrolo-[2,3-b]pyrazin-2yl]methyl]-3,5-dimethylphenyl]carbamate (356 mg, 454 µmol) TFA (518 mg, 4.54 mmol, 336.27 µl) was added to DCM (3 ml). The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with sat. aq. NaHCO ₃ (5 ml) at 20°C, then diluted with H2O (5 ml) and extracted with DCM (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (EA:PE = 0-30%) to give 4-[[7-isopropyl -5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethylaniline as a yellow solid (183 mg, 89%). Ethyl-N-[2-cyano-2-[[4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo-[2,3-b]pyrazin-2-yl]methyl]-3,5- Dimethylphenyl]hydrazono]acetyl]carbamate, yellow solid (90 mg, 47%), was prepared as described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-(( 1-tosyl-1H-indol-5yl)oxy)phenyl)-hydrazinylidene)acetyl)carbamate To a solution of ethyl-N-[2-cyano-2-[[4-[[7-isopropyl-5-(ptolylsulfonyl)pyrrolo [ 2,3-b]pyrazin-2-yl]methyl]-3,5-dimethylphenyl]hydrazono]acetret-yl]carbamate (146 mg, 237 µmol) in AcOH (15 ml) was added NaOAc (97.3 mg, 1 .19 mmol). The mixture was stirred at 130°C for 3 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7~8 with NaHCO ₃ (sat. aq. 5 ml), then extracted with EA (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed under reduced pressure and the filtrate was concentrated under reduced pressure to give 2-[4-[[7-isopropyl-5-(p-tolylsulfonyl )pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethylphenyl]-3,5dioxo-1,2,4-triazine-6-carbonitrile as a yellow solid (100 mg, crude ).

The tosyl group was removed to give 2-[4-[(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2yl)methyl]-3,5-dimethylphenyl]-3,5-dioxo-1,2, 4-triazine-6-carbonitrile, a yellow solid (34.8 mg, 48%), which was prepared in a manner similar to that described for methyl 5-[2,6-dichloro-4-(6cyano-3,5- dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxylate.

1H NMR (400 MHz, DMSOD6) δ ppm: 12.98 (br s, 1H), 11.57 (br s, 1H), 7.96 (s, 1H), 7.53 (s , 1H), 7.16 (s, 2H), 4.29 (s, 2H), 3.19-3.07 (m, 1H), 2.43 (s, 6H), 1.32 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 416.3 [M+H]+.

- 108 047363

Example 61. Synthesis of compounds 67 and 67-A:

he r, um r·^ dG CP

CuCI ₂ , t-BuONO, MeCN

Pd(dppf)Cl2.. Na ₂ CO dioxane, H ₂ O

NaOAc, HOAc

100°C, in

A 100 mL round bottom flask was charged with sodium carbonate (2.03 g, 19.190 mmol), dioxane (20 mL) and water (4 mL). The mixture was stirred for 10 minutes at room. pace. 4-Bromo-6-chloropyridazin3-amine (2 g, 9.595 mmol), 2-naphthaleneboronic acid (1.82 g, 10.555 mmol) and PdCl ₂ (dppf) (783.57 mg, 0.960 mmol) were added. The mixture was stirred for 2 hours at 110°C under N2 atmosphere. The reaction mixture was diluted with EA (20 ml) and filtered through a pad of celite, the celite pad was washed with EA (2x10 ml) and the filtrate was washed with brine (20 ml). The organic layer was dried over anhydrous. sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (PE:EA = 10:1) to give 6-chloro-4-(naphthalene-1yl)pyridazin-3-amine as a yellow solid (1.75 g, 68%).

LCMS (ESI, m/z): 256 [M+H]+.

To a solution of CuCl ₂ (1.10 g, 8.212 mmol) in CH ₃ CN (5 ml) was added tert-butyl nitrite (2.12 g, 20.531 mmol) at 0° C. 6-chloro-4-(naphthalene- 2-yl)pyridazin-3-amine (1.75 g, 6.844 mmol) in CH ₃ CN (15 ml). The reaction mixture was stirred for 18 hours at 60°C. The reaction mixture was cooled to room. pace. and filtered through a pad of celite, the celite layer was washed with EA (3x10 ml) and then quenched with water (10 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous. sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:10) to give 3,6-dichloro-4-(naphthalene-2-yl)pyridazine as a yellow solid (990 mg, 50%).

LCMS (ESI, m/z): 275 [M+H]+.

To a solution of 3,6-dichloro-4-(naphthalene-2-yl)pyridazine (400.00 mg, 1.454 mmol), tert-butyl-N-[2-(3,5dichloro-4-hydroxyphenyl)-3.5 -dioxo-4H-1,2,4-triazin-6-yl]carbamate (565.83 mg, 1.454 mmol) and K2CO3 (602.79 mg, 4.362 mmol) in DMSO (8 ml) was added CuI (83.07 mg, 0.436 mmol) in an N2 atmosphere. The solution was stirred overnight at 110°C, then quenched with water (10 ml). The mixture was acidified to pH ~5 with HCl (1 M, aq), then extracted with EA (3x30 ml). The combined organic layers were washed with brine (1x20 ml), dried over anhydrous. sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 1:1) to give 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(naphthalene-2yl)pyridazin-3- yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione as a red solid (300 mg, 37%).

LCMS (ESI, m/z): 527 [M+H]+.

To a solution of 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(naphthalene-2-yl)pyridazin-3-yl]oxy]phenyl)-4H1,2,4-triazine -3,5-dione (300 mg, 0.568 mmol) in acetic acid (6 ml) was added to NaOAc (233.16 mg, 2.842 mmol). The mixture was stirred overnight at 100°C. The reaction mixture was cooled to room. temp., quenched with water (20 ml), and then stirred for 10 minutes. The solid was filtered and washed with water (2x10 ml) and PE (2x5 ml), then dried under reduced pressure then purified by preparative HPLC (XBridge Prep OBD C18 column, 19x250 mm, 5 µm; mobile phase A: water (0.05% TFA ), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 49 to 69% B in 7 min; 6-amino-2-(3,5-dichloro-4-[[ 5-(naphthalene-2-yl)-6-oxo-III-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazin-3,5-dione as a white solid (40, 4 mg, 14%).

^1H NMR (300 MHz, DMSO-06) δ ppm: 12.55 (s, 1H), 12.29 (s, 1H), 8.67 (s, 1H), 7.97-8, 07 (m, 5H), 7.89 (s, 2H), 7.57-7.64 (m, 2H), 6.55 (lat, 2H).

LCMS (ESI, m/z): 509 [M+H]+.

- 109 047363

6-Amino-2-(3,5-dichloro-4-((4-(naphthalene-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2, 4triazine-3,5(2H,4H)-dione (67-A) was isolated during the synthesis of 6-amino-2-(3,5-dichloro-4-[[5-(naphthalene-2-yl)6-oxo -1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazin-3,5-dione.

^1H NMR (300 MHz, DMSO-06) 12.44 (br, 1H), 12.27 (br, 1H), 8.38 (br, 1H), 8.03-8.11 (m , 3H), 7.88-7.93 (m, 3H), 7.60-7.66 (m, 2H), 7.26 (s, 1H), 6.52 (br, 2H).

Compounds 68-72 were prepared similarly to those described in Example 61. Regioisomeric products 68-A, 69-A, 70-A, 71-A and 72-A were also isolated.

Structure LCMS (ESI, m/z) Η NMR O 1' Ax A. -x η Ax CI σ P L O SG N Cl N NH ⁿ 68 NH ₂ 6-Amino-2-(3,5-dichloro-4-((5-(3chlorophenyl)-6-oxo -1,6-dihydropyridazin-3-yl)oxy(phenyl)1,2,4-triazine-3,5(2H,4H)-dione 493 [Μ+ΗΓ Ή (300 MHz, DMSO-</b) δ 12.55 (br, 1H), 12.28 (br, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.88-7.94 (m, ZN), 7.53 - 7.57 (m, 2H), 6.53 (s, 2H). ν o, /| °yS ft ^H Yo 68-Α ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((4-(3chlorophenyl)-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)1 ,2,4-triazine-3,5(2/-/, 4H)-dione 493 [M+N]* ^J H NMR (300 MHz, DMSO-s/b) δ 12.45 (s, 1H), 12.28 (s, 1H), 7.85 - 7.88 (m, ZH), 7.77 (d , J = 6.6Hz, 1H), 7.60-7.62 (m, 2H), 7.21 (s, 1H), 6.55 (s, 2H). Hi Ϊ ¹ oAr ^N C|-AA _N A _NH ⁿ V 69 NH ₂ 6-Amino-2-(3,5-dichloro-4-((5-(3-fluorophenyl)-6-oxo-1,6- Dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 477 [Μ+ΗΓ *H NMR (300 MHz, DMSO-c) δ 12.46 (br, 1H), 12.28 (s, 1H), 7.88 (s, 2H), 7.61-7.68 (m, ZN), 7.34-7.42 (m, 1H), 7.21 (s, 1H), 6.54 (lat, 2H). ^F v α /н °yS j? <A n' ⁿ ci 4<nh ^H Vo 69-A NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(3fluorophenyl)-6-oxo-1,6dihydropyridazin-3-yl )oxy)phenyl)1,2,4-triazine-3,5(2/-/,4H)-dione 477 [Μ+ΗΓ ^1H NMR (300 MHz, DMSO-s/ ₆ ) δ 12.46 (br, 1H), 12.28 (s, 1H), 7.88 (s, 2H), 7.61 -7.68 ( m, ZN), 7.34-7.42 (m, 1H), 7.21 (s, 1H), 6.54 (lat, 2H). O I ¹ jp* ιί^ ^Tl Ί θ ^H Vo th NH ₂ 473 [Μ+ΗΓ ^J H NMR (300 MHz, dmso-su δ 12.28-12.45 (m, 2H), 7.84 -7.88 (m, ZN), 7.74-7.77 (m, 2H), 7 ,30-7.40 (m, 2H), 6.54 (s, 2H), 2.08 (s, ZN).

- 110 047363

6-Amino-2-(3,5-dichloro-4-((6-oxo-5(m-tolyl)-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine3,5 (2H,4H)-dione Ό _α Χλ,Υ,Λνη ^H 70-A NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-4-(m-tolyl)-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 473 [M+N] ⁺ NMR (300 MHz, DMSOA) δ 12.28 - 12.38 (m, 2H), 7.87 (s, 2H), 7.59 - 7.61 (m, 2H), 7.42 - 7.47 ( m, 2H), 7.35 7.37 (m, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.54 (s, 2H), 2.08 (s, ZN) . O 1' A^ A. ,o. A. t Υί ⁰ ' ^N CI ΎΑ- ν Χν η ^Η νθ 71 ΝΗ ₂ 6-Amino-2-(3,5-dichloro-4-((5-(3ethylphenyl)-6-oxo-1,6-dihydropyridazine -3-yl)oxy)phenyl)-1,2,4-tri azin-3,5(2H,4H)-dione YQ CI V°lS o o^n' ⁿ ck 'Ο^ν'^'νη ^H 71-A NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(3ethylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy (phenyl)1,2 ,4-triazine-3,5(2Н,4Н)-dione ΓΎΊ Τ' uk about οΧν' ^Ν 0|ΉΗ' _ν Α _νη ^Н Vo 72 МН ₂ 6-Amino-2-(3,5-dichloro-4- ((6-oxo-5(5,6,7,8-tetrahydro-naphthalene-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione 487 [M+NG] 487 [M+N] ⁺ 513 [M+N] ^{4 X} H NMR (300 MHz, DMSO-s/ ₆ ) S 12.29-12.45 (m, 2H), 7.79 - 7.88 (m, ZH), JJ1 - 7.79 (m, 2H), 7.33-7.43 (m, 2H), 6.54 (lat, 2H), 2.64-2.74 (m, 2H), 1.23 (t, J= 7.5 Hz, ZN ). ^X H NMR (300 MHz, DMSO- _d6 ) 612.28-12.38 (m, 2H), 7.87 (s, 2H), 7.61-7.65 (m, 2H), 7.45 - 7.50 (m, 1H), 7.38 7.41 (i, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.54 (s, 2H), 2.672.74 ( m,2H), 1.19-1.26 (m,ZN). ^g H NMR (300 MHz, DMSO-<U ₆ ) δ 12.23 - 12.41 (m, 2H), 7.87 (s, 2H), 7.80 (s, 1H), 7.677.69 (m , 2H), 7.14-7.17 (m, 1H), 6.53 (lat, 2H), 2.77 (lat, 4H), 1.76 (lat, 4H). O ci ArV o οΑΛι-^ΎΑνη ⁿ V 72-A nh ₂ 6-amino-2-(3,5-dichloro-4-[[6-oxo-4- (5,6,7,8-tetrahydronaphthalene-2 -yl)-1Hn and ridazin-3-yl]oxy]phenyl)-4/7-1,2,4triazin-3,5-dione 513 [M+N] ⁴ · ^g H NMR (300 MHz, DMSO-s/b) δ 12.34-12.42 (m, 2H), 7.86 (s, 2H), 7.48-7.52 (m, 2H), 7 ,21-7.23 (m, 1H), 7.06 (s, 1H), 6.53 (lat, 2H), 2.78 (lat, 4H), 1.76 (lat, 4H) .

Example 62 Synthesis of compound 73

NH ₂

6-Amino-2-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4triazin-3 ,5(2H,4H)-dione was prepared in the same way as described for 6-amino-2-(3,5-dichloro-4-[[5(oxan-4-yl)-6-oxo-1H-pyridazine -3-yl]oxy]Fsnyl)-4H-1,2,4-triazine-3,5-dione.

1H NMR (300 MHz, DMSO-06) δ ppm: 12.29 (s, 1H), 12.13 (s, 1H), 7.86 (s, 2H), 7.33 (s, 1H ), 6.54 (s, 2H), 1.35 (s, 9H).

LCMS (ESI, m/z): 439 [M+H]+.

- 111 047363

Example 63 Synthesis of compound 74

3-Chloro-7-(4-methoxybenzyl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-c]pyridazin-6-one was prepared according to the literature method (Tet. Lett. 2015, 56, 772-774). A mixture of 3-chloro-7-[(4-methoxyphenyl)methyl]5,5-dimethylpyrrolo[2,3-c]pyridazin-6-one (6 g, 18.88 mmol), \-(3,5-dichloro -4-1'hydro1<siphenyl)-\,\dimethylformamidine (4.40 g, 18.88 mmol), Pd(dbtpf)Cl ₂ (1.23 g, 1.89 mmol), Cs ₂ CO ₃ (18 .46 g, 56.64 mmol) in dioxane (100 ml) was degassed and purged with N2 3 times. The mixture was stirred at 100°C for 16 hours under N2 atmosphere. The reaction mixture was diluted with H2O (200 ml) and extracted with EA (3x150 ml). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EA:PE = 0-50%) to give Na[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo- pyrrolo[2,3-c]pyridazin-3-yl]oxyphenyl]-N,Ndimethylformamidine as a brown solid (6.5 g, 67%).

To a solution of No.[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3c]pyridazin-3-yl]oxyphenyl]-No. ,Ni-dimethylformamidine (4.5 g, 8.75 mmol) in 2-propanol (80 ml) was added NH2NH2 hydrate (4.38 g, 87.48 mmol, 4.25 ml) at 20°C. After addition, the mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with H2O (160 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (3x50 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EA in PE: 0-50%) to give 3-(4-amino-2,6dichlorophenoxy)-7-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolo[2 ,3-c]pyridazin-6-one as a white solid (3.2 g, 80%).

Ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((7-(4-methoxybenzyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5Hpyrrolo[2 ,3-c]pyridazin-3-yl)oxy)phenyl)hydrazin-ylidene)acetyl)carbamate (6.46 g, 5.16 mmol, 74%, 50% purity), an orange solid was obtained in the same manner as described for ethyl-(2cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate.

To a solution of ethyl-N-[2-cyano-2-[[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxopyrrolo[2,3-c ]pyridazin-3-yl]oxyphenyl]hydrazono]acetyl]carbamate (6.46 g, 5.16 mmol) in DMF (60 ml) was added Et ₃ N (2.61 g, 25.78 mmol, 3.59 ml ) in one portion at 20°C. The mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with H2O (150 ml) and extracted with EA (3x150 ml). The combined organic layers were washed with brine (3x100 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (MeOHDCM = 0-5%) to give 2-[3,5-dichloro-4-[7-[(4methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo [2 ,3-c]pyridazin-3-yl]oxyphenyl]-3,5-dioxo-1,2,4triazine-6-carbonitrile as a brown solid (4.1 g, 96%). To a solution of 2-[3,5-dichloro-4[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxopyrrolo[2,3-c]pyridazin-3-yl]oxyphenyl]-3 ,5-dioxo1,2,4-triazine-6-carbonitrile (780 mg, 1.34 mmol) in ACN (10 ml) and H ₂ O (10 ml) was added CAN (2.21 g, 4.03 mmol, 2.01 ml) at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 ml) and extracted with EA (3x30 ml). The combined organic layers were washed with brine (3x20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by preparative HPLC ([Column: Welch Xtimate C18 150x30 mm, 5 µm; mobile phase: 15% ACN in water (0.225% NHyH^) to 45% ACN in water (0.225% NH3-H2O)]) to give 2 -[3,5-dichloro-4-[(5,5-dimethyl-6-oxo-7H-pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-3,5 dioxo-1, 2,4-triazine-6-carbonitrile as a white solid (61.1 mg, 10%).

1H NMR (400 MHz, DMSO-dg) δ ppm: 11.55 (br s, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.09 (br .s, 3H), 1.39 (s, 6H).

LCMS (ESI, m/z): 460.1 [M+H]+.

Example 64 Synthesis of compound 75

n-BuLi (2.5 M, 11.28 ml) in 30 min. After addition, the mixture was stirred at -30°C for 30 min, and then 3,6-dichloropyridazine (3 g, 20.14 mmol) and 2-methylpropanal (1.60 g, 22.15 mmol, 2.02 ml) in THF (20 ml) was added dropwise at -65°C. The mixture was stirred at -65°C in

- 112 047363 for 1 hour. The reaction mixture was quenched with NH ₄ Cl (saturated aq., 10 ml) at -60°C. The mixture was processed with the previous load and then diluted with H2O (100 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (80 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EA:PE = 0-15%) to give 1-(3,6-dichloropyridazin-4-yl)-2methylpropan-1-ol as a yellow liquid (3.34 g, 15%) . To a suspension of NaH (4.11 g, 102.68 mmol, 60% purity) in THF (40 ml) was added 1-(3,6-dichloropyridazin-4-yl)-2-methylpropan-1-ol (2.27 g, 10.27 mmol) and TBSCl (3.10 g, 20.54 mmol, 2.52 ml) in THF (10 ml) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with H ₂ O (10 ml), then diluted with H ₂ O (50 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with brine (3x50 ml), dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (0-5% EA in PE) to give 4-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)- 3,6-dichloropyridazine as a yellow liquid (2.49 g, 72%).

To a solution of 4-amino-2,6-dichlorophenol (3 g, 16.85 mmol) in toluene (30 ml) was added DMF-DMA (2.21 g, 18.54 mmol, 2.46 ml). After addition, the mixture was stirred at 100°C for 2 hours. The mixture was concentrated to obtain a residue, which was triturated (PE:EA = 6:1) to obtain X'-(3,5-dichloro4-hydroxyphenyl)-N,Ni-dimethylformimidamide in as a brown solid (4.05 g).

N-(4-((5-(1-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-chloropyridazin-3-yl)oxy)-3,5dichlorophenyl)-N,Ni-dimethylformimidamide (3.86 g, 74%), a yellow solid, was prepared in a manner similar to that described for 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline, except that the reaction the mixture was heated for 16 hours at 90°C.

N-(4-((5-(1-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-chloro-pyridazin-3-yl)oxy)-3,5dichlorophenyl)-N,Ni-dimethylformimidamide (3 .85 g, 6.84 mmol) in THF (30 mL), TBAF (1 M, 13.68 mL) was added at 25°C and the mixture was stirred at 25°C for 6 hours. The mixture was quenched with NH4C1 (sat. aq. ., 50 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous. Na ₂ SO ₄ , filtered and concentrated to obtain N-(3,5-dichloro-4((6-chloro-5 -(1-hydroxy-2-methylpropyl)pyridazin-3-yl)oxy)phenyl)-N, Ndimethylformimidamide (3.67 g, crude) as a yellow solid.

N(3,5-Dichloro-4-((6-chloro-5 -(1-hydroxy-2-methylpropyl)pyridazin-3-yl)oxy)phenyl)-N,N dimethylformimidamide (3.6 g, crude) in DCM (40 ml), Dess-Martin reagent (6.84 g, 16.12 mmol, 4.99 ml) was added at 25°C in one portion and the mixture was stirred at 25°C for 2 hours. The mixture was diluted with NaHCO ₃ ( sat. aq., 50 ml) and extracted with DCM (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by combi-flash (EA:PE = 0-40%) to give Na(3,5-dichloro-4-((6-chloro- 5-isobutyrylpyridazin-3yl)oxy)phenyl)-N,Ni-dimethylformimidamide as a yellow oil (2.23 g, 53%).

To a solution of Na-(3,5-dichloro-4-((6-chloro-5-isobutyrylpyridazin-3-yl)oxy)phenyl)-H,Nadimethylformimidamide (1.3 g, 3.13 mmol) in 2- propanol (20 ml), NH2NH2 hydrate (5.4 g, 107.87 mmol, 5.24 ml) was added and the mixture was stirred at 90°C for 72 hours under N2 atmosphere. The mixture was diluted with H2O (50 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous. Na2SO4, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (EA in PE: 0-40%) to give 3,5-dichloro-4-[(3-isopropyl-1H- pyrazolo[3,4-c]pyridazin-5yl)oxy]aniline as a yellow solid (435 mg, 40%).

1H NMR (400 MHz, DMSOO δ ppm: 13.83 (s, 1H), 8.03 (s, 1H), 6.71 (s, 2H), 5.63 (s, 2H), 3 .45-3.36 (m, 1H), 1.37 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 338 [M+H]+.

Ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)hydrazinylidene)acetyl )carbamate (960 mg), a yellow solid, was prepared in a manner similar to that described for ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol- 5-yl)oxy)phenyl)-hydrazinylidene)acetyl)carbamate, and was used in the next step without further purification.

2-(3,5-Dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4, 5tetrahydro-1,2,4-triazine-6-carbonitrile (compound 75A, 910 mg, 76%), red solid, was prepared in the same manner as described for 2-(4-[[3-isopropyl-1-( 4-methylbenzenesulfonyl)indol-5yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile, except that the reaction mixture was heated at 120°C for 12 hours and that NaOAc was used.

1H NMR (400 MHz, _DMSOD6 ) δ ppm: 13.97 (s, 1H), 13.28 (br s, 1H), 8.31 (s, 1H), 7.82 (s, 2H), 3.463.39 (m, 1H), 1.40 (d, J=7.0 Hz, 6H).

LCMS (ESI, m/z): 459 [M+H]+.

2-(3,5-Dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4, 5tetrahydro-1,2,4-triazine-6-carboxylic acid (415 mg, 37%), yellow solid, gave ana

- 113 047363 is logical as described for 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo- 4H-1,2,4-triazine-6-carboxylic acid, which was used in the next step without further purification.

LCMS (ESI, m/z): 478 [M+H]+.

To a solution of 2-(3,5-dichloro-4-((3-isopropyl-III-pyrazolo[3,4-c]pyri ₁ dazin-5-yl)oxy)phenyl)-3,5dioxo-2,3, 4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (410 mg, 0.857 mmol) in DMF (8 ml) was added Et ₃ N (260 mg, 2.57 mmol, 0.357 ml) at 0° C followed by slow addition of DPPA (472 mg, 1.71 mmol, 0.371 ml) under N ₂ atmosphere. The mixture was stirred at 25°C for 3 hours. Then H ₂ O (1 ml) was added and the reaction mixture was heated at 100° C for an additional 2 hours. The mixture was diluted with H ₂ O (50 ml) and extracted with EA (3x30 ml ). The combined organic layers were washed with brine (50 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude substance was purified by preparative HPLC [Phenomenex Luna C18 100x30 mmx5 µm; mobile phase: 35% ACN in water (0.225% FA) to 65% ACN in water (0.225% FA)] to give 6-amino-2-(3,5-dichloro-4-((3-isopropyl-III -pyrazolo[3,4-c]pyridazin5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione as a white solid (120 mg, 31%).

^1H NMR (400 MHz, DMSO-dQ δ ppm: 13.92 (s, 1H), 12.28 (br s, 1H), 8.24 (s, 1H), 7.89 (s , 2H), 6.52 (s, 2H), 3.47-3.38 (m, 1H), 1.40 (d, J=7.0 Hz, 6H).

LCMS (ESI, m/z): 449.1 [M+H] ⁺ .

Example 65 Synthesis of compound 76

6-Amino-2-(3,5-dichloro-4-((5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy )phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, white solid (95.2 mg, 27%) was prepared similarly as described for 6-amino-2-( 3,5-dichloro-4-[[5-(oxan-4-yl)-6-oxo-Spiridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazin-3,5-dione .

1H NMR (400 MHz, DMSO-dQ δ ppm: 12.25-12.27 (m, 2H), 7.85 (s, 2H), 7.42 (s, 1H), 6.52 ( s, 2H), 3.683.71 (m, 2H), 3.13-3.20 (m, 1H), 1.68-1.74 (m, 2H), 1.50-1.58 (m, 1h), 1.40 (t, J=12.6 Hz, 1H), 1.25 (s, 3H), 1.19 (s, 3H).

LCMS (ESI, m/z): 495 [M+H] ⁺ .

Example 66 Synthesis of compound 77

A 500 mL round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (6.20 g, 43.9 mmol) in THF (60 mL) under N ₂ atmosphere. n-BuLi (12.1 ml, 30.2 mmol) was added dropwise at -75°C. The mixture was heated to 0°C and stirred for 30 minutes. The mixture was then cooled to -75°C and 3,6-dichloropyridazine (3.00 g, 20.1 mmol) in THF (60 ml) was added dropwise. The mixture was stirred for 30 minutes at -75°C. Cyclopentanecarboxaldehyde (5.93 g, 60.4 mmol) in THF (30 ml) was added dropwise. The reaction solution was stirred for 90 min at -75°C, then quenched with N'l l4C'l (saturated aq, 100 ml) and extracted with EA (3x100 ml), the combined organic layers were washed with brine (2x50 ml), dried over the abyss Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (MeCN:water + 0.05% TFA) = 85:15) to give (6-chloro-3-methoxypyridazin-4yl)(cyclopentyl)methanol as a yellow oil (1.7 g, 30%).

LCMS (ESI, m/z): 247 [M+H] ⁺ .

A 100 ml round bottom flask was charged with cyclopentyl (3,6-dichloropyridazin-4-yl)methanol (1.40 g, 5.66 mmol), imidazole (1.54 g, 22.7 mmol), tert-butyldimethylsilyl chloride (2, 56 g, 17.0 mmol), DMF (15 ml) under N ₂ atmosphere. The reaction mixture was stirred overnight at room. pace. The reaction solution was quenched with water (10 ml), then extracted with EA (3x30 ml), washed with saline (30 ml), dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with (EA:PE = 3:97) to give 4-[[(tertbutyldimethylsilyl)oxy]-(cyclopentyl)methyl]-3,6-dichloropyridazine as a colorless oil (1.3 g, 63 %).

LCMS (ESI, m/z): 361 [M+H] ⁺ .

- 114 047363

An 8 ml vessel was loaded with 4-[[(tert-butyldimethylsilyl)oxy](cyclopentyl)methyl]-3,6-dichloropyridazine (1.30 g, 3.60 mmol), tert-butyl-K-[2-(3 ,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4triazin-6-yl]carbamate (1.40 g, 3.60 mmol), CuI (342 mg, 1.80 mmol ), K ₂ CO ₃ (1.24 g, 9 mmol), DMSO (20 ml) under N2 atmosphere. The reaction solution was stirred overnight at 110°C and quenched with water (80 ml). Solids were removed by filtration. The filtrate was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (2x50 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 15:85) to give 6-amino-2-[4-[(5-[[(t-butyldimethylsilyl)oxy](cyclopentyl)methyl]-6-chloropyridazin-3-yl )oxy]-3,5-dichlorophenyl]-4H-1,2,4triazine-3,5-dione as a brown solid (360 mg, 14%).

LCMS (ESI, m/z): 613 [M+H]+.

A 40 ml vessel was loaded with 6-amino-2-[4-[(5-[[(tert-butyl-dimethylsilyl)oxy](cyclopentyl)methyl]6-chloropyridazin-3-ul)oxy]-3,5-dichlorophenyl ]-4H-1,2,4-triazine-3,5-dione (170 mg, 0.277 mmol), NaOAc (90.8 mg, 1.11 mmol), CH3CO2H (5 ml) under N2 atmosphere. The reaction solution was stirred overnight at 110°C. The pH of the solution was adjusted to 8.0 with NaHCO ₃ (sat. aq.). The solution was extracted with DCM (3x20 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous. Na2SO4, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The product was dissolved in CH3OH (2 ml). NaOH (55.4 mg, 1.38 mmol) in water (2 ml) was added. The reaction solution was stirred for 2 hours at 50°C. The reaction mixture was quenched with H2O (10 ml), then extracted with EA (3x20 ml). The organic layers were combined, washed with saline (2x10 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 6-amino-2-[4-[(5-[[(tert-butyldimethylsilyl)oxy](clopentyl)methyl]-6-oxo-1H -pyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5dione as a brown solid (150 mg, 57%).

LCMS (ESI, m/z): 595 [M+H] ⁺ .

6-amino-2-[3,5-dichloro-4-([5-[tsuklopentyl(hydroxy)methyl]-6-oxo-1H-pyridazin-3-ul]oxy)phenyl]-4H-1,2, 4-triazine-3,5-dione, a white solid (3.4 mg) was prepared in a manner similar to that described for 2-[3,5-dichloro-4-[(3-isopropyl-1H-indole-5- yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carbonitrile, except that the reaction with TBAF occurred at room. pace.

^1H NMR (300 MHz, DMSO^) δ ppm: 12.27 (br, 1H), 7.88 (s, 2H), 7.40 (s, 1H), 6.34 (br. , 2H), 5.41 (d, J=4.8 Hz, 1H), 4.63 (lat, 1H), 2.22 (lat, 1H), 1.44-1.57 (m, 8H).

LCMS (ESI, m/z): 481 [M+H]+.

Example 67. Synthesis of compounds 78 and 79.

To a solution of 1-(benzyloxy)-2-bromobenzene (10 g, 38.003 mmol) and sodium amide (4.45 g, 114.010 mmol) in THF (150 ml) was added 1,1-diethoxyethene (13.24 g, 114.010 mmol ) in an N2 atmosphere. The reaction mixture was stirred at 70°C for 16 hours. The solution was poured into ice water (100 ml), acidified with concentrated hydrochloric acid (25 ml) and extracted with EA (2x200 ml). The organic layers were combined and dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 1:50) to obtain 5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-one as a white solid ( 3.3 g, 37%).

GCMS (IER, m/z): 224 [M].

To a solution of 5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-one (9 g, 40.132 mmol) in CH3OH (250 ml) was added NaBH4 (3.036 g, 80.264 mmol ). The reaction mixture was stirred at room. pace. for 4 hours. The reaction solution was quenched with water and extracted with EA (2x200 ml). The organic layers were combined and dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 1:15) to obtain 5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol as a white solid. GCMS (IER, m/z): 226 [M]. (7.4 g, 77%). To a solution of iodine (11.41 g, 44.945 mmol) in toluene (90 ml) was added triphenylphosphine (10.22 g, 38.953 mmol). The reaction mixture was stirred at room. pace. for 5 min under N ₂ and imidazole (6.12 g, 89.891 mmol) was added. The mixture was stirred at room. pace. for 10 min and 5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol (3.39 g, 14.982 mmol) in toluene (30 ml) was added. The solution was stirred at room. pace. for 1 hour and quenched with sodium sulfite (saturated aq., 100 ml). The mixture was extracted with EA (3x100 ml), dried over anhydrous. Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 1:50) to obtain 2-(benzyloxy)-8-iodobicyclo[4.2.0]octa- 115 047363

1(6),2,4-triene as a yellow oil.

GCMS (IER, m/z): 336 [M]. (4.46 g, 84%).

To a solution of LiAlH ₄ (4.01 g, 105.601 mmol) in THF (100 ml) was added 2-(benzyloxy)-8iodobicyclo[4.2.0]octa-1(6),2,4-triene (14.20 g, 42.240 mmol) in THF (150 ml) dropwise. The reaction mixture was stirred at room. pace. for 30 min and quenched with ice water (200 ml) and adjusted to pH=5 with concentrated hydrochloric acid. The mixture was extracted with EA (3x200 ml) and the organic layers were combined, washed with brine (100 ml) and dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure to give 2-(benzyloxy)bicyclo[4.2.0]octa1(6),2,4-triene as a colorless oil.

GCMS (IER, m/z): 210 [M]. (8,900 g, 90%).

A solution of 2-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-triene (7 g, 33.290 mmol) in methanol (175 ml) was added with Pd/C (3 g). The reaction solution was stirred for 16 hours at room. pace. under a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 1:20) to obtain bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol as a colorless oil.

LCMS (ESI, m/z): 119 [M-N] ^- . (1.66 g, 35%).

To a solution of bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (1 g, 8.323 mmol) and diisopropylamine (84.22 mg, 0.832 mmol) in DCM (37.50 ml) added sulfone chloride (1123.34 mg, 8.323 mmol) in DCM (10 ml) dropwise at 0°C. The reaction mixture was stirred at room. pace. for 16 hours and quenched with water (100 ml). The mixture was extracted with DCM (3x50 ml), washed with brine, dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 1:50) to give 3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol as a yellow oil (760 mg, 51 %).

LCMS (ESI, m/z): 153 [M-N] ^- .

HNO ₃ (326.09 mg, 5.175 mmol) in acetic acid (2 ml) at 0°C. The reaction mixture was stirred at room. pace. overnight and extinguished with water (100 ml). The reaction mixture was extracted with EA (3x50 ml), washed with saline, dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with (EA:PE = 1:50) to obtain 3-chloro-5-nitrobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (500 mg, 41%) as a yellow solid.

LCMS (ESI, m/z): 198 [M-N] ^- .

To a solution of 3-chloro-5-nitrobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (500.00 mg, 2.505 mmol) in ethanol (20 ml) and H2O (10 ml ) Fe (699.50 mg, 12.526 mmol) and NH ₄ Cl (1.072 g, 20.041 mmol) were added. The mixture was stirred for 5 hours at 60°C. The mixture was filtered and the filter cake was washed with DCM (6x50 ml). The filtrate was extracted with dichloromethane (3x300 ml). The combined organic layers were dried over anhydrous. Na ₂ SO ₄ . Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 5-amino-3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (450 mg, 95%) as brown solid matter.

LCMS (ESI, m/z): 170 [M+H]+.

4-Chloro-5-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine (640 mg, 72% ), yellow oil, LCMS (ESI, m/z): 324 [M+H]+, was prepared in the same way as described for 3,5-dichloro-4-[(6-chloro-5-isopropylpyridazine-3 - yl)oxy]aniline.

6-([5-Amino-3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]oxy)-4-isopropyl-2H-pyridazin-3-one (300 mg , 52%), brown solid, LCMS (ESI, m/z): 306 [M+H]+, was prepared as described for 6-(4-amino-2,6-dichlorophenoxy)-4- isopropyl-2H-pyridazin-3-one.

Ethyl-(2-(2-(4-chloro-5-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)bicyclo[4.2.0]octa1(6),2, 4-trien-2-yl)hydrazinylidene)-2-cyanoacetyl)carbamate (250 mg, 77%), yellow solid, was prepared in a manner similar to that described for ethyl-(2-cyano-2-(2-(3 ,5-dichloro-4-((1-tosyl-1H-indol5-yl)oxy)phenyl)-hydrazinylidene)acetyl)carbamate.

LCMS (ESI, m/z): 473 [M+H]+.

2-[4-Chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]bicyclo[4.2.0]octa-1(6),2,4-trien-2- yl]3,5-dioxo-4H-1,2,4-triazine-6-carbonutrile, compound 78 was prepared in the same way as described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl) indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H1,2,4-triazine-6-carbonitrile and isolated as a yellow solid.

^1H NMR (300 MHz, DMSOO δ ppm: 7.56 (s, 1H), 7.37 (s, 1H), 6.90-7.20 (br, 2H), 2.96- 3.13 (m, 5H), 1.18 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 427 [M+H]+).

2-[4-Chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]bicyclo-[4.2.0]octa-1(6),2,4-trien-2yl ]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (180 mg, 82%), white solid (LCMS (ESI, m/z): 446 [M+H]+ ), were prepared in a similar manner as described for 2-[3,5-dichloro-4-[(5

- 116 047363 isopropyl-6-oxo-1H-pyridazin-3 -yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid.

X-(2-[4-Chloro-5-[(5-isopropyl-6-ox.o-1H-pyridazin-3-yl)ox.i|-bicyclo[4.2.0|octa-1(6), 2,4-trien-2yl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate (200 mg, 81%), yellow oil (LCMS (ESI, m/z): 517 [M+H]+) was obtained in the same way as described for tert-butyl-X-(2-[3,5-dichloro-4-[(5-isopropyl6-oxo-1 H-pyridazin-3 -yl )oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate.

6-Amino-2-[4-chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-bicyclo[4.2.0]octa-1(6),2,4triene -2-yl]-4H-1,2,4-triazine-3,5-dione (92.5 mg, 56%), white solid, compound 79 was prepared in a manner similar to that described for 6-amino-2 -[3,5-dichloro-4-[(3-isopropyl-1H-indol-5yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione.

^1H NMR (300 MHz, DMSOL ₆ ) δ ppm: 12.20-12.27 (m, 2H), 7.58 (s, 1H), 7.31 (s, 1H), 6.46 (s, 2H), 3.16 (lat, 2H), 2.99-3.08 (m, 1H), 2.95 (lat, 2H), 1.18 (d, J=6.9 Hz, 6H).

LCMS (ESI, m/z): 417 [M+H] ⁺ )

Example 68. Synthesis of compounds 80 and 81.

Synthesis of 6-amino-2-(3-bromo-5-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)1,2,4-triazine- 3,5(2H,4H)-dione (white solid, 203.7 mg, 57%) and 6-amino-2-(3,5-dibromo-4-((5isopropyl-6-oxo-1,6 -dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was performed in a manner similar to that described for 6-amino-2-(3,5-dichloro -4-((5-isopropyl-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, except that 4-amino2-bromo-6-chlorophenol was used instead of 4-amino-2,6-dichlorophenol in the synthesis of compound 80 and 4-amino-2,6-dibromophenol was used instead of 4-amino-2,6-dichlorophenol in the synthesis of compound 81.

Example 69 Synthesis of compound 82

NH ₂

5-Bromo-3,3-dimethyl-1H-indol-2-one (3.7 g, 67%), a yellow solid, was prepared in a manner similar to that described in WO 2000/066167 and WO 2000/066556.

LCMS (ESI, m/z): 240 [M+H] ⁺ .

A 50 mL round bottom flask was charged with 5-bromo-3,3-dimethyl-1H-indol-2-one (1.50 g, 6.247 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborinan -2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (4.23 g, 18.742 mmol), potassium acetate (1.84 g, 18.742 mmol), DMSO (20 ml), PdCl ₂ ( PPh ₃ ) ₂ (438.50 mg, 0.625 mmol) in an N2 atmosphere. The mixture was stirred for 2 hours at 60°C under N2 atmosphere. The solution was purified by C18 reverse phase chromatography to give 3,3-dimethyl-2-oxo-1H-indol-5-ylboronic acid (1.2 g, 89%) as a white solid.

LCMS (ESI, m/z): 206 [M+H] ⁺ .

A 100 ml 3-neck flask was loaded with tert-butyl-N[4-[(benzyloxy)methyl]-2-(3,5-dichloro-4hydroxyphenyl)-3,5-dioxo-1,2,4-triazine-6 -yl]carbamate (1.20 g, 2.356 mmol), 3,3-dimethyl-2-oxo-1Nindol-5-ylboronic acid (2.42 g, 11.780 mmol), Cu(OAc) ₂ (855.86 mg , 4.712 mmol), pyridine (372.72 mg, 4.712 mmol), dichloromethane (100 ml), 4A molecular sieves (500 mg) in an O ₂ atmosphere. The reaction solution was stirred for 3 days at room. pace. Solids were filtered. The organic layer was concentrated under reduced pressure. The residue was chromatographed on a column

- 117 047363

C18 (CH ₃ CN:H2O + 0.05% TFA = 7:3) to give tert-butyl-U-[4-[(benzyloxy)ethyl]-2-[3,5-dichloro-4[(3, 3-dimethyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate as a yellow solid (830 mg, 45 %).

LCMS (ESI, m/z): 668 [M+H] ⁺ .

Tert-butyl-N4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(3,3dimethyl-2-oxo-N-indol-5-yl)oxy was loaded into a 50-ml round-bottom flask ]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate (500 mg, 0.748 mmol), DCM (10 ml) under N ₂ atmosphere. BBr ₃ (1.499 g, 5.983 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was added dropwise to methanol (5 ml) at 0°C and concentrated under reduced pressure at 0°C. The crude substance was dissolved in methanol (5 ml) and purified by preparative HPLC using the following gradient conditions: XBridge Prep OBD C18 column, 19x250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ + 0.1% ΝΗ ₃ Η ₂ Ο), mobile phase B: ACN; flow rate: 25 ml/min; gradient: from 20 V to 40 V in 7 minutes; 220 nm; RT1: 6.42; injected volume: 6 ml; purification made it possible to obtain 6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-III-indol-5yl)oxy]phenyl]-4H-1,2,4-triazine -3,5-dione as a white solid (59.4 mg, 18%).

^1H NMR (300 MHz, DMSO-dQ δ ppm: 12.25 (br, 1H), 10.27 (s, 1H), 7.90 (s, 2H), 7.05 (d, J=2.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (lat, 2H), 6.45-6.49 (m, 1H), 1 .25 (s, 6H).

LCMS (ESI, m/z): 448 [M+H] ⁺ .

Example 70 Synthesis of compound 83

A 50 ml round bottom flask was charged with 5'-bromo-1Ή-spiro[cyclopentane-1,3'-indole]-2'-one (prepared according to the method in J. Med. Chem. 2008, 51, 1861-1873, 1 g, 3.757 mmol), 2-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (2.55 g, 11.289 mmol), acetate potassium (1.11 g, 11.272 mmol), PdCl ₂ (PPh ₃ ) ₂ (263.8 mg, 0.375 mmol), dimethyl sulfoxide (25 ml) under N2 atmosphere. The resulting solution was stirred for 3 hours at 60°C. The solution was purified by reverse phase column chromatography (C18, H ₂ O:CH ₃ CN = 13:87) to give 2'-oxo-1Ή-spiro[cyclopentane-1,3'-indole]-5'ylboronic acid as yellow solids (1.07 g, 74%).

LCMS (ESI, m/z): 232 [M+H] ⁺ .

The subsequent cross-coupling reaction, deprotection and purification were carried out similarly to those described for 6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indole-5 -yl)oxy]phenyl]-4H1,2,4-triazine-3,5-dione to give 6-amino-2-(3,5-dichloro-4-[1 Ή-spiro[cyclopentane-1,3' -indole]-2'onoxy]phenyl)-4H-1,2,4-triazine-3,5-dione as a white solid (11.3 mg, 13%).

1H NMR (300 MHz, DMSO-d,) δ ppm: 10.23 (s, 1H), 7.91 (s, 2H), 6.96 (s, 1H), 6.72-6, 75 (m, 1H), 6.436.48 (m, 3H), 1.89-2.01 (m, 6H), 1.70-1.81 (m, 2H).

LCMS (ESI, m/z): 474 [M+H] ⁺ .

Example 71 Synthesis of compound 84

3-Isopropyl-3-methyl-III-indol-2-one was obtained as a yellow solid following the following preparation method described in Molecules, 2017, 22, 1-18.

LCMS (ESI, m/z): 190 [M+H] ⁺ .

A 40 ml vessel was loaded with 3-isopropyl-3-methyl-N-indol-2-one (2.80 g, 14.8 mmol), NaOAc (1.23 g, 14.9 mmol), acetic acid (30 ml ). Br ₂ (0.77 ml, 4.84 mmol) in acetic acid (10 ml) was added dropwise. The reaction solution was stirred for 50 min at room. pace. and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE = 25:75) to obtain 5-bromo-3-isopropyl-3-methyl-N-indol-2-one as a white solid (4 g, 95%).

LCMS (ESI, m/z): 268 [M+H] ⁺ .

Subsequent boronic acid formation, cross-coupling reaction, deprotection and purification were carried out similarly to those described for 6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-Shindol -5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione to give 6-amino-2-[3,5-dichloro-4-[(3isopropyl-3-methyl- 2-oxo-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione (52.8 mg, 29%).

^1H NMR (400 MHz, DMSO-d,) δ ppm: 12.28 (s, 1H), 10.28 (s, 1H), 7.89 (s, 2H), 6.86 (d , J=2.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 6.54 -6.58 (m, 3H), 1.91-2.00 (m, 1H), 1.23 (s, 3H), 0.85 (d, J=7.2 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H).

- 118 047363

LCMS (ESI, m/z): 476 [M+H]+.

Example 72 Synthesis of compound 85

6-Amino-2-(3,5-dichloro-4-[1'H-spiro[cyclohexane-1,3'-indole]-2'-onoxy]phenyl)-4H-1,2,4-triazine3, 5-Dione, a white solid, was prepared in a manner similar to that described for 6-amino-2-(3,5dichloro-4-[1H-spiro[cyclopentane-1,3'-indole]-2'-onoxy]phenyl )-4H-1,2,4-triazine-3,5-dione.

1H NMR (300 MHz, DPSO-sb,) δ ppm: 10.26 (s, 1H), 7.90 (s, 2H), 7.12 (s, 1H), 6.76 (d, J=4.8 Hz, 1H), 6.49-6.53 (m, 3H), 1.86 (lat, 2H), 1.53 -1.62 (m, 8H).

LCMS (ESI, m/z): 488 [M+H] ⁺ .

Example 73. Synthesis of compounds 86 to 89.

Compound 86 was prepared in a manner similar to that described for 6-amino-2-(3,5-dichloro-4-((5cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1, 2,4-triazine-3,5(2H,4H)-dione, where

3-methylcyclobutane-1-carboxylic acid was used instead of cyclobutanecarboxylic acid. Compound 86 was purified by SFC-HPLC [Column: (R,R)-Whelk-01, 2.12 x 25 cm, 5 µm; mobile phase A: Hex (0.1% FA)-HPLC, mobile phase B: EUN-HPLC; flow rate: 20 ml/min; gradient: from 20 to 20 V in 41 minutes; 254/220 nm] to obtain compound 86-A (RT1=31.945, 10.8 mg, 98% purity, analytical column COX:(R,R)-Whelk, 0.46x5 cm; 3.5 µm, Hex (0 ,1% FA):EtOH = 75:25, 1.0 ml/min, Rt: 3.788 min), and compound 86-B (RT2 = 37.638, 7.1 mg, purity 98%, SFC column: (R, R)-Whelk, 0.46x5 cm; 3.5 µm, Hex (0.1% FA): EtOH = 75:25, 1.0 ml/min, Rt: 4.378 min), both as white solids.

Compounds 87-A and 87-B were prepared in a manner similar to that described for 6-amino-2-(3,5-dichloro-4((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl) oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, except that 3-(benzyloxy)cyclobutane-1-carboxylic acid was used instead of cyclobutanecarboxylic acid. 6-amino-2-(4-((5-(3-(benzyloxy)cyclobutyl)-6-oxo-1,6-dihydropyridazin-3yl)oxy)-3,5-dichlorophenyl)-1,2, 4-triazine-3,5(2H,4H)-dione was isolated by preparative HPLC (Column: Xcelect CSH F-pheny OBD column, 19x250 mm, 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B :ACN; flow rate: 25 ml/min; gradient: 26 to 46 V in 9 min; RT: 8.85 min). Chiral preparative HPLC was then performed (Column: CHIRALPAK IC, 2x25 cm, 5 µm; mobile phase A: Hex (0.1% FA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 ml/min; gradient: 40 to 40 V for 25 min; RT: 10.881 min; injection volume: 0.6 ml; number of runs: 25) to obtain compound 87-A as a white solid (150 mg, 23%) . Additional separation of the racemic mixture was required using SFC-preparative HPLC (Column: CHIRALPAK IG, 20x250 mm, 5 µm; mobile phase A: CO2, mobile phase B: IPA (2 mM NH3-MEOH); flow rate: 40 ml/min; gradient: 50% B; 220 nm; RT1: 7.1 min; injection volume: 2 ml; number of runs: 4) to obtain 87-B as a white solid with a metallic tint (13.3 mg).

Pd/C (100 mg) was added to compound 87-A (130 mg, 0.239 mmol) in EA (10 mL).

The mixture was stirred for 2 hours at room. pace. in an _H2 atmosphere. The mixture was filtered through a pad of celite and washed with EA (20 ml) and CH3OH (20 ml). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 column, 19x250 mm, 5 µm; mobile phase A: water (10 mmol/l NH4HCO3 + 0.1% NH ₃ -H ₂ O), mobile phase B: ACN; flow rate : 25 ml/min; gradient: 10 to 30 V in 7 min; RT: 6.13 min) to obtain 88-A as a white solid (52.5 mg, 48%).

6-Amino-2-(3,5-dichloro-4-((5-(3,3-dimethylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2, 4-triazine-3,5(2H,4H)-dione was prepared in a manner similar to that described for 6-amino-2-(3,5dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazine -3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione, starting from 3,3-dimethylcyclobutane-1-carboxylic acid.

- 119 047363

Structure LCMS (ESI, m/z) *H NMR 'ΎΛ ^{Cl 0} 0Nn- ⁿ C|AA _n X _nh ^H V° 86 NH ₂ 6-Amino-2-(3,5-dichloro-4-[[5-(3methylcyclobutyl)-6-oxo-1/7pyridazin- 3-yl]oxy]phenyl)-4/71,2,4-triazine-3,5-dione 451[M+N]* H NMR (300 MHz, DMSO-de) δ 12.36 - 12.03 (m, 2H), 7.84 -7.85 (m, 2H), 7.40 -7.50 (m, 1H), 6.52 (s, 2H), 3.60 -3.65 (m, 1H), 2.24 - 2.46 (m, ZN), 1.84 - 2.00 (m, 1H), 1, 61 1.75 (m, 1H), 1.19-1.20 (m, 1H), 1.01 -1.09 (m, 2H). CI ^u ty°yS ° Ο^νΛιΑΧΑνη ^Н Vo 86 A NH ₂ 6-Amino-2-(3,5-dichloro-4-((5((1g,3g)-3-methylcyclobutyl)-6oxo-1,6 -dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine3,5(2/7,4/7)-dione the eluting isomer is labeled 86A. 451 [M+N]* H NMR(300 MHz, DMSO-de) δ 12.13 - 12.27 (m, 2H), 7.84 (s, 2H), 7.40 -7.41 (m, 1H), 6.52 ( s, 2H), 3.15 - 3.25 (m, 1H), 2.29 - 2.45 (m, ZN), 1.60 - 1.78 (m, 2H), 0.98 (d, 7 = 6.0 Hz, ZN). ^H Vo 86-B 6-Amino-2-(3,5-dichloro-4-((5-((15,35)-3-methylcyclobutyl)-6oxo-1,6-dihydropyridazin-3- The 2* eluting isomer is labeled 86B. 451 [M+N] ^{+ X} H NMR (300 MHz, DMSO-de) δ 12.14-12.27 (m, 2H), 7.84 (s, 2H), 7.49 - 7.50 (m, 1H), 6.52 (s, 2H), 3.59 - 3.65 (m, 1H), 2.23 - 2.38 (m, ZN), 1.88 - 1.98 (m, 2H), 1.18 (d , 7 = 6.0 Hz, ZN).

- 120 047363

yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione Βη^ν-Λ Cl ^{Η S7} ' ^A nh ₂ 6-Amino-2-(4-((5-((1g,3g)-3(benzyloxy)cyclobutyl)-6-oxo1,6-dihydropyridazin-3-yl )oxy)3,5-dichlorophenyl)-1,2,4-triazine3,5(2H,4H)-dione 543 [M+N]* ⁷ NMR (400 MHz, DMSO-ds) δ ppm: 12.28 (s, 1H), 12.19 (s, 1H), 7.84 (s, 2H), 7.44 - 7.47 ( m, 1H), 7.24-7.37 (m, 5H), 6.53 (s, 2H), 4.42 (s, 2H), 4.03-4.11 (m, 1H), 2 .99 - 3.06 (m, 1H), 2.53 - 2.63 (m, 2H), 1.93 - 2.05 (m, 2H). ^VP '°'a, _o O ⁱ ^ ^X N' ^N Cl ^x GG _N A _NH ⁿ v° S7-B ΝΗ ₂ 6-Amhho-2-(4-((5-((1s,3s)-3- (benzyloxy)cyclobutyl)-6-oxo1,6-dihydropyridazin-3-yl)oxy)3,5-dichlorophenyl)-1,2,4-triazine3,5(2H,4H)-dione 543 [M+N] ^{+ 7} NMR (400 MHz, dmso-de) δ 12.10 -12.40 (m, 2H), 7.85 (s, 2H), 7.58 (s, 1H), 7.24-7.38 (m , 5H), 6.50 (s, 2H), 4.41 (s, 2H), 4.13 4.22 (m, 1H), 3.47-3.57 (m, 1H), 2.28 - 2.45 (m, 4H). ^Η0 4γ—, Cl oXCV ⁿ v 88-A _Ν η ₂ θ_ Amino-2-[3,5-dichloro-4-([6-oxo-5[(1g3g)-3-hydroxycyclobutyl]1H-pyridazin-3- yl]oxy)phenyl]4W-1,2,4-triazine-3,5-dione 453 [M+N] ^{+ g} NMR (400 MHz, dmso-de) δ 12.10 -12.42 (m, 2H), 7.85 (s, 2H), 7.38-7.41 (m, 1H), 6.51 (s , 2H), 5.09 - 5.15 (m, 1H), 4.06 - 4.13 (m, 1H), 2.88 - 2.95 (m, 1H), 2.50 - 2.60 (m, 2H), 1.85-1.93 (m, 2H). —Va ^{C1 0} _O 4- _N - ^N C|AA _N A _NH ^H 89 nh ₂ 6-Amino-2-(3,5-dichloro-4-((5-(3,3dimethylcyclobutyl)-6-oxo-1 ,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 465 [M+ N] ^{+ X} H NMR (400 MHz, DMSO-HD) δ 12.20 (s, 1H), 12.15 (s, 1H), 7.84 (s, 2H), 7.45 (s, 1H), 6, 54 (s, 2H), 3.34 3.32 (m, 1H), 2.08-2.06 (m, 2H), 2.06-1.93 (m, 2H), 1.24 (s , ZN), 1.10 (s, ZN) The following compounds were prepared in the same manner as described for 6-amino-2-(3,5dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2 ,4triazine-3,5(2H,4H)-dione.

- 121 047363

△hl ^Cl ^“yS ° o^n- ⁿ ci'¥A _n A _nh ^{H 93} nh ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-(spiro[2.3]hexane -5-yl)-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 463 [M+N] ^{+ X} H NMR (400 MHz, DMSO-s/ ₆ ) δ 12.16 (s, 1H), 7.86 (s, 2H), 7.54 (s, 1H), 6.46 (s, 2H), 3.72 - 3.67 (m, 1H), 2.34 (d, J = 8.4 Hz, 4H), 0.54 0.41 (m, 4H). Og\ ^C1 0^^01-^^^14^141-1 ^H Vo ⁹⁴ nh ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-(spiro[3.3]heptane-2 -yl)-1,6dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 477 [M+NG ^1H NMR (400 MHz, DMSO-sH) δ 1.78-1.82 (m, 2H), 1.88-1.92 (m, 2H), 2.05-2.12 (m, 4H) , 2.32 (td, 2H, J = 9.3 Hz, 2.8 Hz), 3.36-3.38 (m, 1H), 6.51 (br s, 2H), 7.4 ( d, 1H, J = 1.5 Hz), 7.84 (s, 2H), 12.13 (s, 1H), 12.26 (br s, 1H) ΓΊ ^{C| 0} Ο^νΎι-'^'^'ν'^ΝΗ ^Н V° ⁹⁵ 14Н ₂ 6-amino-2-(4-((5- (bicyclo[1.1.1]pentan-1-yl)-6oxo-1 ,6-dihydropyridazin-3yl)oxy)-3,5-dichlorophenyl)-1,2,4triazine-3,5(2H,4H)-dione 449 [M+N] ^{+ 1H} NMR (400 MHz, DMSO-sH) δ 12.25 (s, 1H), 12.16 (s, 1H), 7.82 (s, 2H), 7.29 (s, 1H), 6, 49 (s, 2H), 2.56 (s, 1H), 2.14 (s, 6H) 'V ^s| Vy°V o O'7'|4' ^N C|-^ ^x =^N'^NH ⁿ v° ⁹⁶ mig 6-amino-2-(3,5-dichloro-4-((5-(1isopropylcyclopropyl) -6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 463 [M-N]- ¹ H NMR (400 MHz, DMSO-s/ ₆ ) δ 0.64 (t, J = 5.3 Hz, 2H), 0.77 (t, J = 5.1 Hz, 2H), 0.80 ( d, J= 6.9 Hz, 6H), 1.94(p, 1=6.8Hz, 1H), 6.51 (s, 2H), 7.38 (s, 1H), 7.84 (s , 2H), 12.14 (s, 1H), 12.27 (s, lat, 1H)

- 122 047363

F, _ ci ° N ' ^N C1 NNH ^H Vo ⁹⁷ nh ₂ 6-amino-2-(3,5-dichloro-4-((5-(4,4difluorocyclohexyl)-6-oxo-1,6dihydropyridazin-3yl) hydroxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 501 [M+N] ⁺ I NMR (400 MHz, flMCO-d ₆ ) δ 7.85 (s, 2H), 7.48 (s, 1H), 6.53 (s, 2H), 2.90 (t, J = 11.6 Hz, 1H), 1.89 2.11 (m, 6H), 1.62 - 1.68 (m, 2H) Q γη ci ⁰ o^n' ⁿ ci'''^^n^nh ^Η Vo 98 NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-(1,2,3 ,4-tetrahydronaphthalene-2yl)-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 513 [M+N] ⁺ I NMR (400 MHz, DMSO-ds) δ 1.82-1.91 (m. 1H). 2.03-2.08 (m. 1N), 2.85-2.91 (m, ZN), 2.97-3.04 (m, 1N). 3.10-3.18 (m. W), 6.51 (s, 2H). 7.08-7.16 (m, 4H). 7.47 (s. 1H), 7.86 (s. 2H). 12.27 (lat s. 1H), 12.29 (s, 1H) Cl J oXYi-XAAnh 99 NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-((15,35)-3-phenylcyclobutyl)-1,6dihydropyridazin-3-yl)oxy )phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 513 [M+N] ^{+ X} H NMR (400 MHz, DMSO-ds) δ 12.11 -12.31 (m, 2H), 7.87 (s, 2H), 7.71 (s, 1H), 7.32 - 7.37 (m, 4H), 7.20-7.24 (m, 1H), 6.52 (s, 2H), 3.58 - 3.66 (m, 2H), 3.38 - 3.49 (m , 2H), 2.53 - 2.63 (m, 2H) ^ph -r\ ^{C| 0 H} Vo 100 nh ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-((1g,3r)-3-phenylcyclobutyl)-1,6dihydropyridazin-3-yl)oxy)phenyl )-1,2,4-triazine-3,5(2H,4H)-dione 513 [M+N] ⁺ NMR (400 MHz, DMSO-cfc) δ 12.14 -12.34 (m, 2H), 7.85 (s, 2H), 7.53 (s, 1H), 7.29-7.33 (m , 4H), 7.17-7.23 (m, 1H), 6.54 (s, 2H), 3.46 - 3.58 (m, 2H), 2.63 - 2.70 (m, 2H ), 2.20 - 2.29 (m, 2H).

- 123 047363

D—1 Cl O^N' ^N CI'^ ^Xi ^N^ ⁴ 'NH ^H Vo 101 nh ₂ 6-amino-2-(4-((5(bicyclo[2.1.1]hexan-1-yl)- 6oxo-1,6-dihydropyridazin-3yl)oxy)-3,5-dichlorophenyl)-1,2,4triazine-3,5(2/7,4/7)-DION 463 [M+N]* CN NMR (400 MHz, DMSO-s/ ₆ ) δ ppm: 12.27 (s, 1H), 12.13 (s, 1H), 7.84 (s, 2H), 7.29 (s , 1H), 6.53 (s, 2H), 2.08 (s, 1H), 1.71 -1.95 (m, 6H), 1.47-1.55 (m, 2H) ⁿ 102 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((5-((1g _/ 3g)-3-methoxycyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy )phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 467 [M+N] ^{+ L} H NMR (400 MHz, DMSO-dg) δ 12.18-12.27 (m, 2H), 7.85-7.86 (m, 2H), 7.45-7.46 (m, 1H) , 6.53 (s, 2H), 3.85-3.93 (m, 1H), 3.16-3.18 (m, ZN), 2.98-3.10 (m, 1H), 2.582 .65(m, 2H), 1.90-1.99 (m, 2H) ^C| οΑ' ^Ν α ⁿ V° yuz νη ₂ 6-amino-2-(3,5-dichloro-4-((5-((15,35)-3-methoxycyclobutyl)-6-oxo-1,6-dihydropyridazine -3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2/7,4/7)-dione 467 [M+N] ⁺ CN NMR (400 MHz, DMSO-ds) δ 12.19-12.27 (m, 2H), 7.85 -7.86 (m, 2H), 7.56-7.57 (m, 1H), 6.52 (s, 2H), 3.96 - 4.00 (m, 1H), 3.49-3.53 (m, 1H), 3.17-3.18 (m, ZN), 2, 36 -2.42 (m, 2H), 2.24-2.32 (m, 2H) CN GA ^S| οΑ'ν' ^Ν Ο|ΆΧ ^χ _ν Α _νη ^Н Vo 104 NH ₂ gas-6-amino-2-(3,5-dichloro-4-((5-(2methylcyclobutyl)-6-oxo-1,6dihydropyridazin- 3yl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 462 [M+NG ^X H NMR (400 MHz, DMSO-ds) δ 12.29 - 12.31 (m, 1H), 7.96 (s, 2H), 7.59-7.64 (m, 1H), 5.85 (s, 2H), 3.78 - 3.97 (m, 2H), 2.56 - 2.66 (m, 1H), 2.10-2.32 (m, ZN)

- 124 047363

CN g—\ trans 9 ¹ 0 ^< ^'N' ^N CI ^x L==X _n -A _nh ^H 105 NH ₂ trans-2-(6-(4-(6-amino-3,5dioxo-4,5 -dihydro-1,2,4-triazin2(3H)-yl)-2,6-dichlorophenoxy)-3oxo-2,3-dihydropyridazin-4yl)cyclobutan-1-carbonitrile 462 [M+NG ^X H NMR (400 MHz, dmso-de) δ 12.27 (s, 2H), 7.85 (s, 2H), 7.59 (d, J = 1.3 Hz, 1H), 6.44 ( s, 2H), 3.82 3.89 (m, 1H), 3.57 - 3.65 (m, 1H), 2.22 - 2.32 (m, 4H) E fV ? CT^N CI ^ZX/ N NH ^H 106 nh ₂ 6-amino-2-(3,5-dichloro-4-((5-(3,3difluorocyclobutyl)-6-oxo-1,6dihydropyridazin-3-yl)oxy )phenyl)-1,2,4-triazine-3,5(2H,4/-/)-dione 473 [M+N] ^{+ X} H NMR (400 MHz, dmso-de) δ 12.31-12.28 (m, 2H), 7.85 (s, 2H), 7.66 (s, 1H), 6.53 (s, 2H ),3.39-3.31 (m, 1H), 2.94-2.86 (m, 4H) Ph Cl CX6a„ ^H 107 NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo5-(1-phenylcyclopropyl)-1,6-dihydropyridazin-3yl)oxy)phenyl)-1, 2,4-triazine-3,5(2H,4H)-dione 499 [M+N]* Ή NMR (400 MHz, DMSO-de) δ 1.21-1.25 (m, 2H), 1.37-1.43 (m, 2H), 6.50 (s, 2H), 7.17- 7.27 (m, 1H), 7.26-7.34 (m, 4H), 7.58 (s, 1H), 7.84 (s, 2H), 12.17 (s, 1H), 12 .26 (br. s, 1H) ppm. Co 9' A 3 AJL a O^N CI ^/XZ N NH ⁿ V 155 NH ₂ 6-amino-2-(3,5-dichloro-4-((5-(2,3dihydro-1H-inden-2- yl)-6-oxo1,6-dihydropyridazine-Zyl)oxy)phenyl)-1,2,4-triazine3,5(2H,4H)-dione 499 [M+NG ^X H NMR (400 MHz, DMSO-(Ub) δ 3.1 (dd, 2H, J = 15.5 Hz, 8.2 Hz), 3.25 (dd, 2H, J = 15.5 Hz, 7 .8 Hz), 3.72 (quint., 1H, J = 8.2 Hz), 6.49 (s, 2H), 7.17 (dd, 2H, J = 5.7 Hz, 3.0 Hz ), 7.26 (dd, 2H, J = 5.0 Hz, 2.8 Hz), 7.45 (s, 1H), 7.84 (s, 2H), 12.26 (br s, 1H ), 12.27 (s, 1H) ppm.

- 125 047363

GU ^C1 tVAS ⁰ o^n' ⁿ ci-^^'n^nh ⁿ νθ 15a νη ₂ 6-amino-2-(4-((5(bicyclo[4.2.0]octa-1(6),2, 4trien-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5dichlorophenyl)-1,2,4-tria Zin-3,5(2H,4H)-dione 485 [M+N] ⁺ -H NMR (400 MHz, DMSO-s/ ₆ ) δ 12.25 -12.33 (m, 2H), 7.82 (s, 2H>, 7.20 -7.40 (m, 5H), 6 .52 (s, 2H), 4.71 (s, 1H), 3.63 - 3.69 (m, 1H), 3.19 3.24 (m, 1H) 1 ⁰¹ oX' ⁿ c|AA' ⁿ Y ^{NH2 n} cAnAd 167 H 6-amino-2-(3,5-dichloro-4-((5-(1cyclobutylethyl)-6-oxo-1,6dihydropyridazin-3-yl )oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 465 [M+N] ^{+ g} H NMR (300 MHz, DMSO-cfe) δ 12.18 -12.28 (m, 2H), 7.85 (s, 2H), 7.38 (s, 1H), 6.53 (s, 2H ), 3.03 2.90 (m, 1H), 2.55 - 2.67 (m, 1H), 2.02 - 2.13 (m, 1H), 1.68 - 1.93 (m, 4H), 1.53 - 1.66 (m, 1H), 1.08 (d, >6.9Hz, ZN) ΑΧΛγ- ^H θΑΑ> 16S n 6-amino-2-(3,5-dichloro-4-((5-(1cyclobutylethyl)-6-oxo-1,6dihydropyridazin-3yl)oxy)phenyl)-1,2,4 -triazine3,5(2H,4H)-dione 465 [M+N] ^{+ :} H NMR (300 MHz, DMSO-s/b) δ 12.18 -12.28 (m, 2H), 7.85 (s, 2H>, 7.38 (s, 1H), 6.53 (s , 2H), 3.03 2.90 (m, 1H), 2.55 - 2.67 (m, 1H), 2.02 - 2.13 (m, 1H), 1.68 - 1.93 ( m, 4H), 1.53 - 1.66 (m, 1H), 1.08 (d, 1=6.9Hz, ZN) ΑχΑ-γ. ⁿ "6-amino-2-(3,5-dichloro-4-((5-(3methylbutan-2-yl)-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2 ,4-tria Zin3,5(2H,4H)-dione 465 [M+N]* -H NMR (300 MHz, DMSO-de) δ 12.19 (s, 2H), 7.87 (s, 2H), 7.46 (s, 1H), 6.51 (s, 2H), 2. 78 - 2.87 (m, 1H), 1.92 - 2.03 (m, 1H), 1.23 (d, 1=7.5Hz, ZN), 0.86 (d, J=6Hz, 6H ) = CI MMn'V* ¹² n 1 1 O ^Z W 170 n 6-amino-2-(3,5-dichloro-4-((5-(3methylbutan-2-yl)-6-oxo-1,6dihydropyridazin- 3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 465 [M+N] ⁺ !H NMR (300 MHz, DMSO-<U ₆ ) δ 12.19 (s, 2H), 7.87 (s, 2H), 7.46 (s, 1H), 6.51 (s, 2H), 2.78 - 2.87 (m, 1H), 1.92 - 2.03 (m, 1H), 1.23 (d, 1=7.5Hz, ZN), 0.86 (d, J =6Gy ,, 6H)

Example 74 Synthesis of Compound 90

Anhydrous THF (5 ml) was added to a mixture of 6-bromo-4-isopropylquinolin-2(1H)-one (prepared as in Synthesis (6), 934-942; 2011 and International Journal of Chemical Sciences, 7(3), 1784-1792; 2009) (400 mg, 1.50 mmol) and NaH 60% (90 mg) at 0°C, in an N2 atmosphere. The reaction mixture was stirred at 25°C for 1 hour. The mixture was then cooled to -78°C and tert-BuLi (1.94 ml) was added dropwise and the reaction mixture was stirred at -78°C for 30 minutes. Then a solution of 2,2,2-trifluoro-X-(4-formyl-3,5dimethylphenyl)acetamide (368 mg) in anhydrous. THF (5 ml) was added dropwise to the reaction mixture at -78°C. The reaction mixture was further stirred at this temperature for 1.5 hours and finally hydrolyzed sat. aq. NH ₄ Cl (8 ml) and poured into DCM (50 ml). The organic phase was washed with water (3x), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by chromatography on silica gel (20 to 85% EA in cyclohexane) to give 2,2,2-trifluoro-X-(4(hydroxy(4-isopropyl-2-oxo-1,2-dihydroquinolin-6-yl )methyl)-3,5-dimethylphenyl)acetamide as a white solid (162 mg, 25%).

LCMS (ESI, m/z): 433 [M+H]+.

- 126 047363

Et ₃ SiH (1.71 ml) and TMSOTf (0.039 ml) were added dropwise to the solution of 2,2,2-trifluoro-N-(4(hydroxy(4-isopropyl-2-oxo-1,2-dihydroquinoline-6 -yl)methyl)-3,5-dimethylphenyl)acetamide (255 mg, 0.59 mmol) in anhydrous. DCM (29 ml) at 0°C under N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour, the ice bath was removed and the reaction mixture was stirred at 25°C for 6 hours. Additional Et ₃ SiH (0.57 ml) and TMSOTf (0.013 ml) was added and the reaction mixture was stirred at room pace. After 16, 36 and 42 hours, additional Et ₃ SiH (0.57 ml) and TMSOTf (0.013 ml) were added and the mixture was stirred for 64 hours. The reaction mixture was evaporated to dryness. NaHCO ₃ (saturated aq, 50 ml) and EA (3x50 ml) were added. The combined organic layers were washed with brine (150 ml), dried over MgSO ₄ , solids were removed by filtration and the filtrate was evaporated to dryness to give 2,2,2-trifluoro-X-(4-((4-isopropyl-2-oxo-1 ,2-dihydroquinolin-6-yl)methyl)-3,5dimethylphenyl)acetamide (306 mg), which was used without purification in the next step.

¹ H NMR (DMSO, 400 MHz) δ ppm: 1.19 (d, J=6.8 Hz, 6H), 2.22 (s, 6H), 3.20 (hept., J=6 .8 Hz, 1H), 4.06 (s, 2H), 6.31 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.22 (d, J=8 .4 Hz, 1H), 7.37 (s, 2H), 7.42 (s, 1H), 11.09 (br s, 1H), 11.52 (br s, 1H).

LCMS: C ₂₃ H ₂₃ F ₃ N ₂ O ₂ [M+H]+: 417.

NaOH (94 mg) was added to a solution of 2,2,2-trifluoro-X-(4-((4-isopropyl-2-oxo-1,2-dihydroquinolin6-yl)methyl)-3,5-dimethylphenyl)acetamide ( 245 mg, 0.59 mmol) in MeOH (25 ml) and water (2.5 ml) under N ₂ atmosphere. The reaction mixture was stirred at 60°C for 37 hours. An additional portion of NaOH (23 mg) was added and heating was continued for 24 hours. The reaction mixture was then quenched with water (150 ml). The solution was extracted with EA (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO ₄ , solids were removed by filtration and the filtrate was evaporated to dryness. The crude product was purified by silica gel chromatography (MeOH:DCM = 0-10%) to give 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylquinolin-2(1H)-one as a white solid ( 133 mg, 71%).

¹ H-NMR (DMSO, 400 MHz): δ ppm: 1.19 (d, J=6.8 Hz, 6H), 2.06 (s, 6H), 3.17 (hept., J =6.8 Hz, 1H), 3.89 (s, 2H), 4.76 (s, 2H), 6.29 (s, 2H), 6.30 (s, 1H), 7.13 (d , J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.37 (s, 2H), 11.50 (br s, 1H).

LCMS: C ₂₁ H ₂₄ N ₂ O [M+H]+: 321

2-(4-((4-Isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5tetrahydro-1 ,2,4-triazine-6-carbonitrile, compound 90, was prepared in a manner similar to that described for 2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3 ,5-dimethylphenyl)-3,5-dioxo-4H1,2,4-triazin-6-carbonitrile, starting from 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylquinolin-2(1H)-one .

Example 75. Synthesis of compounds 91 and 91-A:

Water (17 ml) was added to a solution of (5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (1 eq., 0.95 g, 5.4 mmol), 4-bromo-6-chloropyridazin-3 -amine (1.12 g, 5.4 mmol), Na ₂ CO ₃ (1.14 g, 10.8 mmol) and Pd(dppf)Cl ₂ DCM (0.37 g, 0.46 mmol) in 1,4-dioxane (51 ml). The reaction mixture was evacuated and backfilled with N ₂ (3x) and stirred at 110°C for 1 hour. After cooling to room. pace. the reaction mixture was diluted in EA and washed with saline. The aqueous phase was extracted with EA (2x). The combined organic phases were dried with Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 10% CH ₃ OH in DCM) to give 6-chloro-4-(5,6,7,8-tetrahydronaphthalene-2-yl)pyridazin-3-amine (1 .12 g, 80%) as a beige solid.

1H-NMR (300 MHz DMSO-dg) δ ppm: 1.75-1.76 (m, 4H), 2.76-2.77 (m, 4H), 6.32 (br. s, 2H), 7.20-7.23 (m, 3H), 7.30 (s, 1H).

tert-Butylnitrite (1.05 ml, 8.78 mmol) was added to a solution of 6-chloro-4-(5,6,7,8tetrahydronaphthalene-2-yl)pyridazin-3-amine (1.14 g, 4.39 mmol) and CuCl (0.87 g, 8.78 mmol) in anhydrous CH ₃ CN (40 ml) under N ₂ atmosphere. The reaction mixture was stirred at 60°C for 24 hours. After cooling to room. pace. the reaction mixture was diluted in EA, washed with sat. aq. NaHCO ₃ (2x), washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 3% CH ₃ OH in DCM) to give 3,6-dichloro-4(5,6,7,8-tetrahydronaphthalene-2-yl)pyridazine (0.81 g , 66%) as a yellow solid.

1H-NMR (300 MHz DMSO-dg) δ ppm: 1.77 (m, 4H), 2.78 (m, 4H), 7.21-7.35 (m, 3H), 8.06 (s, 1H).

- 127 047363

Preparation of 2-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione.

A cooled solution of NaNO ₂ (3.88 g, 56.2 mmol) in water (6.5 ml) was added to a solution of 4-amino-2,6dichlorophenol (10 g, 56.2 mmol) in HCl 37% (23 ml, 281 mmol) and water (63 ml) at 0°C in an N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour. This reaction mixture was slowly added to a mixture of ethyl N-(2-cyanoacetyl)carbamate (10.5 g, 67.4 mmol), ice (20 g), water (25 ml) and pyridine (225 ml) at 0°C. The resulting reaction mixture was stirred at 0°C for 1 hour. The precipitate was filtered and washed with water. The residue was dissolved in DCM and CH ₃ OH and evaporated to dryness to give ethyl (2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazinylidene)acetyl)carbamate (11.94 g, 62%) as a yellow solid, which was used without further purification in the next step. NaOAc (4 eq., 11.35 g, 0.14 mol) was added to the solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazinylidene)acetyl)carbamate (11, 94 g, 35 mmol) in acetic acid (330 ml) under N2. The reaction mixture was heated to boiling for 3 hours and then cooled to 0°C, water (400 ml) was added and the mixture was stirred for 2 hours. The precipitate was then filtered, washed with water, dissolved in CH ₃ OH and evaporated to dryness to obtain 2 -(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5tetrahydro-1,2,4-triazine-6-carbonitrile (6.48 g, 63%) as beige solid, which was used without further purification in the next step.

A mixture of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (1 eq., 6.48 g, 21.7 mmol), HCl 37% (16 ml, 195 mmol) and AcOH (33 ml, 580 mmol) in an atmosphere of N2 were stirred at 120°C for 2.5 hours. After cooling to room. pace. the reaction mixture was diluted in water, and the precipitate was filtered and washed with water. The residue was dissolved in CH3OH and evaporated to dryness to give 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid acid (9.2 g) as a yellow solid, which was used without further purification in the next step.

¹ H-NMR (400 MHz DMSO-de) δ ppm: 7.57 (s, 2H), 10.66 (s, 1H), 12.57 (br s, 1H).

Solution of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (8.88 g, 27.9 mmol) in mercaptoacetic acid (14 ml) under N2 atmosphere was stirred at 170°C for 3 hours. After cooling to room. pace. the reaction mixture was diluted in water, and the precipitate was filtered and washed with water. The residue was dissolved in CH ₃ OH and evaporated to dryness to give 2-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (9.4 g) in as a yellow solid, which was used without further purification in the next step.

Ή-NMR (DMSO, 300 MHz): δ ppm: 4.37 (s, 1H), 7.54 (s, 2H), 7.61 (s, 1H).

Mixture of 3,6-dichloro-4-(5,6,7,8-tetrahydronaphthalene-2-yl)pyridazine (780 mg, 2.79 mmol), 2-(3,5-dichloro-4-hydroxyphenyl)-1 ,2,4-triazine-3,5(2H,4H)-dione (766 mg, 2.79 mmol), K ₂ CO ₃ (1.16 mg, 8.38 mmol) and CuI (266 mg, 1. 4 mmol) in anhydrous DMSO (13 ml) under N2 atmosphere was stirred at 120°C for 16 hours. After cooling to room. pace. the reaction mixture was diluted in EtOAc and washed with sat. aq. NH ₄ Cl (2x). The aqueous phase was extracted with EtOAc (2x) and the organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 3% MeOH in DCM) to give a mixture of 2-(3,5-dichloro-4-((6-chloro5-(5,6,7,8-tetrahydronaphthalene-2-yl )pyridazin-3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione and 2-(3,5-dichloro-4-((6-chloro-4- (5,6,7,8-tetrahydronaphthalene-2-yl)pyridazin-3-yl)oxy)phenyl)-1,2,4-triazine 3^^H^SH-dioju (65:35, 593 mg, 41% ) as a beige solid.

LCMS: C ₂₃ H ₁₆ Cl ₃ N ₅ O ₃ [M+H]+: 516/518.

A mixture of regioisomers of the compound (560 mg, 1.08 mmol) and NaOAc (533 mg, 6.50 mmol) in AcOH (11 ml) under N ₂ was stirred at 118°C for 4 hours. After cooling to room. pace. the reaction mixture was diluted in water, filtered, washed with water (3x) and n-pentane. The precipitate was dissolved in ESA, dried with Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 5% MeOH in DCM) to obtain two fractions. The first fraction was purified by trituration with diethyl ether (3x) to obtain 2-(3,5-dichloro-4-((6-oxo-5-(5,6,7,8tetrahydronaphthalene-2-yl)-1,6-dihydropyridazine -3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (286 mg, 53%) as a beige solid.

¹ H-NMR (400 MHz DMSO-de) δ ppm: 1.76 (br s, 4H), 2.77 (br s, 4H), 7.15-7.17 (m, 1H ), 7.68-7.71 (m, 3H), 7.82 (s, 3H), 12.41 (s, 1H), 12.49 (br s, 1H).

LCMS: C ₂₃ H ₁₆ Cl ₃ N ₅ O ₃ [M+H]+: 516/518.

The second fraction was purified by trituration with Et ₂ O (3x) to obtain 2-(3,5-dichloro-4-((6-oxo-4(5,6,7,8-tetrahydronaphthalene-2-yl)-1,6 -dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione (64 mg, 12%) as a beige solid.

¹ H-NMR (400 MHz DMSO-de) δ ppm: 1.77 (br s, 4H), 2.78 (br s, 4H), 7.06 (d, J=2.4 Hz, 1H), 7.22

- 128 047363 (d, J=7.9 Hz, 1H), 7.48-7.52 (m, 2H), 7.70 (s, 1H), 7.81 (s, 2H), 12.34 (d, J=2.5 Hz, 1H), 12.49 (br s, 1H).

LCMS: C ₂₃ H ₁₆ Cl ₃ N ₅ O ₃ [M+H]+: 516/518.

Example 76. Synthesis of compounds 92 and 92-A:

The title compounds were prepared using a method similar to that described for 2-(3,5-dichloro-4-((6-oxo-5-(5,6,7,8-tetrahydronaphthalene-2-yl)-1,6 -dihydropyridazin-3-yl)oxy)phenyl)1,2,4-triazine-3,5 (2H,4H)-dione and 2-(3,5-dichloro-4-((6-oxo-4-( 5,6,7,8-tetrahydronaphthalene-2-yl)-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, except that 2-naphthylboronic acid was used in the aryl cross-coupling reaction instead of (5,6,7,8tetrahydronaphthalen-2-yl)boronic acid.

92: ¹ H-NMR (400 MHz DMSO-dg) δ ppm: 7.56-7.64 (m, 2H), 7.72 (s, 1H), 7.84 (s, 2H), 7.96-8.07 (m, 5H), 8.68 (s, 1H), 12.51 (s, 1H), 12.55 (s, 1H). LCMS: C ₂₃ H ₁₃ Cl ₂ N ₅ O ₄ [M+H]+: 494/496.

92-A: 1H-NMR (400 MHz DMSO-dg) δ ppm: 7.27 (d, J=2.1 Hz, 1H), 7.59-7.67 (m, 2H), 7 .70 (s, 1H), 7.82 (s, 2H), 7.92 (dd, J=8.5 Hz, 1.9 Hz, 1H), 7.99-8.06 (m, 2H) , 8.09 (d, J=8.7 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 12.45 (d, J=1.9 Hz, 1H), 12 .49 (s, 1H). LCMS: C ₂₃ H ₁₃ Cl ₂ N ₅ O ₄ [M+H]+: 494/496.

The following compounds were prepared in the same manner as described for 6-amino-2-(3,5-dichloro-4-[[5(naphthalene-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl )-4H-1,2,4-triazine-3,5-dione (compound 67).

Structure LCMS (ESI, m/z) NMR ^N Yji? ^Η 108 ΝΗ ₂ [Μ+Η] ⁺ =511 ^2H NMR (400 MHz, DMSO-s/ ₆ ) δ 12.56 (Br,2H), 9.39(d, J = 3.0 Hz, 1H), 8.71(s, 1H), 8, 49-8.46(m,1H), 8.428.38(m,1H), 8.32-

- 129 047363

6-amino-2-(3,5-dichloro-4-((5-(cinnolin-6yl)-6-oxo-1 _? 6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine- 3.5(2H,4^)' DION 8.21(m,1H),8.07(s,1H), 7.92(s, 2H), 5.79 (Br,2H) ⁿ 109 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(cinnolin-6yl)-6-oxo-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2, 4-triazine-3,5(2H,4H)dione [M+NG=511 ^X H NMR (400 MHz, DMSO-s/e) δ 12.54 (Βγ,ΙΗ), 12.30(s, 1H), 9.49(d, J = 3.0 Hz, 1H), 8, 64 (d, J = 4.4 Hz, 1H), 8.52 (s, 1H), 8.358.31 (m, 2H), 7.91 (s, 2H), 7.37 (s, 1H), 6.33 (Br,2H) A JL ₀ Μ ' ^N C1 _{Ν Ν} Η ^Η Vo 110 νη ₂ 6-amino-2-(3,5-dichloro-4-((5-(cinnolin-7yl)-6-oxo-1,6-dihydropyridazin- 3yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N] ⁺ =511 SH NMR (400 MHz, DMSO-s/ ₆ ) δ 12.41 (Βγ,ΙΗ), 9.45(d, J = 3.0 Hz, 1H), 9.21(s, 1H), 8.39 -8.37(m,1H), 8.378.36(m,1H), 8.28(s,1H), 8.23-8.17(m,1H), 7.96(s,2H), 6.10 (Br,2H) ιΐ Α,ν ( J Cl fn °yS ⁰ AN ' ^N Cl ΆίΑ _N JL _NH ^H 111 nh ₂ 6-amino-2-(3,5-dichloro-4-((4-(cinnolin-7yl)-6- oxo-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine-3,5(2/-/, 4H)dione [M+N]*=511 SH NMR (400 MHz, DMSO-s/e) δ 12.48 (Br,2H), 9.48(d, J = 3.0 Hz, 1H), 8.91(s, 1H), 8.34 -8.32(m,1H), 8.298.25(m,2H), 7.94 (s,2H), 7.43(s, 1H), 6.18 (Br,2H) ΎΊ1 ? ⁰ сА N ' ^N С1 Ν Ν ^Н νθ 112 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((5-(3,4-dimethylphenyl)-6-oxo-1,6-dihydropyridazine -3-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione [M+N] ⁺ =487 ^X H NMR (400 MHz, DMSO-s/e) δ 12.40 (s, 1H), 12.28 (s, 1H), 7.72 - 7.87 (m, 5H), 7.77 (d , J= 7.8 Hz, 1H), 6.53 (s, 2H), 2.29 (s, 6H)

- 130 047363

ά _α ^Η ν° 113 νη ₂ 6-amino-2-(3,5-DICHLORO-4-((4-(3,4dimethylphenyl)-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4triazine-3,5(2H,4^)-dione [M+N] ⁺ =487 ^X H NMR (400 MHz, DMSO-(U ₆ ) δ 12.38 (s, 1H), 12.27 (s, 1H), 7.86 (s, 2H), 7.51-7.57 (m , 2H), 7.31 (d, J= 7.8Hz, 1H), 7.06 (s, 1H), 6.51 (s, 2H), 2.29 (s, 6H) r°YQi ? O^N^CI-^^^N^NH ^Η νθ 114 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((5-(chroman-6-yl)6-oxo-1,6 -dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N]*=515 'H NMR (400 MHz, DMSO-ds) δ 12.37 C 12.29 (m, 2H), 7.86 C 7.78 (m, 5H), 6.83 C 6.81 (m, 1H), 6.55 (s, 2H), 4.21 C 4.19 (m, 2H), 2.82 C 2.78 (m, 2H), 1.98 C 1.95 (m, 6H) 4 f» A/ j? o ^< *'n' ⁿ ci' ^x4 ^ ⁴ n ^>4 nh ^H Ao 115 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(chroman-6-yl)-6- oxo-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N] ⁺ =515 ^X H NMR (400 MHz, DMSO-ds) δ 12.92 (s, 2H), 7.86 (s, 2H), 7.56 C 7.54 (m, 2H), 7.03 (s, 1H) ), 6,EOS 6.88 (m, 1H), 6.54 (s, 2H), 4.21 C 4.19 (m, 2H), 2.83 C 2.80 (m, 2H), 1 .97С 1.94 (m, 2Н) ^0Ι ΎΠι 1 o^n'Ai'Y^^n'^nh ^H Vo 116 nh ₂ 6-amino-2-(3,5-dichloro-4-((5-(4-chloro-3methylphenyl)-6- oxo-1,6-dihydropyridazin3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N] ⁺ =507 ^X H NMR (400 MHz, DMSO-de) δ 12.51 (br, 1H), 12.27 (br, 1H), 7.87-8.06 (m, 5H), 7.53 (d , J = 8.1 Hz, 1H), 6.53 (s, 2H), 2.40 (s, ZN).

- 131 047363

Cl fy C! jHtS j? o^n- ⁿ ci- ^x4 ^ ^< n- ^>< nh ^H y _o 117 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(4-chloro-3methylphenyl)-6- oxo-1,6-dihydropyridazin3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N] ⁺ =507 ^X H NMR (400 MHz, DMSO-(U ₆ ) 6 12.28 12.41 (m, 2H), 7.87 (s, 2H), 7.78 (s, 1H), 7.597.67 (m, 2H), 7.16 (s, 1H), 6.54 (s, 2H), 2.41 (s, ZN) O 1' F ₂ HCO T % o J. JI 1 li ^H Vo ^{11tt 2} b-amino-2-(3,5-dichloro-4-((5-(3-difluoromethoxyphenyl)-6-oxo-1,6 -dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+NG=525 ^g H NMR (400 MHz, DMSO-ds) δ 12.2912.57 (m, 2H), 7.99 (s, 1H), 7.82-7.90 (m, 4H), 7.53-7 .60 (m, 1H), 7.23 - 7.40 (m, 2H), 6.55 (s, 2H) ^YUSNR ₂ and s/n j? ^H Vo 119 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(3(difluoromethoxy)phenyl)-6-oxo-1,6dihydropyridazin-3-yl)oxy)phenyl)-1 ,2,4triazine-3,5(2H,4H)-dione [M+NG=525 ^g H NMR (400 MHz, DMSO-ds) δ 12.2812.46 (m, 2H), 7.87 (s, 2H), 7.59 C 7.72 (m, ZH), 7.36-7 .39 (m, 2H), 7.217.23 (m, 1H), 6.55 (s, 2H) SP Ϊ ¹ хнП ° СТ ⁴ Ν ' ^N С1 Ν Ν Н ^Н 120 ^nh 2 6-amino-2-(3,5-dichloro-4-((5-(2,3-dihydro-1H-inden-5- yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+N] ⁺ =525 ^X H NMR (400 MHz, DMSO-s/e) δ 12.27 12.40 (m, 2H), 7.727.87 (m, 5H), 7.33 (d, J = 8.1 Hz, 1H) , 6.53 (s, 2H), 2.50 (t, J = 1.8Hz, 4H), 2.01-2.11 (m, 2H)

- 132 047363

Cl /VyS o (AN ' ^N Cl ΆίΑ N 47 NH ^H Vo 121 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(2,3-dihydro-1H-inden-5- yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazine-3,5(2H,4H)-dione [M+N] ⁺ =525 ^X H NMR (400 MHz, DMSO-de) δ 12.26 12.33 (m, 2H), 7.86 (s, 2H), 7.63 (s, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 6.53 (s, 2H), 2.91 - 2.96 ( m,4N), 2.01 - 2.11 (m,2H) ^Cl 0 ^<! ^N' ^N CI' ^x ^ ^si! 4^N'4 ⁴ NH ^H Vo 122 NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-5(pyrazolo[1,5-a]pyridin-6-yl)- 1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazine-3,5(2H,4H)-dione [M+N] ⁺ =499 ^X H NMR (400 MHz, DMSO-de) δ 12.64 (s, 1H), 12.29 (s, 1H), 9.84 (s, 1H), 8.09 - 8.18 (m, 2H ), 7.76-7.89 (M,4H), 6.66-6.71 (m, 1H), 6.53 (s, 2H) Λ o ci /y°yS ° ^Н Vo 123 NH ₂ 6-amino-2-(3,5-DICHLORO-4-((6-oxo-4(pyrazolo[1,5-a]pyridin-6-yl) -1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazine-3,5(2H,4H)-dione [M+N] ⁺ =499 ^X H NMR (400 MHz, DMSO-de) δ 12.44 (s, 1H), 12.28 (s, 1H), 9.17 (s, 1H), 8.11-8.15 (m, 1H ), 7.82-7.89 (m, ZN), 7.57-7.62 (m, 1H), 7.35 (s, 1H), 6.70 - 6.74 (m, 1H), 6.54 (s, 2H) Cl ° ^H v° 124 ^nh 2 6-amino-2-(3,5-dichloro-4-((6-oxo-5(pyrazolo[1,5-a]pyridin-5-yl)-1,6dihydropyridazin- 3-yl)oxy)phenyl)-1,2,4triazine-3,5(2H,4H)-dione [M+N]*=499 ψ NMR (300 MHz, DMSO-de) δ 12.60 (s, 1H), 12.28 (s, 1H), 8.70 - 8.77 (m, 2H), 8.08 8.11 (m , 2H), 7.88 (s, 2H), 7.46-7.49 (m, 1H), 6.82 (d, J = 1.8 Hz. 1H), 6.54 (lat, 2H )

- 133 047363

c? . f°yS S ο^νΛι-^'^ν-^'νη ^H v° 125 NH ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-4(pyrazolo[1,5 -a]pyridin-5-yl)-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazin-3,5(2H,4H)-dione [M+N]~=499 ^g H NMR (300 MHz, DMSO-ds) δ 0.85 (d, J = 7.2 Hz, 1H), 8.11-8.18 (m, 2H), 7.98 (s, 2H), 8.27- 7.28 (m, 2H), 6.82 (d, J = 1.5 Hz. 1H), 5.87 (lat., 2H) 0 ^< ^N' ^N CI' ^z ^ ^x ^N ^x ^NH ^Η 126 ^ΝΗ 2 6-amino-2-(3,5-dichloro-4-((5-(imidazo[1,5-a]pyridin- 7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+N]*=499 ^X H NMR (300 MHz, DMSO-de) δ 12.52 (s, 1H), 8.80 C 8.81 (m, 1H), 8.39 C 8.47 (m, 2H), 8.01 (s, 1H), 7.87 (s, 2H), 7.62 (s, 1H), 7.25 C 7.29 (m, 1H), 6.47 (s, 2H). /=\ σ o. °vS £ 127 NH ₂ 6-amino-2-(3,5-dichloro-4-((4-(imidazo[1,5a]pyridin-7-yl)-6-oxo-1,6-dihydropyridazin-3 -yl)oxy)phenyl)-1,2,4triazine-3,5(2H,4H)-dione [M+N]*=499 ^X H NMR (300 MHz, DMSO-ds) δ 12.25 C 12.38 (m, 2H), 8.42 C 8.53 (m, 2H), 8.11 (s, 1H), 7.88 (s, 2H), 7.59 (s, 1H), 7.23 (s, 1H), 7.03 C 7.07 (m, 1H), 6.49 (s, 2H) {X - ^Ν χΧζΧ a 0 N Cl N NH ^H Vo 128 ^NH 2 6-amino-2-(3,5-dichloro-4-((6-oxo-5(quinolin-6-yl)-1,6- Dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N]*=510 'H NMR (300 MHz, DMSO-ds) δ 12.52 (br, 1H), 8.97-8.94 (m, 1H), 8.72-8.71 (m, 1H), 8, 51-8.47 (m,1H), 8.28 (d,1=1Hz, 1H), 8.05-8.02 (m, 4H), 7.627.60 (m, 1H), 5.65( s, 2H)

- 134 047363

η ci Ατ°γ\ o Ο^Ν' ^Ν ΟΙ^^ ^χ Ν·^ΝΗ ^H ν° 129 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-4- ( quinolin-6-yl)-1,6-dihydropyridazin-3yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)dione [M+N] ⁺ =510 !n NMR (400 MHz, DMSO-dc) δ 9.01 C 8.99 (m, 1H), 8.49 (d, J = 4.0 Hz, 1H), 8.43 (s, 1H), 8.17 (s, 2H), 8.01 (s, 2H), 7.65 - 7.62 (u, 1H), 7.22 (s, 1H), 5.56 (s, 2H). 4 /=Х 01 ^Ν - A ,ο. 1 ^N yAf γη ⁰ oAn- ⁿ ci AiANA _NH ^H v° 130 ^nh 2 6-amino-2-(3,5-dichloro-4-((6-oxo-5(pyrazolo[1,5-a]pyridin- 2-yl)-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazin-3,5(2H,4H)-dione [M+N] ⁺ =499 Ή NMR (400 MHz, DMSO-de) δ 12.78 11.75 (m, 2H), 8.79 C 8.72 (m, 1H), 8.07 (s, 1H), 7.92 C 7 .74 (m, ZN), 7.62 (d, J = 0.9 Hz, 1H), 7.27-7.15 (m, 1H), 7.036.95 (m, 1H), 6.49 ( s, 2H) Λ ^ν Α ci /y°yS θ O^N^CI-^^N^NH ^Η Vo 131 nh ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-4(pyrazolo[ 1,5-a]pyridin-2-yl)-1,6dihydropyridazin-3-yl)oxy)phenyl)-1,2,4triazin-3,5(2H,4H)-dione [M+N]*=499 NMR (400 MHz, DMSO-cfe) δ 8.84-8.82 (m, 1H), 7.89 (s, 2H), 7.83 (m, 1H), 7.52 (s, 1H), 7.35 (d, J = 0.9 Hz, 1H), 7.34-7.32 (m, 1H), 7.08-7.03 (m, 1H), 6.49 (s, 2H) . γγ ^Ν ι ? c>A _n - ⁿ _C | ΑΑ _ν Α _νη ^Η V° 132 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(quinolin-3-yl)-1,6-dihydropyridazin-3yl)oxy )phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N]*=510 ^1H NMR (400 MHz, dmso-de) δ 9.38 (s, 1H), 9.04 (d, 1 = 2.0Hz, lh), 8.19 (s, 1H), 8.088.11 (m , 2H), 7.93 (s, 2H), 7.84-7.88 (m, 1H), 7.68 - 7.71 (m, 1H), 6.32 (s, 2H>. '%. < fY j? o^nAi^V^n-^nh 133 nh ₂ 6-amino-2-(3,5-dichloro-4-((6-oxo-4(quinolin-3-yl)-1,6-dihydropyridazin-3yl )oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+N] ⁺ =510 SH NMR (400 MHz, DMSO-(U ₆ ) δ 12.25 (br, 2H), 9.28 (d, J = 2.0 Hz, 1H), 8.81 (d,1 = 2.0 Hz, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.89-7.92 (m, ZN), 7.71 - 7.75 (m, 1H), 7.43 (s, 1H), 6.51 (s, 2H). %. Ν - ^N С1 m ν n ^Η ν° 134 ΝΗ ₂ 6-amino-2-(3,5-dichloro-4-((4-(isoquinolin-3yl)-6-oxo-1,6-dihydropyridazin-3yl) hydroxy)phenyl)-1,2,4-triazine-3,5(2H,4H)dione [M+NG=510 !H NMR (400 MHz, DMSO-de) δ 9.53 (s, 1H), 8.66 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.15 ( d, J = 8.4 Hz, 1H), 7.80 7.93 (m, 4H), 7.62 (s, 1H), 6.33 (br, 2H).

- 135 047363

The following compounds were prepared similarly to those described for compounds 91 and 91-A.

Structure LCMS (ESI, m/z) ^X H NMR s ₄ X O 1' ννΛ ° Ο^νΑι'ΥΥν'Υη ^H 135 0 2-(4-((5-(benzo[b]thiophen-5-yl)-6-oxo-1,6-dihydropyridazin-3 -yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+N]*=500 H NMR (400 MHz, DMSO-de) δ 7.57 (d, 1H, 1 = 5.4 Hz), 7.71 (s, 1H), 7.83-7.86 (m, ZN), 7 .93 (dd, 1H, J = 8.6 Hz, 1.8 Hz), 7.98 (s, 1H), 8.12 (d, 1H, J = 8.5 Hz), 8.59 (d , 1H, J = 1.8 Hz), 12.50-12.52 (m, 2H) 13 ΓΥ yy ^{С| H} Ά 136 2-(4-((4-(benzo[b]thiophen-5-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1, 2,4-triazine-3,5(2H,4H)-dione [M+N] ⁺ =500 H NMR (400 MHz, DMSO-de) δ 7.21 (d, 1H, J = 2.1 Hz), 7.58 (d, 1H, J = 5.5 Hz), 7.70 (br. s , 1H), 7.77 (dd, 1H, J = 8.6 Hz, 1.9 Hz), 7.82 (s, 2H), 7.9 (d, 1H, J = 5.5 Hz) , 8.2 (d, 1H, 1 = 8.7 Hz), 8.31 (d, 1H, J = 1.6 Hz), 12.41 (br. s, 1H), 12.49 (br. s, 1H) A 9 ¹ ιΓ^ Υ η θ O^Aci ΥΥ'Ν'Υη ^H n^A 137 2-(3,5-dichloro-4-((5-(5-methylpyridin-3-yl)-6-oxo- 1,6-dihydropyridazin-3-yl (oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+N] ⁺ =459 Ή NMR (400 MHz, DMSO-de) δ 2.37 (s, 3H), 7.59 (br s, 1H), 7.82 (s, 2H), 8.02 (s, 1H), 8 .17-8.19 (m, 1H), 8.51 (d, 1 = 1.7 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 12.50 (br. s, 1H), 12.57 (s, 1H) O 0. A ⁰ A j? ^H 138 ^^0 2-(3,5-dichloro-4-((4-(5-methylpyridin-3-yl)-6-oxo-1,6-dihydropyridazin3-yl)oxy)phenyl)-1,2 ,4-tri azine3,5(2H,4H)-dione [M+N] ⁺ =459 ^X H NMR (400 MHz, DMSO-de) δ 2.40 (s, ZH), 7.27 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.82 ( s, 2H), 8.008.04 (m, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 12.46 ( d, J = 1.6 Hz, 1H), 12.49 (s, 1H) A Ϊ ^{1 0 H} n^A 139 2-(3,5-dichloro-4-((6-oxo-5-(m-tolyl)-1,6-dihydropyridazin-Zyl)oxy)phenyl)-1,2 ,4-triazine-3,5(2H,4H)-dione [M+NG=458 ^X H NMR (400 MHz, DMSO-de) δ 2.38 (s, ZH), 7.31 (d, 1H, J = 7.6 Hz), 7.38 (t, 1H, J = 7.6 Hz), 7.71 (s, 1H), 7.75-7.78 (m, 2H), 7.82 (s, 2H), 7.86 (s, 1H), 12.47 (s, 1H), 12.50 (broad s, 1H) Ά Cl o O^N' ^N CI ^X CA _n Y _nh ^H Ν^Λ 140 2-(3,5-dichloro-4-((b-oxo-4-(m-tolyl)-1,6-dihydropyridazin- Zyl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [M+N]*=458 Ή NMR (400 MHz, DMSO-de) δ 2.38 (s, ZH), 7.1 (d, 1H, J = 2.2 Hz), 7.36 (d, 1H, J = 7.6 Hz ), 7.44 (t, 1H, J = 7.7 Hz), 7.59-7.61 (m, 2H), 7.70 (s, 1H), 7.81 (s, 2H), 12 .38 (width s, 1H), 12.49 (width s, 1H)

- 136 047363

Cl CT N ' ^N C1 NN ^{H H} V 141 Xj 2-(3,5-dichloro-4-((5-(2-methylpyridin4-yl)-6-oxo-1,6-dihydropyridazin3-yl)oxy)phenyl )-1,2,4-triazine-3,5(2H,4H)-dione [Μ+Η] ^ψ =459 ^1H NMR (400 MHz, DMSO-db) δ 2.55 (s, ZH), 7.72 (d, 1H, J = 1.8 Hz), 7.75 (dd, 1H, J = 5.0 Hz, J = 1.8 Hz), 7.82 (br. s, 1H), 7.83 (s, 2H), 8.07 (s, 1H), 8.57 (d, 1H, J = 5 ,3 Hz), 12.50 (br. s, 1H), 12.63 (s, 1H). T j CI ^{0 n} V 142 O 2-(3,5-dichloro-4-((4-(2-methylpyridin4-yl)-6-oxo-1,6-dihydropyridazin3-yl)oxy)phenyl)-1, 2,4-triazine-3,5(2H,4H)-dione [M+N]*=459 H NMR (400 MHz, DMSO-s/ ₆ ) δ 2.62 (s, ZH), 7.32 (s, 1H), 7.71 (d, 1H, J = 1.8 Hz), 7.73 (dd, 1H, J = 5.2 Hz, J = 1.8 Hz), 7.79 (br s, 1H), 7.82 (s, 2H), 8.72 (d, 1H, J = 5.4 Hz), 12.49 (s, 1H), 12.56 (lat s, 1H).

Example 77 Synthesis of compound 143

The title compound was prepared similarly to that described for compound 82, except that 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one was used instead of 5-bromo3,3-dimethylindolin-2 -she.

1H NMR (400 MHz, DMSO-0 ₆ ) δ ppm: 1.44-1.48 (m, 2H), 1.55-1.60 (m, 2H), 6.43 (dd, J =8.4 Hz, 2.6 Hz, 1H), 6.49 (br. s, 2H), 6.75 (d, J=2.6 Hz, 1H), 6.80 (d, J=8 .4 Hz, 1H), 7.89 (s, 2H), 10.47 (s, 1H), 12.26 (br s, 1H).

Example 78 Synthesis of Compound 144

A 500 ml round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (26 ml) in THF (100 ml) under N ₂ atmosphere. n-Butyllithium (60.00 ml, 636.953 mmol) was added dropwise at -78°C. The mixture was heated to -45°C and stirred for 30 minutes. The mixture was then cooled to -78°C and 3,6-dichloropyridazine (10.00 g, 67.128 mmol) in THF (100 ml) was added dropwise. The mixture was stirred for 30 minutes at -78°C. Cyclopentanone (60 ml) in THF (50 ml) was added dropwise. The reaction solution was stirred for 60 minutes at -75°C. The reaction mixture was quenched with saturated ammonium chloride (100 ml) and extracted with EA (3x100 ml), the combined organic layers were washed with brine (2x100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EA/PE (2/5) to give 1-(3,6-dichloropyridazin-4-yl)cyclopentan-1-ol (5 g, 28.76%) as a yellow oil.

LCMS (ESI, m/z): 233 [M+H]+.

A 100 mL round bottom flask was charged with 1-(3,6-dichloropyridazin-4-yl)cyclopentan-1-ol (4.50 g, 19.306 mmol) in CH ₂ Cl ₂ (50 mL) under N2 atmosphere. Bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (12.81 g, 57.918 mmol, 3.00 eq.) was added dropwise at 0°C. The reaction solution was stirred for 16 hours at room. pace. The reaction mixture was diluted with water (50 ml) and filtered through celite, the celite layer was washed with dichloromethane (2x50 ml), the filtrate was washed with brine (2x50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a PE/EA = 5/2 silica gel column to give 3,6-dichloro-4-(1-fluorocyclopentyl)pyridazine (2.5 g, 44%) as a yellow oil.

LCMS (ESI, m/z): 235 [M+H]+.

To a solution of 3,6-dichloro-4-(1-fluorocyclopentyl)pyridazine (500.00 mg, 2.127 mmol), tert-butyl-N[2-(3,5-dichloro-4-hydroxyphenyl)-3,5- dioxo-4H-1,2,4-triazin-6-yl]carbamate (827.78 mg, 2.127 mmol) and K ₂ CO ₃ (881.86 mg, 6.381 mmol, 3.00 eq.) in DMSO (10 ml) CuI (81.01 mg, 0.425 mmol) was added under nitrogen atmosphere. The mixture was stirred for 16 hours at 110°C and then quenched with water (20 ml). The mixture was acidified to pH ~5 with HCl (1 M, aq). The resulting mixture was extracted with ethyl acetate (3x30 ml).

- 137 047363

The combined organic layers were washed with brine (2x20 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (1:1) to give 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(1fluorocyclopentyl)pyridazin-3-yl ]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione (250 mg, 24%) as a yellow solid.

LCMS (ESI, m/z): 487 [M+H]+.

To a solution of 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(1-fluorocyclopentyl)pyridazin-3-yl]oxy]phenyl)4H-1,2,4-triazin- 3,5-dione (200.00 mg, 0.410 mmol) in acetic acid (5 ml) was added with sodium acetate (168.21 mg, 2.050 mmol). The mixture was stirred overnight at 100°C. The reaction mixture was cooled to room. temp., and then quenched with water (10 ml) and then stirred for 10 min, the resulting solid was washed with water (2x10 ml) and petroleum ether (2x5 ml), then dried under high vacuum to obtain the crude product. The crude product (100 mg) was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C18 column, 19x250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ -H ₂ O), mobile phase B: CH3CN; flow rate: 25 ml/min; gradient: from 29 to 49 V in 7 minutes; 220 nm; RT1: 6.98; Purification gave 6-amino-2-(3,5-dichloro-4-[[5-(1-fluorocyclopentyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2, 4triazine-3,5-dione (4 mg, 2.06%) as a white solid.

^1H NMR (400 MHz, DMSO) δ ppm: 12.47 (s, 1H), 12.27 (s, 1H), 7.87 (s, 2H), 7.53 (s, 1H) , 6.50 (s, 2H), 2.50-2.49 (m, 2H), 1.87-1.85 (m, 6H).

Example 79 Synthesis of Compound 145

145CN

A mixture of 2-bromo-5-hydroxybenzonitrile (5 g, 25.25 mmol), 1,2,3-trichloro-5-nitrobenzene (5.72 g, 25.25 mmol) and K ₂ CO ₃ (5.23 g , 37.88 mmol) in DMF (185 ml) under N2 atmosphere was stirred at 60°C for 1 hour. After cooling to room. pace. the reaction mixture was diluted in water and filtered. The precipitate was washed with water and dissolved in DCM.

The solution was dried with MgSO ₄ , filtered and evaporated to dryness to give 2-bromo-5-(2,6-dichloro-4nitrophenoxy)benzonitrile (9.65 g, 98%) as a yellow solid, which was used without further purification.

1H NMR (400 MHz, DMSO-06) δ ppm: 7.36 (dd, J=8.9 Hz, 3.1 Hz, 1H), 7.71 (d, J=3.2 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 8.58 (s, 2H).

A solution of benzophenone hydrazone (1.89 g, 9.64 mmol), Pd(OAc) ₂ (98 mg, 0.44 mmol) and BINAP (300.1 mg, 0.48 mmol) in toluene (17 ml) was evacuated and backfilled with N ₂ (3x) and the reaction mixture was heated at 100°C for 3 min. After cooling to room. pace. added 2-bromo-5-(2,6dichloro-4-nitrophenoxy)benzonitrile (3.4 g, 8.76 mmol), Cs ₂ CO ₃ (4 g, 12.27 mmol) and toluene (5.1 ml) . The reaction vessel was again evacuated and backfilled with N2 (3x) and the reaction mixture was heated at 100°C for 5 hours. After cooling to room. pace. the mixture was filtered through a pad of celite, the celite was washed with DCM and the solution was evaporated to dryness to give 5-(2,6-dichloro-4-nitrophenoxy)-2-(2(diphenylmethylene)hydrazinyl)benzonitrile as a dark red solid (4.41 g, quantity), which was used without additional purification.

1H NMR (400 MHz, DMSO^ ₆ ) δ ppm: 6.76 (d, J=2.9 Hz, 1H), 7.15 (dd, J=9.3 Hz, 2.9 Hz, 1H), 7.32-7.37 (m, 6H), 7.59-7.63 (m, 4H), 7.73 (d, J=9.3 Hz, 1H), 8.08 (s , 1H), 8.31 (s, 2H).

p-toluenesulfonic acid monohydrate (3.33 g, 17.5 mmol) was added to a solution of 5-(2,6-dichloro-4-nitrophenoxy)-2-(2-(diphenylmethylepe)hydrazinyl)benzonitrile (4.4 g, 8.74 mmol) in MeOH (61 ml) under N ₂ atmosphere. The reaction mixture was refluxed for 21 hours. After cooling to room temperature. pace. the reaction mixture was diluted with sat. aq. Na ₂ CO ₃ and extracted with EA (3x). The combined organic layers were washed with brine (3x) and water, dried over MgSO ₄ , filtered and evaporated to dryness. The crude product was purified by silica gel chromatography (20 to 70% EA in DCM) to give 5-(2,6-dichloro-4-nitrophenoxy)-1H-indazol-3-amine (1.45 g, 49%) as yellow solid.

1H NMR (400 MHz, DUSO-A,) δ ppm: 5.20 (s, 2H), 6.99 (d, J=2.4 Hz, 1H), 7.08 (dd, J= 9.0 Hz, 2.4 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 8.57 (s, 2H), 11.40 (s, 1H).

Trifluoroacetic anhydride (0.36 ml, 2.57 mmol) was added to a solution of 5-(2,6-dichloro-4nitrophenoxy)-1H-indazol-3-amine (435 mg, 1.28 mmol) in anhydrous DCM (10 ml ) at 0°C in an N2 atmosphere. The reaction mixture was stirred at room. pace. for 1 hour. The reaction mixture was then diluted in water and extracted with DCM (3x). The combined organic layers were dried over MgSO ₄ , solids were removed by filtration, and the solvent filtrate was evaporated to dryness. Unrefined ochi mixture

- 138 047363 flash chromatography on silica gel (from 20 to 60% EA in cyclohexane) to obtain N-(5-(2,6dichloro-4-nitrophenoxy)-1H-indazol-3-yl)-2,2,2 -trifluoroacetamide (558 mg, quant.) as a yellow solid.

1H NMR (400 MHz, DMSO-06) δ ppm: 7.05 (d, J=2.1 Hz, 1H), 7.17 (dd, J=9.1 Hz, 2.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.56 (s, 2H), 11.82 (s, 1H), 13.18 (s, 1H).

A solution of NH ₄ Cl (685.9 mg, 12.82 mmol) in water (6.4 ml) was added to a solution of \-(5-(2,6-di\lor-4nitrophenoxy)-1H-indazol-3-yl )-2,2,2-trifluoroacetamide (558 mg, 1.28 mmol) in ethanol (13 ml) under N ₂ atmosphere. Fe (358.1 mg, 6.41 mmol) was added and the reaction mixture was stirred at 70°C for 3 hours. After cooling to room. pace. HCl 37% (1 ml) was added and the reaction mixture was diluted in water. K2CO3 was slowly added until the pH was alkaline and the resulting solution was extracted with EA (3x). The combined organic layers were dried with Na ₂ SO ₄ , filtered and evaporated to dryness to give N(5-(4-amino-2,6-dichlorophenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide (365 mg, 70%) as a green solid, which was used without further purification.

1H NMR (400 MHz, DMSO-0 ₆ ) δ ppm: 5.60 (s, 2H), 6.73 (s, 2H), 6.85 (s, 1H), 7.08 (d, J=9.1 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 11.74 (s, 1H), 13.01 (s, 1H).

A solution of NaNO ₂ (94.8 mg, 1.37 mmol) in water (13.7 ml) was added to a solution of \-(5-(4-amino-2,6dichlorophenoxy)-1H-indazol-3-yl)-2 ,2,2-trifluoroacetamide (265 mg, 0.65 mmol) in HCl 37% (5.7 ml, 69.1 mmol), acetic acid (17.5 ml) and water (13.7 ml) at 0° C in N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour. In parallel, a solution of ethyl N-(2-cyanoacetyl)carbamate (153.2 mg, 0.98 mmol) in water (16.5 ml) and pyridine (5.7 ml ) was stirred at 0°C for 15 min. The first reaction mixture was quickly added to the second. The resulting reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was then diluted in water and filtered. The precipitate was washed with water to give ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3-(2,2,2-trifluoroacetamido)-1H-indazol-5-yl)oxy) phenyl)hydrazinylidene)acetyl)carbamate (170 mg, 45%) as a beige solid, which was used without further purification.

Sodium acetate (97.5 mg, 1.19 mmol) was added to a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((3(2,2,2-trifluoroacetamido)- 1H-Indazol-5-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (170 mg, 0.3 mmol) in acetic acid (10 ml) under N2. The reaction mixture was stirred at 120°C for 3 hours. After cooling to 0°C, the reaction mixture was diluted in water, stirred for 30 minutes at 0°C and filtered. The precipitate was washed with water and pentane. The crude mixture was purified by flash chromatography on silica gel (0 to 10% MeOH in DCM) to give N(5-(2,6-dichloro-4-(6cyano-3,5-dioxo-4,5-dihydro-1, 2,4-triazin-2(3H)-yl)phenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide (45 mg, 29%) as an orange solid.

LCMS: C ₁₉ H ₈ Cl ₂ F ₃ N ₇ O ₄ [M+H]+: 525.

Solution No. (5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-1 Nindazole -3-yl)-2,2,2-trifluoroacetamide (158 mg, 0.3 mmol) in ammonia (15 ml, 7 N in MeOH) under N ₂ was stirred at 60°C for 3 hours. The reaction mixture was evaporated to dryness to give 2-(4-((3amino-1H-indazol-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2, 4-triazine-6carbonitrile (127 mg, 98%) as an orange solid, which was used without further purification.

1H NMR (400 MHz, DMSO-06) δ ppm: 5.25 (br s, 2H), 6.96 (d, J=2.6 Hz, 1H), 7.05 (dd, J =9.2 Hz, 2.6 Hz, 1H), 7.09 (br. s, 1H), 7.24 (d, J=8.9 Hz, 1H), 7.81 (s, 2H), 11.34 (br. s, 1H).

Acetone (0.109 ml, 1.48 mmol) was added to a solution of 2-(4-((3-amino-1H-indazol-5-yl)oxy)-3,5dichlorophenyl)-3,5-dioxo-2,3, 4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (127 mg, 0.3 mmol) in ethanol (1.5 ml), THF (1.5 ml) and acetic acid (0.3 ml ) in an N2 atmosphere. After cooling to 0°C, NaCNBH ₃ (2 eq., 37.1 mg, 0.59 mmol) was added and the mixture was stirred at 0°C for 1.5 hours. The reaction mixture was then diluted in water and filtered. The precipitate was washed with water. The crude mixture was purified by flash chromatography on silica gel (0 to 10% MeOH in DCM) and the resulting product was dissolved in MTBE and filtered. The solution was evaporated to dryness to give 2-(3,5-dichloro-4-((3-(isopropylamino)1H-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carbonitrile (12 mg, 9%) as a red solid.

1H NMR (400 MHz, DMSO-06) δ ppm: 1.17 (d, J=6.4 Hz, 6H), 3.76 (br s, 1H), 5.67 (s, 1H ), 6.98 (d, J=2.5 Hz, 1H), 7.09 (dd, J=2.5 Hz, 8.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.81 (s, 2H), 11.34 (s, 1H), 13.28 (br s, 1H).

Example 80 Synthesis of compounds 146 and 147:

A mixture of 4-amino-2,6-dichlorophenol (30 g, 168.52 mmol) and Boc ₂ O (91.95 g, 421.31 mmol, 96.79 ml) in

- 139 047363

THF (400 ml) was heated to 80°C for 2 hours. The mixture was concentrated to give the crude product. The residue was purified by silica gel chromatography (eluent 0-15% EA/PE) to give tert-butyl N(3,5-dichloro-4-hydroxyphenyl)carbamate (35 g, 125.84 mmol, 75% yield) as light yellow solid matter.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.19 (s, 1H), 6.27 (br s, 1H), 5.55 (s, 1H), 1.44 (s , 10H).

A mixture of tert-butyl-N-(3,5-dichloro-4-hydroxyphenyl)carbamate (33.14 g, 119.15 mmol) and 2-bromo-4fluoro-1-nitro-benzene (31.46 g, 142, 98 mmol) and Cs ₂ CO ₃ (54.35 g, 166.81 mmol) in CH3CN (500 ml) was heated to 65°C for 18 hours. The mixture was concentrated to remove CH3CN and diluted with EA (500 ml) and organic layer washed with H2O (200 mlx2). The organic layer was dried over MgSO ₄ and concentrated to give the crude material, purified by silica gel chromatography (eluent 0-15% EA/PE) to give tert-butyl-N-[4-(3-bromo-4-nitrophenoxy)-3, 5-Dichlorophenyl]carbamate (20 g, 41.83 mmol, 35% yield) was obtained as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.97 (d, J=9.0 Hz, 1H), 7.55 (s, 2H), 7.18 (d, J=2 .6 Hz, 1H), 6.88 (dd, J=2.6, 9.0 Hz, 1H), 6.60 (s, 1H), 1.56 (s, 9H).

Mixture of tert-butyl-H-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]carbamate (21.5 g, 44.97 mmol) and TFA (51.27 g, 449.68 mmol , 33.29 ml) in DCM (200 ml) was stirred at 20°C for 4 hours. The mixture was concentrated. NaHCO ₃ (sat. aq., 500 ml) was added to the mixture. The mixture was stirred at 20°C for 4 hours. The precipitated solid was filtered and dried. 4-(3-bromo-4-nitrophenoxy)3,5-dichloroaniline (16.1 g, 39.18 mmol, 87% yield, 92% purity) was obtained as a yellow solid. HCl (12 M, 11.02 mL) was added to a solution of 4-(3-bromo-4-nitrophenoxy)-3,5-dichloroaniline (5 g, 13.23 mmol) in AcOH (60 mL). The mixture was cooled to 5°C in an ice bath. A solution of NaNO ₂ (2.74 g, 39.68 mmol) in H ₂ O (30 ml) was added to the above suspended solution, maintaining the temperature between 5-10°C. The mixture was stirred at 5°C for 30 minutes. A solution of ethyl N-(2cyanoacetyl)carbamate (2.48 g, 15.87 mmol) in pyridine (25 ml) was slowly added to the light yellow clear solution. The mixture was stirred at 5°C for 1 hour and then 20°C for 1 hour. The mixture was filtered and the filtered solid was diluted with ethyl acetate (500 ml) and washed with H2O (200 mlx2). The organic layer was dried over MgSO ₄ and concentrated to obtain the crude product. The crude product was used in the next step without further purification. Ethyl N-[2-[[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]hydrazono]-2-cyano-acetyl]carbamate (6.7 g, 12.29 mmol, yield 93 %) was obtained as a red solid.

^1H NMR (400 MHz, DMSOD6) δ ppm: 10.94 (s, 1H), 8.13-8.06 (m, 3H), 7.51 (d, J=2.6 Hz, 1H), 7.09 (dd, J=2.7, 9.1 Hz, 1H), 4.21 (k, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

Mixture of ethyl H-[2-[[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]hydrazono]-2-cyano-acetyl]carbamate (2 g, 3.67 mmol) and Et ₃ N (1.86 g, 18.34 mmol, 2.55 ml) in DMF (30 ml) was heated to 100°C and stirred for 18 hours under N ₂ atmosphere. The mixture was diluted with EA (200 ml) and washed with H ₂ O (3x 100 ml) and saline (3x 100 ml). The organic layer was dried over MgSO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent 0-100% EA/PE, then 0-10% MeOH/EA). 2-[4-(3-bromo4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (1.3 g, 2.60 mmol, yield 61 .74%) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSOD6) δ ppm: 8.10 (d, J=9.0 Hz, 1H), 7.89 (s, 2H), 7.61 (d, J=2, 8 Hz, 1H), 7.10 (dd, J=2.8, 9.1 Hz, 1H).

To a solution of 2-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (12.1 g, 24.25 mmol) in AcOH (20 ml) was added HCl (70 ml) and the mixture was stirred at 120°C for 16 hours. The mixture was concentrated to remove HCl and AcOH. H2O (80 ml) was added and the mixture was cooled to 0°C. The precipitated solid was isolated by filtration and dried to give 2-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylic acid ( 10.06 g, 19.42 mmol, 80% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO-b6) δ ppm: 13.19-12.22 (m, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.91 ( s, 2H), 7.63 (d, J=2.6 Hz, 1H), 7.10 (dd, J=2.7, 9.1 Hz, 1H).

Mixture of 2-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (9.06 g, 17.49 mmol) and DPPA (7.22 g, 26.23 mmol) and Et ₃ N (7.08 g, 69.95 mmol) in t-BuOH (15 ml) were heated to 85°C for 16 h under nitrogen . The mixture was diluted with EA (30 ml) and washed with H2O (10 mlx2). The organic layer was dried over MgSO ₄ and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent 0-50% EA/PE).

tert-Butyl-H-[2-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazin-6yl]carbamate (5.2 g, 8.83 mmol, 45.47% yield) was obtained as a yellow solid.

^1H NMR (400 MHz, DMSOD6) δ ppm: 12.66 (br s, 1H), 9.18 (s, 1H), 8.10 (d, J=9.1 Hz, 1H) , 7.98 (s, 2H), 7.61-7.55 (m, 1H), 7.08 (dd, J=2.7, 9.1 Hz, 1H), 1.46 (s, 9H ).

To a solution of tert-butyl-H-[2-[4-(3-bromo-4-nitrophenoxy)-3,5-dichlorophenyl]-3,5-dioxo-1,2,4triazin-6-yl]carbamate (1 g, 1.70 mmol) in THF (20 ml), MeOH (10 ml) and H2O (5 ml) added Fe

- 140 047363 (473.92 mg, 8.49 mmol) and NH ₄ Cl (453.95 mg, 8.49 mmol). The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with EA (50 ml), filtered and the filtrate was concentrated under reduced pressure to give tert-butyl-H-|2-|4-(4-amino-3-bromo- phenoxy)-3.5-dichlorophenyl|-3.5-dioxo1,2,4-triazin-6-yl]carbamate (700 mg, 1.25 mmol, 74% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.30 (br s, 1H), 9.15 (s, 1H), 7.88 (s, 2H), 6.87 (d , J=2.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.71-6.64 (m, 1H), 5.10 (lat s, 2H) , 1.45 (s, 9H).

To a solution of tert-but-yl-H-|2-|4-(4-amino-3-bromo-phenoxy)-3.5-dichlorophenyl|-3.5-dioxo-1.2.4triazin-6-yl]carbamate (700 mg, 1.25 mmol) in THF (20 ml) was added DIEA (485.35 mg, 3.76 mmol) and 4-methylpent-2-enoyl chloride (199.17 mg, 1.50 mmol, 11.69 μl) at 25 °C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with H2O (50 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with saturated aqueous sodium chloride (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by flash chromatography on silica gel (eluent 0-35% THF/PE) to give tert-butyl-[2-[4[3-bromo-4-[[4-methylpent-2-enoyl]amino]phenoxy ]-3,5-dichlorophenyl]-3,5-dioxo-1,2,4-triazin-6yl]carbamate (370 mg, 564.61 µmol, 45.10% yield) as a yellow solid.

1H NMR (400 MHz, DMSOA) δ ppm: 12.65 (br s, 1H), 9.52 (s, 1H), 9.09 (br s, 1H), 7.97-7 .94 (m, 2H), 7.53 (d, J=8.9 Hz, 1H), 7.23 (d, J=2.9 Hz, 1H), 6.87 (s, 1H), 6 .80 (dd, J=6.3, 15.4 Hz, 1H), 6.67 (s, 1H),6.58 (s, 1H), 6.18 (br.d, J=15.1 Hz, 1H), 1.46 (s, 9H), 1.05 (d, J=6.8 Hz, 6H).

To a solution of tert-butyl-N-[2-[4-[3-bromo-4-[[4-methylpent-2-enoyl]amino]phenoxy|-3,5-dichlorophenyl]3,5-dioxo-1, 2,4-triazin-6-yl]carbamate (320 mg, 488.31 µmol) in dioxane (2 ml) added TEA (148.24 mg, 1.46 mmol, 203.90 µl) and tri-tert-butylphosphane palladium (24.96 mg, 48.83 µmol) at 25°C. The mixture was then stirred at 130°C for 1.5 hours. LCMS showed complete uptake of the starting material and a mass peak of the desired product was detected. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by preparative HPLC [Column: Welch Xtimate C18 150x30 mmx5 µm; mobile phase: 50% _CH3CN in water (0.225% FA) to 80% CH3CN in water (0.225% FA)] to give tert-butyl-[2[3,5-dichloro-4-[(4-isopropyl -2-oxo-1H-quinolin-6-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6yl]carbamate (20 mg, 34.82 µmol, 1H NMR (400 MHz, DMSOD ₆ ) δ ppm: (br s, 1H), 11.66 (s, 1H), 9.15 (br s, 1H), 7.94 (s, 2H), 7.35 ( d, J=9.0 Hz, 1H), 7.23 (d, J=2.9 Hz, 1H), 7.11 (dd, J=2.6, 9.0 Hz, 1H),6, 39 (s, 1H), 3.20 (br.d, J=6.4 Hz, 1H), 1.46 (s, 9H), 1.21 (d, J=6.8 Hz, 6H)) , as a yellow solid and tert-butyl-H-[2-[3,5-dichloro-4-[(32)-3-(2-methylpropylidene)-2-oxo-indolin-5-yl]oxyphenyl] -3,5dioxo-1,2,4-triazin-6-yl]carbamate (26 mg, 45.26 µmol, 1H NMR (400 MHz, _DMSOD6 ) δ ppm: 12.63 (s, 1H) , 10.45 (s, 1H), 9.17 (s, 1H), 7.90 (s, 2H), 7.25 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.68 (d, J=10.0 Hz, 1H), 6.55 (dd, J=2.5, 8.5 Hz, 1H), 3.14 ( cd, J=6.7, 16.5 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J=6.5 Hz, 6H), as a yellow solid.

To a solution of tert-butyl-N[2-[3,5-dichloro-4-[(4-isopropyl-2-oxo-1H-quinolin-6-yl)oxy|phenyl]-3,5dioxo-1,2, 4-triazin-6-yl]carbamate (20 mg, 34.40 µmol) in MeOH (1 ml) was added with HCl/dioxane (4 M, 43.00 µl) at 15°C. The mixture was stirred at 15°C for 6 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC [Column: Welch Xtimate C18 150x30mmx5 µm; mobile phase: 30% CH3CN in water (0.04% NH3H2O + 10 mM NH4HCO3) to 60% CH3CN in water (0.04% NH3H2O + 10 mM NH4HCO3)] to give 6-amino-2-[3.5 -dichloro-4-[(4-isopropyl-2-oxo-1H-quinolin6-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione (1.95 mg, 4.07 µmol, yield 11.82%, purity 99%) as a white solid.

1H NMR (400 MHz, _DMSOD6 ) δ ppm: 12.30 (br s, 1H), 11.65 (s, 1H), 7.95 (s, 2H), 7.34 (d, J=8.9 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.11 (dd, J=2.7,8.9 Hz, 1H), 6.56 ( lat. s, 2H), 6.39 (sDN), 3.23-3.14 (m, 1H), 1.20 (d, J=6.8 Hz, 6H).

To a solution of tert-butyl-N-[2-[3,5-dichloro-4-[(32)-3-(2-methylpropylidene)-2-oxo-indolin-5yl]oxyphenyl]-3,5-dioxo- 1,2,4-triazin-6-yl]carbamate (26 mg, 45.26 µmol) in MeOH (1 ml) was added HCl/dioxane (4 M, 0.057 ml) at 15°C. The mixture was stirred at 15°C for 16 hours. The reaction mixture was concentrated in vacuo to obtain the crude product, which was purified by preparative HPLC [Column: Welch Xtimate C18 150x30 mmx5 μm; mobile phase: 10% CH3CN in water (0.2% FA) to 50% CH3CN in water (0.2% FA) to give 6-amino-2-[3,5-dichloro-4-[(32) -3-(2-methylpropylidene)-2oxoindolin-5-yl]oxyphenyl]-1,2,4-triazine-3,5-dione (4.64 mg, 9.73 µmol, purity 99.44%) as yellow solid.

1H NMR (400 MHz, DMSO^) δ ppm: 12.30 (br s, 1H), 10.44 (s, 1H), 7.91 (s, 2H), 7.24 (d, J=2.5 Hz, 1H), 6.78(d, J=8.5 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 6.54 (d, J= 2.6 Hz, 1H), 6.53-6.50 (m, 2H), 3.14 (td, J=6.5, 9.8 Hz, 1H), 1.14 (d, J=6 .5 Hz, 6H).

- 141 047363

Example 81 Synthesis of compound 148

148CN

Anhydrous THF (20 ml) was added to a mixture of 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (400 mg, 1.68 mmol) and NaH 60% (1.5 eq., 101 mg ) at 0°C in an N2 atmosphere. The resulting reaction mixture was stirred at 25°C for 1 hour. The mixture was then cooled to -78°C and t-BuLi (2.2 eq., 2.17 ml) was added dropwise and the reaction mixture was stirred at -78°C in for 30 minutes. Then, a solution of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (1 equiv., 412 mg) in anhydrous THF (5 ml) was added dropwise to the reaction mixture at -78°C . The reaction mixture was then left to warm to room. pace. for 2 hours and finally quenched with NH ₄ Cl (saturated aq., 4 ml) and poured into CH ₂ Cl ₂ (100 ml). The organic phase was washed with water (3x), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 50% EA in cyclohexane) to give 2,2,2-trifluoro-N-(4-(hydroxy(2'-oxospiro[cyclopropane-1,3'-indoline] -5'-yl)methyl)-3,5-dimethylphenyl)acetamide (269 mg, 40%) as a white solid.

¹ H NMR (400 MHz, DMSO-de) δ ppm: 1.38-1.52 (m, 4H), 2.20 (s, 6H), 5.75 (d, J=4.0 Hz, 1H), 6.06 (d, J=4.0 Hz, 1H), 6.78 (s, 2H), 6.92 (s, 1H), 7.28 (s, 2H), 10, 46 (s, 1H), 11.06 (br s, 1H), Et ₃ SiH (0.64 ml).

TMSOTf (0.027 ml) was added dropwise to the solution of 2,2,2-trifluoro-N-(4-(hydroxy(2'oxospiro[cyclopropan-1,3'-indolin]-5'-yl)methyl)-3, 5-dimethylphenyl)acetamide (268 mg, 0.66 mmol) in anhydrous CH ₂ Cl ₂ (30 ml) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour, at which point the ice bath was removed and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with sat. aq. NaHCO ₃ (20 ml) and extracted with CH ₂ Cl ₂ (3x40 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO ₄ , filtered and evaporated to dryness to give N(3,5-dimethyl-4-((2'-oxospiro[cyclopropane-1,3'-indoline]-5 'yl)methyl)phenyl)-2,2,2-trifluoroacetamide (229 mg, 89%) as a white solid, which was used without further purification.

1H NMR (400 MHz, DMSO-06) δ ppm: 1.41-1.48 (m, 4H), 2.18 (s, 6H), 3.91 (s, 2H), 6.58 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.75 (d, J=8.0 Hz, 1H), 7.35 (s, 2H), 10.43 (s, 1H), 11.06 (br s, 1H).

NaOH (6 eq., 141 mg) was added to a solution of Na(3,5-dimethyl-4-((2'-oxospiro[cyclopropan-1,3'indolin]-5'-yl)methyl)phenyl)-2, 2,2-trifluoroacetamide (229 mg, 0.59 mmol) in CH ₃ OH (25 ml) and water (2.5 ml) under N ₂ atmosphere. The mixture was stirred at 60°C for 23 hours. The mixture was then quenched with water (100 ml). The resulting solution was extracted with CH ₂ Cl ₂ (3x100 ml). The combined organic layers were washed with brine (300 ml), dried over MgSO ₄ , filtered and evaporated to dryness to give 5'-(4-amino-2,6-dimethylbenzyl)spiro[cyclopropane-1,3'-indoline]-2' -one (147 mg, 85%) as a white solid, which was used without further purification.

1H NMR (400 MHz, DMSO-е ₆ ) δ ppm: 1.40-1.46 (m, 4H), 2.02 (s, 6H), 3.76 (s, 2H), 4, 71 (s, 2H), 6.26 (s, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.73 (d, J=8 .0 Hz, 1H), 10.39 (s, 1H).

tert-Butylnitrite (0.090 ml) and pyridine (0.12 ml) were added to a solution of 5'-(4-amino-2,6dimethylbenzyl)spiro[cyclopropan-1,3'-indolin]-2'-one (1 eq. , 147 mg, 0.503 mmol) and ethyl N-(2cyanoacetyl)carbamate (118 mg) in anhydrous CH ₃ CN (15.5 ml) under N ₂ atmosphere. The reaction mixture was stirred at 60°C for 1.5 hours. After cooling to room. pace. NaOAc (6 eq., 248 mg) was added and the reaction mixture was heated at 80°C for 3 hours. Additional NaOAc (82 mg) was added and heating was continued for 64 hours. The reaction mixture was cooled to 0°C and water was added. (50 ml). The mixture was stirred for 30 min at 0°C and the resulting solution was extracted with EA (3x20 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 7.5% CH ₃ OH in CH ₂ Cl ₂ ) to give 2-(3,5-dimethyl-4-((2'-oxospiro[cyclopropane-1,3 '-indolin]-5'-yl)methyl)phenyl)-3,5-dioxo2,3,4,5-tetrahydro-1,2,4-triazin-6-carbonitrile (143 mg, 69%) as white solid matter.

1H NMR (400 MHz, DMSO-06) δ ppm: 1.42-1.50 (m, 4H), 2.24 (s, 6H), 3.98 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 7.16 (s, 2H), 10.45 (s, 1H), 12.98 (br s, 1H).

Example 82 Synthesis of compound 149

Anhydrous THF (6 ml) was added to a mixture of 6-bromo-1-isopropyl-1,3-dihydro-2H-benzo^]imidazol-2one (prepared according to Bioorganic & Medicinal Chemistry Letters 2005, 15(15), p. 3600- 3603, 300 mg,

- 142 047363

1.18 mmol) and NaH 60% (70.6 mg, 1.76 mmol) at 0°C, in an N2 atmosphere. The resulting reaction mixture was stirred at room. pace. for 1 hour. The mixture was then cooled to -78°C and t-BuLi (1.5 ml, 2.59 mmol, 1.7 M in pentane) was added dropwise and the reaction mixture was stirred at -78°C for 1 hour. Then, a solution of 4-bromo-2,6-dimethylbenzaldehyde (250.6 mg, 1.18 mmol) in anhydrous THF (3.8 ml) was added dropwise to the reaction mixture at -78°C. The reaction mixture was heated to room. pace. for 1 hour, and then extinguished sat. aq. NH ₄ Cl and extracted with CH ₂ Cl ₂ (3x). The combined organic phases were washed with water (3x), dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 60% AcOEt in cyclohexane) to give 6-((4-bromo-2,6-dimethylphenyl)(hydroxy)methyl)-1-isopropyl-1,3-dihydro- 2H-benzo[d]imidazol-2-one (277 mg, 61%) as a white solid.

H NMR (400 MHz, DMSO-06) δ ppm: 1.36-1.43 (m, 6H), 2.22 (s, 6H), 4.53 (p, J=6.9 Hz , 1H), 5.85 (d, J=3.3 Hz, 1H), 6.12 (d, J=3.0 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H ), 6.84 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 7.21 (s, 2H), 10.66 (s, 1H).

Et ₃ SiH (0.69 mL, 4.27 mmol) and TMSOTf (28.8 μL, 0.16 mmol) were added dropwise to the 6-((4-bromo-2,6-dimethylphenyl)(hydroxy)methyl solution )-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (277 mg, 0.71 mmol) in anhydrous CH2Cl2 (32.2 ml) at 0°C under N2. The reaction mixture was stirred at 0°C for 30 minutes, at which point the ice bath was removed and the reaction mixture was stirred at room temperature. pace. for 2 hours. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with CH ₂ Cl ₂ (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give 6-(4-bromo-2,6-dimethylbenzyl)-1-isopropyl-1,3-dihydro-2Hbenzo^]imidazole-2 -one (242 mg, 91%) as a white solid, which was used in the next step without further purification.

Solution of 6-(4-bromo-2,6-dimethylbenzyl)-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (195 mg, 0.52 mmol), 6-amino- 4-[(benzyloxy)methyl]-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione (142.6 mg, 0.57 mmol), K ₂ CO ₃ (288 .8 mg, 2.09 mmol), CuBr (74.9 mg, 0.52 mmol) and trans-N,Ndimethylcyclohexane-1,2-diamine (74.3 mg, 0.52 mmol) in anhydrous DMSO ( 3.9 ml) under N2 atmosphere was stirred at 120°C for 4 hours. After cooling to room. pace. the reaction mixture was diluted in water and filtered. The precipitate was washed with water and dissolved in CH ₂ Cl ₂ . The solution was dried with Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 5% CH ₃ OH in CH ₂ Cl ₂ ) to give 6-amino-4-((benzyloxy)methyl)-2-(4-((3-isopropyl-2 -oxo-2,3dihydro-1 H-benzo[d]imidazol-5-yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5 (2H,4H)-dione (81 mg, 29%) as a white solid.

^1H NMR (400 MHz, DMSO-06) δ ppm: 1.39 (d, J=6.9 Hz, 6H), 2.25 (s, 6H), 4.06 (s, 2H) , 4.51 (p, J=6.9 Hz, 1H), 4.66 (s, 2H), 5.41 (s, 2H), 6.38 (s, 2H), 6.46 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 7.00 (s, 1H), 7.19 (s, 2H), 7.26-7, 35 (m, 5H), 10.63 (s, 1H).

BBr ₃ (1.2 ml, 1.2 mmol, 1 M in CH ₂ Cl ₂ ) was added dropwise to the solution to give 6-amino-4((benzyloxy)methyl)-2-(4-((3-isopropyl -2-oxo-2,3-dihydro-1H-benzo^]imidazol-5-yl)methyl)-3,5dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (81 mg, 0.15 mmol) in CH ₂ Cl ₂ (50 ml) at 0°C in an N ₂ atmosphere. The reaction mixture was stirred at 0°C for 2 hours. Then cold CH ₃ OH was added dropwise at 0°C and the reaction mixture was slowly warmed to room. pace. then evaporated to dryness and the crude mixture was purified by chromatography on silica gel (0 to 10% CH ₃ OH in CH ₂ Cl ₂ ). The resulting product was purified by reverse phase flash chromatography (5 to 100% CH ₃ CN in water (0.1% TFA)) to give 6-amino-2-(4-((3-isopropyl-2-oxo-2 ,3-dihydro-1H-benzo^]imidazol-5-yl)methyl)3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (26 mg, 41%) as a white solid.

1H NMR (400 MHz, DMSO-dQ δ ppm: 1.39 (d, J=6.9 Hz, 6H), 2.23 (s, 6H), 4.04 (s, 2H), 4 .51 (hept., J=7.0 Hz, 1H), 6.30 (s, 2H), 6.44 (d, J=8.0 Hz, 1H), 6.83 (d, J=7 .9 Hz, 1H), 7.01 (s, 1H), 7.20 (s, 2H), 10.67 (s, 1H), 12.07 (s, 1H).

Example 83 Synthesis of Compound 150

6-Amino-2-(3,5-dimethyl-4-((2'-oxospiro[cyclopentane-1,3'-indolin]-5'-yl)methyl)phenyl)-1,2,4triazine-3, 5(2H,4H)-dione was prepared using a method similar to that described for compound 149, where 5'-bromospiro[cyclopentane-1,3'-indolin]-2'-one was used in the first step instead of 6-bromo-1 - isopropyl-1,3-dihydro-2H-benzo[^]imidazol-2-one.

1H NMR (400 MHz, DMSO-06) δ ppm: 1.65-1.73 (m, 2H), 1.84-1.98 (m, 6H), 2.21 (s, 6H) , 3.96 (s, 2H), 6.29 (s, 2H), 6.59 (dd, J=7.9 Hz, 1H); 6.69 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 7.19 (s, 2H), 10.17 (s, 1H), 12.07 (s, 1H ).

- 143 047363

Example 84 Synthesis of compound 151

6-Amino-2-(3,5-dimethyl-4-((2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)methyl)phenyl)-1,2,4triazine-3, 5(2H,4H)-dione was prepared using a method similar to that described for compound 149, where 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one was used in the first step instead of 6-bromo-1isopropyl- 1,3-dihydro-2H-benzo^]imidazol-2-one.

^1H NMR (400 MHz, DMSO^b) δ ppm: 1.42-1.49 (m, 4H), 2.20 (s, 6H), 3.94 (s, 2H), 6, 30 (s, 2H), 6.58 (dd, J=8.0 Hz, 1.9 Hz, 1H), 6.76 (dd, J=5.2 Hz, 3.3 Hz, 2H), 7 .19 (s, 2H), 10.44 (s, 1H), 12.08 (br s, 1H).

Example 85 Synthesis of compound 152

KOH (10 eq., 140 mg, 2.49 mmol) was added to the solution of 2-(3,5-dimethyl-4-((2'oxospiro[cyclopropan-1,3'-indolin]-5'-yl)methyl )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6carbonitrile (103 mg, 0.25 mmol) in water (1.3 ml) and EtOH (1 .3 ml) in an N2 atmosphere. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was evaporated to dryness, water and 1N were added. aqueous HCl solution was added until the pH was acidic. The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were dried with Na ₂ SO ₄ , filtered and evaporated to dryness to give 2-(3,5-dimethyl-4((2'-oxospiro[cyclopropan-1,3'-indolin]-5'-yl)methyl)phenyl )-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4triazine-6-carboxylic acid (102 mg, 95%) as a brown oil, which was used without further purification. A solution of 2-(3,5-dimethyl-4-((2'-oxospiro[cyclopropane-1,3'-indolin]-5'yl)methyl)phenyl)-3,5-dioxo-2,3,4, 5-tetrahydro-1,2,4-triazine-6-carboxylic acid (1 eq., 69 mg, 0.16 mmol) in mercaptoacetic acid (25 eq., 276 μl, 4 mmol) was quickly stirred and heated to 100° C for 3 hours. After cooling to room. pace. the reaction mixture was diluted in water, filtered and washed with water. The precipitate was dissolved in MeOH and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0 to 5% MeOH in DCM), triturated with MeCN (2x) and co-evaporated with EtOH (2x) to give 2-(3,5-dimethyl-4-((2'- Oxospiro[cyclopropan-1,3'-indolin]-5'yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (11 mg, 18%) as a yellow solid substances.

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.43-1.48 (m, 4H), 2.23 (s, 6H), 3.96 (s, 2H), 6. 59 (d, J=7.7 Hz, 1H), 6.77 (d, J=8.0 Hz, 2H), 7.17 (s, 2H), 7.61 (s, 1H), 10, 44 (s, 1H), 12.30 (br. s, 1H).

Example 86 Synthesis of compound 153

2-(3,5-Dimethyl-4-((2'-oxospiro[cyclobutan-1,3'-indolin]-5'-yl)methyl)phenyl)-3,5-dioxo-2,3,4, 5tetrahydro-1,2,4-triazine-6-carbonitrile was prepared using a method similar to that described for the preparation of 2-(3,5-dimethyl-4-((2'-oxospiro[cyclopropane-1,3'-indoline]- 5'-yl)methyl)phenyl)-3,5dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carbonitrile, where 5'-bromospiro[cyclobutane-1,3'-indoline ]-2'one was used instead of 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one.

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 2.11-2.27 (m, 10H), 2.37-2.43 (m, 2H), 4.04 (s, 2H), 6.60 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 7.18 (s, 2H), 7 .37 (s, 1H), 10.13 (s, 1H), 12.99 (br s, 1H).

Example 87: Receiving connection 154

To a solution of 6-bromo-3-methyl-1H-quinolin-2-one (3 g, 12.60 mmol) in THF (50 ml) was added NaH (2.02 g, 50.40 mmol, 60% purity) at 20°C. The mixture was stirred at 40°C for 0.5 h. Then SEM-Cl (4.20 g, 25.20 mmol, 4.46 ml) was added. The mixture was stirred at 40°C for 16 hours. The reaction mixture was quenched by adding NH4Cl (saturated aq, 20 ml) at 10°C and then diluted with H2O (60 ml) and extracted with EA (3x60 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (EA/PE = 0-10%) to give 6-bromo -3-methyl

- 144 047363

1-(2-trimethylsilylethoxymethyl)quinolin-2-one (3.25 g, 8.82 mmol, 70% yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.64 (d, J=2.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.52-7, 44 (m, 2H), 5.79 (s, 2H), 3.77-3.65 (m, 2H), 2.29 (d, J=0.9 Hz, 3H), 1.03-0 .89 (m, 2H), 0.04-0.05 (m, 9H).

Mixture of 6-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (3.25 g, 8.82 mmol, 1 eq.), Pin ₂ B ₂ (3.36 g, 13.24 mmol, 1.5 eq), KOAc (2.60 g, 26.47 mmol), PdCl ₂ (dppf) (720.55 mg, 882.34 µmol) in dioxane (60 ml) degassed and purged with N2 3 times , and then the mixture was stirred at 100°C for 16 hours under N2 atmosphere. The reaction mixture was diluted with H2O (100 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (100 mlx2), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to leave a residue. The residue was purified by silica gel chromatography (EA/PE = 0-10%) to give 3-methyl-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2 -trimethylsilylethoxymethyl)quinolin-2-one (4.1 g, crude) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.99 (s, 1H), 7.93 (dd, J=1.1, 8.4 Hz, 1H), 7.64-7, 54 (m, 2H), 5.83 (s, 2H), 3.79-3.66 (m, 2H), 2.29 (s, 3H), 1.41 (s, 12H), 1.02 -0.89 (m, 2H), 0.00 (s, 9H).

To a solution of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (4.1 g, 9.87 mmol) in acetone (60 ml) and H2O (30 ml) added NaIO ₄ (21.11 g, 98.70 mmol, 5.47 ml) and NH ₄ OAc (7.61 g, 98.70 mmol ) at 20°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with H2O (60 ml) and extracted with EA (3x60 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4, solids were removed under reduced pressure, and the filtrate was concentrated under reduced pressure to give [3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6- quinolinyl]boronic acid (2.7 g, 7.38 mmol, 75% yield, 91% purity) as a pink solid.

1H NMR (400 MHz, DMSOO δ ppm: 8.20 (s, 2H), 8.09 (s, 1H), 8.03-7.95 (m, 1H), 7.90-7, 81 (m, 1H), 7.55 (d, J=8.5 Hz, 1H), 5.79 (s, 2H), 3.68 (t, J=7.9 Hz, 2H), 2, 26-2.16 (m, 3H), 0.94 (t, J=7.9 Hz, 2H), 0.05-0.05 (m, 9H).

To a solution of [3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolinyl]boronic acid (500 mg, 1.50 mmol) in DMF (20 ml) was added 4 A MS (5 g, 1.50 mmol). 50 mmol), N(3,5-dichloro-4hydroxyphenyl)-Ndimethylformamidine (384.69 mg, 1.65 mmol), bis-(trifluoromethylsulfonyloxy) copper (542.64 mg, 1.50 mmol) and triethylamine (759 .08 mg, 7.50 mmol) at 15°C. The mixture was stirred at 15°C for 16 hours under an O ₂ atmosphere. The reaction mixture was diluted with H2O (50 ml) and extracted with EA (2x50 ml). The combined organic layers were washed with brine (2x50 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to leave a residue. The residue was purified by flash chromatography on silica gel (EA/PE = 0-35%) to give Na-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6- quinolinyl]oxy]phenyl]-XNi of dimethylformamidine (250 mg, 480.29 µmol, 32% yield) as a green solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.56 (s, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.43 (s, 1H), 7 .11 (dd, J=2.8, 9.2 Hz, 1H), 7.01 (s, 2H), 6.81 (d, J=2.9 Hz, 1H), 5.77 (s, 2H), 3.73-3.66 (m, 2H), 3.07 (br.d, J=11.0 Hz, 6H), 2.23 (d, J=0.9 Hz, 3H), 0.98-0.92 (m, 2H), -0.01-0.04 (m, 8H), -0.01-0.04 (m, 1H).

To a solution of Na[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolinyl]oxy]phenyl]-XNadimethylformamidine (658 mg, 1. 26 mmol) in isopropanol (20 ml) was added NH2NH2-H2O (630.76 mg, 12.60 mmol) at 20°C. The mixture was stirred at 80°C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (50 ml) and extracted with EA (2x30 ml). The aqueous phase was brought to pH 7 with 1 M aq. HCl. The combined organic layers were washed with saturated aqueous sodium chloride (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by silica gel chromatography (EA/PE = 0-30%) to give 6-(4-amino-2,6-dichlorophenoxy)-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin2-one (387 mg, 831 .46 µmol, 66% yield) as a white solid.

1H NMR (400 MHz, DMSOO δ ppm: 7.77 (s, 1H), 7.48 (d, J=9.3 Hz, 1H), 7.10 (dd, J=2.9, 9.3 Hz, 1H), 6.94 (d, J=2.9 Hz, 1H), 6.73 (s, 2H), 5.67 (s, 4H), 3.60-3.54 ( m, 2H), 2.08 (d, J=0.6 Hz, 3H), 0.89-0.81 (m, 2H), 0.04--0.15 (m, 9H).

To a mixture of 6-(4-amino-2,6-dichlorophenoxy)-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (387 mg, 665.17 µmol, 80% purity) in AcOH (5 ml ) HCl (12 M, 0.554 ml) was added. A solution of NaNO ₂ (137.69 mg, 2.00 mmol) in H2O (5 ml) was then added dropwise, maintaining the temperature below 0°C. After addition was complete, the reaction mixture was stirred for 0.5 hours. A mixture of ethyl N(2cyanoacetyl)carbamate (207.72 mg, 1.33 mmol) in pyridine (2.5 ml) was added dropwise to the resulting solution of diazonium salt at below 0°C and stirred for an additional 2 hours. The reaction mixture was diluted with H2O (50 ml), then extracted with EA (3x50 ml). The combined organic layers were washed with brine (60 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA in PE = 0-40%) to give ethyl-N[2-cyano-2-[[3,5-dichloro-4-[[3-methyl-2oxo-1-(2- trimethylsilylethoxymethyl)-6-quinolinyl]oxy]phenyl]hydrazono]acetyl]carbamate (315 mg,

- 145 047363

497.97 µmol, 74.8% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-de) δ ppm: 10.93 (br s, 1H), 10.89 (s, 1H), 8.07 (s, 2H), 7.77 (s , 1H), 7.51 (d, J=9.3 Hz, 1H), 7.17 (dd, J=3.0, 9.3 Hz, 1H), 7.02 (d, J=3, 0 Hz, 1H), 5.69 (s, 2H), 4.24-4.18 (m, 2H), 3.58 (t, J=7.9 Hz, 2H), 2.08 (d, J=0.8 Hz, 3H), 1.25-1.19 (m, 3H), 0.86 (t, J=7.9 Hz, 2H), -0.05--0.12 (m , 9H).

A[2-Cyano-2-[[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolinyl|oxy]phenyl]hydrazono]acetyl]carbamate ( 315 mg, 497.97 µmol) to AcOH (10 ml) was added NaOAc (204.25 mg, 2.49 mmol). The reaction mixture was concentrated in vacuo, then quenched by adding sat. aq. NaHCO ₃ (15 ml), then diluted with H2O (25 ml) and extracted with EA (3x25 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-[3,5-dichloro-4-[[3-methyl-2-oxo-1-( 2trimethylsilylethoxymethyl)-6-quinolinyl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile (300 mg, 406.48 µmol, 81.6% yield, 79% purity) as orange solid.

A mixture of 2-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolinyl]oxy]phenyl]-3,5-dioxo-1,2,4 -triazine-6-carbonitrile (265 mg, 359.06 µmol, purity 79.5%), TBAF (1 M, 10.77 ml) in THF (10 ml) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C for 16 hours in N2 atmosphere. The reaction mixture was quenched with NH4C1 (saturated aq, 20 ml) at 15°C and then diluted with H2O (10 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with sat. NH4C1 (30 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Column: Welch Xtimate C18 150x30 mmx5 µm; mobile phase: 48% CH ₃ CN in water (0.225% FA) to 78% CH ₃ CN in water (0.225% FA)] to give 2-[3,5-dichloro-4-[(3-methyl-2 -oxo-1H-quinolin-6-yl)oxy]phenyl]-3,5-dioxo1,2,4-triazine-6-carbonitrile (60.05 mg, 128.59 µmol, yield 35.8%, purity 98 %) as a light yellow solid.

1H NMR (400 MHz, DMSO-de) δ ppm: 13.28 (br s, 1H), 11.75 (s, 1H), 7.82 (s, 2H), 7.76 (s , 1H), 7.31 (d, J=9.0 Hz, 1H), 7.17 (dd, J=2.8, 8.9 Hz, 1H), 7.00 (d, J=2, 8 Hz, 1H), 2.05 (s, 3H).

Example 88 Synthesis of compound 156

A 40 ml vessel was charged with 2,2,6,6-tetramethylpiperidine (10.3 g, 73.2 mmol) in THF (100 ml) under a nitrogen atmosphere, n-butyllithium (26.8 ml, 67.1 mmol) was added drop by drop at -75°C. The reaction mixture was heated to 0°C and stirred for 30 minutes. 3,6-Dichloropyridazine (5 g, 33.6 mmol) in THF (100 ml) was added dropwise at -75°C. The reaction solution was stirred for 30 minutes. 2,3-Dihydro-1H-inden-1-one (5.32 g, 40.3 mmol) in THF (50 ml) was added dropwise at -75°C. The reaction solution was stirred for 90 minutes at -75°C. The reaction solution was stirred for 90 minutes at -75°C. The resulting solution was quenched with NH4C1 (saturated aq., 100 ml). The resulting solution was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (2x100 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/4) to obtain 2.28 g (yield 12%) of 1-(3,6-dichloropyridazin-4-yl)-2,3-dihydroinden-1-ol in as a yellow solid.

1H NMR (400 MHz, DMSO-ds) δ ppm: 8.17 (s, 1H), 7.28-7.37 (m, 2H), 7.14-7.19 (m, 1H) , 6.41 (m, 1H), 3.21-3.32 (m, 1H), 3.02-3.11 (m, 1H), 2.70-2.81 (m, 1H), 2 .19-2.27 (m, 1H).

LC-MS (ESI, m/z): 281 [M+H]+.

A 40 ml vessel was loaded with 1-(3,6-dichloropyridazin-4-yl)-2,3-dihydroinden-1-ol (800 mg, 2.85 mmol), 4-methylbenzenesulfonic acid (245 mg, 1.42 mmol ), toluene (10 ml). The reaction solution was stirred overnight at 60°C. The resulting solution was quenched with water (20 ml). The resulting solution was extracted with EA (3x20 ml) and the organic layers were combined, washed with brine (2x20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/9) to obtain 520 mg (50% yield) of 3,6-dichloro-4-(3H-inden-1-yl)pyridazine as a yellow solid.

1H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.59-7.62 (m, 2H), 733-7.40 (m, 2H), 723-7.26 (m, 1H), 6.92 (t, J=2.1 Hz, 1H), 3.68 (br, 2H).

LCMS (ESI, m/z): 263 [M+H]+.

A 100 ml round bottom flask was charged with 3,6-dichloro-4-(3H-inden-1-yl)pyridazine (800 mg, 0.380 mmol), platinum oxide hydrate (400 mg), EA (5 ml), ethanol (5 ml ). The contents of the flask were placed in a hydrogen atmosphere. The reaction mixture was stirred overnight at room. pace. Solid things

- 146 047363 stva filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (12/88) to obtain 165 mg (yield 19%) of 3,6-dichloro-4-(2,3dihydro-N-inden-1-yl)pyridazine as a white solid substances.

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.31-7.40 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 7.01 (s , 1H), 4.74 (t, J=7.5 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.74-2.86 (m, 1H), 1 .94-2.06 (m, 1H).

LCMS (ESI, m/z): 265 [M+H]+.

A 40 ml vessel was loaded with 3,6-dichloro-4-(2,3-dihydro-1H-inden-1-yl)pyridazine (200 mg, 0.754 mmol), tert-butyl-N-[2-(3.5 -dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (382 mg, 0.981 mmol), potassium carbonate (313 mg, 2.26 mmol), CuI (57.5 mg, 0.302 mmol), DMSO (10 ml) under nitrogen atmosphere. The reaction solution was stirred for 16 hours at 110°C. The reaction solution was quenched with water (10 ml). The resulting solution was extracted with ethyl acetate (3x20 ml) and the organic layers were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to obtain 120 mg (21% yield) of 6-amino-2-(3,5dichloro-4-[[6-chloro-5-(2,3- dihydro-1H-inden-1-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazin-3,5dione as a brown solid.

LCMS (ESI, m/z): 517 [M+H] ⁺ .

A 40 ml vessel was loaded with 6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(2,3-dihydro-1H-inden-1yl)pyridazin-3-yl]oxy]phenyl )-4H-1,2,4-triazine-3,5-dione (120 mg, 0.232 mmol, 1.00 eq.), sodium acetate (114 mg, 1.39 mmol), acetic acid (5 ml) in nitrogen atmosphere. The reaction solution was stirred overnight at 100°C. The reaction mixture was poured into water (5 ml). The solids were collected by filtration to obtain the crude product. The crude product was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C18, 19x250 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: CH3CN; flow rate: 25 ml/min; gradient: from 48 to 68 V in 7 minutes; 220 nm; RT1: 5.38; Purification gave 26.6 mg (31% yield) 6-amino-2-(3,5-dichloro-4[[5-(2,3-dihydro-1H-inden-1-yl)-6-oxo-1H -pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-Ίriazin-3,5-dione as a light yellow solid.

^1H NMR (300 MHz, DMSO-06) δ ppm: 12.27-12.36 (m, 2H), 7.84 (s, 2H), 7.33 (d, J=6.3 Hz, 1H), 7.167.26 (m, 3H), 7.03 (s, 1H), 6.53 (s, 2H), 4.55 (t, J=7.2 Hz, 1H), 2, 88-3.09 (m, 2H), 2.42-2.45 (m, 1H), 2.08-2.18 (m, 1H).

LCMS (ESI, m/z): 499 [M+H] ⁺ .

Example 89 Synthesis of compound 157

n

To a solution of 5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (1.9 g, 4.83 mmol) in MeOH (20 ml) and THF (5 ml) was added Et ₃ N (1.47 g, 14.49 mmol, 2.02 ml, 3 eq.) and Pd(dppf)Cl ₂ (706.97 mg, 0.966 mmol) and the mixture was stirred at 80°C for 12 hours under CO atmosphere (50 psi), then diluted with H2O (100 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EA in PE 0-30%) to give methyl 3-isopropyl-1-(ptolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carboxylate (1.61 g, 4.29 mmol, yield 88.77%, purity 99.2%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 9.34 (d, J=0.6 Hz, 1H), 8.38 (d, J=0.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.49 (d, J=0.8 Hz, 1H), 7.28-7.23 (m, 3H), 4.02 (s, 3H) , 3.14 (spt, J=6.8 Hz, 1H), 2.37 (s, 3H), 1.35 (d, J=6.9 Hz, 6H).

DIBAL-H (1 M, 7.99 ml) drop by drop at -65°C. After addition, the resulting mixture was stirred at -65°C for 0.5 h under N2 atmosphere. The reaction mixture was quenched with methanol (10 ml) and citric acid (sat. aq., 10 ml). The mixture was diluted with H2O (100 ml) and extracted with EA (3x50 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluent 0-15% EA/PE) to give 3-isopropyl- 1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carbaldehyde (807 mg, 2.28 mmol, 85.61% yield, 96.694% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 10.18 (s, 1H), 9.42 (d, J=0.8 Hz, 1H), 8.23 (d, J=0, 9 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.53 (d, J=0.8 Hz, 1H), 7.31 (d, J=8.3 Hz , 2H), 3.16 (td, J=6.8, 13.4 Hz, 1H), 2.40 (s, 3H), 1.37 (d, J=6.9 Hz, 6H).

- 147 047363

To a solution of 5-bromo-2-iodo-1,3-dimethylbenzene (544.88 mg, 1.75 mmol) in THF (20 ml) was added dropwise n-BuLi (2.5 M, 0.701 ml) at -70°C for 30 minutes. After addition, the mixture was stirred at -70°C for 1 hour, then 3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carbaldehyde (200 mg, 584.09 µmol) in THF (2 ml) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 1 hour. The mixture was then stirred for 12 hours at 20°C. The reaction mixture was quenched by adding NH4C1 (saturated aq., 80 ml) at 15°C, extracted with EA (3x40 ml). The combined organic layers were combined with the same previous charges, washed with H2O (60 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure to leave a residue. The residue was purified by flash chromatography on silica gel (eluent 0-15% EA/PE) to give (4-bromo-2,6-dimethylphenyl)-[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c ]pyridin-5yl]methanol (341 mg, 646.48 µmol) as a white solid.

^1H NMR (400 MHz, CDC13) δ ppm: 9.15 (d, J=1.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.33 (d, J=1.0 Hz, 1H), 7.21 (s, 2H), 7.09 (s, 2H), 6.87 (s, 1H), 6.13 (s, 1H), 5 .25 (s, 1H), 2.85 (dd, J=6.0, 6.9 Hz, 1H), 2.31 (s, 3H), 2.10 (s, 6H), 1.13 ( dd, J=1.9, 6.9 Hz, 6H).

(4-Bromo-2,6-dimethylphenyl)-[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5yl]methanol (1.11 g, 2.10 mmol) and HI (1.47 g, 6.31 mmol, 0.864 mL, 55% purity) was transferred into a microwave tube in AcOH (24 mL). The hermetically sealed tube was heated at 140°C for 1 hour in a microwave reactor. The reaction mixture was quenched by adding NaHCO ₃ (sat. aq., 50 ml) at 25°C, then diluted with H2O (20 ml) and extracted with EA (2x40 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by silica gel chromatography (eluent 0-15% EA/PE) to give 5-[(4-bromo-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(i-tolylsulfonyl)pyrrolo[2,3 -c]pyridine (920 mg, 1.80 mmol, 85% yield) as a brown solid.

^1H NMR (400 MHz, CDCl ₃ ) δ ppm: 9.12 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.28 (d, J=0 .9 Hz, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 7.15 (s, 2H), 6.75 (s, 1H), 4.16 (s, 2H ), 2.84 (spt, J=6.8 Hz, 1H), 2.33-2.26 (m, 3H), 2.15 (s, 6H), 1.13 (d, J=6, 9 Hz, 6H).

Mixture of 5-[(4-bromo-2,6-dimethylphenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3c]pyridine (340 mg, 398.25 µmol), Pin ₂ B ₂ (202.26 mg, 796.50 µmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (32.52 mg, 39.82 µmol), KOAc (97.71 mg, 995.62 µmol) in DMSO ( 5 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 130°C for 16 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The crude product was combined with the previous batch, then purified by silica gel chromatography eluting with PE:EA (1/0 to 6/1) to give 5-[[2,6-dimethyl-4-(4,4,5,5- tetramethyl1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (350 mg, crude) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 9.12 (d, J=0.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7, 45 (s, 2H), 7.24 (d, J=1.0 Hz, 1H), 7.17 (s, 2H), 6.71 (s, 1H), 4.23 (s, 2H), 2.79 (td, J=6.5, 13.4 Hz, 1H), 2.29 (s, 3H), 2.17 (s, 6H), 1.29 (s, 12H), 1.10 (d, J=6.8 Hz, 6H).

Mixture of 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl1-(p-tolylsulfonyl) pyrrolo[2,3-c]pyridine (680 mg, 1.22 mmol), NaIO ₄ (781.21 mg, 3.65 mmol, 202.39 μl), NH ₄ OAc (281.53 mg, 3.65 mmol) in acetone (20 ml) and H2O (10 ml) was stirred at 25°C for 42 hours. The reaction mixture was diluted with H2O (30 ml) and extracted with EA (30 mlx3). The combined organic layers were washed with brine (3x20 ml), dried over Na ₂ SO ₄ , solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude substance was purified by preparative TLC (SiO ₂ , PE:EA = 1:2) to obtain 4-[[3-isopropyl-1-(ptolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]-3 ,5-dimethylphenyl]boronic acid (380 mg, 785.31 µmol, 64.5% yield, 98% purity) as a white solid. A mixture of 6-amino-4(benzyloxymethyl)-2H-1,2,4-triazine-3,5-dione (186.22 mg, 750.18 µmol), [4-[[3-isopropyl-1-(ptolylsulfonyl )pyrrolo[2,3-c]pyridin-5-yl]methyl]-3,5-dimethylphenyl]boronic acid (330 mg, 681.98 µmol), pyridine (107.89 mg, 1.36 mmol), 4 A MS (5 g, 681.98 µmol) and Cu(OAc) ₂ (61.93 mg, 340.99 µmol) in DMF (10 ml) were degassed and purged with O ₂ 3 times, and then the mixture was stirred at 60°C for 16 hours in an O ₂ atmosphere. EA (60 ml) was added and stirred at 25°C for 10 minutes. Then filtered and the filtrate was washed with H2O (3x20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude substance was purified by preparative TLC (SiO ₂ , PE:EA = 1:2) to obtain 6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl1-(p-tolylsulfonyl)pyrrolo[2,3 -c]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione (120 mg, 138.10 µmol, 20% yield, 78% purity) in in the form of a yellow resin.

1H NMR (400 MHz, CDC13) δ ppm: 9.12 (s, 1H), 7.72 (d, J=8.3 Hz, 3H), 7.35-7.23 (m, 7H ), 7.18-7.13 (m, 4H), 6.83 (s, 1H), 5.52 (s, 2H), 4.69 (s, 2H), 4.22 (s, 2H) , 2.90-2.81 (m, 2H), 2.30 (s, 4H), 2.22 (s, 6H), 1.13 (d, J=6.9 Hz, 6H).

- 148 047363

To a solution of 6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3c]pyridin-5-yl]methyl]-3,5-dimethylphenyl ]-1,2,4-triazine-3,5-dione (120 mg, 138.10 µmol) in DCM (5 ml) was added BBr ₃ (276.79 mg, 1.10 mmol, 0.106 ml) at 0° WITH. The mixture was stirred at 0°C for 2 hours. The reaction mixture was added dropwise to methanol (5 ml) at 0°C and concentrated under reduced pressure to give 6-amino-2-[4-[[3-isopropyl-1- (p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5yl]methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione (160 mg, crude) as a yellow solid substances.

To a solution of 6-amino-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]3,5-dimethylphenyl]-1,2 ,4-triazine-3,5-dione (160 mg, 286.40 µmol) in THF (6 ml) was added TBAF (1 M, 5.73 ml) under N2. The mixture was stirred at 65°C for 16 hours. The reaction mixture was quenched by adding sat. aq. NH4Cl (10 ml) at 25°C, then diluted with H2O (10 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [Column: Welch Xtimate C18 150x30 mmx5 µm; mobile phase: 15% CH3CN in water (0.225% FA) to 45% CH3CN in water (0.225% FA)] to give 6-amino-2-[4-[(3-isopropyl-1Hpyrrolo[2,3-c ]pyridin-5-yl)methyl]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione (12.34 mg, 30.30 µmol, 10.6% yield, 99% purity ) as a white solid.

^1H NMR (400 MHz, D\1SS)-s16) δ ppm: 11.15 (br s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7 .27 (d, J=2.0 Hz, 1H), 7.18 (s, 2H), 7.13 (s, 1H), 6.31 (s, 2H), 4.18 (s, 2H) , 3.01 (td, J=7.0, 13.7 Hz, 1H), 2.31 (s, 6H), 1.23 (d, J=6.9 Hz, 6H).

Example 90 Synthesis of compound 159

To a stirred mixture _of 3,4,6-trichloropyridazine (4.00 g, 21.808 mmol) and 3,3-dimethylazetidine (2.93 g, 23.989 mmol) in DMF (50 ml) was added _K2CO3 (9.04 g , 65.424 mmol) in portions at room. pace. The resulting mixture was stirred for 3 hours at 40°C and quenched with water (150 ml) at room. pace. The resulting mixture was filtered, the filter cake was washed with water (2x50 ml) and dried under an IR lamp to obtain 3,6-dichloro-4-(3,3-dimethylazetidin-1-yl)pyridazine (4.6 g, 88, 15%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ ppm: 6.21 (s, 1H), 4.00 (s, 4H), 1.38 (s, 6H).

LCMS (ESI, m/z): 232 [M+H]+.

To a stirred mixture of 3,6-dichloro-4-(3,3-dimethylazetidin-1-yl)pyridazine (4.60 g, 19.818 mmol) in methanol (30 ml) was added NaOCH ₃ (1.28 g, 23.693 mmol) drop by drop at room pace. The resulting mixture was stirred overnight at 60°C and concentrated under reduced pressure. Then water (60 ml) was added. The resulting mixture was filtered, the filter cake was washed with water (2x40 ml) and dried under IR lamp to obtain 6-chloro-4-(3,3-dimethylazetidin-1-yl)-3methoxypyridazine (4.22 g, 87%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ ppm: 6.02 (s, 1H), 4.03 (s, 3H), 3.86 -3.91 (m, 4H), 1.35 ( s, 6H).

LCMS (ESI, m/z): 228 [M+H]+.

To a stirred mixture of 6-chloro-4-(3,3-dimethylazetidin-1-yl)-3-methoxypyridazine (4.00 g, 17.568 mmol), Na-(3,5-dichloro-4-hydroxyphenyl)LC-dimethylmethanimidamide (4.09 g, 17.568 mmol), Pd ₂ (dba) ₃ (2.73 g, 2.635 mmol) and ^)-1-[^)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (1.46 g , 2.631 mmol) in dioxane (80 ml) was added Cs ₂ CO ₃ (11.45 g, 35.135 mmol) in portions at room temperature. pace. The resulting mixture was stirred overnight at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and diluted with water (60 ml). The resulting mixture was extracted with ethyl acetate (3x120 ml) and the organic layers were combined, washed with brine (2x80 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with CH ₂ Cl ₂ /methanol (40/1) to give N(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6methoxypyridazin-3 -yl]oxy]phenyl)-XNi-dimethylmethanimidamide (6 g, 74.05%) as a brown solid.

1H NMR (400 MHz, DMSO-dD δ ppm: 7.90 (s, 1H), 7.07 (s, 2H), 6.11 (s, 1H), 3.81-3.91 ( m, 7H), 2.903.05 (m, 6H), 1.26-1.30 (m, 6H).

LCMS (ESI, m/z): 424 [M+H]+.

To a stirred mixture of Na(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-methoxypyridazin-3yl]oxy]phenyl)-X^dimethylmethanimidamide (2.00 g, 4.713 mmol) in CH ₃ CN (20 ml) was added TMSI (1.89 g, 9.446 mmol) dropwise at room temperature. pace. The resulting mixture was stirred overnight at

- 149 047363

70°C and quenched with water (50 ml). The resulting solution was extracted with EA (3x60 ml) and the organic layers were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with CH ₂ Cl ₂ /methanol (16:1) to give N(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo -III-pyridazin-3-yl]oxy]phenyl)-HX-dimethylmethanimidamide (950 mg, 44.70%) as a yellow solid.

^1H NMR (400 MHz, DMSO-dg) δ ppm: 11.62 (s, 1H), 7.85 (s, 1H), 7.02 (s, 2H), 5.80 (s, 1H), 3.59-4.13 (m, 4H), 3.01 (s, 3H), 2.89 (s, 3H), 1.24 (s, 6H).

LCMS (ESI, m/z): 410 [M+H]+.

To a stirred solution of Na(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-Spiridazin-3-yl]oxy]phenyl)-HX-dimethylmethanimidamide (950, 00 mg, 2.315 mmol) in ethanol (10 ml), ethylenediamine (626.19 mg, 10.419 mmol) was added dropwise at room. pace. The resulting mixture was stirred overnight at 70°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with GIAB/methanol (49/1) to give 6-(4-amino-2,6dichlorophenoxy)-4-(3,3-dimethylαzetidin-1-yl)-2H-pyridαzin-3- it (420 mg, 49.53%) as a yellow solid.

^1H NMR (400 MHz, DMSO-dp δ ppm: 11.59 (s, 1H), 6.60 (s, 2H), 5.74 (s, 1H), 5.53 (s, 2H ), 3.86 (br, 4H), 1.24 (s, 6H).

LCMS (ESI, m/z): 355 [M+H]+.

To a stirred solution of 6-(4-amino-2,6-dichlorophenoxy)-4-(3,3-dimethylazetidin-1-yl)-2Hpyridazin-3-one (250.00 mg, 0.706 mmol) in HCl (8, 0 ml), acetic acid (22 ml) and water (16 ml), sodium nitrite (102.0 mg, 1.483 mmol) in water (2 ml) was added dropwise at 0°C. The resulting mixture was stirred for 45 minutes at 0°C. Ethyl N-(2-cyanoacetyl)carbamate (165.0 mg, 1.059 mmol) in water (52 ml) and pyridine (8 ml) was stirred for 10 min at 0°C. The above solution was added to the mixture, and the resulting mixture was stirred for 1 hour at 0°C. The resulting mixture was filtered, the filter cake was washed with water (2x10 ml) and dried under an IR lamp to obtain ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((5-(3, 3-Dimethylazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3 yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (300 mg, crude) as a yellow solid.

¹ H NMR (400 MHz, DMSOHO δ ppm: 12.07-12.10 (m, 1H), 11.66 (s, 1H), 10.90 (s, 1H), 7.93 (s , 2H), 5.83 (s, 1H), 4.15-4.22 (m, 2H), 3.61-4.01 (m, 4H), 1.26 (s, 9H).

LCMS (ESI, m/z): 522 [M+H]+.

To a stirred mixture of ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((5-(3,3-dimethylazetidin-1-yl)-6-oxo1,6-dihydropyridazin-3- yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (300 mg, 0.574 mmol) in DMA (8 ml) was added KOAc (225.47 mg, 2.297 mmol) portionwise at room temperature. pace. The resulting mixture was stirred for 6 hours at 110°C and quenched with water (15 ml) at room. pace. The mixture was extracted with ethyl acetate (3x40 ml) and the organic layers were combined, washed with brine (2x40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(3,5-dichloro-4-[[5-( 3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H1,2,4-triazin-6-carbonitrile (300 mg, crude ) as a yellow solid.

^1H NMR (400 MHz, DMSO^) δ ppm: 13.27 (s, 1H), 11.70 (s, 1H), 7.73 (s, 2H), 5.91 (s, 1H ), 3.92 (br, 4H), 1.27 (s, 6H).

LCMS (ESI, m/z): 476 [M+H]+.

To a stirred mixture of 2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-III-pyridazin-3yl]oxy]phenyl)-3,5-dioxo -4H-1,2,4-triazine-6-carbonitrile (180.00 mg, 0.378 mmol) in methanol (4 ml) was added dropwise NaOH (8 ml, 2M) at room temperature. pace. The resulting mixture was stirred for 30 min at 55°C and diluted with water (30 ml) at room. pace. The resulting mixture was extracted with EA (3x50 ml) and the organic layers were combined, washed with brine (2x40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(3,5-dichloro-4-[[5- (3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H1,2,4-triazine-6-carboxylic acid (180 mg , crude) as a yellow solid.

LCMS (ESI, m/z): 495 [M+H]+.

To a stirred mixture of 2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-III-pyridazin-3yl]oxy]phenyl)-3,5-dioxo -4H-1,2,4-triazine-6-carboxylic acid (180.00 mg, 0.363 mmol) and triethylamine (147.11 mg, 1.454 mmol) in tert-butanol (5 ml) was added diphenylphosphoryl azide (300.05 mg , 1.090 mmol) drop by drop at room. pace. The resulting mixture was stirred overnight at 85°C. The resulting mixture was concentrated under reduced pressure. The residue was extracted with EA (3x40 ml) and the organic layers were combined, washed with brine (2x30 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane/methanol (24/1) to give tert-butyl-H-[2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidine-1- yl)-6-oxo-III-pyridazine

- 150 047363

3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (48 mg, 18%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 12.79 (s, 1H), 11.13 (s, 1H), 7.59 (s, 1H), 7.55 (s, 2H) , 5.72 (s, 1H), 4.02 (s, 4H), 1.51 (s, 9H), 1.25 (s, 6H).

LCMS (ESI, m/z): 566 [M+H]+.

To a stirred solution of tert-buty.t-X-[2-('3,5-dih.tor-4-[[5-('3,3-dimethy.tazetidine-1-i.t)-6oxo-1H -pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (38.00 mg, 0.067 mmol) in CH ₂ Cl ₂ (5 ml ) TFA (1 ml) was added dropwise at room. pace. The resulting mixture was stirred for 2 hours at room. pace. and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: XBridge Prep Phenyl OBD, 19x150 mm, 5 µm 13 nm; mobile phase A: water (10 mmol/l NH4CO ₃ + 0.1% NH4OH), mobile phase B: Acetonitrile; speed flow: 25 ml/min; gradient: from 20 V to 39 V in 8 min; RT1: 6.52) to obtain 6-amino2-(3,5-dichloro-4-[[5-(3, 3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4triazin-3,5-dione (8.1 mg, 26%) as white solid.

^1H NMR (300 MHz, DMSO-de) δ ppm: 11.67 (br, 2H), 7.79 (s, 2H), 6.44 (s, 2H), 5.87 (s , 1H), 3.77 (br, 4H), 1.27 (s, 6H).

LCMS (ESI, m/z): 466 [M+H] ⁺ .

Example 91 Synthesis of Compound 160

A 500 ml autoclave was loaded with 3-chloro-6-methoxypyridazine (50.00 g, 345.877 mmol), Pd(dppf)Cl ₂ (15.18 g, 20.753 mmol), triethylamine (12.25 g, 121.057 mmol) and methanol (150 ml) and CO (30 atm.). The reaction mixture was stirred at 60°C for 3 days. The resulting solution was concentrated under reduced pressure to obtain a residue. The residue was chromatographed on a PE/EA (3/1) silica gel column to give methyl 6-methoxypyridazine-3-carboxylate (16.4 g, 27%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ ppm: 8.10 (d, J=9.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.25 (s, 3H), 4.06 (s, 3H).

LCMS (ESI, m/z): 169 [M+H]+.

To a solution of methyl 6-methoxypyridazine-3-carboxylate (16.40 g, 97.531 mmol) in methanol (55 ml) and THF (275 ml) was added NaBH ₄ (11.07 g, 292.592 mmol) and CaCl ₂ (10. 82 g, 97.531 mmol) portions. The reaction mixture was stirred at room. pace. for 1 hour and quenched with water and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol/CH ₂ Cl ₂ (1/17) to give (6-methoxypyridazin-3-yl)methanol (10.5 g, 73%) as a brown oil.

1H NMR (300 MHz, methanolL ₄ ) δ ppm: 7.24 (d, J=9.0 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 4.79 (s, 2H), 4.10 (s, 3H).

LCMS (ESI, m/z): 141 [M+H]+.

To a solution of (6-methoxypyridazin-3-yl)methanol (10.20 g, 72.783 mmol) in dichloromethane (500 ml) was added Dess-Martin periodinane (43.22 g, 101.897 mmol). The reaction mixture was stirred at room. pace. for 16 hours and quenched with water (200 ml). The resulting solution was extracted with CH ₂ Cl ₂ (3x200 ml) and the organic layers were combined, washed with brine (2x100 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/3) to give 6-methoxypyridazine-3-carbaldehyde (7.5 g, 67%) as a yellow solid.

1H NMR (300 MHz, CDCl ₃ ) δ ppm: 10.27 (s, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.12 (d, J=9, 0 Hz, 1H), 4.29 (s, 3H).

LC-MS (ESI, m/z): 139 [M+H]+.

To a solution of 2,2,6,6-tetramethylpiperidine (6.83 g, 48.332 mmol) in THF (100 ml) was added nbutyllithium (17.7 ml, 2.5 M in hexane, 44.304 mmol) at -85°C in nitrogen atmosphere, and then the solution was allowed to warm to 0°C and stirred for 30 minutes. The solution was then cooled to -85°C and a solution of 3,6-dichloropyridazine (6 g, 40.277 mmol) in THF (25 ml) was added. The reaction mixture was stirred at -85°C for 30 minutes and a solution of 6-methoxypyridazine-3-carbaldehyde (6.12 g, 44.304 mmol) in THF (25 ml) was added. The resulting solution was stirred at -85°C for 1 hour and quenched with NH ₄ Cl (aq, 100 ml). The resulting solution was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (1x100 ml), dried over anhydrous sodium sulfate, filtered and concentrated

- 151 047363 were carried out at reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (2/3) to obtain the crude product. The crude product was purified by a C18 column (CH ₃ CN/water = 1/3) to give (3,6-dichloropyridazin-4-yl)(6-methoxypyridazin-3-yl)methanol (2.38 g, 18.52%) as a brown solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.94 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.13 (d, J=9 .0 Hz, 1H), 6.27 (s, 1H), 4.76 (b, 1H), 4.29 (s, 3H).

LCMS (ESI, m/z): 287 [M+H]+.

2,6-lutidine ( _{5 ,} 9718 g, 55.73 mmol) and thionyl chloride (3.3151 g, 27.86 mmol). The reaction mixture was stirred at room. pace. for 16 hours and quenched with water (100 ml). The resulting solution was extracted with CH ₂ Cl ₂ (3x100 ml) and the organic layers were combined, washed with brine (2x100 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/3) to give 3,6-dichloro-4-[chloro(6-methoxypyridazin-3-yl)methyl]pyridazine (2.6 g, 61.2%) in the form of a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 8.07 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.12 (d, J=9 .0 Hz, 1H), 6.43 (s, 1H), 4.16 (s, 3H).

LCMS (ESI, m/z): 305 [M+H] ⁺ .

To a solution of 3,6-dichloro-4-[chloro(6-methoxypyridazin-3-yl)methyl]pyridazine (2.600 g, 8.510 mmol) in toluene (104 ml) was added tributyltin hydride (4954 mg, 17.019 mmol) and 2.2 '-azo-bis-(2methylpropionitrile) (279.47 mg, 1.702 mmol). The reaction mixture was stirred at 100°C for 16 hours and quenched with water (100 ml). The mixture was extracted with ethyl acetate (3x100 ml) and the organic layers were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/2) to give 3,6-dichloro-4-[(6-methoxypyridazin3-yl)methyl]pyridazine (1.9 g, 76%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.55 (s, 1H), 7.41 (d, J=6.0 Hz, 1H), 7.05 (d, J=6 .0 Hz, 1H), 4.35 (s, 2H), 4.16 (s, 3H).

LC-MS (ESI, m/z): 271 [M+H]+.

To a solution of 3,6-dichloro-4-[(6-methoxypyridazin-3-yl)methyl]pyridazine (1.100 g, 4.058 mmol) and 4-amino-2,6-dichlorophenol (866.74 mg, 4.869 mmol) in DMSO (22 ml) was added K ₂ CO ₃ (1401.94 mg, 10.144 mmol). The reaction mixture was stirred at 90°C for 8 hours and quenched with water (100 ml). The mixture was extracted with EA (3x100 ml) and the organic layers were combined, washed with brine (1x50 ml), dried over anhydrous sodium sulfate, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/2) to give 3,5-dichloro-4-([6-chloro-5-[(6-methoxypyridazin-3-yl)methyl]pyridazin-3yl]oxy )aniline (430 mg, 25%) as a brown solid.

^1H NMR (300 MHz, DMSOO δ ppm: 7.68-7.71 (m, 2H), 7.26 (d, J=9.0 Hz, 1H), 6.72 (s, 2H ), 4.97 (b, 2H), 4.40 (s, 2H), 3.99 (s, 3H).

LC-MS (ESI, m/z): 412 [M+H]+.

To a solution of 3,5-dichloro-4-([6-chloro-5-[(6-methoxypyridazin-3-yl)methyl]pyridazin-3-yl]oxy)aniline (435.00 mg, 1.054 mmol) in water (32 ml), conc. HCl (12 ml) and acetic acid (36 ml) were added dropwise to sodium nitrite (152.73 mg, 2.214 mmol) in water (5 ml) at 0°C. After addition, the reaction mixture was stirred at 0°C for 45 minutes. The reaction mixture was then slowly added to a solution of ethyl X-(2-cyanoacetyl)carbamate (246.89 mg, 1.581 mmol) in water (32 ml) and pyridine (14 ml) at 0°C. The resulting mixture was stirred at 0°C for 1 hour and filtered. The filter cake was dried under an IR lamp to obtain ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((6-methoxypyridazin-3yl)methyl) pyridazin-3-yl)oxy)phenyl)hydrazinylidene) acetyl)carbamate (410 mg, 62.01%) as a tan solid.

LCMS (ESI, m/z): 579 [M+H]+.

To a solution of ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((6-methoxypyridazin-3-yl)methyl)pyridazin-3-yl)oxy )phenyl)hydrazinylidene)acetyl)carbamate (410.00 mg, 0.707 mmol) in acetic acid (10 ml) was added sodium acetate (290.3 mg, 3.54 mmol). The reaction mixture was stirred at 105°C for 4 hours and cooled to room. pace. The reaction mixture was poured into water (100 ml) and filtered. The filter cake was dissolved in DMF and purified with a C18 column (CH ₃ CN/water = 2/3) to give 2-[3,5-dichloro-4-([5-[(6-methoxypyridazin-3-yl)methyl ]-6-oxo-III-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile (270 mg, 67%) as a brown solid .

^1H NMR (300 MHz, meganol-f) δ ppm: 7.83-7.87 (m, 2H), 7.78 (s, 2H), 7.56 (s, 1H), 4, 15 (s, 3H), 2.05 (s, 2H).

LCMS (ESI, m/z): 515 [M+H]+.

- 152 047363

A solution of 2-[3,5-dichloro-4-([5-[(6-methoxypyridazin-3-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5- dioxo-4H-1,2,4-triazine-6-carbonitrile (160.00 mg, 0.311 mmol) in acetic acid (5 ml) and conc. HCl (2.5 ml aq) was stirred at 105°C for 3 hours. The reaction mixture was adjusted to pH 10 with NaHCO ₃ (sat aq) and extracted with EA (2x20 ml) and the organic layers were discarded. The pH of the aqueous layers was adjusted to 4 with conc. HCl and extracted with isopropanol/CHC1 ₃ (1/3) (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[3,5-dichloro-4-([5-[(6hydroxypyridazin-3-yl)methyl]-6-oxo-1H -pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carboxylic acid (120 mg, 66.8%) as a brown solid.

LCMS (ESI, m/z): 520 [M+H]+.

To a solution of 2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1H-pyridazin-3yl]oxy)phenyl]-3 ,5-dioxo-4H-1,2,4-triazine-6-carboxylic acid (110 mg, 0.211 mmol) in tert-butanol (4 ml) was added with DPPA (174.57 mg, 0.634 mmol) and triethylamine (85.58 mg , 0.846 mmol). The reaction mixture was stirred at 80°C for 16 hours and concentrated under reduced pressure. The residue was dissolved in EA (50 ml). The resulting mixture was washed with sodium bicarbonate solution (3x30 ml) and saline. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give Ίret-butyl-N-[2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl ]-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (60 mg, 38%) as a white solid.

LCMS (ESI, m/z): 591 [M+H] ⁺ .

To a solution of Ίret-butyl-N-[2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1Hpyridazin-3-yl ]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (60 mg, 0.101 mmol) in CH ₂ Cl ₂ (5 ml) was added TFA (2 ml). The reaction mixture was stirred at room. pace. for 2 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase A: inWater (10 mmol/l NH4HCO3 + 0.1% NH3-H2O), mobile phase B: CH3CN; flow rate: 25 ml/min; gradient: from 10 to 35 V in 7 min; RT1:6.35) to obtain 6-amino-2-[3,5-dichloro-4-([6-oxo-5-[ (6-oxo-1H-pyridazin-3-yl)methyl]1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-Ίriazin-3,5-dione (5.7 mg, 11 .32%) as a white solid.

1H NMR (300 MHz, DMSO-06) δ ppm: 7.86 (s, 2H), 7.56 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 6.88 (d, J=9.6 Hz, 1H), 6.48 (s, 2H), 3.83 (s, 2H).

LC-MS (ESI, m/z): 491 [M+H] ⁺ .

Example 92 Synthesis of compound 161

Potassium tert-Butoxide (43.19 g, 384.869 mmol) was added to 6-methylpyridin-3-ol (40.00 g, 366.542 mmol) in THF (1.6 L) at 0°C. The mixture was stirred at room. pace. within 30 min. CH ₃ I (54.63 g, 384.869 mmol) was added dropwise at 0° C. and stirring was continued at room temperature. pace. during the night. Water (500 ml) was added and the mixture was evaporated to half its volume and extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/3) to give 5-methoxy-2methylpyridine (17.5 g, 36.8%).

1H NMR (300 MHz, methanol^ ₄ ) δ ppm: 8.09 (d, J=3.0 Hz, 1H), 7.33 (dd, J=8.6, 3.0 Hz, 1H ), 7.22 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 2.46 (s, 3H).

LCMS (ESI, m/z): 124 [M+H] ⁺ .

To a solution of 2,2,6,6-tetramethylpiperidine (13.76 g, 97.438 mmol) in THF (75 ml) was added nbutyllithium (39 ml, 2.5 M in hexane, 97.438 mmol) at -75°C under nitrogen atmosphere , and then the solution was allowed to warm to 0°C and stirred for 30 minutes. The solution was then cooled to -75°C and a solution of 5-methoxy-2-methylpyridine (10.00 g, 81.198 mmol) in THF (75 ml) was added. The reaction mixture was stirred at -75°C for 30 minutes and a solution of 3,4,6-trichloropyridazine (17.87 g, 97.438 mmol) in THF (50 ml) was added. The resulting solution was stirred at -75°C for 1 hour. The reaction mixture was quenched with NH4C1 (aq, 100 ml). The resulting solution was extracted with EA (3x300 ml) and the organic layers were combined, washed with brine (1x100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with

- 153 047363

EA/PE (1/3) to give 3,6-dichloro-4-[(5-methoxypyridin-2-yl)methyl]pyridazine (3.2 g, 13.8%) as a light brown solid.

^1H NMR (300 MHz, methanol^) δ ppm: 8.19-8.20 (m, 1H), 7.67 (s, 1H), 7.33-7.48 (m, 2H) , 4.26 (s, 2H), 3.89 (s, 3H).

LC-MS (ESI, m/z): 270 [M+H]+.

4-Amino-2,6-dichlorophenol (2 .53 g, 14.216 mmol) and potassium carbonate (4.91 g, 35.541 mmol). The mixture was stirred at 90°C for 2 hours and quenched with water (100 ml). The resulting solution was extracted with EA (3x200 ml) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a C18 column with acetonitrile/water (2/3) to give 3,5-dichloro-4([6-chloro-5-[(5-methoxypyridin-2-yl)methyl]pyridazin-3-yl]oxy )aniline (1.51 g, 165.13%) as a brown solid.

¹ H NMR (300 MHz, DMSOO δ ppm: 8.27 (s, 1H), 7.55 (s, 1H), 7.39-7.52 (m, 2H), 6.70 (s , 2H), 4.80 (br, 2H), 4.26 (s, 2H), 3.83 (s, 3H).

LC-MS (ESI, m/z): 411 [M+H]+.

To a solution of 3,5-dichloro-4-([6-chloro-5-[(5-methoxypyridin-2-yl)methyl]pyridazin-3-yl]oxy)aniline (1.50 g, 3.635 mmol) in acetic acid acid (130 ml), concentrated HCl (45 ml) and water (100 ml), a solution of sodium nitrite (0.53 g, 7.633 mmol) in water (10 ml) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 45 minutes. The reaction mixture was then quickly added to a mixture of ethyl N-(2-cyanoacetyl)carbamate (0.85 g, 5.452 mmol) in pyridine (50 ml) and water (100 ml) at 0°C. The resulting mixture was stirred for 30 minutes at 0°C. The precipitated solid was collected by filtration and washed with water and PE (50 ml) to give ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5((5-methoxypyridinium- 2-yl)methyl)pyridazin-3-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate (1.03 g, 45.5%) as a yellow solid.

LCMS (ESI, m/z): 578 [M+H]+.

To a solution of ethyl-(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((5-methoxypyridin-2-yl)methyl)pyridazin3-yl)oxy)phenyl )hydrazinylidene)acetyl)carbamate (1.00 g, 1.785 mmol) in acetic acid (30 ml) was added sodium acetate (0.73 g, 8.923 mmol). The mixture was stirred at 105°C for 3 hours and quenched with water (100 ml). The precipitated solid was collected by filtration and washed with water and PE (20 ml). The residue was chromatographed on a C18 column with CH ₃ C Na water (2/3) to obtain 2-[3,5-dichloro-4-([5-[(5methoxypyridin-2-yl)methyl]-6-oxo-III- pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6carbonitrile (200 mg, 20.27%) as a brown solid.

LCMS (ESI, m/z): 514 [M+H]+.

To a solution of 2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-III-pyridazin-3-yl]oxy)phenyl]-3,5 -dioxo-4H-1,2,4-triazine-6-carbonitrile (200.00 mg, 0.390 mmol) in acetic acid (4 ml) was added with concentrated hydrochloric acid (2 ml). The mixture was stirred at 105°C for 3 hours. The pH of the reaction mixture was adjusted to 10 with NaHCO ₃ (sat. aq.) and extracted with EA (2x20 ml) and the organic layers were discarded. The pH of the aqueous layers was adjusted to 4 with concentrated hydrochloric acid and extracted with isopropanol/chloroform (1/3) (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give 2-[3,5-dichloro-4-([5-[(5methoxypyridin-2-yl)methyl]-6- oxo-III-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6carboxylic acid (200 mg, 77.15%) as a yellow solid.

LCMS (ESI, m/z): 533 [M+H]+.

To a solution of 2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-III-pyridazin-3-yl]oxy)phenyl]-3,5 -dioxo-4H-1,2,4-triazine-6-carboxylic acid (200 mg, 0.375 mmol) in tert-butyl alcohol (8 ml) was added DPPA (309.63 mg, 1.125 mmol), triethylamine (151.80 mg, 1,500 mmol). The mixture was stirred at 85°C overnight and concentrated under reduced pressure. The residue was dissolved in EA (50 ml). The resulting mixture was washed with sodium bicarbonate solution (3x30 ml) and saline.

The combined organic layers were dried over anhydrous sodium sulfate. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a C18 column with _CH3CNO2 water (1/2) to obtain tert-butyl-N-[2-[3,5-dichloro-4-([5-[(5methoxypyridin-2-yl)methyl] -6-oxo-III-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6yl]carbamate (112 mg, 47.38%) as a brown solid substances.

LCMS (ESI, m/z): 604 [M+H]+.

To a solution of tert-butyl-H-[2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-Spiridαzin-3-yl]oxy)phenyl ]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate (50.00 mg, 0.083 mmol) in CH ₂ Cl ₂ (3 ml) was added BBr ₃ (414.50 mg, 1.655 mmol) at 0°C. The mixture was stirred at room. pace. Within 2 days. The reaction mixture was quenched with methanol and concentrated under reduced pressure.

- 154 047363

The residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD, 19x250 mm, 5 µm; mobile phase A: water (10 mmol/l NH4CO3 + 0.1% NH4OH), mobile phase B: CH3CN; flow rate: 25 ml/ min; gradient: 10 to 30 V in 8 min; RT1:6.65) to give 6-amino-2-[3,5-dichloro-4-([5[(5-hydroxypyridine-2- yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dione (8 mg, 19.41%) as a white solid substances.

^1H NMR (400 MHz, DMSO-dg) δ ppm: 12.26 (br, 2H), 9.82 (br, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.85 (s, 2H), 7.13-7.28 (m, 3H), 6.49 (br, 2H), 3.89 (s, 2H).

LC-MS (ESI, m/z): 490 [M+H] ⁺ .

Example 93 Synthesis of compound 162

162 |

A mixture of 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl^(p-tolylsulfonyl^ irrolo^^-^pyridine (200 mg, 322.27 µmol, 90% purity), 6-bromo-2-methyl1,2,4-triazine-3,5-dione (69.71 mg, 338.38 µmol) , K2CO3 (89.08 mg, 644.54 µmol) and palladium;triphenylphosphane (74.48 mg, 64.45 µmol) in dioxane (8 ml) and H2O (1.6 ml) were stirred at 110°C for 12 h under N2 atmosphere. The reaction mixture was cooled, diluted with H2O (30 ml) and extracted with EA (2x30 ml), washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain. The residue was purified by silica gel chromatography (Eluent 0-50% EA/PE) to give 6-[4-[[3isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl. ]-3,5-dimethylphenyl]-2-methyl-1,2,4triazine-3,5-dione (96 mg, 106.73 µmol, 33.12% yield, 62% purity) as a yellow solid.

To a solution of 6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5dimethylphenyl]-2-methyl-1, 2,4-triazine-3,5-dione (96 mg, 172.15 µmol) in THF (8 ml) was added with TBAF (1 M, 1.38 ml) at 20°C. After addition, the mixture was stirred at 65°C for 12 hours. LCMS showed complete uptake of the starting material and detected 29% of the desired mass peak. The reaction mixture was diluted with sat. aq. NH4Cl (120 ml) and extracted with EA (30 mlx2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC [Column: Phenomenex luna C18 80x40 mmx3 µm; mobile phase: from 15% CH3CN in water (0.05% HCl) to 45% CH3CN in water (0.05%HC1)] to give 6-[4-[(3-isopropyl-1H-pyrrolo[3,2 -b]pyridin-5yl)methyl]-3,5-dimethylphenyl]-2-methyl-1,2,4-triazine-3,5-dione], 6-[4-[(3-isopropyl-1H-pyrrolo [3,2b]pyridin-5-yl)methyl]-3,5-dimethylphenyl]-2-methyl-1,2,4-triazine-3,5-dione (14.07 mg, 33.87 µmol, yield 19.68%, purity 97.13%) as a white solid.

Example 94. Synthesis of compounds 163 and 164:

Synthesis of 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(1-phenylethyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)1,2,4 -triazin-3,5(2H,4H)-dione 6-bromo-4-isopropyl-1,5-naphthyridin-2(1H)-one was synthesized using a method similar to that described for the synthesis of 6-amino-2-(3 ,5-dichloro-4-((5-(2-fluoro-3methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5( 2H,4H)-dione, where (1-phenylvinyl)boronic acid was used instead of (2-fluoro-3-methylphenyl)boronic acid.

The crude product (200 mg) was purified by preparative HPLC (Column: CHIRALPAK IE-3, 4.6x50 mm, 3 µm, hexane (0.1% TFA): EUN = 55:45, flow rate: 1 ml/min) to obtain the first desired enantiomer (Rt: 2.340 min), compound 163 (37.9 mg, 19.69%), as a white solid. And the second eluting isomer (Rt: 2.903 min), compound 164 (41.5 mg, 21.65%) as a white solid.

¹ NMR (400 MHz, DMSO-dg) δ ppm: 12.24-12.27 (m, 2H), 7.85 (s, 2H), 7.51 (s, 1H), 7.31 -7.35 (m, 4H), 7.21-7.26 (m, 1H), 6.52 (s, 2H), 4.27-4.33 (m, 1H), 1.55 (d , J=7.2 Hz, 3H).

LCMS (ESI, m/z): 487 [M+H] ⁺ .

- 155 047363

Example 95. Synthesis of compounds 165 and 166:

Chiral separation was performed on 6-amino-2-(4-((5-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-6oxo-1,6-dihydropyridazin- 3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione to give compounds 165 (Rt: 2.845 min on chiral HPLC) and 166 (Rt: 3.697 min on chiral HPLC) (Chiral HPLC conditions: column name: (R,R)-WHELK-O1 4.6x50 mm 3.5 µm, mobile phase: Hex (0.1% DEA): ethanol = 70:30, temperature: 25°C, flow 1,000 ml/min, instrument: Agilent 1260).

1H NMR (400 MHz, DMSO-dQ δ ppm: 12.33 (br, 2H), 7.84 (s, 2H), 7.19-7.39 (m, 5H), 6.50 (s, 2H), 4.71 (s, 1H), 3.63-3.69 (m, 1H), 3.19-3.24 (m, 1H).

Example 96 Synthesis of compound 171

Mixture of 5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl1-(p-tolylsulfonyl) pyrrolo[3,2-b]pyridine (320 mg, 0.516 mmol, 90% purity), 6-bromo-2H-1,2,4triazine-3,5-dione (148.48 mg, 0.773 mmol), K ₂ CO ₃ (142.53 mg, 1.03 mmol) and palladium; triphenylphosphane (119.17 mg, 0.103 mmol) in dioxane (10 ml) and H ₂ O (1 ml) were stirred at 100°C for 12 hours in atmosphere N ₂ . The reaction mixture was diluted with H ₂ O (20 ml) and extracted with EA (2x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (Eluent 0-50% EA/PE) to give 6-[4 -[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2b]pyridin-5-yl]methyl]-3,5-dimethylphenyl]-2H-1,2,4-triazine-3,5- dione (246 mg, 0.453 mmol, 88% yield) as a colorless oil.

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

To a solution of 6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5dimethyl-phenyl]-2H-1,2, 4-triazine-3,5-dione (200 mg, 0.368 mmol) in THF (8 ml) was added with TBAF (1 M, 1.84 ml) at 20°C. The mixture was stirred at 65°C for 12 hours. The reaction mixture was diluted with H ₂ O (50 ml), extracted with EA (100 ml). The organic layer was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC [Column: Phenomenex luna C18 80x40 mmx3 µm; mobile phase: from 10% CH3CN in water (0.05% HCl) to 40% CH3CN in water (0.05% HCl)], then dissolved in EA (20 ml), washed with NH ₄ Cl (saturated aq. 20 ml), saline (20 ml) and concentrated to give 6-[4-[(3-isopropyl1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethylphenyl]-2 -methyl-1,2,4-triazine-3,5-dione (5 mg, 12.84 µmol, 3.5% yield, 100% purity) as a white solid.

1H NMR (400 MHz, DMSO-f,) δ ppm: 12.43 (d, J=1.8 Hz, 1H), 12.04 (s, 1H), 10.80 (br s, 1H), 7.587.52 (m, 3H), 7.29 (d, J=1.6 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 4.23 (s, 2H), 3.24-3.16 (m, 1H), 2.37 (s, 6H), 1.33 (d, J=6.9 Hz, 6H).

Example 97 Synthesis of 6-bromo-4-isopropyl-1,5-naphthyridin-2(1H)-one

To a solution of 2,6-dibromopyridin-3-amine (30 g, 119.09 mmol) in DCM (500 ml) was added Et ₃ N (36.15 g, 357.27 mmol, 49.73 ml) and 2,2 -dimethylpropanoyl chloride (28.72 g, 238.18 mmol, 29.31 ml) at 0°C, and the mixture was stirred at 15°C for 12 hours. The mixture was quenched with sat. aq. NH ₄ Cl (sat. aq., 100 ml), extracted with DCM (3x200 ml). The combined organic layers were washed with brine (2x100 ml), dried over MgSO ₄ , filtered and concentrated to give a residue which was purified by chromatography on silica gel (Eluent 0-20% EA/PE) to give N(2,6-dibromopyridin-3yl) pivalamide (41.4 g, crude) as a yellow solid.

¹ H NMR (400 MHz, DMSO-f,) δ ppm: 9.18 (s, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.71 (d, J =8.3 Hz, 1H), 1.24 (s, 9H).

To a solution of Na(2,6-dibromopyridin-3-yl)pivalamide (21 g, 62.50 mmol) in toluene (300 ml) was added dropwise n-BuLi (2.5 M, 62.50 ml) at -70 °C under N ₂ atmosphere, the mixture was stirred at -70°C for 2 hours. Then 2-methylpropanal (9.01 g, 124.99 mmol, 11.41 ml) was added to the mixture, the resulting mixture

- 156 047363 was stirred at -70°C for 2 hours. The mixture was quenched with sat. aq. NH ₄ Cl (60 ml) at -70°C, then warmed to 10°C, diluted with H ₂ O (200 ml) and extracted with EA (3x200 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (0-10% EA in PE) to give Na(6-bromo- 2-(1-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (13 g, 37.71 mmol, 30.17% yield, 95.5% purity) as a yellow solid.

1H NMR (400 MHz, DMSO-de) δ ppm: 10.27 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 7.49 (d, J=8 .8 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 4.45 (dd, J=4.6, 6.8 Hz, 1H), 2.06-1.93 (m, 1H), 1.21 (s, 9H), 0.93 (d, J=6.6 Hz, 3H), 0.77 (d, J=6.8 Hz, 3H).

To a solution of Na(6-bromo-2-(1-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (13 g, 39.49 mmol) in DCM (350 ml) was added Dess-Martin reagent (50.24 g, 118.46 mmol, 36.67 ml) in portions at 20°C. After addition, the mixture was stirred at 20°C for 3 hours. LCMS showed complete absorption of the starting material and 47.3% of the desired product formed at 220 nm. The mixture was quenched by adding sat. aq. Na ₂ SO ₃ (100 ml) and sat. aq. NaHCO ₃ (200 ml), extracted with DCM (3x100 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (EA in PE=0-10%) to give Na(6-bromo-2 -isobutyrylpyridin-3-yl)pivalamide (11 g, 33.48 mmol, 84.80% yield, 99.6% purity) as a colorless oil.

^1H NMR (400 MHz, DMSOHO δ ppm: 11.59 (s, 1H), 8.94 (d, J=9.0 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 4.02 (spt, J=6.9 Hz, 1H), 1.26 (s, 9H), 1.13 (d, J=6.9 Hz, 6H).

To a solution of LDA (2 M, 35.30 ml) in THF (250 ml) was added tert-butyl acetate (8.20 g, 70.60 mmol, 9.47 ml) at -70°C, the mixture was stirred at -70° C for 30 min. Na(6-bromo-2-isobutyrylpyridin-3-yl)pivalamide (11 g, 33.62 mmol) in THF (50 ml) was then added to the mixture at -70°C, and the resulting mixture was stirred at -70°C for 1 hour. The mixture was quenched with sat. aq. NH ₄ Cl (100 ml) at -70°C. Then heated to 20°C, diluted with H2O (100 ml) and extracted with EA (3x100 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to give a residue, which was purified by flash silica gel chromatography (0-10% EA in PE) to give tert-butyl-3-(6 -bromo-3-pivalamidopyridin-2-yl)-3-hydroxy-4-methylpentanoate (14.92 g, 26.55 mmol, 78.98% yield, 78.9% purity) as a yellow oil. The reaction was set to 4 loads.

tert-Butyl 3-(6-bromo-3-pivalamidopyridin-2-yl)-3-hydroxy-4-methylpentanoate (2 g, 3.56 mmol, 78.9% pure) and HBr (18.42 mmol, 5 ml, 20%) was transferred into a microwave tube in dioxane (1 ml). The hermetically sealed tube was heated at 160°C for 25 min under irradiation in a microwave reactor. The combined reaction mixture was diluted with H ₂ O (100 ml) and EA (100 ml). The suspension was filtered and the filtrate was extracted with EA (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (0-70% EA in PE) to give 6-bromo-4isopropyl-1, 5-naphthyridin-2(III)-one (4.36 g, 15.64 mmol, 60.60% yield, 95.8% purity) as a yellow solid

1H NMR (400 MHz, DMSOHO δ ppm: 11.89 (br s, 1H), 7.75-7.66 (m, 1H), 7.60 (d, J=8.6 Hz, 1H), 6.60 (s, 1H), 3.70-3.56 (m, 1H), 1.23 (d, J=7.0 Hz, 6H).

Example 98: LCMS methodology.

1. Description of LCMS conditions.

Several different conditions were used to evaluate the purity, retention time and [M+H]+ or [M-H] ^- compounds described herein using LCMS methods. The conditions are listed in table. 1 below. All data were obtained using a Shimadzu LCMS-2020 instrument unless otherwise noted. For all conditions, the column temperature was 40°C and the run time was 3 min, except where otherwise noted. Flow rate is given in units of ml/min. C is a numerical indicator for the listed LCMS condition, which is then referenced in the table. 2 below.

- 157 047363

Table 1

WITH Column Mobile phase Gradient Flow 1 Asccntis Express C18 (2.7 µm, 3.0x50 mm) temp, columns: 40°C A: H ₂ O +0.05% TFA B: CH ₃ CN +0.05% TFA From 95% A to 5% A in 1.99 minutes, holding for 0.6 minutes. up to 95% A in 0.15 min, holding for 0.25 min 1.5 2 ACE Excel 3 Super (3.0 µm, 3.0x50 mm) temp, columns: 40°C A: HO + 5 mM Η H.HCO, B: CHiCN From 90% A to 5% A in 2.09 minutes. holding for 0.6 min, up to 90% A in 0.05 min. holding for 0.25 min 1.2 3 YMC-Triart C18 (3.0 µm, 3.0x50 mm) temp, columns: 40°C A: H ₂ O +0.04% NHjOH B: CH ₃ CN From 90% A to 5% A in 1.89 minutes. holding for 0.8 min, up to 90% A in 0.05 min. holding for 0.25 min 1.5 4 Poroshell NRN-C18 (2.7 µm. 3.0x50 mm) temp, columns: 40°C A:6.5mMNH ₄ HCO.,+ NH3H2O B: CH ₃ CN From 90% A to 5% A in 1.99 minutes, holding for 0.6 minutes, to 90% A in 0.15 minutes. holding for 0.25 min 1.2 5 HALOCI8 (2.0 µm, 3.0x30 mm) temp, columns: 40°C A: H ₂ O +0.05% TFA B: CH ₃ CN +0.05% TFA From 95% A to 50% A in 1.79 minutes. up to 5% A in 0.7 min. holding for 0.3 min. up to 95% A in 0.01 min, holding for 0.19 min. Running time 3 min 1.5 5A HALOC18 (2.7 µm, 3.0 x 50 mm), temp, columns: 40°C From 95% A to 0% Aza 1.99 min. holding for 0.7 min, up to 95% A in 0.05 min. holding for 0.15 min. Running time 2.9 min 5V (2.7 µm, 3.0x50 mm). temp, speakers: 45°C From 70% A to 5% A in 3.99 min, holding for 0.8 min, to 95% A in 0.2 min, holding for 0.2 min. Running time 5.2 min 1.5 5C From 95% A to 45% A in 2.99 minutes, to 0% A in 1 minute. holding for 0.6 min. up to 95% A in 0.1 min. holding for 0.5 min. Running time 5.2 min

- 158 047363

6 Shim-pack XR-ODS (2.2 mkm, 3.0x50 mm) temp, speakers: 40°C From 95% A to 0% A in 1.99 minutes. holding for 0.7 min, up to 95% A in 0.05 min, holding for 0.25 min 1.2 7 Xsclcct CSH C18 (2.5 mkm, 3.0x50 .mm) temp, speakers: 40°C A:H _; O /0.1% FA B: CHiCN/0.1% FA From 95% A to 5% A in 2.09 minutes. holding for 0.6 min, up to 95% A in 0.05 min, holding for 0.25 min 1.2 8 C0RTECSCI8 (2.7 mkm, 2.1x50 mm) temp, speakers: 40°C A: H ₂ O +0.05% TFA B: CH,CM +0.05% TFA From 95% A to 0% A in 1.99 min, holding for 0.8 min, to 95% A in 0.1 min. holding for 0.1 min. 1.0 9 Ascentis Express C18 (2.7 mkm, 3.0x50 mm) temp, speakers: 40°C A: H _: O +0.05% TFA B: CH,CN +0.05% TFA From 95% A to 0% A in 1.99 minutes. holding for 0.8 min, up to 95% A in 0.1 min. holding for 0.1 min. 1.5 10 From 95% A to 5% A in 1.99 min, holding for 0.7 min, to 95% A in 0.1 min, holding for 0.2 min. 1.0 eleven Ascentis Express C18 (2.7 µm, 3.0x50 mm), temp, speakers: 45°C A: H:O +0.05% TFA B: CH,CN +0.05% TFA From 95% A to 60% A in 3.19 minutes, to 0% A in 0.8 minutes, holding for 0.6 minutes, to 95% A in 0.1 minutes, holding for 0.5 minutes. Running time: 5.2 min 1.5 12 Kinctcx 2,6 mkm EVOCI8 Ι00Α (2,6 mkm, 3,0x50 mm), temp, speakers: 40°C A: H2O + 5 mM NH4HCO3 B: CH ₃ CN From 90% A to 5% A in 1.99 min for 0.6 min, to 90% A in 0.15 min for 0.10 min. Running time: 2.85 min 1.2 12A From 90% A to 5% A in 1.99 minutes, holding for 0.7 minutes. up to 90% A in 0.05 min, holding for 0.10 min. Running time: 2.85 min 13 Ascentis Express C18 (2.7 µm.3.0x50 mm), temp, speakers: 40°C A: H ₂ O +0.05% TFA B: C1I.CN +0.05% TFA From 95% A to 40% A in 3.19 minutes, to 5% A in 0.9 minutes, holding for 0.9 minutes, to 95% A in 0.1 minutes. holding for 0.2 min. Running time: 5.3 min 1.5

- 159 047363

13V From 95% A to 30% A in 3.59 min, to 5% A in 0.6 min, holding for 0.8 min, to 95% A in 0.1 min, holding for 0.2 min 14A /B/F Xlimalc C l 8 2.1x30 mm, 3 μΜ temp, columns: 50°C A: N _; O (4 l) + TFA (1.5 ml) B: SN.SK (4 l) + TFU (0.75 ml) From 90% A to 20% Aza 3 minutes and maintaining at 20% for 0.5 minutes to 90% A in 0.01 minutes. holding up to 0.49 min. Running time: A/B/F: 4 min 14A:0.8 14V: 1.2 14F: 1.0 14C From 95% A to 5% A in 0.9 minutes and maintaining at 5% for 0.2 minutes, to 95% A in 0.01 minutes maintaining for 0.49 minutes. Running time 2 min 1.2 14D From 95% A to 5% A in 0.9 min\t and maintaining at 5% for 0.2 minutes, to 95% A in 0.01 min maintaining for 0.49 minutes. Running time 2 min 14E From 10% B to 80% B in 0.9 minutes and holding at 80% for 0.6 minutes to 10% B in 0.01 minutes, holding for 0.49 minutes. Running time 2 min 15 Agilent Poroshell 120, EC-C18, 4.6x100 mm - 4 µm temp, columns: 30°C Agilent 1260 Infinity 11 ' A: 0.1% FA g. 11-0 B: 0.05% FA in CH,CN 2.0 min 98% A, from 98% A to 0% A in 10 min, holding for 3.4 min. Running time: 15.4 min 1 16A HALO 90AC18 (2.0 µm. 2.1x30 mm) temp, columns: 40°C A: NU +0.05% TFU B: CH.1CN +0.05%TFA From 95% A to 0% A in 2.19 minutes, holding for 0.5 minutes, to 95% A in 0.05 minutes. holding for 0.25 min. Run time: 3 mg/ml 1 16V From 95% А to 50% А in 2.79 min, to 0°/· А in 1 min, holding for 0.6 min, to 95% А in 0.1 min. holding for 0.5 min. Running time: 5 min 1

- 160 047363

16C From 95% A to 40% A in 2.79 minutes. up to 0% A in 1 min. holding for 0.6 min, up to 95% A in 0.1 min, holding for 0.5 min. Running time: 5 min 1 17 Ascends Express C18 (2.7 µm, 3.0x50 mm) Temp, columns: 45°C A: H ₂ O /0.05% TFA B: CH ₃ CN /0.05% TFA Running time: 5.2 min From 95% A to 50% A in 2.99 min, to 0% A in 1.0 min, holding for 0.6 min, to 95% A in 0.1 min, holding for 0.5 min 1.5 18 Kinetex EVOC18 100A (2.6 µm, 3.0x50 mm) temp, columns: 40°C A: IIO/5 mMNHjHCO, B: ATP\ From 90% A to 5% A in 2.99 minutes, holding for 0.6 minutes. up to 90% A in 0.10 min, holding for 0.30 min. Running time: 4 min 1-2 18V From 90% A to 60% A in 3.19 minutes, to 5% in 0.8 minutes, holding for 0.9 minutes, to 90% A in 0.2 minutes, holding for 0.20 minutes. Run time; 5.3 min 19 Asccntis Express C18 (2.7 microns, 3.0x50 mm), tempo, columns: 404' A: H;O/0.05%TFA B: CH3SY/0.05% TFA From 95% A to 5% A in 1.99 minutes. holding for 0.7 min, up to 95% A in 0.05 min. holding for 0.25 min 1.5 19A From 95% A to 0% A in 1.99 minutes. holding for 0.7 min, up to 95% A in 0.05 min. holding for 0.25 min. Running time 3 min 19V From 95% A to 0% Aza 1.09 min. holding for 0.6 min, up to 95% A in 0.05 min. holding for 0.1 min. Running time 1.85 min 20 HALO 90AC18 (2.0 µm. 3.0 x 30 mm), temp, columns: 40°C A: H ₂ 0/0.05% TFA B: CH ₃ SY/0.05% TFA From 95% A to 50% A in 3.09 min. up to 5% A in 1.0 min. holding for 0.9 min, up to 95% A in 0.1 min, holding for 0.2 min. Running time: 5.3 min 1.5

- 161 047363

20A From 95% A to 0% A in 1.99 minutes. holding for 0.7 min, up to 95% A in 0.05 min. holding for 0.25 min. Running time: 3 min 20V From 95% A to 0% A in 1.99 min, holding for 0.7 min, to 95% A in 0.05 min, holding for 0.45 min. Running time 3.2 min 20C From 95% A to 60% A in 3.09 min, to 10% A in 1.0 min, holding for 0.9 min, to 95% A in 0.1 min, holding for 0.2 min. Running time: 5.3 min 21 Poroshell HPNS 18 (2.7 microns, 3.0x50 mm). Temp, speakers: 40 °C A:6.5 mM NH4HCO3+NH3H2O In: CHiCN From 90% A to 5% A in 1.99 minutes. holding for 0.7 min, up to 90% A in 0.05 min. holding for 0.25 min 1.2 21A From 90% A to 55% A in 2.99 minutes. up to 5% in 1 min. holding for 0.7 min. up to 90% A in 0.2 min, holding for 0.1 min (Running time 5 min) 21B From 90% A to 60% A in 2.99 minutes. up to 5% in 1 min. holding for 0.7 min. up to 90% A in 0.2 min. holding for 0.1 min, Running time 5 min 22 Asccntis Express C18 (2.7 microns, 4.6x100 mm) Temp, speakers: 40 °C A: Water/0.05% TFA B: CH ₃ SSh0.05% TFA From 90% A to 5% A in 7.99 minutes. holding for 2.0 minutes, up to 90% A in 0.5 minutes, holding for 1.5 minutes. Running time: 12 min 1.5 23 HALO C18 (2.7 µm. 3.0x50 .mm) Temp, columns: 40 °C From 95% A to 0% A in 1.99 minutes. holding for 0.7 min, up to 95% A in 0.05 min. holding for 0.25 min. Running time: 3 min 1.5 24 NRN-S18 (2.7 microns, 3.0*50 mm) A:6.5 mM NHjHCOj+NHjELO In: CHiCN From 90% A to 50% A in 2.99 min, to 5% A in 0.3 min, maintaining for 0.45 1.2 Temp, columns: 35°C min. up to 90% A in 0.05 min. holding for 0.2 min. Running time 4 min

2. LCMS results.

The LCMS characterization results and the specific set of conditions used for the compounds disclosed herein are presented in Table. 2.

- 162 047363

No. connections Rt (min) [M+N] ⁺ or [M-N] Method LCMS 1 1,660 [M-N] =454 2 2 1.035 [M-N]‘=414 3 3 1,394 [M+N]*=414 4 4 1.217 [M-N] =470 4 5 1.461 [M-N] =480 4 6 1.428 [M-N] =516 4 7 1.429 [M-N] = 488 4 8 1.375 [M+N]’=454 5 9 0.734 [M+N]*=453 3 10 1,392 [M+N]’=425 6 eleven 1.379 [M+N]*=434 1 12 1,304 [M+N]’=449 8 13 0.808 [M+N]*=468 4 14 1,310 [M+N]*=439 1 15 1,489 [M+N]’=453 1 16 1,363 [M+N]*=424 8 17 1.131 [M-N]-= 437 4 18 1,592 [M+N]*=457 1 19 1,572 [M+N]*=457 1 20 2,692 (M+N]*=499 13 21 1.331 [M+N]*=485 1 22 1.536 [M+N]’=573 1 23 1,504 [M+N]*=438 1 24 2,246 [M+N]’=453 eleven 25 1.141 [M+N]*=440 9 26 1.234 [M+N]*=467 10 27 1.004 [M+N]*=490 9 28 1.133 [M+N]’=460 12 29 1,293 [M+N]*=454 9 thirty 0.950 [M+N]’=439 9 31 1.862 [M+N]+=415 14A 32 10.91 [M+N]+=443 15

table 2

Connection no. Rt (min) [M+N]* or [M-N] Method LCMS 33 1.427 [M+N]*=470 9 34 1.036 [M+N]*=502 4 35 1.237 [M+N]’=439 1 36 1.107 [M+H) ⁺ =423 16A 37 1,099 [M+I]*-405 16A 38 1.075 [M+N]'=385 9 39-A 2,295 [M+N]‘=439 16V 39-B 2,298 [M+N]+=439 16V 40-A 2,614 [M+N]+=447 16V 40 1.229 [M+Na]*=459 9 41 1.441 [M+N]‘=446 16A 42 1.323 [M+N] ⁺ =451 9 43 0.865 [M+N]‘=416 4 44 1.193 [M+N]‘=471 16A 45 1,348 [M-N]’=508 12 46 1,348 [M-N] = 502 4 47 1,199 [M-N] = 412 4 48 1,361 [M-N] = 454 4 49 1,394 [M-N] = 468 4 50 1.324 [M-N] = 466 4 51 1.182 [M-N]=456 4 52 2,541 [M+N]*=458 16C 53 1.338 [M+N]’=448 9 54 0.992 [M+Hf=390 14C 55 1,144 [M+N]*=405 14C 56 2,557 [M+N]*=391 14V 57 10,149 [M+N]*=415 15 58 1.576 [M+N]*=465 18 59 0.796 [M+N] ⁺ =467 4 60 1,020 [M+N]*=441 1 60-A 0.933 [M+N] ⁺ =423 4 61 1.191 [M+Na] ⁺ =523 9

- 163 047363

62 1,042 [M+N)’=453 1 63 1.013 [M+N] ⁴ =459 4 63-A 2,290 [M+N] ⁴ =459 eleven 64 1,410 [M+N]*=491 1 65 2.657 [M+IM-4S5 17 66 1.195 [M+N] ⁺ -416 140 67 1.525 [M+N] ⁴ =509 19 67-A 1.105 [M+N) ⁴ =509 21 68 1.452 [M+N] ⁴ -493 19 68-A 1,340 [M+N] ⁴ =493 19 69 1,084 [M+N]’=477 21 69-A 0.988 [M+N] ⁴ =477 21 70 1.428 [M+NG-473 19 70-A 1.313 [M+N] ⁴ =473 19 71 1.518 [M+N]*=487 19 71-A 1,392 [M+NG=487 19 72 1,286 [M+N] ⁺ -513 21 72-A 2,349 [M+N] ⁴ =513 21 73 1,393 [M+N) ⁴ =439 1 74 0.849 [M+NG=460 14D 75 2,167 [M+N] ⁴ =449 14V 75A 0.928 [M+NG-459 14D 76 1,209 [M+N] ⁴ =495 19 77 2,348 [M+N]’=481 17 78 1.238 [M+N] ⁺ =427 9 79 0.977 [M+NG-417 21 80 1.019 [M+N] ⁴ =469 21 81 1.017 [M+N] ⁴ =513 21 82 1.223 [M-IIJ--448 19 83 1,079 [M+NG=474 21 84 2,612 [M+N] ⁴ =476 17 85 2,864 [M+N] ⁴ =488 20 86 1,270 [M+N] ⁴ =451 19 86-A 1.268 [M+N] ⁴ =451 19 86-B 1.219 [M+NG-451 19 87-A 1.462 [M+N] ⁺ =543 20 87-B 1.453 [M+N] ⁴ =543 20 88-A 0.910 [M+N]’=453 20 89 2,872 [M+N] ⁴ =465 13 90 9,502 [M+N]*=442 15 91 11,305 [M+N] ⁴ =498 15 92 10,622 [M+N]*-494 15 93 2,276 [M+N]—463 21A 135 10,362 [M+N] ⁺ =500 15 136 9,674 [M+N] ⁺ =500 15 137 7,539 [M+N] ⁺ =459 15 138 7.52 [M+N]'-459 15 139 10.135 [M+N]'=458 15 140 9.48 [M+N] ⁺ -458 15 141 6,874 [M+N]'=459 15 142 6,669 [M+N] -459 15 143 8,458 [M+N] -446 15 144 1.124 [M+N] ⁴ =469 21 145 9.305 [M+N]'-472 15 146 0.831 [M+N]*=474 14D 147 0.870 [M+N)’=474 14A 148 9.338 [M+N)’=414 15 149 8.28 [M+N)*=421 15 150 8,915 [M+N] ⁴ -432 15 151 8,195 [M+N]*=404 15 152 8,695 [M+N]'-ZE9 15 153 9,801 [M+N] ⁺ =428 15

94 10,309 [M+N]’=477 15 95 1.231 [M-N['-449 12A 96 9.653 [M+N]-463 15 97 1.352 [M+N]*=501 19 98 10,265 [M+N] ⁴ -513 15 99 1.195 [M+N] ⁴ =513 21 100 1,188 [M+N] ⁴ =513 21 101 1,448 [M+N] ⁴ =463 19 102 0.973 fM-Hl-467 20V 103 2,502 [M+N] ⁴ =467 20C 104 1.647 [M+N]*=462 24 105 1.712 [M+N] ⁴ =462 24 106 1.416 [M-N[ ⁴ -I73 19A 107 9,809 [M+N] ⁴ =499 15 108 0.842 [M+N] ⁴ =511 21 109 0.727 [M+N] ⁴ =511 21 110 0.86 [M+N] ⁴ =511 21 111 0.751 [M+N] ⁴ =511 21 112 1.341 [M+N] ⁴ =487 5A 113 1.34 [M+N] ⁴ =487 19A 114 1.146 [M+N] ⁴ =515 5V 115 1.023 [M+N] ⁴ =515 21 116 2,964 [M+N] ⁴ =507 13V 117 2,709 [M+N] ⁴ =507 5C 118 2,733 [M+N] ⁴ =525 13 119 1.257 [M+N] ⁴ =525 19A 120 2,733 [M+N] ⁴ =525 13 121 1.257 [M+N] ⁴ =525 19A 122 1.208 [M+N] ⁴ =499 19 123 1,098 [M+N] ⁴ =499 19 124 0.94 [M+N] ⁴ =499 21 125 1,941 [M+N] ⁴ -499 18V 126 2,381 [M+N] ⁴ =499 22 127 0.731 [M+N] ⁴ =499 21 128 0.941 [M+N] ⁴ =510 21 129 0.844 [M+N] ⁴ =510 21 130 2,283 [M+N] ⁴ =499 21B 131 1.842 [M+N]*=499 21B 132 1.003 [M+N] ¹ =510 21 133 0.906 [M+N] ⁺ =5 10 21 134 1,196 [M+N] ¹ =510 19A 154 1,963 [M+N] ⁴ =456 14A 155 9.865 |M+N]--4Х9 15 156 1.418 [M+N]-4H9 19A 157 0.740 [M+N] ⁴ -405 14D 158 1.239 [M+N]-485 23 159 1.533 [M+N] ⁴ =466 19A 160 0.696 [M+N] ⁴ =491 21 161 0.705 [M+N] ⁴ =490 20A 162 0.681 [M+N] ⁴ =404 14E 163 1.125 [M+N]-487 21 164 1.122 [M+N]--487 21 165 0.945 [M+N] ⁴ =485 19V 166 1.373 [M+N] ⁴ =485 19A 167 2.345 [M+N] ⁴ -465 21A 168 1,092 [M+N] ⁴ =465 21 169 1,041 [M+N] ⁴ =453 21 170 1,046 [M+N] ⁴ =453 21 171 1.036 [M+N] ⁴ =390 14F

Example 99. Biological research.

Biochemical analysis of THR.

Thyroid receptor beta coactivator assay was used

TR-FRET with minor optimized modifications to the manufacturer's protocol (Invitrogen). The assay uses terbium-labeled anti-GST antibody, glutathione Stransferase (GST)-labeled human thyroid receptor beta or alpha, ligand binding domain (LBD), and fluorescein-labeled SRC2-2 coactivator peptide. The antibody interacts with the LBD, where the agonist also binds, resulting in increased affinity for the SRC2-2 coactivator peptide, causing an energy transfer of the acceptor fluorophore and a shift in FRET emission from 495 to 520 nm. Energy transfer is detected as an increase in the fluorescence emission of the fluorescein acceptor and a decrease

- 164 047363 fluorescence emission from terbium donor. The assay is performed in a 384-well black plate in a final volume of 20 µl. Serial dilutions of the various test agonists were carried out in DMSO (final DMSO concentration 1%) and added to the test plate. Thyroid receptor beta LBD is added to the plate at a final concentration of 1 nM, followed by a mixture of fluorescein-labeled SRC2-2 coactivator peptide and terbium-labeled anti-GST antibody at final concentrations of 200 and 2 nM, respectively. Incubate the sample for 1 hour at room. temp., protected from light. TR-FRET is then measured on a Victor multichannel plate reader (Perkin Elmer) using an excitation wavelength of 340 nm with emission filters of 495 and 520 nm. Quantitative analysis is expressed by expressing the intensity ratio (520:495) and the resulting activation curves; EC ₅₀ values were obtained using the sigmoidal dose-response equation (variable slope) in GraphPad™ Prism 8.0.

Reporter analysis HEK293T.

THR-alpha/beta/RXR reporter assay (assay 2).

The purpose of this assay is to evaluate the effects of compounds on the nuclear thyroid hormone receptor pathway in HEK293T cells. To this end, HEK293T cells were transiently transfected with a thyroid response element (TRE) luciferase reporter, an RXR expression plasmid, and a THR alpha or THR beta expression plasmid. Transfected cells are stimulated with test compounds for 18-24 h before activation of the thyroid hormone pathway is measured using a luciferase readout.

Methodology. 24 hours prior to transfection, approximately 7x105 HEK293T (ATCC, part number CRL-3216) are seeded into one well of a 6-well plate using DMEM (Hyclone, part number SH30022) supplemented with 10% FBS (Gibco, part number 16000-044 ) and incubate overnight. Transfection complexes are prepared by mixing 12 μl of Lipofectamine 2000 (Invitrogen catalog no. 11668019) with 4 μg of a 1:1:4 plasmid mixture (TR-alpha or TR-beta: RXR: TRE-Luc) in 200 μl of OptiMem (cat. no. Invitrogen 11058-021) and added to the cells. After overnight incubation, transfected cells are reseeded (1x104 cells/well, 30 μl/well) into a 384 microplate and incubated for an additional 5-6 hours. Ten five-fold dilutions of the test substances are prepared in DMSO and 30 nl is dispensed into the cells. Pure DMSO serves as a negative control, while T3 (MCE part number HY-A0070) and GC-1 (MCE part number HY-14823) are used as positive controls. Approximately 18-24 hours after addition of compound, the 384-well plates are allowed to adjust to room temperature, 30 μl of One-Glo (Promega part number E6120) is added to each well and luminescence is measured on a Perkin Elmer Enspire plate reader. The percentage of agonism is calculated using the following equation: 100x (sample - negative control)/(positive control - negative control). Differential expression of the Huh-7 gene (analysis 3).

Removing whey.

AG® 1-X8 anion exchange resin (analytical grade, 200-400 mesh, chloride form; 1401451, Bio-Rad) was pre-washed with distilled water three times; water was separated from the resin by centrifugation. Fetal bovine serum (FBS) was incubated with washed resin (50 mg resin/ml FBS; resin weight is the dry weight of the resin before washing) for 5 h at room temperature on a rotor. FBS was separated from the resin by centrifugation and incubated with new washed resin for 18 h at room temperature on a rotor. Resin-treated FBS (rFBS) was separated by centrifugation and then filter sterilized (0.22 μM PES membrane).

Cell culture and drug treatment.

Huh-7 cells were cultured in DMEM (10-013-CM, Corning) supplemented with 10% FBS and 1% Pen-Strep at 37°C and less than 5% CO ₂ . When 70–80% confluency was reached, cells were removed by trypsinization. The medium was aspirated from the cell culture dish, the cell monolayer was washed with 1x PBS, and 0.05% trypsin solution, 0.53 mM EDTA (25-052-CV, Corning) was added to the dish. After 3 min of incubation, the cells were completely separated by repeated pipetting of the solution onto the monolayer. An equal volume of DMEM supplemented with 10% rFBS and 1% Pen-Strep (TH-depleted DMEM) was added to the plate to inactivate trypsin. The cell suspension was centrifuged at 350 x g at room temperature for 3 min. The supernatant was aspirated, and the cell pellet was resuspended in TH-depleted DMEM. Cell density was quantified using a Vi-CELL XR Cell Viability Analyzer (Beckman Coulter), and cells were seeded onto 96-well collagen I plates (356407, Corning) at 50,000 cells/well in 150 μl TH-depleted DMEM; external holes along the perimeter were not used to avoid edge effects. After 24-hour incubation, the medium was replaced with drug-containing medium. All compounds were serially diluted in DMSO, and final concentrations were achieved by dilution in TH-depleted DMEM (0.1% DMSO). Cells were incubated in drug-containing medium for 24 hours. Treatment was carried out in biological duplicates.

Cell lysis and RT-qPCR.

After 24 h in drug media, cells were lysed directly on culture plates and cDNA was prepared using the TaqMan™ Fast Advanced Cells-to-CT™ kit

- 165 047363 (A35374, Invitrogen) and following the manufacturer's protocol. RT-qPCR for CPT1A (Hs00912671_ml) and two housekeeping genes, ACTB (Hs01060665_gl) and TFG (Hs02832013_gl), was performed using TaqMan™ Fast Advanced Master Mix. RT-qPCR reactions were performed on qTOWER ³ 84 G (Analytik Jena) in technical duplicates.

Analysis data.

ARn values were obtained using qPCRsoft384 1.0 software and CPT1A gene expression was quantified using the 2-AAC'L method. Dose-response curves were generated using GraphPad Prism 8 using a four-parameter logistic equation with no upper limit to obtain EC ₅₀ and E _max .

The compounds of formula (I) are active as THR-beta agonists, as illustrated in table. 3, where:

for assay 1: A indicates _EC50 <50 nM, B indicates _EC50 >50 and <250 nM, C indicates EC50 >250 and <1000 nM, D indicates EC50 >1000 and <25000 nM, and E indicates EC50 >25,000 nM;

for assay 2: A indicates EC ₅₀ <50 nM, B indicates EC ₅₀ >50 and <250 nM, C indicates EC ₅₀ >250 and <1000 nM, D indicates EC ₅₀ >1000 and <10000 nM, and the letter E indicates EC ₅₀ >10,000 nM.

- 166 047363

17 A D 18 A D 19 A D 20 E E 21 IN E 22 E 23 D 24 E 25 D 26 E 27 E 28 IN C 29 c C thirty E 31 A c 32 A V 33 C 34 D 35 D D 35-A IN E 36 A A 37 IN IN 38 c C 39-A A IN 39-B A A 40-A C D 40 A IN 41 A A 42 A IN 43 A 44 IN E 45 A IN 46 A D 47 A D 48 A IN 49 A C 50 A IN 51 D E 52 IN E 53 A C 54 A A 55 A A 56 A IN 57 A IN 58 A IN

- 167 047363

59 D D 60 C D 60-A A C 61 A IN 61-A A A 61-B IN C 62 D E 63 IN IN 63-A E E 64 A IN 65 A IN 66 IN D 67 IN IN 67-A A 68 A A 68-A E 69 IN IN 69-A E 70 A A 70-A E 71 A A 71-A E 72 IN IN 72-A A IN 73 IN IN 74 D E 75 A A 75A A 76 D C 77 IN IN 78 C 79 D E 80 A A 81 A A 82 A A 83 A A 84 A IN 85 A 86-A IN IN 86-B IN WITH 87-A WITH E 87-B E 88-A D E 89 A 90 A E

- 168 047363

91 A IN 91-A A IN 92 IN V 92-A A With 93 IN With 94 IN V 95 IN V 96 A A 97 WITH D 98 V IN 99 V E 100 V IN 101 V IN 102 D D 103 D D 104 WITH D 105 D 106 WITH D 107 A IN 108 E 109 E 110 E 111 E 112 IN IN 113 IN WITH 114 IN With 115 V With 116 V V 117 V E 118 A A 119 D E 120 A IN 121 IN IN 122 D 123 E 124 D E 125 D 126 E 127 E 128 E E 129 WITH E

- 169 047363

130 E 131 D 132 E 133 WITH 134 A WITH 135 E 136 D 137 D 138 E 139 IN A 140 E 141 D 142 E 143 A A 144 IN WITH 145 A D 146 A A 147 A A 148 A D 149 A A 150 A A 151 A A 152 A A 153 A 154 IN E 155 IN WITH 156 A IN 157 A A 158 A IN 159 IN IN 160 D E 161 WITH D 162 A 163 E 164 A 165 A 166 IN 167 IN 168 A 169 A 170 IN

The compounds of formula (I) may have activity as THE-alpha agonists, as illustrated in table. 4, where:

for assay 1: A indicates EC50 <50 nM, B indicates EC50 >50 and <250 nM, C indicates EC ₅₀ >250 and <1000 nM, D indicates EC ₅₀ >1000 and <25000 nM, and E indicates EC ₅₀ >25,000 nM;

for assay 2, A indicates EC ₅₀ <50 nM, B indicates EC ₅₀ >50 and <250 nM, C indicates EC ₅₀ >250 and <1000 nM, D indicates EC ₅₀ >1000 and <10000 nM, and the letter E indicates EC ₅₀ >10,000 nM.

- 170 047363

Table 4

Connection number Activity category Analysis 1 Analysis 2 1 A WITH 2 A WITH 3 E WITH 4 E E 5 E D 6 E 7 E 8 D 9 E 10 WITH IN AND IN WITH 12 D D 13 WITH D 14 E 15 E E 16 WITH WITH 17 E E 18 E D 19 E D 20 E E 21 E E 22 E 23 D 24 E 25 D 26 E 27 E 28 WITH D 29 D WITH thirty E 31 A D 32 A IN 33 WITH 34 E 35 D D 35-A WITH IN 36 IN A 37 WITH IN 38 D E 39-A WITH IN 39-B IN A 40-A WITH D 40 IN WITH 41 A A 42 WITH WITH 43 A A 44 E E 45 A WITH 46 E E 47 A D 48 A WITH 49 A WITH 50 A WITH 51 E E 52 D E 53 WITH D 54 A A 55 A IN 56 WITH IN 57 A WITH 58 WITH With 59 D E 60 D D 60-A IN WITH

- 171 047363

61 C C 61-A IN IN 61-B D C 62 D E 63 C C 63-A E E 64 C C 65 C D 66 c D 67 D E 67-A E D 68 IN IN 68-A E 69 C IN 69-A E 70 IN IN 70-A E 71 IN V 71-A E 72 E E 72-A IN E 73 c WITH 74 D E 75 IN WITH 75-A IN E 76 E E 77 c WITH 78 D 79 D D 80 IN IN 81 A A 82 A A 83 A A 84 A IN 85 A A 86-A C WITH 86-B D D 87-A C E 87-B E 88-A E E 89 C D 90 IN E 91 D E 91-A D E 92 D E

- 172 047363

92-A D E 93 WITH D 94 WITH D 95 WITH WITH 96 IN IN 97 D E 98 E E 99 E E 100 E E 101 WITH IN 102 D E 103 E E 104 D E 105 D 106 D D 107 D WITH 108 E 109 E BUT E 111 E 112 WITH D FROM WITH E 114 E E 115 E E 116 E E 117 E E 118 IN IN 119 E E 120 E E 121 WITH E 122 D 123 E 124 D E 125 E 126 E 127 E 128 E E 129 E E 130 D 131 D 132 E 133 E 134 WITH E 135 E 136 D 137 E 138 E 139 IN IN 140 E 141 E 142 E 143 A A 144 WITH D 145 A D 146 IN IN 147 A A 148 A D 149 A A 150 A A 151 A A 152 A A 153 A

- 173 047363

154 E 155 E E 156 IN D 157 WITH IN 158 With D 159 With D 160 D E 161 WITH E 162 IN 163 E 164 IN WITH 165 WITH 166 E 167 D 168 IN 169 WITH 170 E

The compounds of formula (I) have activity as THR-alpha/beta agonists, as illustrated in table. 5, where:

for analyzes 1 and 2: C indicates _Emax <50%, B indicates _Emax >50 and <75%, A indicates Emax >75%.

- 174 047363

36 IN V With V 37 IN V V A 38 A V With A 39-A IN With A A 39-B IN V A A 40-A With With With A 40 V V A A 41 V V V A 42 With V A A 43 A A A A 44 WITH With With WITH 45 With With A A 46 With With With V 47 With With A A 48 V V A A 49 With With WITH A 50 V V A A 51 A With WITH WITH 52 WITH With IN A 53 With V A A 54 With V IN A 55 V V A A 56 With With IN A 57 With With A A 58 With With IN A 59 With With IN A 60 With With A A 60-A With With WITH V 61 V With A A 61-A V V IN A 61-B With With WITH A 62 With With V A 63 With With V A 63-A With With With WITH 64 With With With V 65 With With With A 66 With V V A 67 With With With IN 67-A With With With WITH 68 With V V A 68-A With With 69 With With V IN 69-A With With 70 With With V A 70-A With With

- 175 047363

71 C With V A 71-A C With 72 C With With V 72-A C With With V 73 IN With A A 74 C V With With 75 A A A A 75-A C V With IN 76 C With With IN 77 IN With A A 78 c With 79 c V V A 80 V V A A 81 V V A A 82 A A A A 83 IN V A IN 84 V With A A 85 With With V A 86-A With With V A 86-B With With With A 87-A With With With WITH 87-B With With 88-A With With A WITH 89 With With WITH IN 90 With With With V 91 V With With V 91-A With With With V 92 With With With With 92-A V With With With 93 With With With V 94 With With With V 95 With With With A 96 With With V A 97 With With With WITH 98 With With With With 99 A With With With 100 With With With With 101 With With With V 102 With With With With 103 With With With With 104 V With With V 105 With With 106 With With With V 107 With With With V 108 With With

- 176 047363

109 WITH With 110 WITH With 111 With With 112 With With With With FROM With With With With 114 With With With With 115 With With With With 116 With With With With 117 With With With With 118 With V V V 119 With With With With 120 With With With V 121 With With With V 122 With With 123 With With 124 With With With With 125 With With 126 With With 127 With With 128 With With With With 129 With With With With 130 With With 131 With With 132 With With 133 With With 134 With With With V 135 With With 136 With With 137 With With 138 With With 139 With With With V 140 With With 141 With With 142 With With 143 A V A A 144 With With V V 145 V With V V 146 With With With V 147 With V A A 148 V With With V 149 With With A A 150 With With V V 151 A V V V 152 V With V V 153 With With 154 With With With 155 With With With With 156 With With With V 157 V A V A 158 With With With V 159 With With With V 160 With With With With 161 With With With With 162 With V 163 With With 164 With With V A 165 With With 166 With With 167 With With 168 V With 169 With With 170 With With

The compounds of formula (I) have activity as THE agonists, as illustrated in table. 6, where:

for assay 3 in the EC50 column: A indicates EC50 <100 nM, B indicates EC50 >100 and <1000 nM, C indicates EC50 >1000 nM; in the Emax column: C indicates Emax >50%, B indicates Emax >50 and <75%, A indicates Emax >75%.

- 177 047363

Example 100: X-ray diffraction data.

The chemical structures of compounds 67 and 67-A were confirmed by X-ray crystallography as described below.

Experimental data Single colorless crystals of compound 67 were recrystallized from a mixture of THF and acetonitrile by slow evaporation. A suitable crystal with dimensions of 0.39x0.20x0.10 mm ³ was selected and mounted on a nylon loop with paraton oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at a constant T=173(2) K during data collection. The structure was solved using the XT solver (Sheldrick, 2015) using dual methods and using OLEX2 as the GUI. The model was refined using ShelXL 2018/3 (Sheldrick, 2015) using full least squares matrix minimization on F2.

Crystallographic data C ₂₉ H ₂₅ Cl ₂ N ₇ O ₅ , M _r = 622.46, triclinic, P-1 (No. 2), a = 8.91530 (10) A, b = 10.93240 (10) A , с=16.2174(2) А, α=75.7870(10)°, β=83.5020(10)°, γ=67.6090(10)°, V=1416.39(3) А ³ , T=173(2) K, Z=2, Z'=1, μ^πΚα)=2.518, 22070 measured reflections, 5231 unique (Rint=0.0434), which were used in all calculations. The final wR2 was 0.1228 (all data) and R1 was 0.0445 (I>2(I)).

- 178 047363

Experimental data

Single colorless block crystals of compound 67-A were recrystallized from THF by slow evaporation. A suitable crystal with dimensions of 0.14x0.07x0.04 mm ³ was selected and mounted on a nylon loop with paraton oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at a constant T=173(1) K during data collection. The structure was solved using ShelXT (Sheldrick, GM (2015). Acta Cryst. A71, 3-8) dual method solver using OLEX2 as the GUI. The model was refined by ShelXL (Sheldrick, Acta Cryst. A64 2008, 112-122) using full matrix least squares minimization on F2.

Crystallographic data C ₂₇ H ₂₂ Cl ₂ N ₆ O ₅ , M _g = 581.40, monoclinic, C2/c (No. 15), a = 38.956 (17) A, b = 8.001 (3) A, c = 23.093 (13) A, β=125.580(12)°, α=γ=90°, V=5854(5) A ³ , T=173(1) K, Z=8, Z'=1, μ(ΓϊιΙ< α)=2.389. 44732 measured reflections, 5360 unique (Rint=0.1596), which were used in all calculations. The final wR2 was 0.3362 (all data) and R7 was 0.1018 (I>2(I)).

Example 101 Comparison of compounds 42, 40 and 10 with CN analogues.

Compounds 42, 40 and 10 have R ₉ =NH ₂ . These compounds were compared with direct analogues, where R ₉ = CN, in the HEK293T THR-alpha/beta/RXR reporter assay.

Table 7

Reporter analysis HEK293T Reporter analysis __

Compound 42 Analogue CN 1 Compound 40 Analogue CN 2 Compound 10 Analogue CN 3 ECso a (mkM) 0.834 (87%) >10 0.564 (95%) 9.65 (35%) 0.191 (79%) 16.9 (62%)

Είίοβ(ΜκΜ) 0.077 (94%) >10 0.058 (92%) 3.78 (81%) 0.050 (91%) 2.37 (93%) Ratio (α/β) 11 (π = 5) — 10 (η = 3) 2.5 (η = 1) 4 (η = 7) >4 (η =4)

Links:

1. Younossi, Z.M., Koenig, A.V., Abdelatif, D., Fazel, Y., Henry, L., Wymer, M., 2016. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1): 73e84.

2. Gastroenterology. 2012 Jun;142(7): 1592-609.

doi: 10.1053/j.gastro.2012.04.001. Epub 2012 May 15.

3. Serfaty, L., Lemoine, M, 2008. Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes and Metabolism 34 (6 Pt 2): 634e637.

4. Hepatology. Oct 2012; 56(4): 1580-1 584. doi: 10.1002/hep.26031

5. Dulai, P.S., Singh, S., Patel, J., Soni, M., Prokop, L.J., Younossi, Z., et al, 2017. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 65(5): 1557el565.

6. Younossi, Z.M., Loomba, R, Rinella, M.E., Bugianesi, E, Marchesini, G., NeuschwanderTetri, B.A., et al., 2018. Current and future therapeutic regimens for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty liver disease (NAFLD) -alcoholic steatohepatitis (NASH). Hepatology 68(1): 349e360.

7. Thyroid. 2002 Jun; 12(6): 441-6. Mechanism of thyroid hormone action. Harvey CB, Williams GR.

- 179 047363

8. A.L Bookout, Y. Jeong, M. Downes, R.T. Yu, R.M. Evans, D.J. Mangelsdorf Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell, 126 (2006), pp. 789-799

9. F, Flamant, J.D., Baxter, D. Forrest, S. Refetoff, H.H. Samuels, T.S. Scanlan, B. Vennstrom, J. Samarut International union of pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol. Rev., 58 (2006), pp. 705-711

10. Bioorg Med Chem Lett. 2005 Apr 1;15(7): 1835-40. Novel heterocyclic thyromimetics. Haning Hl, Woltenng M, Mueller U, Schmidt G, Schmeck C, Voehrmger V, Kretschmer A, Pernerstorfer J.

11. Expert Opin Ther Pat. 2010 Feb;20(2): 213-28.

doi: 10.1517/13543770903567069. Thyromimetics: a review of recent reports and patents (2004 - 2009). Hirano Tl, Kagechika H.

12. Front Endocrinol (Lausanne) 2018 Jul 10;9: 382.

doi: 10.3389/fendo.2018.00382. eCollection 2018. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Kowalik MA, Columbano A, Perra A

13. Proc Natl Acad Sci USA. 2007 Sep 25;104(39): 15490-5. Epub 2007 Sep 18.Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Erion MD1, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL,

Embodiment 1. Compound of formula (I) (I) TL-L _a -CE-HD or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where: i) TL is a fragment of formula (IIa), (IIb) , (IIIa), (IIIb), (IIIc) or (IIId):

(IIIb) (IIIc) (Hid) wherein each of Q1, Q2, _Q3 , Q4, Q5, _Q6 and _Q8 is independently nitrogen or -CR _b -, wherein each R _b is independently hydrogen, halogen or lower alkyl;

Ri represents hydrogen, 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 group, an optionally substituted heteroarylalkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure;

R ₂ represents hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R ₃ represents hydrogen or lower alkyl;

R ₄ represents 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 group, an optionally substituted heteroarylalkyl group, optional substituted amino group, optionally substituted sulfamoyl group, optionally

- 180 047363 a substituted carbamoyl group or an optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

_R4 and R5, taken together with the carbon atoms to which they are attached, form a 7 to 11 membered, optionally substituted spirocyclic ring or a 7 to 11 membered, optionally substituted spiroheterocyclic ring; or when Q6 is nitrogen and R5 is hydroxy, then the tautomer of the moiety of formula (III) and Alk is hydrogen or optionally substituted alkyl;

ii) CE is a fragment of formula (IV)

wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R ₈ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

optionally R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring;

Q ₇ represents nitrogen or -CRc-, where Re represents hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

iii) HD is a fragment of formula (V) or (VI):

where R9 is selected from hydrogen, -(C(R)2)nC(Rdb> -(C(R)2)n-ORd, -(C(R)2)nN(Rd)2> -(C(Rdh) nS(=O)qRd, -(C(Rd)2)n-CN, -(C(R _d )2) _n -C^CR _d , -(C(Rd)2) _n -C(=O) -OR _d , -(C(Rdh)n-HeAr or -(C(Rd)2)nC(=O)-N(Rd)2;

each R _d independently represents hydrogen or optionally substituted lower alkyl;

each q is independently selected from 0, 1 or 2; and each n is independently selected from 0, 1, 2, 3, 4 or 5;

R ₁₀ represents hydrogen, -C(Re) ₃ where each Re independently represents hydrogen, halogen or optionally substituted lower alkyl; And

R11 represents an aryl group, preferably substituted with lower alkyl, halogen, cycloalkyl; or a bicyclic ring system containing aromatic or saturated rings; or a bicyclic heterocycle containing aromatic or saturated ring systems iv) La independently represents a bond; -(C(Ra)2) _n -; oxygen; sulfur; -NRa-; wherein each Ra is independently hydrogen or lower alkyl; and n is 0, 1, 2, 3, 4 or 5.

Embodiment 2. The compound of Embodiment 1, wherein R ₁ is hydrogen, an optionally substituted alkyl group, an optionally substituted carbocyclic group, an optionally substituted aryl group, and an optionally substituted C-carboxy group.

Embodiment 3. The compound of Embodiment 2, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Embodiment 4. The compound of Embodiment 3, wherein at least one carbon atom of the listed alkyl moieties is perfluorinated.

Embodiment 5. The compound of Embodiment 3 wherein the alkyl is substituted with cycloalkyl or aryl.

- 181 047363

Embodiment 6. The compound of Embodiment 5, wherein the cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl.

Embodiment 7. The compound of Embodiment 5, wherein aryl is an optionally substituted phenyl.

Embodiment 8. The compound of Embodiment 2, wherein the carbocyclic group is cyclohexane or cyclopentane.

Embodiment 9. The compound of Embodiment 2, wherein the aryl group is phenyl.

Embodiment 10. The compound of Embodiment 2, wherein the C-carboxy group is a fragment of the formula -C(=O)-O-R, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl and tert-butyl.

Embodiment 11. The compound of Embodiment 1, wherein R ₂ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Embodiment 12. The compound of Embodiment 1, wherein Qi, Q2, Q3 and Q4 are -CRb-, wherein each Rb is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl and tert-butyl.

Embodiment 13. The compound of Embodiment 1, wherein Q5 and _Q6 are each independently nitrogen or -NH.

Embodiment 14. The compound of Embodiment 13, wherein Q5 is nitrogen and _Q6 is -NH.

Embodiment 15. The compound of Embodiment 1, wherein R ₄ is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Embodiment 16. The compound of Embodiment 1, wherein R5 is hydroxy.

Embodiment 17. The compound of Embodiment 1, wherein R6 and _R7 are each independently chlorine, bromine and iodine.

Embodiment 18. The compound of Embodiment 17, wherein R6 and R7 are each independently -CN, an optionally substituted lower alkyl, or an optionally substituted lower alkoxy, wherein the lower alkyl and the lower alkoxy alkyl group are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

Embodiment 19. The compound of Embodiment 1, wherein R6 and R7 are the same.

Embodiment 20. The compound of Embodiment 1, wherein R6 and R7 are each independently chlorine or methyl.

Embodiment 21. The compound of Embodiment 1, wherein R ₈ is hydrogen.

Embodiment 22. The compound of Embodiment 1, wherein Rc is hydrogen or methyl.

Embodiment 23. The compound of Embodiment 1, wherein:

TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId);

wherein each of Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q5 , Q ₆ and Q ₈ is independently nitrogen or -CRb-, wherein each R _b is independently hydrogen, halogen or lower alkyl;

R ₁ represents 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 group, an optionally substituted heteroarylalkyl group, optional a substituted amino group, an optionally substituted C-carboxy or O-carboxy group, -CN, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group

- 182 047363 ny group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

R ₂ represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R ₃ represents hydrogen;

R4 represents 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 group, an optionally substituted heteroarylalkyl group, an optionally substituted an amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoylalkyl group, wherein the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in the ring structure; And

R5 is hydroxy, NH2, alkylamino, alkanoylamino or alkylsulfonylamino; or

R4 and R5, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; or

R4 and _R5 , taken together with the carbon atoms to which they are attached, form a 7 to 11-membered, optionally substituted spirocyclic ring or a 7 to 11-membered, optionally substituted spiroheterocyclic ring; or when Q ₆ is nitrogen and R ₅ is hydroxy, then the tautomer of the moiety of formula (III) and Alk is hydrogen or optionally substituted alkyl;

CE is a fragment of formula (IV)

wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R" is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q7 is nitrogen or -CRc-, where Rc is hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V) or (VI):

where R ₉ is selected from -NH2, -CN, -CH2-S-CH3 or -CH2-S(=O)2-CH ₃ ;

R ₁₀ represents -CH3; And

La represents oxygen or -CH2-.

Embodiment 24. The compound of Embodiment 1, wherein:

TL is a fragment of formula (II)

wherein each of Q1, Q2, and Q3 is independently nitrogen or -CRb-, wherein each Rb is independently hydrogen, halogen, or lower alkyl;

R1 represents 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 group, an optionally substituted heteroarylalkyl group, optional

- 183 047363 optionally substituted amino group, optionally substituted C-carboxy or O-carboxy group, -CN, optionally substituted carbamoyl group or optionally substituted carbamoyl alkyl group, wherein the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in the ring structure;

R2 represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl or CN;

R3 represents hydrogen;

CE is a fragment of formula (IV)

(IV) ^r 8 wherein each of R6 and _R7 is independently selected from halogen, -CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;

R8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano or halogen;

Q ₇ represents nitrogen or -CRc-, where Rc represents hydrogen, halogen or lower alkyl;

(TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD;

HD is a fragment of formula (V)

(V) ^R 9 where R ₉ represents hydrogen, -CN, -C(R _d )2-SR _d , -C(R _d ) ₂ -S(=O)2R _d or -C CR _d , where each R _d independently represents hydrogen or lower alkyl; And

La represents oxygen or -CH2-.

Embodiment 25. A compound selected from the group consisting of:

- 184 047363

- 185 047363

- 186 047363

- 187 047363

- 188 047363

Embodiment 26. A method for treating a thyroid hormone receptor disorder in a patient, comprising the steps of identifying a patient in need of treatment for a thyroid hormone receptor disorder and administering or exposing the patient to a compound of an embodiment of the invention. 1.

Embodiment 27. The method of Embodiment 26, wherein the thyroid hormone receptor disorder is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism and thyroid cancer.

Embodiment 28. A method for selectively modulating the activity of a thyroid hormone receptor beta (THR-β), comprising contacting a compound of Embodiment 1 with a thyroid hormone receptor.

Embodiment 29. The method according to Embodiment 28, characterized in that the contacting is carried out in vitro or ex vivo.

Embodiment 30. The method according to Embodiment 28, characterized in that the contacting is carried out in vivo. Although some options have been implemented

- 189 047363 While the invention has been illustrated and described, it is understood that changes and modifications may be made thereto by those of ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

The embodiments illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms containing, including, containing, etc. should be read widely and without restrictions. In addition, the terms and expressions used herein are used as terms of description and not limitation, and in the use of such terms and expressions it is not intended to exclude any equivalents of the illustrated and described functions or portions thereof, but it is recognized that within the scope of the claimed technology Various modifications are possible. In addition, the phrase essentially consisting of will be understood to include those elements specifically enumerated and those additional elements that do not materially affect the essential and novel characteristics of the claimed technology. The phrase consisting of excludes any unspecified element.

This description should not be limited in terms of the specific embodiments of the invention described in this application. Many modifications and changes can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of this specification, in addition to those listed herein, will be apparent to those skilled in the art from the above descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. This description is to be limited only by the terms of the appended claims together with the full scope of equivalents to which such claims are entitled. It should be understood that this description is not limited to specific methods, reagents, compounds or compositions, which, of course, may vary. It is also understood that the terminology used herein is intended solely to describe specific embodiments of the invention and is not intended to limit the scope of the description.

Moreover, if features or aspects of this disclosure are described in terms of Markush groups, those skilled in the art will understand that this disclosure is also thus described in terms of any individual member or subset of members of a Markush group.

As will be appreciated by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations thereof. Any range listed can be easily recognized as sufficiently descriptive to allow the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, and an upper third, etc. As will also be understood by one skilled in the art, all expressions such as up to, at least more than, less than, and for example, include the specified number and refer to ranges that can subsequently be broken down into subranges as described above. Finally, as one skilled in the art will appreciate, the range includes each individual term.

Claims (16)

1. A compound of formula (I') (D) TL-L _a -CE-HD or a stereoisomer thereof, or a pharmaceutically acceptable salt, where: i) TL is a fragment of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId): wherein each of Q1, Q2, _Q3 , Q4, Q5, _Q6 and _Q8 is independently nitrogen or -CRb-, wherein each Rb is independently hydrogen, halogen or C-^-alkyl; R ₁ is hydrogen, -CN, C-^-alkyl, cyclopentyl, phenyl, (cyclopropyl^-^-alkyl, benzyl or -C(O)-R _j ; where Rj is -NRmR _n or -ORm; Rm is hydrogen or - 190 047363 C1-C ₆ -alkyl; _Rn represents C1- _C6 alkyl or Rm and _Rn , together with the nitrogen atom to which they are attached, form 1,2,3,4-tetrahydroisoquinoline; And R1 is optionally substituted with one to three _Rk independently selected from phenyl and C1- _C6 haloalkyl; R2 represents hydrogen; R ₃ represents hydrogen or C1-C ₅ -alkyl; R4 represents C1- _C6 alkyl, C2-C10 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, (cyclopropyl) C1-C ₆ -alkyl group, (cyclobutyl) C1-C ₆ -alkyl group, (cyclopentyl ) a C1- _C6 alkyl group, a benzyl group, a (tetrahydrofuranyl) C1- _C6 alkyl group or a (tetrahydropyranyl) C1- _C6 alkyl group; And R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, CN halogen, C1- _C6 -alkyl, _C6 - _C10 -aryl, C1- _C6 -alkoxy, C1- _C6 -haloalkoxy and C ₆ -C ₁₀ -arylkoxy, or two R _g together with the atoms to which they are attached form an aromatic or non-aromatic 3-6 membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen; And R5 is hydroxy, NH2, C1-C6 _- alkylamino, C1-C6 _- alkanoylamino or C1- _C6- alkylsulfonylamino; or R ₄ and R ₅ , taken together with the carbon atoms to which they are attached, form a 3-6 membered heterocycloalkyl ring containing from one to four ring heteroatoms independently selected from oxygen, sulfur or nitrogen; and wherein said 3-6 membered heterocycloalkyl ring is optionally substituted with one to five R _g independently selected from the group consisting of -CN; C1- _C6 alkyl, optionally substituted with phenyl or _C3 - _C9 cycloalkyl; C1-C ₆ haloalkyl; C-carboxy; C-amido; C ₃ -C ₉ -cycloalkyl; phenyl; amino; and the oxo and/or optionally two Rgs together with the atom(s) to which they are attached form a 3-6 membered non-aromatic carbocyclic group; Alk represents hydrogen or C1- _C6 alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen and C1- _C6 alkoxy; And R11 is phenyl, optionally substituted with C1- _C5 alkyl, C1- _C5 alkoxy, C1- _C5 haloalkoxy, halogen or _C3 - _C9 cycloalkyl; pyridine, optionally substituted with C1- _C5 alkyl; cinnoline; isoquinoline; quinoline; pyrazolo[1,5-a]pyridine; imidazo[1,5-a]pyridine; benzo[b]thiophene; lame; 1,2,3,4-tetrahydronaphthalene or naphthalene; ii) CE is a fragment of formula (IV) wherein each of Rg and R ₇ independently represents a halogen; -CN; C1-C5 alkyl, optionally substituted with one to five substituents independently selected from hydroxy, halogen and C1- _C6 alkoxy; or cyclopropyl; R ₈ is hydrogen, C1-C5 alkyl, cyano or halogen; optionally R ₇ and R ₈ taken together with the carbon atoms to which they are attached form a 4-, 5- or 6-membered non-aromatic carbocyclic ring; Q ₇ represents nitrogen or -CRc-, where Rc represents hydrogen, halogen or C1-C-alkyl; (TL) denotes the point where a fragment of formula (IV) connects to TL-L _a -; and (HD) denotes the point where a moiety of formula (IV) joins -HD; iii) HD is a fragment of formula (V) where R ₉ represents -(C(Rd) ₂ ) _n -N(Rd) ₂ ; where each Rd independently represents hydrogen or C1- _C5 alkyl; each n is independently selected from 0, 1, 2, 3, 4 or 5; And La independently represents a bond; -(C(Ra) ₂ )z-; oxygen; sulfur or -NRa-; wherein each Ra is independently hydrogen or C1- _C5 alkyl; and z is 0, 1, 2, 3, 4 or 5. 2. A compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt, where: TL is a fragment of formula (IIIb) - 191 047363 3. A compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein R ₉ is -(CH ₂ )nN(Rd) ₂ . 4. A compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt, where R ₉ represents -(CH ₂ )-N(Rd) ₂ or -N(Rd)2. 5. A compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein R ₉ represents -NH2. 6. A compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein Q4 is -CH- and _Q5 is nitrogen. 7. A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein Alk represents hydrogen. 8. A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein Alk represents C ₁ -C ₆ -alkyl, optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen and P-C-alkoxy. 9. A compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein R ₄ represents Q^-alkyl. 10. A compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein R4 is phenyl, optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C'i -C'6-alkyl, C'i-C'6-alkoxy and C ₁ -C ₆ -haloalkoxy, or two R _g together with the atoms to which they are attached form an aromatic or non-aromatic 3-6 membered ring, optional containing one or two ring heteroatoms independently selected from oxygen, sulfur or nitrogen. 11. A compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein R ₄ is naphthyl, optionally substituted with one to five R _g independently selected from the group consisting of hydroxy, halogen, C'i -C'6-alkyl and C'i-C'6-alkoxy. 12. A connection selected from the group consisting of: - 192 047363 - 193 047363 - 194 047363 - 195 047363 - 196 047363 - 197 047363 198 047363 or a stereoisomer thereof, or a pharmaceutically acceptable salt. 13. A pharmaceutical composition containing a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 14. A method of treating a disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a therapeutically effective amount of a pharmaceutical composition according to claim 13, characterized in that the disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism and thyroid cancer. 15. Use of a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt for the treatment of a disorder or disease selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular vascular diseases, hypothyroidism and thyroid cancer. 16. A method of selectively modulating the activity of thyroid hormone receptor beta (THR-β), comprising contacting a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt with a thyroid hormone receptor, wherein contacting is carried out in vitro.