Compounds for splicing modulation

Abstract

The present invention relates to compounds of formula (Ia) and their pharmaceutical composition These compounds are for the use in the treatment of a disease or disorder selected from the group consisting of fungal infections, bacterial infections, neurological and neurodevelopmental disorders and cancer.

Description

[0001] "COMPOUNDS FOR SPLICING MODULATION" DESCRIPTION FIELD OF THE INVENTION The present invention relates to novel compounds for bacterial, fungal, and mammalian splicing modulation. BACKGROUND OF THE INVENTION Recent genomic and transcriptomic studies have revealed that the cells express a myriad of non-coding RNAs, besides protein-coding mRNAs. Non-coding RNAs control vital physiological processes and are consequently crucially implicated in human diseases. RNA molecules are thus emerging as an appealing novel target for therapeutic intervention, whereby various strategies are being explored, either by targeting RNAs with small molecules or by using the RNA molecules themselves as drugs. Importantly, targeting non- coding RNAs and thereby modulating the expression of genes allows to indirectly modulate pathways that implicate otherwise undruggable proteins. Splicing is a key cellular process which involves both coding and non-coding RNAs that act as substrates and catalysts, respectively. In this two-step reaction, an evolutionary conserved RNA machine – called the spliceosome in humans and the self-splicing group II intron in bacteria and organelles of fungi and plants – removes non-functional portions (called introns) from precursor messenger RNAs and ligates together the functional portions (the exons), to produce mature, protein-coding (mRNAs) or non-coding RNAs (ncRNAs). In fungi, including human pathogens, splicing ensures the production of key enzymes of the mitochondrial respiratory chain and thus inhibiting group II introns is an established antifungal strategy. Moreover, in mammals, including humans, splicing ensures the maturation of ~90% of all genes and is thus crucial for cell survival, development and adaptation to the environment. Aberrant splicing generates non-functional mRNAs / ncRNAs or mRNAs / ncRNAs that disrupt the cellular homeostasis leading to congenital disorders, cancer or metabolic and neurological diseases. Modulating splicing has been experimentally proven to cause a vulnerability of cancer cells and to be a suitable approach to treat certain congenital genetic diseases. For instance, a splicing modulator that efficiently treats spinal muscular atrophy (risdiplam) has recently entered the market, and others are emerging as potential anticancer drugs (e.g. pladienolide derivatives). Despite this progress, splicing modulators mostly target spliceosomal remodeling proteins, leading to gene-unspecific splicing inhibition and severe toxicity. Moreover, the exact mechanism of action of these splicing modulators is still largely unknown, partly because of lack of structural and molecular insights. SUMMARY Therefore, the aim of the present invention is to provide a new class of splicing modulators with a distinct, and well- characterized mechanism of action that can be used in the treatment of viral, bacterial, and fungal infections, and of cancer and neurodegenerative disorders. The aforementioned objective has been met according to compounds according to claim 1, to their use according to claims 6 and 7, to a pharmaceutical composition according to claim 9 and to intermediates according to claim 11. Preferred embodiments are set out within the dependent claims. In particular, the inventors discovered that the RNA modulators of the present invention bind the catalytic site of group II introns – which is structurally and functionally conserved in the human spliceosome - and inhibit the related splicing activity. Because of the evolutionary, structural and functional conservation between the catalytic site of the group II introns and of the spliceosome, compounds of the present invention are able to modulate the activity of the human spliceosome, as well. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be now described in detail also with reference to the annexed figure wherein: - Figure 1 illustrates the synthesis of compounds 5a-c; - Figure 2 illustrates the synthesis of amides of type 8; - Figure 3 illustrates the synthesis of amides of compounds 10a-c; - Figure 4 illustrates the synthesis of starting material 13; - Figure 5 illustrates the synthesis of compounds 18a-b; - Figure 6 illustrates the synthesis of compounds 20a-b; - Figure 7 illustrates the synthesis of compound 25; - Figure 8 illustrates the synthesis of compound 30; - Figure 9 illustrates the synthesis of building blocks of type 35, 38, 42; - Figure 10 illustrates the synthesis of compounds of type 46; - Figure 11 illustrates the synthesis of compounds 48, 50; - Figure 12 illustrates the synthesis of compound 57; - Figure 13 illustrates the synthesis of compounds 59, 61. -Figure 14 illustrates the synthesis of compound 66; - Figure 15 summarizes the activity of 16 compounds according to the invention in a spliceosome-specific gene reporter assay in ad hoc CRISPR-engineered human HEK293T cells; - Figure 16 illustrates the crystal structures of O. iheyensis group II intron bound to 6 compounds according to the invention. DESCRIPTION OF EMBODIMENTS The following paragraphs provide definitions of the various chemical moieties of the compounds according to the invention and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition. The term “alkyl”, as used herein, refers to saturated aliphatic hydrocarbon groups. Such term includes straight (unbranched) chains or branched chains. Non-limiting examples of alkyl groups according to the invention are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso- pentyl, n-hexyl and the like. The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic group having a single ring. Non-limiting examples of cycloalkyl groups according to the invention are, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like. The term “heterocycloalkyl” group, ("non-aromatic heterocycle" group), refers to a cycloalkyl group (non- aromatic group) wherein at least one of the carbon atoms has been replaced by a heteroatom selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, 1-(1,2,5,6-tetrahydropyridyl), tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine (2-piperidinyl, 3- piperidinyl), 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3- oxathiane, 1,4- oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2- oxazine, morpholine (4-morpholinyl, 3-morpholinyl) trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran (tetrahydrofuran-2-yl, tetrahydrofuran-3- yl), pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3 dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3- oxathiolane. The term “halogen”, as used herein, refers to fluorine, chlorine, bromine and iodine. The term “aryl”, as used herein, refers to a hydrocarbon consisting of a unsubstituted or substituted mono-, bi- or tricarbocyclic ring system, wherein the rings are fused together and at least one of the carbocyclic ring is aromatic. The term “aryl” means for example a cyclic aromatic such as a 5 or 6-membered hydrocarbon ring, a two six- membered fused hydrocarbon rings. Non-limiting examples of aryl groups are, for example, phenyl, alpha- or beta- naphthyl, 9,10-dihydroanthracenyl, indanyl, fluorenyl and the like. The term “heteroaryl”, as used herein, refers to an aryl as defined above wherein one to four carbon atoms are independently replaced by heteroatoms chosen from the group consisting of nitrogen, oxygen and sulphur. Non-limiting examples of heteroaryl groups are, for example, pyrrolyl, furyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl. Heteroaryl groups according to the present invention may be unsubstituted or substituted by one or more substituents. The term “aromatic ring”, as used herein, refers to a moiety wherein the constituent carbon atoms make up an unsaturated ring system, all atoms in the ring system are sp2hybridized and the total number of π-electrons is equal to 4n+2, wherein n is an integer. The term “heteroaromatic ring”, as used herein, refers to an “aromatic ring” as defined above wherein one or more carbon atoms are independently replaced by heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise indicated, the term “substituted”, as used herein, means that one or more hydrogen atoms of the above- mentioned groups are replaced with another non-hydrogen atom or functional group, provided that normal valencies are maintained and that the substitution results in a stable compound. The term “pharmaceutically acceptable salts” refers to salts of the below identified compounds of Formula (I) that retain the desired biological activity and are accepted by regulatory authorities. As used herein, the term “salt” refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base and internally formed salts. Typically, such salts have a physiologically acceptable anion or cation. Furthermore, the compounds of Formula (I) may form an acid addition salt or a salt with a base, depending on the kind of the substituents, and these salts are included in the present invention, as long as they are pharmaceutically acceptable salts. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), salts formed with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, alginic acid, polyglutamic acid and naphthalene sulfonic acid. The compounds of Formula (I) containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Physiologically or pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Pharmaceutically acceptable salts may also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of Formula (I) using conventional methods. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compounds of the invention are within the scope of the invention. The compounds of Formula (I) may readily be isolated in association with solvent molecules by crystallization or evaporation of an appropriate solvent to give the corresponding solvates. The compounds of Formula (I) may be in crystalline form. In certain embodiments, the crystalline forms of the compounds of Formula (I) are polymorphs. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but differ for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 35S, 18F, 36Cl. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically- labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3H, and carbon-14, i.e. 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (Positron Emission Tomography). Furthermore, substitution with heavier isotopes such as deuterium, i.e. 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labelled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples below, by replacing a non- isotopically-labelled reagent with a readily available isotopically-labelled reagent. Certain groups / substituents included in the present invention may be present as isomers or in one or more tautomeric forms. Accordingly, in certain embodiments, the compounds of Formula (I) may exist in the form of other tautomers or geometrical isomers in some cases, depending on the kinds of the substituents. In the present specification, the compounds may be described in only one form of such isomers, but the present invention includes all such isomers, isolated forms of the isomers, or a mixture thereof. Furthermore, the compounds of Formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases and, correspondingly, they may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like. The present invention includes within the scope all such isomers, including racemates, enantiomers and mixtures thereof. In particular, within the scope of the present invention are included all stereoisomeric forms, including enantiomers, diastereoisomers, and mixtures thereof, including racemates and the general reference to the compounds of Formula (I) includes all the stereoisomeric forms, unless otherwise indicated. In general, the compounds or salts of the invention should be interpreted as excluding those compounds (if any) which are so chemically unstable, either per se or in water, that they are clearly unsuitable for pharmaceutical use through all administration routes, whether oral, parenteral, or otherwise. Such compounds are known to the skilled chemist. According to the present disclosure, compounds of formula (I) or its pharmaceutically acceptable salts, solvates and tautomers are provided. In the compounds of formula (I): T is selected from the group consisting of N and CH; X is selected from the group consisting of O and NR5; Y is selected from the group consisting of –C(=O)NR6-, - (CH2)1-6NR6C(=O)-, -NR6C(=O)NH-, -C(=O)-, -C(=NOH)-, provided that when Y is -C(=O)-, T is N; R1is selected from the group consisting of H, halogen, saturated or partially unsaturated C1-C6cycloalkyl optionally substituted with one or more R7, saturated or partially unsatured C1-C6heterocycloalkyl optionally substituted with one or more R7, a C1-C10aryl group optionally substituted with one or more R7and C1-C10heteroaryl group optionally substituted with one or more R7; R2, R3and R4are independently selected from the group consisting of H, -OH, -COOH, -COO-C1-C6alkyl, -CONH-C1- C6alkyl, -C(=O)H, -C1-C6alkyl-OH, -O-C1-C6alkyl, provided that at least one of R2, R3 and R4is not H; R5 is selected from the group consisting of hydrogen, C1- C8alkyl, halo-C1-C8alkyl, -C(=O)NH2, -C(=S)NH2, -C1-C8alkyl- NH2, -C1-C8alkyl-NH(C1-C6alkyl), -C1-C8alkyl-N(C1-C6alkyl)2, - C1-C8alkyl-NH(C1-C6cycloalkyl), -C1-C8alkyl-N(C1- C6cycloalkyl)2and -C1-C8alkyl-OH; R6 is selected from the group consisting of H, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkyl-OH, C-Calkyl-NH, -C-Calkyl-NH(C- Calkyl), -C-Calkyl-N(C-Calkyl), -C-Calkyl-NH(C- Ccycloalkyl), -C-Calkyl-N(C-Ccycloalkyl); or,R5and R6form a ring with the N atoms to which they are linked to form compounds of formula (Ic): (Ic) wherein L is selected from the group consisting of –C(=O)-, -C1-C3alkylene, -C1-C3alkyleneC(=O)- R7 is selected from the group consisting of halogen, C1-C8alkyl optionally substituted with halogen, OH, amino, - NH-C3-C6cycloalkyl, -NH-C1-C6alkyl, -NH-haloC1-C6alkyl, - N(C1-C6alkyl)(C3-C6cycloalkyl), -N(haloC1-C6alkyl)(COO C1- C6alkyl), cyclic amine having a formula selected from: OH, amino, -NH(C-Calkyl), -N(C-Calkyl), -O-C1-C8alkyl, -C(=O)R8, phenyl thiophene, –SO2NHR9, sulfonyl piperazine, sulfonylmethyl piperazine, sulfonyl piperidine, methylsulfonyl; R8 is selected from the group consisting of H, OH, C1-C8alkyl, O-C1-C8alkyl, amino, aminoC1-C8alkyl, aminodi-C1-C8alkyl, - NH-C1-C8alkyl-amino-C1-C8alkyl, -NH-C1-C8alkyl-amino-diC1- C8alkyl, -NH-C(=NH)NH2, -NH- C1-C8alkyl-OH, -NH-halo-C1- C8alkyl, piperidinyl, -NH-C1-C8alkyl- pyrrolidinyl, methylpiperazinyl; R9is selected from the group consisting of H and C1-C6alkyl; provided that the compound of formula (Ia) is not one of the following compounds: N-(4-hydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-hydroxyphenyl)-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3,4-diethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3-hydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-[4-(aminocarbonyl)phenyl]-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, Ethyl 4[(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)amino] benzoate, N-(3-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-ethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, Methyl 4[(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)amino] benzoate. In a first embodiment, X is NR5. According to a second embodiment, R1is selected from the group consisting of H, halogen, saturated or partially unsaturated piperidine optionally substituted with one or more R7, phenyl optionally substituted with one or more R7, pyridine optionally substituted with one or more R7, quinoline optionally substituted with one or more R7, isoquinoline optionally substituted with one or more R7, indole optionally substituted with one or more R7, benzofuran optionally substituted with one or more R7. In an alternative embodiment, R1 has the structure: wherein Z is selected from CH, CR7and N and each of R7 is independently selected from the group consisting of - H - halogen, - C1-C8alkyl optionally substituted with halogen, OH, amino, -NH-C3-C6 cycloalkyl, -NH-C1-C6alkyl, -NH- haloC1-C6alkyl, cyclic amine having a formula selected from: - OH, - amino, - amino-C1-C8alkyl, - amino-di-C1-C8alkyl, - -O-C1-C8alkyl, - -C(=O)R8, - phenyl - thiophene - –SO2NHR9, - sulfonyl piperazine, - sulfonylmethyl piperazine, - sulfonyl piperidine, - methylsulfonyl. According to a first aspect of the present invention, the compound of formula (I) has the following formula (Ia): (Ia) Moreover, the compound of formula (Ia) can have the following formula (Ic): (Ic) According to an embodiment, is selected from the group consisting of –C(=O)-, -C1-C3alkylene. Alternatively, according to the present disclosure, the compound of formula (I) can have the following formula (Ib): (Ib) According to anembodiment of the present invention, the compound of formula (I) can be selected from the group consisting of: 5a 5-chloro-N-(3,4,5-trihydroxyphenyl)-1H- (ARN25414) pyrrolo[3,2-b]pyridine-2-carboxamide 5b 5-chloro-N-methyl-N-(3,4,5- (ARN25459) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 5c N-methyl-N-(3,4,5-trihydroxyphenyl)-1H- (ARN27074) pyrrolo[3,2-b]pyridine-2-carboxamide 8aa 5-(4-(dimethylamino)phenyl)-N-(3,4,5- (ARN25424) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 8ab 5-(2-hydroxyphenyl)-N-(3,4,5- (ARN25425) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8ba 5-(4-(dimethylamino)phenyl)-N-methyl-N- (ARN25885) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 8bc N-methyl-5-phenyl-N-(3,4,5- (ARN26849) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bd N-methyl-5-(pyridin-4-yl)-N-(3,4,5- (ARN25917) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide, hydrobromic salt 8be 5-(2-aminopyridin-4-yl)-N-methyl-N- (ARN25918) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bf 5-(4-(bromomethyl)phenyl)-N-methyl-N- (ARN26715) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bg N-methyl-5-(1,2,3,6-tetrahydropyridin-4- (ARN25954) yl)-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 8bk N-methyl-5-(piperidin-4-yl)-N-(3,4,5- (ARN25955) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bh 5-(4-hydroxyphenyl)-N-methyl-N-(3,4,5- (ARN26717) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bi 4-(2-(methyl(3,4,5- (ARN26958) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)benzoic acid 8bj 5-(3-carbamoylphenyl)-N-methyl-N-(3,4,5- (ARN26716) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bl 3-(2-(methyl(3,4,5- (ARN26977) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)benzoic acid 8bm N-methyl-5-(pyridin-3-yl)-N-(3,4,5- (ARN26928) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bn 5-(isoquinolin-5-yl)-N-methyl-N-(3,4,5- (ARN27025) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bp N-methyl-5-(4-(piperidin-1- (ARN27072) ylmethyl)phenyl)-N-(3,4,5- trihydroxyphenyl)-1Hpyrrolo[3,2- b]pyridine-2 carboxamide dihydrobromide 10a 5-(4-((2- (ARN26718) (dimethylamino)ethyl)carbamoyl)phenyl)- N-methyl-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 10b N-methyl-5-(4-(4-methylpiperazine-1- (ARN26729) carbonyl)phenyl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 10c 5-(4-(carbamimidoylcarbamoyl)phenyl)-N- (ARN26730) methyl-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46a N-methyl-5-(2-(piperazin-1- (ARN26936) ylmethyl)pyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 46b N-methyl-5-(2-(pyrrolidin-1- (ARN26975) ylmethyl)pyridin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 46c 5-(2-((3,3-difluoropyrrolidin-1- (ARN26976) yl)methyl)pyridin-4-yl)-N-methyl-N- (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide di-hydrobromide 46d 5-(2-((cyclobutylamino)methyl)pyridin-4- (ARN27043) yl)-N-methyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide di-hydrobromide 46e 5-(2-(((2,2- (ARN27103) difluoroethyl)amino)methyl)pyridin-4- yl)-N-methyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46f N-methyl-5-(2-(((3,3,3- (ARN27120) trifluoropropyl)amino)methyl)pyridin-4- yl)-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46g N-methyl-5-(2-phenylpyridin-4-yl)-N- (ARN26907) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 46h 4-(2-(methyl(3,4,5- (ARN26929) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)-2-(thiophen- 3-yl)pyridin-1-ium 48 5-chloro-N,1-dimethyl-N-(3,4,5- (ARN27079) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 50 4-(2-(methyl(3,4,5- (ARN27071) trihydroxyphenyl)carbamoyl)-1-(4,4,4- trifluorobutyl)-1H-pyrrolo[3,2- b]pyridin-5-yl)pyridin-1-ium 57 N-(4-hydroxy-3,5-dimethoxyphenyl)-N- (ARN27073) methyl-5-(pyridin-4-yl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrochloride 59 2-chloro-8-(3,4,5-trihydroxyphenyl)-7,8- (ARN27097) dihydropyrido[2',3':4,5]pyrrolo[1,2- a]pyrazin-9(6H)-one 61 2-chloro-7-(3,4,5-trihydroxyphenyl)-6H- (ARN27044) imidazo[1',5':1,5]pyrrolo[3,2- b]pyridine- 6,8(7H)-dione 66 5-(5-chloro-N-methyl-1H-pyrrolo[3,2- (ARN26004) b]pyridine-2-carboxamido)-2,3- dimethoxybenzoic acid According to a further aspect of the invention the following intermediates for the preparation of the compounds of formula (Ia) are provided. These intermediates are selected from the group consisting of: 4a 5-chloro-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 4b 5-chloro-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 4c N-methyl-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 43 (5-chloro-N-methyl-N-(3,4,5- trimethoxyphenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide) 45a tert-butyl 4-((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)piperazine-1-carboxylate 45b N-methyl-5-(2-(pyrrolidin-1- ylmethyl)pyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 45c 5-(2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridin-4-yl)-N-methyl-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 45d tert-butyl cyclobutyl((4-(2- (methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)carbamate 45e tert-butyl (2,2-difluoroethyl)((4-(2- (methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)carbamate 45f tert-butyl ((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)(3,3,3- trifluoropropyl)carbamate 45g N-methyl-5-(2-phenylpyridin-4-yl)-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 45h N-methyl-5-(2-(thiophen-3-yl)pyridin-4- yl)-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 64 methyl 5-(5-chloro-N-methyl-1H- pyrrolo[3,2-b]pyridine-2-carboxamido)- 2,3-dimethoxybenzoate 65 5-(5-chloro-N-methyl-1H-pyrrolo[3,2- b]pyridine-2-carboxamido)-2,3- dimethoxybenzoic acid The compounds exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures for example exemplified in Michael B. Smith - March’s Advanced Organic Chemistry: reactions, mechanisms, and structure - 7th Edition, John Wiley & Sons Inc., 2013. It is well known to one of ordinary skill in the art that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent de-protection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in Peter G.M. Wuts – Green’s Protective Groups in Organic Synthesis, Fifth Edition, John Wiley & Sons Inc., 2014. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The synthesis of a compound of formula (I), according to the synthetic processes described below, can be conducted in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques such as, for example, column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthetic sequence can be carried out in a so-called “one- pot” procedure, as known in the art, whereby only the compound resulting from the two or more steps is isolated and purified. The compounds of formula (I), prepared with the methods described herein below, may be treated or purified by conventional techniques or means for example by filtration, distillation, chromatography, recrystallization and combination thereof. The salts of compounds of formula (I) may be prepared by reacting a basic compound with the desired acid in solution, or by reacting an acidic compound with the desired base in solution. A second aspect of the present invention is related to a pharmaceutical composition comprising a compound of formula (I) as disclosed above and a pharmaceutically acceptable excipient such as carrier, stabilizer, diluent or excipient thereof. A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition. The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral administration (including subcutaneous and intravenous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Pharmaceutical compositions containing a compound of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, subcutaneous, intravenous, intramuscular, intranasal and pulmonary routes. The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavours and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The pharmaceutical compositions may be in the form of tablets, pills, capsules, solutions, suspensions, emulsion, powders, suppository and as sustained release formulations. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. In certain embodiments, such compositions and preparations can contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 1 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that therapeutically active dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring agent such as cherry or orange flavor. To prevent breakdown during transit through the upper portion of the gastrointestinal tract, the composition be an enteric coated formulation. Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound of formula (I) or a salt thereof, and the powder of a suitable carrier and / or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art. Administration of the compositions is performed under a protocol and at a dosage sufficient to reduce the inflammation and pain in the subject. In some embodiments, in the pharmaceutical compositions of the present invention the active principle or active principles are generally formulated in dosage units. The dosage unit may contain from 0.1 to 1000 mg of a compound of formula (I) per dosage unit for daily administration. In some embodiments, the amounts effective for a specific formulation will depend on the severity of the disease, disorder or condition, previous therapy, the individual’s health status and response to the drug. In some embodiments, the dose is in the range from 0.001% by weight to about 60% by weight of the formulation. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredient may be used in lower doses than when each is used singly. Concerning formulations with respect to any variety of routes of administration, methods and formulations for the administration of drugs are disclosed in Remington’s Pharmaceutical Sciences, 17th Edition, Gennaro et al. Eds., Mack Publishing Co., 1985, and Remington’s Pharmaceutical Sciences, Gennaro AR ed. 20th Edition, 2000, Williams & Wilkins PA, USA, and Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins Eds., 2005; and in Loyd V. Allen and Howard C. Ansel, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition, Lippincott Williams & Wilkins Eds., 2014. The above-described components for orally administered or injectable compositions are merely representative. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A third aspect of the present invention is related to compounds of formula (I) as disclosed above or the pharmaceutical composition thereof, for the use as a medicament. In particular, the compounds of formula (I) can be used in the treatment of a disease or disorder selected from the group consisting of viral infections, fungal infections, bacterial infections, neurological and neurodevelopmental disorders, lysosomal storage diseases (LSDs), and cancer. Neurological and neurodevelopmental disorders can be selected from the group consisting of Spinal Muscular Atrophy SMA, Duchenne Muscular Distrophy (DMD), Alzheimer, Huntington, Myotonic Distrophy 1 (MD1), Familial Dysautonomia, dementia, Parkinson. Cancers can be selected from the group consisting of gliomas, neuroblastoma, rhabdomyosarcoma, primary brain tumors, medulloblastoma, myelodysplastic syndrome, central nervous system cancer, skin cancer, melanoma, lung cancer, non-small cell lung cancer, bladder cancer, kidney cancer, urinary tract cancer, urothelial carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck squamous cell cancer, oral squamous cell cancer, esophageal cancer, malignant carcinoid, gastric cancer, stomach cancer, upper digestive tract cancer, colon cancer, colorectal cancer, seminoma, prostate cancer, testicular cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, malignant insulinoma, intraductal papillary mucinous neo plasm carcinoma of the pancreas, thyroid cancer, head / neck squamous cell cancer, hematopoietic cancers, lymphoid cancers, leukemias, solid tumors, sarcomas, adenocarcinomas, adrenal cortical cancer. In the following, the present invention will be shown by means of some examples, which are not intended to be considered limiting of the scope of the invention. EXAMPLES Synthesis: General considerations: all the commercially available reagents and solvents were used as purchased from vendors without further purification. Dry solvents were purchased from Sigma-Aldrich. Automated column chromatography purifications were done using a Teledyne ISCO apparatus (CombiFlash® Rf) with pre-packed silica gel columns of different sizes (from 4 g up to 40 g) and mixtures of increasing polarity of cyclohexane and ethyl acetate (EtOAc) or dicloromethane (DCM) and methanol (MeOH). NMR experiments were run on a Bruker Avance III 400 system (400.13 MHz for1H, and 100.62 MHz for13C) and 600 system (600.13 for1H and 150.92 for13C), equipped with a BBI probe and Z-gradients. Spectra were acquired at 300 K, using deuterated dimethylsulfoxide (DMSO-d6) as solvent. For1H-NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = double of doublets,ddd = doublet of doublet of doublets,t = triplet, td = triplet of doublets, q = quartet,p = quintet, m = multiplet), coupling constants (Hz) and integration. UPLC / MS analyses were run on a Waters ACQUITY UPLC / MS system consisting of a SQD (single quadrupole detector) mass spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The PDA range was 210–400 nm. Mobile phase was 10 mM NH4OAc in H2O at pH 5 adjusted with CH3COOH (A) and 10 mM NH4OAc in CH3CN–H2O (95:5) at pH 5.0 (B). The analyses were performed on different columns using different gradients increasing the proportion of mobile phase B depending on LogD of the compounds, and their stability. For compounds with LogD>1, gradients 1, 2 or 3 were used, whereas for compounds with LogD<1 gradients 4 and 5 were used. The five types of applied gradients are reported here below: Gradient 1: (5 % to 100 % B in 2 min), run on an ACQUITY UPLC BEH C18 column (50x2.1mmID, particle size 1.7 µm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm); Gradient 2: 10 % to 90% mobile phase B in 6min run on on an ACQUITY UPLC BEH C18 (100x2.1 mmID, particle size 1.7μm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm); Gradient 3: for compounds unstable under normal gradient conditions, conditions similar to gradient 2 were applied, with 0.1% v / v formic acid in both phases A and B as a stabilizer; Gradient 4: 0 % to 50 % mobile phase B in 2 min run on ACQUITY UPLC HSS T3 C18 column (50x2.1mmID particle size 1.8μm) with VanGuard HSS T3 C18 pre-column (5x2.1mmID, particle size 1.8μm); Gradient 5: 0 % to 50% mobile phase B in 6min run on an ACQUITY UPLC HSS T3 (100x2.1 mmID, particle size 1.8μm) with a VanGuard HSS T3 pre-column (5x2.1 mmID, particle size 1.8 µm). Gradient 6: (50 % to 100 % B in 3 min), run on an ACQUITY UPLC BEH C18 column (50x2.1mmID, particle size 1.7 µm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm); Electrospray ionization in positive and negative mode was applied in the mass scan range 100-650Da. General procedure 1 (Scheme 1 (fig. 1), Scheme 3 (fig. 3), Scheme 5 (fig. 5), Scheme 8 (fig. 8)). Amide coupling for the obtainment of compounds 4a-b, 9a-c, 15a-b, 26. Method A Carboxylic acid suspended / dissolved in dry DCM (50V) under nitrogen; system connected to a Schlenck line. Mixture refluxed with SOCl2 (3-6 eq) after addition of catalytic DMF. Reaction monitored via LC / MS as follows: Aliquot withdrawn, quenched in diethylamine, dried with nitrogen flow, dissolved in MeOH and analysed via UPLC / MS (gradient 1) to assess the presence of diethylamide product. Upon reaction completion, the mixture was concentrated to dryness, and the crude acyl chloride taken up in dry DCM (same volume used for the reaction) and added dropwise (10- 60 mins) to a stirring mixture of the appropriate amine in dry Py / dry DCM (50V / 50V vs acid), at 0°C or RT. Reaction stirred at RT for 2-16 hrs, monitored via TLC and / or LC / MS as described afterwards. The reaction mixture was then subjected to liquid / liquid work up (DCM / water), water extracted with DCM. Organic phases combined were dried over Na2SO4, filtered, concentrated to dryness. Crude product was purified by column chromatography or slurry in the appropriate solvent, as described afterwards. Pure products were subjected to brief drying (50°C, max vacuum, 30-60 min). Method B Reaction carried out as per General procedure A. Upon reaction completion, water was added and the mixture was concentrated to dryness to remove all excess of volatiles; the crude was taken up in the appropriate solvent, slurried, filtered, washed with the same solvent and subjected to brief drying (50°C, max vacuum, 30-60min) to yield the pure products. Method C Carboxylic acid suspended / dissolved in dry CHCl3 (50V) under nitrogen; system connected to a Schlenck line. Mixture refluxed with SOCl2 (10eq) after addition of catalytic DMF. Reaction monitored via LC / MS as follows: Aliquot withdrawn, quenched in diethylamine, dried with nitrogen flow, dissolved in MeOH and analysed via UPLC / MS (gradient 1) to assess the presence of diethylamide product. Upon reaction completion, the mixture was concentrated to dryness and the resulting crude acyl chloride was taken up in dry dioxane (20V vs acid) and added dropwise (over 15 mins) to a pre-cooled (ice / water bath) 30% w / w aqueous ammonia (25V vs acid, 50 eq) under vigorous stirring. Reactions worked-up as detailed afterwards. Pure products were subjected to brief drying (50°C, max vacuum, 30-60min). General procedure 2 (Scheme 2 (Fig. 2), Scheme 5 (Fig. 5)). Suzuki coupling for the obtainment of compounds of type 7, compounds 14a-b. Method A Amide of type 4 (1 eq), boronic acid or ester (1-1.5 eq), K2CO3 (1.4-3 eq) and PdCl2(dppf)∙DCM complex (0.1-0.15 eq) were suspended in fresh 1,4-dioxane / water 3:1 mixture (50V vs amide, approx. c = 0.05M), subjected to vigorous stirring while argon was bubbled through for 5-10 mins. The mixture was then heated up at 100°C; the resulting solution was stirred at the same temperature for 2-24 h. Reaction progression was assessed via TLC and / or LC / MS, as detailed afterwards. Upon reaction completion, the mixture was cooled to RT, diluted with DCM / water, aqueous phase was extracted with DCM. Organic phases combined were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was then purified by chromatography or slurry in the appropriate solvent, as detailed afterwards. In certain cases, upon reaction completion the mixture was directly concentrated to dryness, taken-up in water (3-4mL), pH adjusted, if necessary, suspension sonicated and filtered; the solid was taken up in MeOH (1-2mL), sonicated, filtered, and subjected to a brief drying (30 mins, 50°C) in vacuo to obtain the final product. Method B Substrate of type 3 (1 eq), boronic acid (1.5 eq), K2CO3(3eq), sSPhos (0.02eq), and Pd(OAc)2(0.01eq) were suspended in water (MilliQ grade, 20V vs substrate, approx. c = 0.25M). The suspension was subjected to vigorous stirring while argon was bubbled through for 5-10mins. The mixture was then heated up at 80°C; the resulting solution was stirred at the same temperature for 5-6h. Reaction progression was assessed via TLC and / or LC / MS. Upon reaction completion, the mixture was cooled to RT, acidified by 2M HCl till pH~ 2; the suspension was diluted with water (10-20 mL), and product recovered as detailed afterwards. The solid was dried at 60°C with max vacuum for 60mins to afford the product. General procedure 3 (Schemes 1-3 (Fig. 1-3), Schemes 5-8 (Fig. 5-8)), Scheme 10-11 (Fig. 10-11), Scheme 13-14 (Fig. 13-14): demethylation for the obtainment of compounds of type 5, 8, 10, 18, 20, 25, 30, 46, 48, 50, 59, 61, 66. Starting material was subjected to 3 V / N2 cycles in the appropriate reaction vessel; dry DCM was added (approx. c = 0.05M) and the mixture cooled down to -78°C; BBr3 / DCM 1M solution (6-12 eq) was added dropwise over 5 mins. The mixture was stirred while the temperature was left to gradually reach RT overnight and stirring continued at RT for 16-24 h. Upon reaction completion (reaction was monitored by1H-NMR), the suspension was cooled back to - 78°C, and quenched by dropwise addition of dry MeOH (same V of reaction solvent); the resulting suspension was left warming up to RT and stirred at the same temperature for additional 0.5-1hrs; the mixture was then concentrated to dryness and stripped with MeOH (2 x 5mL), yielding a crude solid that was subjected to a liquid / liquid work-up or directly sonicated / triturated with the appropriate solvent as described afterwards. All solids were subjected to brief drying (50°C, max vacuum, 30-60 min) to yield the pure products. General procedure 4 (Scheme 5 (Fig. 5)). Reduction for the obtainment of primary amines, compounds 16a-b. Amide (1eq) was placed in a screw-capped vial equipped with a teflon septum; 3 cycles vacuum / nitrogen were performed, and dry THF (2 mL) was added via syringe. The mixture was cooled to 0-4°C, and LiAlH4 / THF 2M solution (6-7 eq) was added dropwise in 10 mins; the mixture turned to yellow solution and was stirred at RT for 15 mins before being heated up at reflux (turned suspended with time). Progression was assessed via TLC (5% MeOH in DCM) and LC / MS. Upon reaction completion, the mixture was then cooled to RT, ice- water was added (0.5-1 mL dropwise), followed by additional RT water. Extractions with DCM, organic phases combined and dried over Na2SO4, filtered and concentrated to dryness to yield the crude products. Purification details described afterwards. General procedure 5 (Scheme 6 (Fig. 6)). One-pot acyl azide- urea synthesis for the obtainment of ureas, compounds 19a- b. Aniline 1 or 2 (1eq), acid 3b (1.5 eq), diphenylphosphorylazide (DPPA, 1.2 eq), TEA (3 eq) were suspended in dry toluene, in a MW tube; headspace was filled with nitrogen before closure, and the mixture was subjected to irradiation (5 mins slope, then 15min at 100°C). The resulting greenish solution was cooled to RT, diluted with DCM, washed with HCl 2M, water, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by column chromatography as detailed afterwards to afford the pure title compounds. General procedure 6 (Scheme 8 (Fig. 8), Scheme 10 (Fig. 10)): Sem deprotection for the obtainment of compounds 29, and 45. Suitable intermediates 28 or type 44 (1 eq) was dissolved in dry DMF (50.2 M solution) under nitrogen atmosphere. Sodium hydride 60 wt% (.5 eq) was then added and the resulting mixture was stirred for 30 minutes. 2- (trimethylsilyl)ethoxymethyl chloride (1.2 eq) was then added. Upon reaction completion (2 hours) the mixture was diluted with DCM (15 ml) and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The resulting crude was purified by flash column chromatography. General procedure 7 (Scheme 9 (Fig. 9)): Miyaura Borylation Reaction for the obtainment of compounds 35, 38, 42. Compound of type 34 or 37 or 41 (1 eq), Bis(pinacolato)diboron (1.2 eq), potassium acetate (5 eq), Pd(dppf)Cl2·DCM (15 mmol %) were suspended in degassed 1,4- dioxane dry (0.1 M solution). Reaction mixture stirred at 100-110°C until complete conversion of starting material. After that reaction mixture was filtered over a pad of celite, raised with EtOAc, concentrated under vacuum. Resulted crude was used as such in the next step. General procedure 8 (Scheme 9(Fig. 9)): Reductive amination for the obtainment of compounds 37. Acetic acid (2 eq), and a suitable amine (2 eq) were added to a solution of Aldehyde 36 (1 eq) in 1,2-dichloroethane (0.2 M) under argon at room temperature. Reaction mixture stirred for 30 minutes, and after that NaBH(OAc)3 (2 eq) was added and reaction mixture stirred since until complete conversion. NaHCO3 sat. solution was added since pH = 7, and aqueous layer was extracted with EtOAC. Resulting crude was purified by silica. General procedure 9 (Scheme 9 (Fig. 9)): Regioselective Suzuki on 2,6 dibromo pyridine for the obtainment of compounds 41. 2,4-dibromopyridine (1 eq), suitable boronic acid (1 eq) and Pd(PPh3)4 (10 mol%) were added in a previously degassed vial and dissolved in anhydrous THF dry (0.4 M). Potassium carbonate (2 eq) were dissolved in water (0.8 M) and degassed with N2 prior to be dripped to the reaction mixture. The vial was heated at 70 °C and left to stir until complete conversion. Progression was assessed via LC / MS. Upon reaction completion, the mixture was then cooled to and diluted with DCM. The mixture was filtered over celite and the filtrate concentrated to dryness to yield the crude product. The pure product was obtained after purification via column chromatography. General procedure 10 (Scheme 10 (Fig. 10)). Suzuki reaction for the obtainment of compounds 44. Crude of boronic ester of type 35, 38, 42 (theoretical 2 eq), intermediate of type 43 (1 eq), X-Phos (10 mol %), Pd(PPh3)4 (10 mol %), K2CO3 (3 eq) were suspended in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture (0.05 M). After complete conversion, water was added, and aqueous layer was extracted with EtOAc. The product was purified via column chromatography. Synthesis of 3,4,5-trimethoxy-N-methylaniline (compound 2, Scheme 1 (Fig. 1)) Trimethoxyaniline 1 (2.0g, 10.91 mmol) was dissolved in dry methanol (40mL, 20V); MeONa (2.95g, 54.55 mmol,5 eq) was added, and the suspension stirred for 5mins under nitrogen; this slurry was added to a suspension of paraformaldehyde (656.0 mg, 21.83 mmol,2 eq) in MeOH (20mL, 10V vs S.M.). The resulting mixture was stirred at RT for 6 hrs under nitrogen, then NaBH4 (1.07 g, 22.837 mmol, 2.2 eq) was added and the mixture refluxed. Reaction was monitored by TLC (EtOAc / cyclohexane, 6:4) and LC / MS (gradient 1). Upon reaction completion (3 hrs) the reaction volume was concentrated to 15mL, KOH 1M (70mL, 70mmol) was added, and the mixture stirred for 5 mins. Extractions with EtOAc were performed (2x60mL), the organic layers combined were dried over Na2SO4, filtered and concentrated to dryness yielding a sticky brownish oil. This material was pre-absorbed on silica gel (8g) and purified by column chromatography (CombiFlash, 40g cartridge) eluting with 10% to 60% EtOAC in cyclohexane over 10 C.V.. Core fractions concentrated to dryness to yield pure title compound 2 as a yellow oil (1.7g, 79% yield). TLC: Rf = 0.48 (EtOAc : cyclohexane = 6 :4). LC / MS: Rt: 1.45 min (gradient 1) (ESI) m / z: 198.0 [M+H]+. [M+H]+Calculated for C10H16NO3= 198.11H NMR (400 MHz, DMSO-d6) δ 5.81 (s, 2H,), 5.47 – 5.27 (m, 1H), 3.70 (s, 6H), 3.52 (s, 3H), 2.64 (d, J = 5.2 Hz, 3H). Synthesis of 5-chloro-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (compound 4a, Scheme 1 (Fig. 1)). General procedure 1, Method A. 5-chloro-4-azaindole-3- carboxylic acid 3a (250mg, 0.61mmol), neat SOCl2(2mL, 8V), trimethoxyaniline 1 (253mg 1.4mmol,1.1eq), Py (2.5mL). Reaction completion was assessed by TLC. (EtOAc / cyclohexane = 7:3). Reaction worked-up (water / DCM+10%MeOH), crude product slurried in MeOH (10mL) and filtered to yield pure title compound 4a as a white solid (330 mg, 72% yield). TLC: Rf = 0.50 (EtOAc : cyclohexane = 7 :3). LC / MS: Rt: 1.84 min (gradient 1) (ESI) m / z: 362.0 [M+H]+. [M+H]+Calculated for C17H17ClN3O4 = 362.1.1H NMR (400 MHz, DMSO-d6): δ 12.23 (s, 1H), 10.32 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.22 (s, 2H), 3.80 (s, 6H), 3.66 (s, 3H). Synthesis of 5-chloro-N-methyl-N-(3,4,5-trimethoxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 4b, Scheme 1 (Fig. 1)). General procedure 1, Method B. 5-chloro-4-azaindole-3- carboxylic acid 3a (1.0 g, 5.08 mmol), SOCl2(3.63 g, 2.2 mL) in DCM dry (10 mL, 10V vs acid), aniline 2(1.1 g, 5.59 mmol, 1.1 eq), Py (10mL). Crude product slurried in MeOH (15mL) for 15mins before filtration to yield pure title compound 4b as a white solid (1.61 g, 85% yield). TLC: Rf= 0.62 (acetone / DCM = 1:9). LC / MS: Rt: 1.86 min (gradient 1) (ESI) m / z: 375.9 [M+H]+. [M+H]+Calculated for C18H19ClN3O4= 376.1.1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.81 (dd, J = 8.6, 0.9 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.79 (s, 2H), 5.45 (s, 1H), 3.73 (s, 3H), 3.72 (s, 6H), 3.39 (s, 3H). Synthesis of N-methyl-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (Compound 4c, Scheme 1 (Fig. 1)) General procedure 1, Method B. 5-chloro-4-azaindole-3- carboxylic acid 3b (81 mg, 0.5 mmol), SOCl2(0.22 mL, 3.0 mmol, 6.0 eq)) in DCM dry (1.0 mL), aniline 2(118 mg, 0.6 mmol, 1.1 eq), Py (1.0 mL). Upon reaction completion the mixture was diluted with EtOAc (15 ml) and washed with water (15 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The resulting crude was purified by flash column chromatography to yield the title compound 4cas a brown solid (70 mg, 41%).LC / MS: Rt: 1.48 min (gradient 1) (ESI) m / z: 342.2 [M+H]+. [M+H]+Calculated for C18H20N3O4 = 342.15.1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.42 (d, J = 4.4, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 8.3, 4.4 Hz, 1H), 6.54 (s, 2H), 5.82 (s, 1H), 3.93 (s, 3H), 3.80 (s, 6H), 3.51 (s, 3H). Synthesis of 5-chloro-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (compound 5a (ARN25414), Scheme 1 (Fig. 1)). Demethylation general procedure 3. Amide 4a (100mg, 0.276 mmol), BBr3 / DCM 1M solution (2.1mL, 2.07 mmol, 7.5 eq). Crude mixture subjected to work-up (water / EtOAc, EtOAc 3x50mL extractions), dried over Na2SO4, filtered, concentrated to dryness. Slurried in MeOH (1mL) for 10 mins before filtration, to yield pure title compound 5a as a yight yellow solid (70 mg, 79%). LC / MS: Rt: 2.30 min (gradient 2) (ESI) m / z: 319.97 [M+H]+. [M+H]+Calculated for C14H11ClN3O4= 320.04.1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 9.97 (s, 1H), 8.92 (s, 2H), 7.95 (s, 1H), 7.86 (d, J = 8.6Hz, 1H), 7.44 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.81 (s, 2H).13C NMR (101 MHz, DMSO-d6) δ 158.2 (Cq), 145.8 (Cq, 2C), 144.3 (Cq), 143.6 (Cq), 135.7 (Cq), 129.9 (Cq), 129.7 (Cq), 128.4 (Cq), 123.2 (CH), 118.5 (CH), 102.4 (CH), 100.4 (CH, 2C). Synthesis of 5-chloro-N-methyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 5b (ARN25459), Scheme 1 (Fig. 1)). Demethylation general procedure 3. Amide 4b (17mg, 0.045 mmol), BBr3 / DCM 1M solution (0.54mL, 0.54 mmol, 12 eq). Crude mixture subjected to work-up (water / EtOAc 20mL / 20mL), dried over Na2SO4, filtered, concentrated to dryness to yield pure title compound 5b. LC / MS: Rt: 1.27 min (gradient 1) (ESI) m / z: 334.0 [M+H]+. [M+H]+Calculated for C15H13ClN3O4= 334.0.1H NMR (400 MHz, DMSO-d6) δ 11.99 (d, J = 2.3 Hz, 1H), 9.18 (s, 2H), 8.46 (s, 1H), 7.80 (dd, J = 8.6, 0.9 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.25 (s, 2H), 5.46 (s, 1H, 3.30 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 160.4 (Cq), 146.7 (Cq, 2C), 143.8 (Cq), 143.4 (Cq), 134.2 (Cq), 133.7 (Cq), 133.5 (Cq), 127.2 (Cq), 123.0 (CH), 118.5 (CH), 106.5 (CH, 2C), 104.6 (CH), 38.6 (CH3). Synthesis of N-methyl-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (Compound 5c ARN27074, Scheme 1 (Fig. 1)). General procedure 3. Amide 4c (70 mg, 0.2 mmol), BBr31M DCM solution (2.0 mL, 2.0 mmol, 10 eq). Crude triturated in saturated NaHCO3(aq) and then washed with Et2O:MeOH 9:1 (5 mL) to yield pure title compound 5c as a grey solid (22.5 mg, 37%). LC / MS: Rt: 0.91 min (gradient 1) (ESI) m / z: 300.1 [M+H]+. [M+H]+Calculated for C15H14N3O4 = 300.10.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 4.5, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.12 (dd, J = 8.3, 4.5 Hz, 1H), 6.20 (s, 2H), 5.57 (s, 1H), 3.29 (s, 3H). Synthesis of 5-(4-(dimethylamino)phenyl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7aa, Scheme 2 (Fig. 2)). General procedure 2, Method A. Amide 4a (20.0 mg, 0.06 mmol), 4-dimethylaminophenylboronic acid 6a (9.2 mg, 0.055 mmol), K2CO3(11.0 mg, 0.08 mmol) and PdCl2(dppf)∙DCM complex (4.5 mg, 0.005 mmol,), reaction time: 4hrs. Upon completion, reaction mixture cooled to RT, diluted with water and extracted with EtOAc. Organic phases combined, dried (Na2SO4) and concentrated to dryness. Final trituration in MeOH (0.5 mL) to yield pure title compound 7aa as an ochre solid (15.0 mg, 61% yield). TLC: Rf = 0.4 (EtOAc / Cyclohexane = 7:3). LC / MS: Rt: 2.24 min (gradient 1) (ESI) m / z: 447.1 [M+H]+. [M+H]+Calculated for C25H27N4O4 = 447.2.1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 10.22 (s,1H), 7.97 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz,1H), 7.49 (d, J = 2.0 Hz, 1H), 7.24 (s, 2H), 6.81 (d, J = 9.1 Hz, 2H), 3.81 (s, 6H), 3.66 (s, 3H), 2.97 (s, 6H). Synthesis of 5-(2-methoxyphenyl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7ab, Scheme 2 (Fig. 2)). General procedure 2, Method A. Amide 4a (90mg, 0.248 mmol), 2-methoxyphenylboronic acid 6b (42.0 mg, 0.27 mmol), K2CO3 (48.0 mg, 0.35 mmol) and PdCl2(dppf)∙DCM complex (20.0 mg, 0.025 mmol), reaction time: 7 hrs. Upon completion and DCM / water work-up, a final slurry in MeOH (1.5 mL) was applied for 3 hrs before filtration, to yield pure title compound 7ab as a grey solid (70.0 mg, 65% yield). TLC: Rf = 0.4 (EtOAc / Cyclohexane = 7 : 3). LC / MS: Rt: 2.02 min (gradient 1) (ESI) m / z: 434.1 [M+H]+. [M+H]+Calculated for C24H24N3O5 = 434.2.1H NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 10.27 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 1.3 Hz,1H), 7.39 (m, 1H), 7.24 (s, 2H), 7.15 (d, J = 8.5 Hz, 1H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 6H), 3.66 (s, 3H). Synthesis of N-methyl-5-phenyl-N-(3,4,5-trimethoxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bc, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (90 mg, 0.248 mmol), phenylboronic acid 6c (42.0 mg, 0.27 mmol), K2CO3 (48.0 mg, 0.35 mmol) and PdCl2(dppf)∙DCM complex (20.0 mg, 0.025 mmol), reaction time: 7 hrs. Upon completion and DCM / water work-up, a final slurry in MeOH (1.5 mL) was applied for 3 hrs before filtration, to yield pure title compound 7bc as a grey solid (60.0 mg, 58% yield). LC / MS: Rt: 2.14 min (gradient 1) (ESI) m / z: 417.9 [M+H]+. [M+H]+Calculated for C24H24N3O4 = 418.2. NMR (400 MHz, CDCl3): δ 7.95 – 7.93 (m 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.46 – 7.35 (m, 4H), 6.55 (s, 2H), 5.87 (s, 1H), 3.96 (s, 3H), 3.82 (s, 6H), 3.49 (s, 3H). Synthesis of 5-(4-(dimethylamino)phenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7ba, Scheme 2 (Fig. 2)). General procedure 2, Method A. Amide 4b (40.0 mg, 0.11 mmol), 4-dimethylaminophenylboronic acid 6a (22.0 mg, 0.137 mmol), K2CO3 (21.0 mg, 0.15 mmol) and PdCl2(dppf)∙DCM complex (9.0 mg, 0.01 mmol), reaction time: 8hrs. Upon completion and work-up Na2CO3 s.s. / DCM, the crude product was pre-absorbed on silica gel and purified by flash chromatography (5g silica bed) eluting with 5% acetone in DCM. Core fractions to dryness to yield pure title compound 7ba as a yellow solid (36.0 mg, 74% yield). TLC: Rf= 0.4 (acetone / DCM = 1:9). LC / MS: Rt: 2.17 min (gradient 1) (ESI) m / z: 461.0 [M+H]+. [M+H]+Calculated for C26H29N4O4= 461.2.1H NMR (400 MHz, DMSO- d6) δ 11.69 (s, 1H), 7.89 – 7.84 (m, 2H), 7.75 (dd, J = 8.7, 0.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 6.80 (s, 2H), 6.74 (d, J = 9.0 Hz, 2H), 5.51 (s, 1H), 3.75 (s, 3H), 3.74 (s, 6H), 3.40 (s, 3H), 2.94 (s, 6H). Synthesis of N-methyl-5-(pyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bd, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (50.0 mg, 0.13 mmol), pyridine-4-boronic acid 6d (22.0 mg, 0.17 mmol), K2CO3(26.0 mg, 0.19 mmol) and PdCl2(dppf)∙DCM complex (11.0 mg, 0.01 mmol), reaction time: 7hrs. Upon completion, reaction mixture cooled to RT, diluted with water / Na2CO3s.s. and extracted with DCM. Organic phases combined, dried (Na2SO4) and concentrated to dryness. Crude material slurried in MeOH (2mL) for 15 min before filtration; MeOH process repeated twice to yield pure title compound 7bd as a light grey solid (30.0 mg, 54% yield). TLC: Rf= 0.20 (EtOAc:cyclohexane = 6:4), UV. LC / MS: Rt: 1.67 min (gradient 1) (ESI) m / z: 419.0 [M+H]+. [M+H]+Calculated for C23H23N4O4 = 419.2.1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.64 – 8.58 (m, 2H), 8.04 – 7.97 (m, 2H), 7.94 – 7.87 (m, 2H), 6.82 (s, 2H), 5.61 (s, 1H), 3.75 (s, 3H), 3.74 (s, 6H), 3.42 (s, 3H). Synthesis of 5-(2-aminopyridin-4-yl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7be, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (50.0 mg, 0.133mmol), 2-aminopyridine-4-boronic acid pinacol ester 6e (38 mg, 0.173mmol), K2CO3 (26 mg, 0.186mmol) and PdCl2(dppf)∙DCM complex (11 mg, 0.013mmol), reaction time: 7.5hrs. Upon completion, reaction mixture cooled to RT, diluted with water / Na2CO3 s.s. and extracted with DCM:MeOH = 95:5. Organic phases combined, dried (Na2SO4) and concentrated to dryness. Crude material pre-absorbed on silica (700mg) and purified by chromatography (CombiFlash, 4g Gold cartridge) eluting with 5% to 10% MeOH in DCM over 20C.V.. Core fractions concentrated to dryness and the material triturated in MeOH (0.7mL) to yield pure title compound 7be as a white solid (24.0 mg, 42% yield). TLC: Rf= 0.3 (MeOH / DCM = 1:9). LC / MS: Rt: 1.69 min, broad peak (gradient 1) (ESI) m / z: 434.1 [M+H]+. [M+H]+Calculated for C23H24N5O4= 434.2.1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.94 (d, J = 5.4 Hz, 1H), 7.85 (dd, J = 8.8, 0.9 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 7.06 (dd, J = 5.5, 1.6 Hz, 1H), 6.83 (s, 2H), 5.91 (s, 2H), 5.58 – 5.46 (m, 1H), 3.75 (s, 3H), 3.74 (s, 6H), 3.41 (s, 3H). Synthesis of 5-(4-(hydroxymethyl)phenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bf, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (50mg, 0.13 mmol), 4-(hydroxymethyl)phenylboronic acid 6f (30.0 mg, 0.20 mmol), K2CO3(37.0 mg, 0.27 mmol), PdCl2dppf•DCM (16.0 mg, 0.02 mmol). Reaction time: 5 hrs. Upon reaction completion, the mixture was diluted with water and extracted with DCM. Organic phases were combined, dried (Na2SO4) and concentrated to dryness. This material was pre-absorbed on silica gel (700mg) and purified by chromatography (CombiFlash, 4g gold cartridge), eluting with a gradient of 30% to 70% EtOAc in cyclohexane over 20C.V. Product 7bf was obtained as white solid (15.0 mg, 25% yield). TLC: Rf= 0.78 (EtOAc:cyclohexane = 7:3). LC / MS: Rt: 1.69 min (gradient 1) (ESI) m / z: 448.1 [M+H]+. [M+H]+Calculated for C25H26N3O5 = 448.2. NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.99 – 7.95 (m, 2H), 7.83 (dd, J = 8.6, 0.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.81 (s, 2H), 5.56 (s, 1H), 5.21 (t, J = 5.7 Hz, 1H), 4.53 (d, J = 5.1 Hz, 2H), 3.74 (m, 9H), 3.41 (s, 3H). Synthesis of tert-butyl 4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (compound 7bg, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (50.0 mg, 0.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-1(2H)-carboxylate 6g (54.0 mg, 0.17 mmol), K2CO3(26.0 mg, 0.19 mmol) and PdCl2(dppf)∙DCM complex (11.0 mg, 0.01 mmol), reaction time: 2hrs. Upon completion, reaction mixture cooled to RT, diluted with water and extracted with DCM. Organic phases combined, dried (Na2SO4) and concentrated to dryness. Trituration of the crude with MeOH (5 mL) afforded pure desired compound 7bg as grey solid (52.0 mg, 75% yield). TLC: Rf= 0.50 (EtOAc / cyclohexane = 7:3). LC / MS: Rt: 2.24 min (gradient 1) (ESI) m / z: 523.1 [M+H]+. [M+H]+Calculated for C28H35N4O6= 523.2.1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (dd, J = 8.7, 0.9 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.78 (s, 2H), 6.48 (s, 1H), 5.47 (s, 1H), 4.00 (br s, 2H), 3.73 (s, 3H), 3.73 (br s, 6H), 3.48 (t, J = 5.7 Hz, 2H), 3.39 (s, 3H), 2.57 (br s, 2H), 1.41 (s, 9H). Synthesis of tert-butyl 4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)piperidine-1-carboxylate (compound 7bk, Scheme 2 (Fig. 2)). Alkene 7bg (50.0 mg, 0.10 mmol), ammonium formate (35.0 mg, 0.57 mmol) and 10mg of Pd(OH)2(10-20% w / w on carbon, moisturized with water 50% w / w) were suspended in MeOH dry / THF dry (0.75 mL / o.75 mL) and stirred under N2at 55°C (external T). After 6hrs, the mixture was concentrated to dryness, taken up in MeOH / DCM (5:95) and filtered on silica gel (glass column, 1g silica) to remove black insolubles. Eluate was concentrated to dryness yielding pure title compound 7bk as a white solid (50.0 mg, 95% yield). TLC: Rf= 0.48 (EtOAc / cyclohexane = 7:3). LC / MS: Rt: 2.11 min (gradient 1) (ESI) m / z: 525.1 [M+H]+. [M+H]+Calculated for C28H37N4O6 = 523.2.1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.78 (s, 2H), 5.46 (s, 1H), 4.02 (m, 1H), 3.73 (s, 9H), 3.38 (s, 3H), 2.81 (d, J = 13.5 Hz, 4H), 1.77 (m, J = 12.8 Hz, 2H), 1.53 (m, 2H), 1.40 (s, 9H). Synthesis of 5-(4-methoxyphenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bh, Scheme 2 (Fig. 2)). General procedure 2, Method B. Amide 4b (50.0 mg, 0.13 mmol), 4-methoxyphenylbornoic acid 6h (31.0 mg, 0.2 mmol), K2CO3 (37.0 mg, 0.27 mmol), PdCl2dppf.DCM (11mg, 0.013mmol). Reaction time: 4hrs. Upon completion, reaction mixture concentrated to dryness and crude material slurried in water (4mL) for 5mins before filtration. Process repeated in MeOH (1mL). Pure product 7bh was obtained as a grey solid (50.0 mg, 84% yield). LC / MS: Rt: 2.07 min (gradient 1) (ESI) m / z: 448.1 [M+H]+. [M+H]+Calculated for C25H26N3O5= 448.2. NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.01 – 7.93 (m, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.03 – 6.93 (m, 2H), 6.81 (s, 2H), 5.55 (s, 1H), 3.79 (s, 3H), 3.78 – 3.71 (m, 9H), 3.41 (s, 3H). Synthesis of 4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)benzoic acid (compound 7bi, Scheme 2 (Fig. 2)). General procedure 2, Method B. Amide 4b (500 mg, 1.3 mmol), boronic acid 6i (441 mg, 2.7 mmol), K2CO3 (551 mg, 4mmol), PdCl2dppf.DCM (160 mg, 0.2 mmol). Reaction time: 24hrs. Upon completion, reaction mixture was concentrated to dryness and crude material was taken in water (30mL), acidified (pH ~ 2 by HCl 2M), slurried for 45 mins before filtration. Process repeated in MeOH (17mL). Pure compound 7bi was obtained as grey solid (436 mg, 71% yield). LC / MS: Rt: 1.50 min (gradient 1) (ESI) m / z: 460.2 [M-H]-. [M-H]- Calculated for C25H22N3O6 = 460.2.1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 11.92 (d, J = 2.3 Hz, 1H), 8.20 – 8.11 (m, 2H), 8.02 – 7.95 (m, 2H), 7.91 – 7.82 (m, 2H), 6.82 (s, 2H), 5.59 (s, 1H), 3.78 – 3.71 (m, 9H), 3.41 (s, 3H). Synthesis of 5-(3-carbamoylphenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bj Scheme 2 (Fig. 2)) General procedure 2, Method B. Amide 4b (50.0 mg, 0.13 mmol), 3-aminocarbonylphenylboronic acid 6j (33.0 mg, 0.2 mmol), K2CO3 (37.0 mg, 0.19 mmol) and PdCl2(dppf)∙DCM complex (11.0 mg, 0.01 mmol), reaction time: 2hrs. Upon completion, reaction mixture concentrated to dryness and crude material slurried in water (3mL) for 5 mins before filtration. Process repeated in MeOH (2mL). Pure compound 7bj was obtained as a grey solid (47.0 mg, 75% yield). TLC: Rf = 0.50 (EtOAc / cyclohexane = 7:3). TLC: Rf= 0.33 (MeOH / DCM = 1:9). LC / MS: Rt: 1.62 min (gradient 1) (ESI) m / z: 461.1 [M+H]+. [M+H]+Calculated for C25H25N4O5= 461.2.1H NMR (400 MHz, DMSO- d6) δ 11.88 (s, 1H), 8.48 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.93 – 7.78 (m, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 2H), 5.61 (s, 1H), 3.74 (s, 9H), 3.41 (s, 3H). Synthesis of 3-(2-(methyl(3,4,5-trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)benzoic acid (compound 7bl, Scheme 2 (Fig. 2)). General procedure 2, Method B. Amide 4b (200 mg, 0.5 mmol), boronic acid 6l (176 mg, 1.1 mmol), K2CO3 (220 mg, 1.6 mmol), PdCl2dppf.DCM (64 mg, 0.08 mmol). Reaction time: 24hrs. Upon completion, reaction mixture was concentrated to dryness and crude material was taken in water (30mL), acidified (pH ~ 2 by HCl 2M), slurried for 45 mins before filtration. Process repeated in MeOH (17mL). Pure compound 7bl was obtained as grey solid (186 mg, 81% yield). LC / MS: Rt: 1.52 min (gradient 4) (ESI) m / z: 462 [M+H]+. [M+H]+Calculated for C25H24N3O6= 462.2.1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.56 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 6.84 (s, 2H), 5.67 (s, 1H), 3.75 (s, 9H), 3.43 (s, 3H). Synthesis of N-methyl-5-(pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bm, Scheme 2 (Fig. 2)). General procedure 2, Method B. Amide 4b (200 mg, 0.5 mmol), boronic acid 6m (176 mg, 1.1 mmol), K2CO3 (220 mg, 1.6 mmol), PdCl2dppf.DCM (64 mg, 0.08 mmol). Reaction time: 24hrs. Upon completion, reaction mixture concentrated to dryness and crude material slurred in water (3mL) for 5 mins before filtration. Process repeated in MeOH (2mL). Pure compound 7bm was obtained as grey solid (132 mg, 63% yield).1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 8.56 (dd, J = 4.7, 1.6 Hz, 1H), 8.46 – 8.32 (m, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 6.82 (s, 2H), 5.61 (s, 1H), 3.75 (s, 9H), 3.42 (s, 3H), 3.32 (s, 3H). Synthesis of 5-(isoquinolin-5-yl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (Compound 7bn, Scheme 2 (Fig. 2)) General procedure 2, Method A. Amide 4b (150 mg, 0.40 mmol), 5-isoquinoline boronic acid 6n (103 mg, 0.60 mmol), K2CO3(83 mg, 0.08 mmol) and PdCl2(dppf)∙DCM complex (37 mg, 0.6 mmol,), reaction time: 16hrs. Upon completion, the reaction mixture was cooled to RT, diluted with water and extracted with DCM. Organic phases combined, dried (Na2SO4) and concentrated to dryness. The resulting crude was purified by flash column chromatography to yield pure title compound 7bn as a white solid (38.3 mg, 20% yield). LC / MS: Rt: 1.81 min (gradient 1) (ESI) m / z: 469.4 [M+H]+. [M+H]+Calculated for C27H25N4O4 = 469.19.1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 9.31 (s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.96 – 7.89 (m, 2H), 7.86 (d, J = 7.1 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 6.57 (s, 2H), 5.95 (s, 1H), 3.89 (s, 3H), 3.80 (s, 6H), 3.53 (s, 3H). Synthesis of 5-(4-formylphenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 7bo, Scheme 2 (Fig 2)). General procedure 2, Method A. Amide 4b (50 mg, 0.13 mmol), 4-formylphenylboronic acid 6o (30 mg, 0.20 mmol), K2CO3 (37 mg, 0.27 mmol), Pd(dppf)Cl2^DCM (11 mg, 0.013 mmol). Reaction time: 6 hrs. Upon reaction completion, the mixture was concentrated to dryness and the crude product was suspended and stirred in H2O (5 mL) for 5 mins before filtration. Process repeated with MeOH (1 mL). Pure product 7bo obtained as an ochre solid (48 mg, 81% yield). TLC: Rf = 0.52 (10 % acetone / DCM, UV). LC / MS: Rt: 1.96 min (gradient 1) (ESI) m / z: calculated for [C25H23N3O5+ H]+ = 446.2; found: 446.1.1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.04 (s, 1H), 8.30 – 8.24 (m, 2H), 7.99 – 7.93 (m, 2H), 7.93 – 7.86 (m, 2H), 6.82 (s, 2H), 5.60 (s, 1H), 3.74 (d, J = 1.8 Hz, 9H), 3.42 (s, 3H). Synthesis of N-methyl-5-(4-(piperidin-1-ylmethyl)phenyl)-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide (compound 7bp, Scheme 2 (Fig 2)). Aldehyde 7bo (48 mg, 0.11 mmol), and NaBH(OAc)3 (70 mg, 0.32 mmol, 3 eq) were suspended in dry DCE (3 mL) under nitrogen. Piperidine (12 mg, 14 μL, 0.14 mmol, 1.3 eq) was added, and the mixture stirred at RT. After 7 days, the incomplete reaction was diluted with DCM / H2O; the aqueous phase was extracted with DCM, organic phases combined were dried on Na2SO4, filtered, concentrated to dryness. The crude material was pre-absorbed on silica gel (1 g), and purified by column chromatography (CombiFlash system, 4g cartridge), eluting with a gradient 6% to 10% MeOH / DCM over 15 C.V.. Core fractions were combined and concentrated to dryness to yield the title product 7bp as an orange solid (26 mg, 47 % yield). TLC: Rf = 0.22 (10 % MeOH / DCM, UV) LC / MS: Rt: 1.73 min (gradient 1) (ESI) m / z: calculated for C30H34N4O4 + H]+: 515.2; found: 515.2.1H-NMR (400 MHz, DMSO-d6) δ 11.82 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 8.7, 0.9 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 6.81 (s, 2H), 5.56 (s, 1H), 3.74 (s, 6H), 3.74 (s, 6H), 3.41 (s, 3H), 2.40 – 2.29 (br s, 4H), 1.50 (m, 4H), 1.39 (br s, 2H). Synthesis of 5-(4-(dimethylamino)phenyl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide dihydrobromide (compound 8aa (ARN25424), Scheme 2 (Fig. 2)) General procedure 3. Amide 7aa (33mg, 0.086mmol), BBr3 / DCM 1M solution (0.73mL, 0.725 mmol, 8.5eq). Crude mixture subjected to work-up (water / EtOAc, EtOAc 3x50mL extractions), dried over Na2SO4, filtered, concentrated to dryness. The material was triturated with MeOH and filtered to yield the pure title compound 8aa as an orange powder (47mg, 96% yield). LC / MS: Rt: 2.81 min (gradient 3) (ESI) m / z: 405.03 [M+H]+. [M+H]+Calculated for C22H21N4O4= 405.16.1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 10.35 (s, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 9.1 Hz, 2H), 7.66 (s, 1H), 6.96 (d, J = 9.2 Hz, 2H), 6.85 (s, 2H), 3.08 (s, 6H).13C NMR (101 MHz, DMSO-d6) δ 157.0 (Cq), 152.2 (Cq), 147.5 (Cq), 145.8 (Cq, 2C), 138.6 (Cq), 134.7 (Cq), 130.3, 130.1, 129.4 (CH, 2C), 129.2 (CH), 117.0 (CH), 112.2 (CH, 2C) 100.6 (CH, 2C), 97.2 (CH), 38.9 (CH3, 2C. Synthesis of 5-(4-(dimethylamino)phenyl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide dihydrobromide (compound 8ba (ARN25885) Scheme 2 (Fig. 2)). General procedure 3. Amide 7ba (32 mg, 0.08 mmol), BBr31 M DCM solution (0.7 mL, 0.70 mmol, 9 eq). Final triturations in DCM (1 mL), followed by H2O (2 mL) yielded pure title compound 8ba as a red solid (24 mg, 55 % yield). LC / MS: Rt: 2.65 (gradient 2) (ESI) m / z: calculated for [C23H22N4O4+ H]+ = 419.16; found: 418.83. 1H-NMR (400 MHz, DMSO-d6) δ 14.88 (br s, 1H), 12.93 (br s, 1H), 9.32 (br s, 3H), 8.36 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.88 – 7.76 (m, 2H), 6.95 – 6.84 (m, 2H), 6.33 (s, 2H), 5.82 (s, 1H), 3.33 (s, 3H- N-CH3, overlapped with H2O), 3.04 (s, 6H). 13C-NMR (101 MHz, DMSO-d6) δ 159.2 (Cq), 152.2 (Cq), 147.5 (Cq), 146.6 (Cq, 2C), 136.6 (Cq), 133.7 (Cq), 133.6 (Cq), 129.2 (CH, 2C), 129.0 (CH), 117.0 (CH), 112.1 (CH, 2C), 105.9 (CH, 2C), 99.37 (CH), 39.52 (CH3, 2C. Overlapped with DMSO-d5 signal, recovered by HSQC), 38.89 (CH3, 2C. Overlapped with DMSO-d6 signal, recovered by HSQC). Synthesis of 5-(2-hydroxyphenyl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 8ab (ARN25425), Scheme 2 (Fig. 2)) General procedure 3. Amide 7ab (50 mg, 0.115mmol), BBr3 / DCM 1M solution (1.38mL, 1.38 mmol, 12eq). Crude mixture subjected to work-up (water / EtOAc, EtOAc 3x50mL extractions), dried over Na2SO4, filtered, concentrated to dryness. The material was triturated with DCM, and 10% MeOH / DCM, filtered and dried to yield the pure title compound 8ab as a yellow / ochre solid (16 mg, 37% yield). LC / MS: Rt: 2.73 min (gradient 2) (ESI) m / z: 377.71 [M+H]+. [M+H]+Calculated for C20H16N3O5 = 378.11.1H NMR (600 MHz, DMSO-d6) δ 14.67 (s, 1H), 12.21 (s, 1H), 9.96 (s, 1H), 8.94 (s, 2H), 8.11 – 8.00 (m, 3H), 7.96 (s, 1H), 7.57 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.85 (s, 2H).13C NMR (151 MHz, DMSO-d6) δ 158.9 (Cq), 158.3 (Cq), 151.9 (Cq), 145.8 (Cq, 2C), 140.9 (Cq), 135.7 (Cq), 130.5 (CH), 129.9 (Cq, 2C), 128.7, 126.9 (CH), 122.6 (CH), 119.8 (Cq), 118.8 (CH), 117.7 (CH), 115.2 (CH), 101.8 (CH), 100.2 (CH, 2C). Synthesis of N-methyl-5-phenyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 8bc (ARN26849), Scheme 2 (Fig. 2)) General procedure 3. Amide 7bc (30.0 mg, 0.07 mmol), BBr31M DCM solution (0.65 mL, 0.65 mmol, 9eq). Final trituration in water (2 mL) yielded pure pure title compound 8bc as an ochre solid (5.8 mg, 22%). LC / MS: Rt: 2.63 min (gradient 2) (ESI) m / z: 375.8 [M+H]+. [M+H]+Calculated for C21H18N3O4 = 376.1.1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.29 (br s, 2H), 8.37 (bs, 1H), 8.00 – 7.95 (m, 4H), 7.60 – 7.58 (m, 4H), 6.33 (s, 2H), 5.81 (s, 1H), 3.34 (s, 3H). Synthesis of N-methyl-5-(pyridin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, hydrobromic salt (compound 8bd (ARN25917), Scheme 2 (Fig. 2)) General procedure 3. Amide 7bd (30.0 mg, 0.07 mmol), BBr31M DCM solution (0.65mL, 0.65mmol, 9eq). Final trituration in water (2 mL) yielded pure title compound 8bd as an ochre solid (27.0 mg, 82%). LC / MS: Rt: 1.44 min (gradient 2) (ESI) m / z: 377.25 [M+H]+. [M+H]+Calculated for C20H17N4O4 = 377.12.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.28 (br s, 2H), 8.91 – 8.83 (m, 2H), 8.73 – 8.57 (m, 2H), 8.18 (dd, J = 8.6, 2.1 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 6.31 (s, 2H), 5.69 (s, 1H), 3.33 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 160.3 (Cq), 154.4 (Cq), 146.7 (Cq, 2C), 145.5 (Cq), 144.4 (Cq), 142.4 (CH, 2C), 135.3 (Cq), 134.2 (Cq), 133.6 (Cq), 129.5 (Cq), 123.2 (CH, 2C), 120.8 (CH), 118.0 (CH), 106.6 (CH, 2C), 105.9 (CH), 38.8 (CH3). Synthesis of 5-(2-aminopyridin-4-yl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide (compound 8be (ARN25918), Scheme 2 (Fig. 2)) General procedure 3. Amide 7be (24.0 mg, 0.05 mmol), BBr31M DCM solution (0.5mL, 0.5 mmol, 10eq). Final trituration in water (2 mL) yielded pure compound 8be as a yellow solid (20.0 mg, 77% yield). LC / MS: Rt: 1.53 min (gradient 2) (ESI) m / z: 32.28 [M+H]+. [M+H]+Calculated for C20H18N5O4= 392.14.1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 12.10 (s, 1H), 9.29 (s, 2H), 8.59 (s, 1H), 7.98 (d, J = 6.9 Hz, 1H), 7.94 – 7.83 (m, 4H), 7.79 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 6.8, 1.8 Hz, 1H), 6.31 (s, 2H), 5.59 (s, 1H), 3.32 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 160.3 (Cq), 154.4 (Cq), 146.7 (Cq, 2C), 145.5 (Cq), 144.4 (Cq), 142.4 (Cq, 2C), 135.3 (CH), 134.2 (Cq), 133.6 (Cq), 129.5 (Cq), 123.2 (Cq, 2C), 120.8 (CH), 118.0 (CH), 109.4 (CH), 108.8 (CH), 106.6 (CH, 2C), 106.0 (CH), 38.8 (CH3). Synthesis of 5-(4-(bromomethyl)phenyl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 8bf (ARN26715), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bf (15.0 mg, 0.03 mmol), BBr31M DCM solution (0.33 mmol, 0.33 mL). Crude triturated in Et2O (2 mL) to yield the title compound 8bf as an ochre solid (13mg, 83% yield). LC / MS: Rt: 1.82 min (gradient 1) (ESI) m / z: 468.1 [M+H]+. [M+H]+Calculated for C22H19BrN3O4 = 468.1. (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.23 (s, 2H), 8.39 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.98 – 7.93 (m, 2H), 7.66 (d, J = 8.1 Hz, 2H), 6.33 (s, 2H), 5.82 (s, 1H), 4.80 (s, 2H), 3.34 (s, 3H). Synthesis of N-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-N- (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide hydrobromide (compound 8bg (ARN25954), Scheme 2 (Fig. 2)) General procedure 3. Amide 7bg (25.0 mg, 0.0478mmol), BBr3 1M DCM solution (0.43mL, 0.43mmol, 9eq). Crude dissolved in water (1 mL), filtered to remove insolubles; mother liquors lyophilized to yield the title compound 8bg as a yellow solid (17.0 mg, 77% yield). LC / MS: Rt: 1.96 min (gradient 5) (ESI) m / z: 381.29 [M+H]+. [M+H]+Calculated for C20H21N4O4 = 381.16.1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.15 (br s, 2H), 8.87 (br s, 2H), 8.04 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 6.62 (s, 1H), 6.29 (s, 2H), 5.66 (s, 1H), 3.83 (m, 2H), 3.32 (m, 5H), 2.83 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 173.7 (Cq), 159.9 (Cq), 146.6 (Cq, 2C), 134.0 (Cq), 133.6 (Cq), 129.0 (Cq), 115.6 (CH), 106.4 (CH, 2C), 41.7 (CH2), 40.1 (CH2), 38.8 (CH3), 22.3 (CH2). Synthesis of 5-(4-hydroxyphenyl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 8bh (ARN26717), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bh (22.0 mg, 0.04 mmol), BBr31M DCM solution (0.38 mL, 0.38 mmol, 10eq). Crude triturated dissolved in MeOH / water (1mL / 10mL) and freeze-dried to yield the pure title compound 8bh as a yellow solid (19.0 mg, 99% yield). LC / MS: Rt: 1.85 min (gradient 5) (ESI) m / z: 383.30 [M+H]+. [M+H]+Calculated for C20H21N4O4= 383.17.1H NMR (400 MHz, DMSO-d6) δ 12.88 (br s, 1H), 9.29 (br s, 2H), 8.77 (d, J = 11.4 Hz, 1H), 8.46 (m, 1H), 8.37 (br s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.31 (s, 2H), 5.71 (s, 1H), 3.41 (m, 2H), 3.32 (s, 3H), 3.23 (m, 1H), 3.05 (m, 2H), 2.14 – 2.04 (m, 2H), 1.95 (m, 2H). Synthesis of 4-(2-(methyl(3,4,5- trihydroxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)benzoic acid (compound 8bi (ARN26958), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bi (60.0 mg, 0.13 mmol), BBr31M DCM solution (1.17 mL, 1.17 mmol, 9eq). Final trituration in water (2 mL) yielded pure pure title compound 8bi as an ochre solid (10 mg, 18%). LC / MS: Rt: 1.10 min (gradient 1) (ESI) m / z: 420.1 [M+H]+. [M+H]+Calculated for C22H18N3O6= 419.1. NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 9.53 (s, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.08 (s, 3H), 6.33 (s, 2H), 5.70 (s, 1H), 3.32 (s, 3H). Synthesis of 5-(3-carbamoylphenyl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 8bj (ARN26716), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bj (30.0 mg, 0.065 mmol), BBr3 1M DCM solution (0.65 mL, 0.65 mmol, 10eq). Crude triturated in Et2O (3 mL) to yield the pure title compound 8bj as an ochre solid (26.0 mg, 99% yield). LC / MS: Rt: 1.24 min (gradient 1) (ESI) m / z: 419.0 [M+H]+. [M+H]+Calculated for C22H19N4O5 = 419.1.1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.52 – 8.39 (m, 2H), 8.17 (s, 1H), 8.13 – 8.09 (m, 1H), 8.09 – 8.03 (m, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.57 (s, 1H), 6.33 (s, 2H), 5.84 (s, 1H), 3.34 (s, 3H).13C NMR (101 MHz, DMSO- d6) δ 167.1 (Cq), 159.2 (Cq), 146.7 (Cq, 2C), 146.6 (Cq), 137.9 (Cq), 136.2 (Cq), 133.8 (Cq), 133.6 (Cq), 132.9 (Cq), 130.9 (Cq), 130.4 (CH), 129.8 (Cq), 129.5 (CH), 128.6 (CH), 127.4 (CH), 118.3 (CH, 2C), 106.3 (CH, 2C), 100.1 (CH), 38.9 (CH3). Synthesis of 3-(2-(methyl(3,4,5- trihydroxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)benzoic acid (compound 8bl (ARN26977), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bl (80.0 mg, 0.17 mmol), BBr31M DCM solution (1.56 mL, 1.56 mmol, 9eq). Final trituration in water (2 mL) yielded pure title compound 8bl as an ochre solid (60 mg, 83%). LC / MS: Rt: 1.13 min (gradient 1) (ESI) m / z: no ionization.1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.51 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 6.34 (s, 2H), 5.81 (s, 1H), 3.35 (s, 3H). Synthesis of N-methyl-5-(pyridin-3-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide (compound 8bm (ARN26928), Scheme 2 (Fig. 2)). General procedure 3. Amide 7bm (71.0 mg, 0.17 mmol), BBr31M DCM solution (1.53 mL, 1.53 mmol, 9eq). Final trituration in water (2 mL) yielded pure title compound 8bm as an ochre solid (12 mg, 16%). LC / MS: Rt: 1.24 min (gradient 1) (ESI) m / z: 377.1 [M+H]+. [M+H]+Calculated for C20H17N4O4= 377.1.1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 9.53 (s, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.08 (s, 3H), 6.33 (s, 2H), 5.70 (s, 1H), 3.32 (s, 3H). Synthesis of 5-(isoquinolin-5-yl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (Compound 8bn (ARN27025), Scheme 2 (Fig. 2)) General procedure 3. Amide 7bn (38 mg, 0.08 mmol), BBr31M DCM solution (0.8 mL, 0.8 mmol, 10 eq). Crude triturated in saturated NaHCO3(aq) and then washed with Et2O:MeOH 9:1 (5 mL) to yield pure title compound 8bn as a yellow solid (10.8 mg, 32% yield). LC / MS: Rt: 1.81 min (gradient 1) (ESI) m / z: 427.3 [M+H]+. [M+H]+Calculated for C24H19N4O4= 427.14.1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.90 (s, 1H), 8.66 (d, J = 6.6 Hz, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.35 – 8.23 (m, 3H), 8.07 (dd, J = 8.3, 7.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 6.32 (s, 2H), 5.72 (s, 1H), 3.34 (s, 3H). Synthesis of N-methyl-5-(4-(piperidin-1-ylmethyl)phenyl)-N- (3,4,5-trihydroxyphenyl)-1Hpyrrolo[3,2-b]pyridine-2 carboxamide dihydrobromide (compound 8bp, ARN27072, Scheme 2 (Fig. 2)). General procedure 3. Amide 7bp (26 mg, 0.05 mmol), BBr31 M DCM solution (0.5 mL, 0.5 mmol, 10 eq). Crude triturated with MeOH (1 mL) to yield pure title compound 8bp as a pale yellow solid (6 mg, 19 % yield). LC / MS: Rt: 2.04 min (gradient 2) (ESI) m / z: calculated for [C27H28N4O4+ H]+ = 473.22; found: 473.32 . 1H-NMR (400 MHz, DMSO-d6) δ 12.71 (br s, 1H), 9.57 (br s, 1H), 8.41 – 8.24 (m, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.98 (dd, J = 8.7, 3.4 Hz, 1H), 7.81 – 7.64 (m, 2H), 6.33 (s, 2H), 5.79 (s, 1H), 4.39 (br t, J = 4.8 Hz, 2H), 3.36-3.30 (m, 5H, overlapped with H2O), 2.93 (q, J = 12.1 Hz, 2H), 1.87 – 1.76 (m, 2H), 1.75 – 1.59 (m, 3H), 1- 45-1.27 (m, 1H). Synthesis of N-methyl-5-(piperidin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide (compound 8bk, Scheme 2 (Fig. 2)) General procedure 3. Amide 7bk (22.0 mg, 0.04 mmol), BBr31M DCM solution (0.38 mL, 0.38 mmol, 10eq). Crude triturated dissolved in MeOH / water (1mL / 10mL) and freezed-ried to yield the pure title compound 8bk as a yellow solid (19.0 mg, 99% yield). LC / MS: Rt: 1.85 min (gradient 5) (ESI) m / z: 383.30 [M+H]+. [M+H]+Calculated for C20H21N4O4= 383.17. (400 MHz, DMSO-d6) δ 12.88 (br s, 1H), 9.29 (br s, 2H), 8.77 (d, J = 11.4 Hz, 1H), 8.46 (m, 1H), 8.37 (br s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.31 (s, 2H), 5.71 (s, 1H), 3.41 (m, 2H), 3.32 (s, 3H), 3.23 (m, 1H), 3.05 (m, 2H), 2.14 – 2.04 (m, 2H), 1.95 (m, 2H). Synthesis of 5-(4-((2- (dimethylamino)ethyl)carbamoyl)phenyl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (9a, Scheme 3 (Fig. 3)) General procedure 1, Method A. Acid 7bi (44.0 mg, 0.095 mmol), SOCl2 (40µL, 0.57 mmol), N,N-Dimethylethylenediamine (33µL, 0.28 mmol), Py (1 mL). Reaction worked-up (Na2CO3s.s. / DCM), organic phase concentrated to dryness and crude product dissolved in MeOH : DCM : NH3 / MeOH 7N solution = 1 : 9 : 0.1, loaded and purified by flash chromatography eluting with the same eluent (4g silica bed). Core fractions to dryness to yield compound 9a as a yellow solid (40.0 mg, 76% yield). LC / MS: Rt: 1.57 min (gradient 1) (ESI) m / z: 532.2 [M+H]+. [M+H]+Calculated for C29H34N5O5 = 532.3. NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.43 (t, J = 5.7 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.92 – 7.87 (m, 2H), 7.87 – 7.82 (m, 2H), 6.82 (s, 2H), 5.59 (s, 1H), 3.74 (m, 9H), 3.41 (s, 3H), 2.40 (t, J = 6.9 Hz, 2H), 3.38 (m, 2H, water signal overlapping), 2.17 (s, 6H). Synthesis of N-methyl-5-(4-(4-methylpiperazine-1- carbonyl)phenyl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrochloride (compound 9b, Scheme 3 (Fig. 3)). General procedure 1, Method B. Acid 7bi (50.0 mg, 0.11 mmol), SOCl2 (50 µL, 0.65 mmol), N-methylpiperazine (25 µL, 0.22 mmol), Py (1 mL). Upon completion, reaction mixture concentrated to dryness and crude material triturated with MeOH (1mL) to yield pure title compound 9b as a white solid (40.0 mg, 67%). LC / MS: Rt: 1.56 min (gradient 1) (ESI) m / z: 544.1 [M+H]+. [M+H]+Calculated for C30H34N5O5 = 544.3.1H NMR (400 MHz, DMSO-d6) δ 11.90 (d, J = 2.2 Hz, 1H), 10.67 (s, 1H), 8.16 – 8.09 (m, 2H), 7.88 (dd, J = 8.7, 0.9 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.55 – 7.47 (m, 2H), 6.82 (s, 2H), 5.57 (s, 1H), 3.74 (m, 9H), 3.41 (s, 3H), 3.40-3.00 (overlapped with water signal, 8H), 2.77 (s, 3H). Synthesis of 5-(4-(carbamimidoylcarbamoyl)phenyl)-N-methyl- N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide (compound 9c, Scheme 3 (Fig. 3)). Acyl chloride prepared as usual (general procedure 1, Method A). Acid 7bi (60.0 mg, 0.13 mmol), SOCl2(56µL, 0.78 mmol); crude acyl chloride was taken up in dry THF (2 mL) and slowly added (20 mins) to a cold (ice / water bath) stirring solution of guanidine hydrochloride (31.0 mg, 0.32mmol) and NaOH (0.22 mL, 2M solution) in water (1 mL). The resulting solution was stirred at the same T for 45 mins, then warmed up to RT and stirred overnight. Diluted with water, further basified (NaOH) and extracted in DCM. Organic phases combined were dried (Na2SO4) and concentrated to dryness. Crude material was dissolved in MeOH:DCM:NH3 / MeOH 7N solution = 0.5:9:0.1, loaded and purified by flash chromatography eluting with the same eluent (4g silica bed) to give pure pure title compound 9c as yellow solid (22.0 mg, 34% yield). TLC: Rf = 0.4 (MeOH:DCM:NH3 / MeOH 7N solution = 1:9:0.1), LC / MS: Rt: 1.63 min (gradient 1) (ESI) m / z: 503.1 [M+H]+. [M+H]+Calculated for C26H27N6O5= 503.2.1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.13 – 8.08 (m, 2H), 8.06 – 8.00 (m, 2H), 7.85 (dd, J = 8.8, 0.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.82 (s, 2H), 5.58 (s, 1H), 3.75 (s, 3H), 3.74 (s, 6H), 3.41 (s, 3H). Synthesis of 5-(4-((2- (dimethylamino)ethyl)carbamoyl)phenyl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide (compound 10a (ARN26718), Scheme 3 (Fig. 3)). General procedure 3. Amide 9a (40.0 mg, 0.072 mmol), BBr31M DCM solution (0.7mL, 0.7mmol, 10eq). Crude triturated in Et2O (3mL) to yield pure title compound 10a as a yellow solid (41.0 mg, 99% yield). LC / MS: Rt: 1.73 min (gradient 2) (ESI) m / z: 490.20 [M+H]+. [M+H]+Calculated for C26H28N5O5 = 490.21.1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.42 (s, 1H), 8.91 (t, J = 5.7 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.15 – 7.98 (m, 5H), 6.33 (s, 2H), 5.82 (s, 1H), 3.65 (q, J = 5.7 Hz, 2H), 3.36 – 3.28 (m, 5H), 2.87 (d, J = 4.8 Hz, 6H).13C NMR (101 MHz, DMSO-d6) δ 166.1 (Cq), 159.5 (Cq), 146.7 (Cq, 2C), 135.0 (Cq), 133.7 (Cq), 129.9 (Cq), 128.1 (CH, 2C), 127.8 (CH, 2C), 126.5 (CH), 117.9 (CH), 106.4 (CH, 2C), 100.7 (CH), 55.9 (CH2), 42.6 (CH3, 2C), 39.0 (CH3), 34.7 (CH2). Synthesis of N-methyl-5-(4-(4-methylpiperazine-1- carbonyl)phenyl)-N-(3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide (compound 10b (ARN26729), Scheme 3 (Fig. 3)). General procedure 3. Amide 10b (40.0 mg, 0.073 mmol), BBr31M DCM solution (0.73 mL, 0.73 mmol, 10eq). Crude triturated with MeOH (1mL) to yield the pure title compound 10b as a yellow solid (40.0 mg, 94% yield). LC / MS: Rt: 1.18 min (gradient 1) (ESI) m / z: 502.0 [M+H]+. [M+H]+Calculated for C27H26N5O5 = 502.2.1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.90 (s, 1H), 9.24 (s, 2H), 8.25 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.96 (dd, J = 8.5, 2.3 Hz, 1H), 7.69 – 7.54 (m, 2H), 6.32 (s, 2H), 5.79 – 5.72 (br s, 1H), 3.33 (s, 3H), 3.80-3.34 (overlapped with water signal 4H), 3.21 – 3.06 (m, 4H), 2.83 (d, J = 3.5 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 168.5 (Cq), 159.3 (Cq), 146.7 (Cq), 146.6 (Cq, 2C), 137.6 (Cq), 137.1 (Cq), 136.7 (Cq), 134.9 (Cq), 133.8 (Cq), 133.6 (Cq), 130.2 (Cq), 128.3 (CH, 2C), 128.0 (CH, 2C), 127.8 (CH), 118.1 (CH), 106.4 (CH, 2C), 100.7 (CH), 52.0 (CH2, 2C), 42.3 (CH3), 38.9 (CH3). Synthesis of 5-(4-(carbamimidoylcarbamoyl)phenyl)-N-methyl- N-(3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide hydrobromide (compound 10c (ARN26730), Scheme 3 (Fig. 3)). General procedure 3. Amide 10c (22.0 mg, 0.044mmol), BBr31M DCM solution (0.44mL, 0.44 mmol, 10eq). Crude triturated with Et2O (5mL) to yield the pure title compound 10b as a pale yellow solid (23.0 mg, 96% yield). Rt: 1.94 min (gradient 2) (ESI) m / z: 461.15 [M+H]+. [M+H]+Calculated for C23H21N6O5 = 461.16.1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 11.39 (s, 1H), 8.41 (s, 4H), 8.29 – 8.18 (m, 3H), 8.13 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.7 Hz, 1H), 6.32 (s, 2H), 5.76 (d, J = 8.4 Hz, 1H), 3.33 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 166.9 (Cq), 159.6 (Cq), 155.2 (Cq), 146.7 (Cq, 2C), 146.4 (Cq), 137.0 (Cq), 133.8 (Cq), 133.7 (Cq), 132.2 (Cq), 130.1 (Cq), 129.0 (CH, 2C), 128.2 (CH, 2C), 126.2 (CH), 118.1 (CH), 106.4 (CH, 2C), 101.8 (CH), 39.0 (CH3). Synthesis of methyl 3,4,5-trimethoxybenzoate (compound 12, Scheme 4 (Fig. 4)). Gallic acid monohydrate 11 (600.0 mg, 3.19 mmol) was dissolved in EtOAc, dried over Na2SO4, filtered and concentrated to dryness. The crude material was dissolved in dry DMF (15 mL) under N2, along with K2CO3 (, 2.2 g, 15.94 mmol) and stirred at RT for 10mins. Iodomethane (1mL, 15.94 mmol) was then added via syringe and the mixture stirred vigorously at 60°C (quickly turned to a dark brown suspension). After 6hrs, the mixture was cooled to RT, and the solids were filtered off; the cake was rinsed with DCM (3 x 15mL). Mother liquors were concentrated to dryness yielding a brown oil, which was taken up in DCM (50mL); the organic layer was washed with successively with water (1x50mL) and NaHCO3 s.s. (1 x 25mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield the product as brown crystals (718.0 mg, quantitative yield). The product compound 12 was carried on to the successive step without further purification. TLC: Rf= 0.73 (EtOAc / Cyclohexane = 3:7), LC / MS: Rt: 1.73 min (gradient 1) (ESI) m / z: 227.0 [M+H]+. [M+H]+Calculated for C11H15O5 = 227.1.1H NMR (400 MHz, DMSO-d6) δ 7.24 (s, 2H), 3.84 (s, 3H), 3.84 (s, 6H), 3.74 (s, 3H). Synthesis of 3,4,5-trimethoxybenzoic acid (compound 13, Scheme 4 (Fig. 4)). Methyl 3,4,5-trimethoxybenzoate 12 (719.0 mg, 3.19 mmol) was suspended in MeOH / water = 1:1 (7mL : 7mL), LiOH (153 mg, 6.38 mmol, 2eq) was added and the suspension was stirred at RT for 2hrs, after which time additional LiOH was added (153mg, 6.38 mmol, 2eq). Reaction progression was assessed via TLC (EtOAC / cyclohexane = 3 :7). The mixture was stirred for an additional hour, then cooled to 0°C, and acidified by 2M HCl (7mL). The suspension was stirred at RT for 5 mins, then diluted with water (7 mL) and filtered; the cake was rinsed with water (2 x 7mL) and left on the filter with max vacuum for 2hrs. Brief drying in vacuo (3 hrs at 50°C) yielded the pure title compound 13 as a white / yellowish powder (557.0 mg, 82% yield). LC / MS: Rt: 1.00 min (gradient 1) (ESI) m / z [M-H]- = 211.1 [M-H]- calculated for C10H11O5= 211.1.1H NMR (400 MHz, DMSO-d6) δ 12.91 (br s, 1H), 7.23 (s, 2H), 3.82 (s, 6H), 3.73 (s, 3H). Synthesis of 5-(2-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine- 2-carboxylic acid (compound 14a, Scheme 5 (Fig. 5)). General procedure 2, Method B. 5-chloro-4-azaindole-3- carboxylic acid 3a (150mg, 0.76 mmol), 2- methoxyphenylboronic acid (174.0 mg, 1.14mmol), K2CO3 (316.0 mg, 2.28mmol), sSPhos (7.8 mg, 0.015mmol), Pd(OAc)2(1.7 mg, 0.008mmol), 3 mL water. Upon reaction completion and acidification, suspension was filtered, and the cake washed with water (3-4mL) before drying. Pure title compound 14a was obtained as white solid (203.0 mg, 99% yield). LC / MS: Rt: 1.17 min (gradient 1) (ESI) m / z: 267.1 [M-H]-. [M-H]- Calculated for C15H11N2O3: 267.1.1H NMR (400 MHz, DMSO-d6) δ 13.20 (br s, 2H), 8.46 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.34 – 7.25 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 3.87 (s, 3H). Synthesis of 5-(2-methoxyphenyl)-1H-indole-2-carboxylic acid (compound 14b, Scheme 5 (Fig. 5)). General procedure 2, Method B. 5-chloroinidole-2-carboxylic acid 3b (50.0 mg, 0.26 mmol), 2-methoxyphenylboronic acid (58.0 mg, 0.39), K2CO3(106.0 mg, 0.78mmol), sSPhos (2.6 mg, 0.005mmol), Pd(OAc)2 (0.6 mg, 0.003mmol), 1mL water. Upon reaction completion and acidification, the suspension was diluted with water (20mL), and extracted with DCM (5 x 20mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (3g silica gel) eluting with 10% MeOH in DCM. Core fractions combined were concentrated to dryness to yield pure title compound 14b as a white solid (52mg, 76% yield). TLC: Rf= 0.3 (MeOH / DCM = 1 : 9. LC / MS: Rt: 1.55 min (gradient 1) (ESI) m / z: 266.1 [M-H]-. [M-H]- Calculated for C16H12NO3= 266.1.1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.69 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.37 – 7.27 (m, 3H), 7.13 – 7.07 (m, 2H), 7.02 (td, J = 7.4, 1.2 Hz, 1H), 3.75 (s, 3H). Synthesis of 5-(2-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine- 2-carboxamide (compound 15a, Scheme 5 (Fig. 5)). General procedure 1, Method C. Acid 14a (190.0 mg, 0.71 mmol). 30% aqueous NH4OH (5 mL, 34mmol). After 45mins of reaction at 0°C, the suspension was filtered, and the cake washed with cold water (3-4mL); the resulting solid was dried at 60°C with max vacuum for 60mins to yield the pure title compound 15a as a white powder (129.0 mg, 68% yield). TLC: Rf = 0.5 (MeOH / DCM = 1 : 9). LC / MS: Rt: 1.46 min (gradient 1) (ESI) m / z: 268.0 [M+H]+. [M+H]+Calculated for C15H14N3O2: 268.1.1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.10 (br s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 7.5, 1.8 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.51 (br s, 1H), 7.41 – 7.34 (m, 1H), 7.27 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H). Synthesis of 5-(2-methoxyphenyl)-1H-indole-2-carboxamide (compound 15b, Scheme 5 (Fig. 5)). General procedure 1, Method C. Acid 14b (50.0 mg, 0.187mmol) 30% aqueous NH4OH (1.3mL, 9.35mmol). After 45 mins of reaction at 0°C, the mixture was diluted with water (20 mL) and extracted with 5% MeOH / DCM (4x25mL). Organic phases combined, dried over Na2SO4, filtered and concentrated to dryness to yield the crude product. This material was pre- adsorbed on silica gel (500mg) and purified by column chromatography (CombiFlash, 12g cartridge) eluting with a gradient 0% to 2.5% MeOH / DCM over 25 C.V.. Core fractions concentrated to dryness yielding pure title compound 15b as a white solid (41.0 mg,78% yield). TLC: Rf= 0.24 (MeOH / DCM = 5 : 95). LC / MS: Rt: 1.81 min (gradient 1) (ESI) m / z: 265.2 [M-H]-. [M-H]- Calculated for C16H13N2O2= 265.1.1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.37 – 7.28 (m, 4H), 7.12 – 7.07 (m, 2H), 7.02 (td, J = 7.4, 1.2 Hz, 1H), 3.75 (s, 3H). Synthesis of (5-(2-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridin- 2-yl)methanamine (compound 16a, Scheme 5 (Fig. 5)). General procedure 1, Method C. Amide 15a (129mg, 0.482mmol), dry THF (2mL), LiAlH4 / THF 2M solution (1.7mL, 3.37mmol). After 16hrs, reaction was quenched and extracted with DCM. Crude product was dissolved in MeOH:DCM = 1:9, loaded and purified with the same eluent by flash chromatography (2g silica bed). Core fractions combined were concentrated to dryness yielding a white foam, consisting of a ratio of the product of interest (compound 16a) and demethylated product = 27:73. The mixture of products was carried on in the successive coupling as such. LC / MS: Rt: 2.39 min (gradient 4) (ESI) m / z: 254.0 [M+H]+. [M+H]+Calculated for C15H16N3O: 254.1. Synthesis of (5-(2-methoxyphenyl)-1H-indol-2-yl)methanamine (compound 16b, Scheme 5 (Fig. 5)). General procedure 1, Method C. Amide 15b (41.0 mg, 0.15 mmol), dry THF (2mL), LiAlH4 / THF 2M solution (0.5 mL, 0.91 mmol). After 8 hrs, a second addition of LiAlH4(0.5 mL, 0.91 mmol) was made and the reaction was continued for 45 mins before being quenched and extracted with DCM. Crude product was dissolved in MeOH / DCM = 1:9, loaded and purified with the same eluent by flash chromatography (2g silica bed). Core fractions combined were concentrated to dryness to yield the pure title compound 16b a white foam (31mg, 78% yield). TLC: Rf= 0.33 (MeOH:DCM = 1:9), LC / MS: Rt: 1.64min (gradient 1) (ESI) m / z: 253.1 [M+H]+. [M+H]+Calculated for C16H17N2O = 253.1.1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.34 – 7.24 (m, 3H), 7.12 (dd, J = 8.4, 1.7 Hz, 1H), 7.07 (dd, J = 8.8, 1.1 Hz, 1H), 7.00 (td, J = 7.4, 1.2 Hz, 1H), 6.24 (s, 1H), 3.84 (d, J = 0.9 Hz, 2H), 3.74 (s, 3H). Synthesis of 3,4,5-trimethoxy-N-((5-(2-methoxyphenyl)-1H- pyrrolo[3,2-b]pyridin-2-yl)methyl)benzamide (compound 17a, Scheme 5 (Fig. 5)). General procedure 1, Method A. Acid 13 (0.271mmol, 58mg), SOCl2(0.2mL, 2.71 mmol), mixture of amines (compound 17a and demethylated side product) (65.0 mg, 0.27 mmol), dry Py / dry DCM (2mL / 1mL). Acyl chloride addition performed slowly (over 40 mins) in a pre-cooled solution of the amines in Py / DCM to disfavor phenol acylation. After 16hrs, the mixture was directly concentrated to dryness, pre-absorbed on silica gel (900mg) and purified by column chromatography (CombiFlash, 12g Gold cartridge) eluting with 0% to 5% MeOH in DCM over 15 C.V.. Fractions containing the product of interest were combined and concentrated to dryness to yield the tile compound 17a as a yellowish solid (20.0 mg, 64% yield, calculated on the starting material compound of interest). TLC: Rf = 0.22 (MeOH : DCM = 5 : 95). LC / MS: Rt: 1.77 min (gradient 1) (ESI) m / z: 448.1 [M+H]+. [M+H]+Calculated for C25H26N3O5 = 448.2.1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.07 (d, J = 5.9 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.67 (dd, J = 7.7, 1.8 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.28 (s, 2H), 7.14 – 7.09 (m, 1H), 7.06 – 7.00 (m, 1H), 6.46 (d, J = 1.6 Hz, 1H), 4.73 – 4.64 (m, 2H), 3.84 (s, 6H), 3.79 (s, 3H), 3.71 (s, 3H). Synthesis of 3,4,5-trimethoxy-N-((5-(2-methoxyphenyl)-1H- indol-2-yl)methyl)benzamide (compound 17b, Scheme 5 (Fig. 5)). General procedure 1, Method A. Acid 13 (38.0 mg, 0.18 mmol), SOCl2(0.13 mL, 1.78 mmol), amine compound 16b (30.0 mg, 0.12 mmol), dry Py / dry DCM (0.5mL / 0.5mL). Upon reaction completion, the mixture was diluted with water and DCM, washed with NaHCO3ss (1x15mL), dried over Na2SO4, filtered and concentrated to dryness. This crude material was purified by column chromatography (CombiFlash, 4g Gold cartridge) eluting with 10% to 50% EtOAc in cyclohexane, over 20 C.V.. Core fractions combined, concentrated to dryness to yield the pure title compound 17b as a yellow foam (40.0 mg, 75% yield). TLC: Rf = 0.28 (EtOAc / cyclohexane = 1:1). LC / MS: Rt: 2.22min (gradient 1) (ESI) m / z: 447.1 [M+H]+. [M+H]+Calculated for C26H27N2O5= 447.2.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.97 (t, J = 5.7 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.31 – 7.24 (m, 4H), 7.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.00 (td, J = 7.5, 1.3 Hz, 1H), 6.32 (s, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.83 (s, 6H), 3.73 (s, 3H), 3.71 (s, 3H). Synthesis of 3,4,5-trihydroxy-N-((5-(2-hydroxyphenyl)-1H- pyrrolo[3,2-b]pyridin-2-yl)methyl)benzamide (compound 18a (ARN25625), Scheme 5 (Fig. 5)). General procedure 3. Amide 17a (15.0 mg, 0.03 mmol), BBr31M solution (0.41mL 0.41mmol, 13eq). Crude material was dissolved in MeOH:DCM = 1:9, loaded and slowly eluted on a manual column (silica gel, 4g). Core fractions were combined and concentrated to dryness to yield the pure title compound 18a as a yellowish solid (3mg, 22% yield). TLC: Rf = 0.3 (MeOH / DCM = 1 : 9), LC / MS: Rt: 2.02 min (gradient 3) (ESI) m / z: 391.98 [M+H]+. [M+H]+Calculated for C21H18N3O5= 392.12.1H NMR (600 MHz, DMSO-d6) δ 14.95 (s, 1H), 11.45 (s, 1H), 10.21 (s, 1H), 9.07 (s, 2H), 8.70 (t, J = 5.7 Hz, 1H), 8.00 – 7.93 (m, 2H), 7.87 (d, J = 8.9 Hz, 1H), 7.25 – 7.20 (m, 1H), 6.91 (s, 2H), 6.90 – 6.85 (m, 2H), 6.47 (s, 1H), 4.61 (d, J = 5.7 Hz, 2H). Synthesis of 3,4,5-trihydroxy-N-((5-(2-hydroxyphenyl)-1H- indol-2-yl)methyl)benzamide (compound 18b (ARN25522), Scheme 5 (Fig. 5)). General procedure 3. Amide 17b (16.0 mg, 0.04 mmol), BBr31M solution (0.43 mL, 0.43mmol, 10eq). Crude material was dissolved in MeOH / DCM = 1:9, loaded and slowly eluted on a manual column (silica gel, 3.3g). Core fractions were combined and concentrated to dryness to yield the pure title compound 18b as a yellowish solid (3.0 mg, 21% yield). LC / MS: Rt: 3.19 min (gradient 2) (ESI) m / z: 391.25 [M+H]+. [M+H]+Calculated for C22H19N2O5 = 391.13. NMR: (600 MHz, DMSO- d6) δ 10.81 (br s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.26 – 7.18 (m, 2H), 7.08 (t, J = 7.7 Hz, 1H), 6.92 – 6.87 (m, 3H), 6.84 (t, J = 7.4 Hz, 1H), 6.25 (s, 1H), 4.54 (d, J = 4.2 Hz, 2H).13C NMR (151 MHz, DMSO-d6) δ 166.6 (Cq), 154.2 (Cq), 145.5 (Cq), 138.1 (Cq), 146.8 (Cq, 2C), 135.1 (Cq), 130.7 (CH), 129.5 (Cq), 129.3 (Cq), 127.8 (Cq), 127.3 (CH), 124.3 (Cq), 122.4 (CH), 120.0 (CH), 119.3 (CH), 115.9 (CH, 2C), 110.4 (CH), 106.8 (CH), 99.1 (CH), 36.7 (CH2). Synthesis of 1-(5-chloro-1H-indol-2-yl)-3-(3,4,5- trimethoxyphenyl)urea (compound 19a, Scheme 6 (Fig. 6)). General procedure 5. Aniline 1 (80.0 mg, 0.44 mmol), 5- chloroinidole-2-carboxylic acid 3b (128.0 mg, 0.66 mmol,), diphenylphosphorylazide (0.13 mL, 0.52 mmol), TEA (0.18 mL, 1.31 mmol) in dry toluene (2 mL). The crude material was pre-absorbed on silica gel (600 mg) and purified by column chromatography (CombiFlash, 12g gold cartridge) eluting with 10% to 60% EtOAc in cyclohexane over 17 C.V.. Core fractions were combined and concentrated to dryness yielding a crude green solid, that was triturated with MeOH (0.5mL), filtered and dried in vacuo for 40mins at 50°C to yield the pure title compound 19a as a white powder (40.0 mg, 24% yield). TLC: Rf = 0.29 (EtOAc / cyclohexane = 1:1). LC / MS: Rt = 2.22 min (gradient 1) (ESI) m / z [M+H]+= 376.1 [M+H]+calculated for C18H19ClN3O4= 376.1.1H NMR (400. MHz, DMSO-d6) δ 11.20 (br s, 1H, NH), 9.26 (br s, 1H, NH), 8.92 (br s, 1H, NH), 7.39 – 7.31 (m, 2H), 6.90 (dd, J = 8.5, 2.1 Hz, 1H), 6.85 (s, 2H), 5.98 (s, 1H), 3.77 (s, 6H), 3.63 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 152.9 (Cq, 2C), 151.8 (Cq), 137.5 (Cq), 135.4 (Cq), 132.7 (Cq), 131.3 (Cq), 129.0 (Cq), 123.6 (Cq), 118.5 (CH), 117.0 (CH), 112.2 (CH), 96.1 (CH, 2C), 84.9 (CH), 60.1 (CH3), 55.7 (CH3, 2C). Synthesis of 3-(5-chloro-1H-indol-2-yl)-1-methyl-1-(3,4,5- trimethoxyphenyl)urea (compound 19b, Scheme 6 (Fig. 6)). General procedure 5. Aniline 2 (94.0 mg, 0.48 mmol), acid 3b (140.0 mg, 0.71 mmol), diphenylphosphorylazide (0.12 mL, 0.57 mmol), TEA (0.2 mL, 1.43 mmol) in dry toluene (2 mL). The crude material was pre-absorbed on silica gel (1.5 g) and purified by chromatography (CombiFlash, 24g gold cartridge) eluting with 25% to 40% EtOAc in cyclohexane over 5 C.V., followed by 40% for 5 C.V., then increased to 60% EtOAc / cyclohexane. Core fractions were combined, concentrated to dryness, pre-absorbed on silica gel (600 mg) and purified again by column chromatography (24g silica, manual column) eluting with 0% to 1% MeOH in DCM. Core fractions were combined and concentrated to dryness yielding a green solid, that was triturated with MeOH (1mL), filtered and dried in vacuo for 60 mins at 60°C to yield the pure title compound 19b as a grey solid (26.0 mg,14% yield). TLC: Rf = 0.5 (EtOAc / cyclohexane = 1:1). LC / MS: Rt = 2.34min (gradient 1) (ESI) m / z [M+H]+= 390.1. [M+H]+calculated for C19H21ClN3O4= 390.1.1H NMR (400 MHz, DMSO-d6) δ 10.84 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.1 Hz, 1H), 6.71 (s, 2H), 6.09 (d, J = 0.9 Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.25 (s, 3H). Synthesis of 1-(5-chloro-1H-indol-2-yl)-3-(3,4,5- trihydroxyphenyl)urea (compound 20a (ARN25626), Scheme 6 (Fig. 6)). General procedure 3. Urea 19a (27.0 mg, 0.07 mmol), BBr3 / DCM 1M solution (0.65 mL, 0.65 mmol, 9eq). Crude ochre material was triturated in ACN (0.7mL) with sonication, and filtered; recovered solid was freeze-dried in MeOH:water = 1:4, to yield the pure title compound 20a as a yellow solid (20mg, 86% yield). LC / MS: Rt = 3.16min (gradient 3), (ESI) m / z [M+H]+= 333.82. [M+H]+C15H13ClN3O4= 334.06.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.00 (s, 1H), 8.45 (s, 1H), 7.34 – 7.29 (m, 2H), 6.88 (dd, J = 8.5, 2.1 Hz, 1H), 6.46 (s, 2H), 5.94 (s, 1H).13C NMR (151 MHz, DMSO-d6) δ 151.7 (Cq), 146.2 (Cq, 2C), 137.9 (Cq), 131.2 (Cq), 130.6 (Cq), 129.2 (Cq), 128.5 (Cq), 123.6 (Cq), 118.3 (CH), 116.9 (CH), 112.1 (CH), 98.5 (CH, 2C), 84.6 (CH). Synthesis of 3-(5-chloro-1H-indol-2-yl)-1-methyl-1-(3,4,5- trihydroxyphenyl)urea (compound 20b (ARN25628), Scheme 6 (Fig. 6)). General procedure 3. Urea 19b (26.0 mg, 0.07 mmol), BBr3 / DCM 1M solution (0.67 mL, 0.67 mmol, 10eq). Crude white powder was triturated with MeOH (0.5mL) with sonication, then filtered; the solid was washed with additional MeOH, freeze- dried in CH3CN / water = 1:4, to yield the pure title compound 20b as a white solid (10mg, 43% yield). LC / MS: Rt = 3.32 min (gradient 3), (ESI) m / z [M+H]+= 347.93. [M+H]+calculated for C16H15ClN3O4= 348.07.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.33 (s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 2.1 Hz, 1H), 6.24 (s, 2H), 6.08 (s, 1H), 3.13 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 153.5 (Cq), 146.6 (Cq, 2C), 138.5 (Cq), 132.9 (Cq), 132.8 (Cq), 130.5 (Cq), 129.3 (Cq), 123.4(Cq), 118.2 (CH), 117.0 (CH), 111.8 (CH), 106.2 (CH, 2C), 85.3 (CH), 37.7 (CH3). Synthesis of (5-bromo-1H-indol-2-yl)(3,4,5- trimethoxyphenyl)methanone (compound 23, Scheme 7 (Fig. 7)). Aldehyde 21 (350mg, 1.736mmol) was dissolved in methyl ethyl ketone (16 mL) along with dry K2CO3 (360mg, 2.6mmol, 1.5eq), the mixture was stirred under N2 at RT for 15min; Br- acetophenone 22 (502mg, 1.736mmol, 1eq), dissolved in methyl ethyl ketone (8mL) under N2, was added in one portion to the suspension of the aldehyde, and the resulting mixture stirred under N2at 50° for 21hrs. The mixture was concentrated to a small volume (~5mL) and extracted with EtOAc / water (70mL / 30mL). The aqueous phase was re-extracted with EtOAc (1x50mL), the organic phases were combined and dried over Na2SO4, filtered and concentrated to dryness to yield compound 23 as a yellow solid (680mg, quant. yield), that was used in the next step without further purification.LC / MS: Rt = 2.44 min (gradient 1), (ESI) m / z [M+H]+= 390.8. [M+H]+calculated for C18H16BrO5= 391.0.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 1.4 Hz, 1H), 7.82 (d, J = 1.0 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.9, 2.1 Hz, 1H), 7.30 (s, 2H), 3.88 (s, 6H), 3.80 (s, 3H). Synthesis of (5-bromo-1H-indol-2-yl)(3,4,5- trimethoxyphenyl)methanone oxime (compound 24, Scheme 7 (Fig. 7)). Ketone 23 (50mg, 0.128mmol 1eq) and hydroxylamine hydrochloride (62mg, 0.896mmol, 7eq) were heated up in absolute EtOH (1.5mL) at 85°C, in a screw-capped vialfor 10hrs. The mixture was then cooled to RT, diluted with EtOAc (20mL), washed with water (2x20mL), and the organic layer dried on Na2SO4, filtered and concentrated to dryness to yield compound 24 as a yellowish solid (53mg, quantitative yield), that was used in the next step without further purification.LC / MS: mixture of E and Z isomers Rt = 2.23 and 2.29 min (gradient 1), (ESI) m / z [M+H]+= 405.9. [M+H]+calculated for C18H17BrNO5= 406.0.1H NMR (600 MHz, DMSO-d6), mixture of E and Z isomers: Major isomer: δ 12.51 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 1.0 Hz, 1H), 7.60 (d, J = 5.9 Hz, 1H), 7.53 (dd, J = 8.7, 2.1 Hz, 1H), 6.83 (s, 3H), 3.77 (s, 6H), 3.73 (s, 3H) Minor isomer: δ 11.85 (s, 1H), 7.83 (d, J = 2.1 Hz, 1H)), 7.61 (d, J = 5.8 Hz, 1H), 7.49 (dd, J = 8.8, 2.1 Hz, 1H), 6.77 (d, J = 1.0 Hz, 1H), 6.73 (s, 2H), 3.77 (s, 6H), 3.73 (s, 3H). Synthesis of (5-bromobenzofuran-2-yl)(3,4,5- trihydroxyphenyl)methanone oxime (compound 25 (ARN25497), Scheme 7 (Fig. 7)). General procedure 3. Oxime 24 (20mg, 0.05mmol, 1eq), BBr3 / DCM 1M solution (0.5mL, 0.5mmol, 10 eq). Crude powder purified by quick column chromatography (2g silica gel) eluting with 12% MeOH / DCM. Core fractions combined and concentrated to dryness to yield the pure title compound 25 as a yellowish solid (4mg, 22% yield). LC / MS: mixture of E and Z isomers Rt = 3.36 and 3.55 min (gradient 2), (ESI) m / z [M+H]+= 363.99, [M+H]+calculated for C11H15BrNO5= 363.98.1H NMR (mixture of E / Z isomers in 36:64 ratio, asterisks [*] denote minor isomer that could be resolved, 400 MHz, DMSO- d6):δ 7.98 (d, J = 2.0 Hz, 1H), 7.85* (d, J = 2.0 Hz, 1H), 7.59* (d, J = 5.8 Hz, 1H), 7.58 – 7.56 (m, 2H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.47* (dd, J = 8.8, 2.1 Hz, 1H), 6.76* (d, J = 0.9 Hz, 1H), 6.46 (s, 2H), 6.40* (s, 2H). Synthesis of 5-chloro-N-methoxy-N-methyl-1H-pyrrolo[3,2- b]pyridine-2-carboxamide (compound 26, Scheme 8 (Fig. 8)) General procedure 1, Method B. 5-chloro-4-azaindole-3- carboxylic acid 3a (200 mg, 1.0 mmol), SOCl2(0.71 g, 0.43 mL) in DCM dry (2 mL, 10V vs acid), N,O-dimethylhydroxylamine hydrochloride(117 mg, 1.2 mmol, 1.2 eq), Py (2 mL). Crude mixture subjected to work-up (water / EtOAc 20mL / 20mL) to yield pure title compound 26 as a white solid (186 mg, 78% yield). LC / MS: Rt: 1.58 min (gradient 1) (ESI) m / z: 240.1 [M+H]+. [M+H]+Calculated for C10H11ClN3O2 = 240.05.1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.73 (dd, J = 8.6, 1.0 Hz, 1H), 7.34 (dd, J = 2.1, 0.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.45 (s, 3H). Synthesis of 5-chloro-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide (Compound 27, Scheme 8 (Fig. 8)) 5-chloro-N-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamide 26 (269 mg, 1.1 mmol) was dissolved in dry DMF (5.5 ml, 20V vs amide) under nitrogen atmosphere. Sodium hydride 60 wt% (68 mg, 1.7 mmol) was then added and the resulting mixture was stirred or 30 minutes. 2- (Trimethylsilyl)ethoxymethyl chloride (0,23 ml, 1.3 mmol, 1.2 eq) was then added. Upon reaction completion (2 hours) the mixture was diluted with EtOAc (15 ml) and washed with water (4x15 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The resulting crude was purified by flash column chromatography to yield the title compound 27 as a brown solid (295 mg, 73%). LC / MS: Rt: 2.58 min (gradient 1) (ESI) m / z: 370.0 [M+H]+. [M+H]+Calculated for C16H25ClN3O3Si = 370.14.1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.7, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.16 (s, 1H), 5.80 (s, 2H), 3.67 (s, 3H), 3.48 – 3.42 (m, 2H), 0.87 – 0.79 (m, 2H), -0.08 (s, 9H). Synthesis of (5-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2- yl)(3,4,5-trimethoxyphenyl)methanone (Compound 28, Scheme 8 (Fig. 8)) A solution of 5-bromo-1,2,3-trimethoxybenzene (296 mg, 1.2 mmol, 4.0 eq) was dissolved in dry THF (2 ml, 8V) under nitrogen and the solution was cooled to -78°C using a dry ice / acetone bath. n-butyl lithium as 2.5 M solution in hexanes (0.24 ml, 0.6 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred for 30 minutes and then transferred to a solution of 5-chloro-N-methoxy-N-methyl-1- ((2(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 27 (110 mg, 0.3 mmol, 1.0 eq) in dry THF (1.0 ml, 9V) at -78°C. After 30 minutes the reaction was quenched by adding sat. NH4Cl(aq) (5 ml) and diluted with EtOAc (15 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The resulting crude was purified by flash column chromatography (cyclohexane: EtOAc 9:1) to afford the title compound 28 as brown solid (78 mg, 54%). LC / MS: Rt: 2.14 min (gradient 1) (ESI) m / z: 477.2 [M+H]+. [M+H]+Calculated for C23H30ClN2O5Si = 477.16. (400 MHz, CDCl3) δ 7.91 (dd, J = 8.7, 0.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.22 (s, 2H), 7.13 (d, J = 0.8 Hz, 1H), 5.92 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H), 3.57 – 3.49 (m, 2H), 0.88 – 0.78 (m, 2H), -0.13 (s, 9H). Synthesis of (5-chloro-1H-pyrrolo[3,2-b]pyridin-2- yl)(3,4,5-trimethoxyphenyl)methanone (Compound 29, Scheme 8 (Fig. 8)) Compounds 29 was prepared according to general procedure 6 using: compound 28(30 mg, 0.06 mmol), TBAF as 1.0 M solution in THF (0.6 ml, 0.6 mmol, 10 eq) in dry THF (0.6 ml) was added. The resulting crude was purified by flash column chromatography to yield the title compound 29 as a brown solid (20.7 mg, 96%). LC / MS: Rt: 2.05 min (gradient 1) (ESI) m / z: 347.0 [M+H]+. [M+H]+Calculated for C17H16ClN2O4= 347.08.1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.33 – 7.28 (m, 4H), 3.97 (s, 3H), 3.93 (s, 6H). Synthesis of (5-chloro-1H-pyrrolo[3,2-b]pyridin-2- yl)(3,4,5-trihydroxyphenyl)methanone (compound 30 (ARN26974), Scheme 8 (Fig. 8)) Compound 30 was prepared according to General procedure 3 using: compound 29 (32 mg, 0.08 mmol), BBr31M DCM solution (0.7 mL, 0.7 mmol, 10 eq). Crude triturated in Et2O:MeOH 9:1 (5 mL) to yield pure title compound 30 as a yellow solid (6.4 mg, 18% yield).LC / MS: Rt: 1.85 min (gradient 1) (ESI) m / z: 304.1 [M+H]+. [M+H]+Calculated for C14H10ClN2O4= 304.03.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.11 (s, 1H), 7.06 (s, 2H). Synthesis of (4-bromo-2-pyridyl)methanol (compound 32, Scheme 9 (Fig. 9), equation I) To a suspension of bromopyridine-2-carboxylic acid 31 (1500 mg, 7.42 mmol) in dry toluene (15 mL) under argon atmosphere were added Et3N (1.55 mL, 11.13 mmol) and methylchloroformate (0.86 mL, 1.13 mmol). The reaction mixture stirred at room temperature for 18 hours, then resulted trimethylamine hydrochloride was filtered off and the filtrate was concentrated under reduce pressure. The crude obtained was dissolved in EtOH under argon, and NaBH4(562.0 mg, 14.84 mmol) was added portion-wise. The reaction mixture stirred for 6 hours, upon completion of conversion the reaction was quenched by the addition of acetone and reaction mixture stirred for 15 minutes. The solvent was removed under vacuum and the layers were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by silica eluting from 100 / 0 to 95 / 5 SCM / MeOH affording pure compound 32 (1082 mg, 78% yield). LC / MS: Rt = 1.24 min (gradient 1), (ESI) m / z [M+H]+= 189.0, [M+H]+calculated for C6H7BrNO = 187.7 / 189.7.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 5.4 Hz, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 4.76 (s, 2H). Synthesis of 4-bromo-2-(chloromethyl)pyridine (compound 33, Scheme 9 (Fig. 9), equation I) Thionyl chloride (1.10 mL, 14.04 mmol) was portion-wise added to a solution of compound 32 (1.10 g, 5.85 mmol) in DCM dry under argon. Reaction mixture stirred for 48h, and the mixture was concentrated under vacuum. The product was used as such without further purification. LC / MS: Rt = 1.88 min (gradient 1), (ESI) m / z [M+H]+= 205.7 / 207.7 / 209.9, [M+H]+calculated for C6H6BrClN = 207.5. Synthesis of (tert-butyl 4-((4-bromopyridin-2- yl)methyl)piperazine-1-carboxylate) (compound 34, Scheme 9 (Fig. 9), equation I) N-Boc piperazine (145.0 mg, 0.77 mmol), potassium carbonate (106.0 mg) and potassium iodide were sequentially added to a solution of compound 33 (145.0 mg of the crude, theoretical 0.70 mmol) under argon. Reaction mixture stirred for 5 hours at 50°C. Upon completion of the reaction, water was added, and the product was extracted with EtOAc (4 mL x 3). Collected organic layers were dried over Na2So4, filtered and concentrated under vacuum. Product 34 was purified by silica eluting by gradient from 100 / 0 to 55 / 45 cyclohexane / EtOAc yielding pure title product (154.5 mg, 58% yield after 2 steps). LC / MS: Rt = 2.29 min (gradient 1), (ESI) m / z [M+H]+= 356.0 / 358.0, [M+H]+calculated for C15H23BrN3O2 = 357.2.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 5.3 Hz, 1H), 7.63 (bs, 1H), 7.36 (d, J = 4.8 Hz, 1H), 3.64 (bs, 2H), 3.47 (bs, 4H), 2.46 (bs, 4H), 1.46 (s, 9H). 4-bromo-2-(pyrrolidin-1-ylmethyl)pyridine (compound 37a, Scheme 9 (Fig. 9), equation II) Compound 37a was prepared according to General Procedure 8 using: 4-bromopicolinaldehyde 36 (100.0 mg, 0.54 mmol), pyrrolidine (0.09 mL, 1.07 mmol), acetic acid (0.07 mL, 1.07 mmol), and NaBH(OAc)3(128.8 mg, 1.07 mmol) in 1,2- dichloroethane (2.6 mL). The product was purified by silica eluting by gradient from 100 / 0 to 95 / 5 DCM / MeOH affording pure title compound 37a (71.2 mg, 54% yield). LC / MS: Rt = 1.18 min (gradient 1), (ESI) m / z [M+H]+= 240.8 / 242.8, [M+H]+calculated for C10H14BrN2= 242.1. NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.3 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 5.4, 1.9 Hz, 1H), 3.76 (s, 2H), 2.61 – 2.58 (m, 4H), 1.90 – 1.75 (m, 4H). Synthesis of 4-bromo-2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridine (compound 37b, Scheme 9 (Fig. 9), equation II) Compound 37b was prepared according to General Procedure 8 using: 4-bromopicolinaldehyde 36 (186.0 mg, 1.00 mmol), 2,2- difluoropyrrolidine (286.0 mg, 2.00 mmol), acetic acid (0.12 mL, 2.00 mmol), and NaBH(OAc)3(423.9 mg, 2.00 mmol) in 1,2- dichloroethane (5.0 mL). The product was purified by silica eluting by gradient from 100 / 0 to 80 / 20 DCM / EtOAc affording pure title compound 37b (176.6 mg, 64% yield). LC / MS: Rt = 2.03 min (gradient 1), (ESI) m / z [M+H]+= 276.8 / 278.8, [M+H]+calculated for C10H12BrF2N2= 278.0.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 5.3 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 5.3, 2.0 Hz, 1H), 3.75 (bs, 2H), 2.95 (t, J = 13.4 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.35 – 2.17 (m, 2H). Synthesis of tert-butyl ((4-bromopyridin-2- yl)methyl)(cyclobutyl)carbamate (compound 37c, Scheme 9 (Fig. 9), equation II) Compound 37c was prepared in two steps. STEP-1. N-((4- bromopyridin-2-yl)methyl)cyclobutanamine was prepared according to General Procedure 8 using: 4- bromopicolinaldehyde 36 (186.0 mg, 1.00 mmol), cyclobutanamine (0.16 mL, 2.00 mmol), acetic acid (0.12 mL, 2.00 mmol), and NaBH(OAc)3(423.9 mg, 2.00 mmol) in 1,2- dichloroethane (5.0 mL). The product was as such without further purification, resulting pure from the NMR analysis of the crude (482.0 mg, quantitative yield). LC / MS: Rt = 1.16 min (gradient 1), (ESI) m / z [M+H]+= 241 / 243, [M+H]+calculated for C10H14BrN2= 241.0.1H NMR (400 MHz, CDCl3) 8.29 (d, J = 5.4 Hz, 1H), 7.46 (s, 1H), 7.30 (dd, J = 5.0, 1.6 Hz, 1H), 3.82 (s, 2H), 3.33 (qu, J = 7.4 Hz, 1H), 2.12 (m, 2H), 1.80 (m, 2H), 1.63 (m, 2H). STEP-2. TEA (0.08 mL, 0.06 mmol) and Boc2O (118.0 mg, 0.54 mmol) were sequentially added to a solution of N-((4-bromopyridin-2- yl)methyl)cyclobutanamine (167.0 mg, 0.54 mmol) in DCM dry (4.0 mL) under argon at 0°C, and reaction mixture stirred for 2 hours. Upon completion of the reaction, water was added and the product was extracted with DCM (2 x 3 mL). The product was purified by silica eluting by gradient from 100 / 0 to 95 / 5 DCM / MeOH affording pure title product (127.0 mg, 69% yield). LC / MS: Rt = 2.64 min (gradient 1), (ESI) m / z [M+H]+ = 341 / 343, [M+H]+calculated for C15H22BrN2O2= 341.1.1H NMR (400 MHz, CDCl3) δ 8.28 – 8.24 (m, 1H), 7.26-7.24 (m, 2H), 4.49 (s, 2H), 2.14 – 1.83 (m, 5H), 1.56 – 1.48 (m, 2H), 1.43 – 1.15 (m, 9H). Synthesis of tert-butyl ((4-bromopyridin-2-yl)methyl)(2,2- difluoroethyl)carbamate (compound 37d, Scheme 9 (Fig. 9), equation II). Compound 37d was prepared in two steps. STEP-1. N-((4- bromopyridin-2-yl)methyl)-2,2-difluoroethan-1-amine was prepared according to General Procedure 8 using: 4- bromopicolinaldehyde 36 (100.0 mg, 0.54 mmol), 2,2- difluoroethan-1-amine hydrochloride (117.44 mg, 1.08 mmol), acetic acid (0.07 mL, 1.08 mmol), and NaBH(OAc)3(228.9 mg, 1.08 mmol) in 1,2-dichloroethane (2.6 mL). The product was purified by silica eluting by gradient from 80 / 20 to 60 / 40 cyclohexane / EtOAc (90.0 mg, 67% yield). LC / MS: Rt = 1.58 min (gradient 1), (ESI) m / z [M+H]+= 251.0 / 253.0, [M+H]+calculated for C8H10BrF2N2= 251.0. STEP-2. TEA (0.06 mL, 0.04 mmol) and Boc2O (78.0 mg, 0.36 mmol) were sequentially added to a solution of N-((4-bromopyridin-2-yl)methyl)-2,2- difluoroethan-1-amine (90.0 mg, 0.36 mmol) in DCM dry (2.5 mL) under argon at 0°C, and reaction mixture stirred for 2 hours. Upon completion of the reaction, solvent was removed under vacuum and the product was purified by silica eluting by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc affording pure title product 37d (88.5 mg, 70% yield). LC / MS: Rt = 2.33 min (gradient 1), (ESI) m / z [M+H]+= 351.0 / 353.0, [M+H]+calculated for C13H18BrF2N2O2 = 351.0. Synthesis of tert-butyl ((4-bromopyridin-2- yl)methyl)(3,3,3-trifluoropropyl)carbamate (compound 37e, Scheme 9 (Fig. 9), equation II). Compound 37e was prepared in two steps. STEP-1. N-((4- bromopyridin-2-yl)methyl)-3,3,3-trifluoropropan-1-amine was prepared according General Procedure 8 using: 4- bromopicolinaldehyde 36 (100.0 mg, 0.54 mmol), 3,3,3- trifluoropropan-1-amine hydrochloride (160.9 mg, 1.08 mmol), acetic acid (0.07 mL, 1.08 mmol), and NaBH(OAc)3(228.9 mg, 1.08 mmol) in 1,2-dichloroethane (2.6 mL). The product was purified by silica eluting by gradient from 100 / 0 to 97 / 3 DCM / MeOH (74.9 mg, 49% yield). LC / MS: Rt = 1.57 min (gradient 1), (ESI) m / z [M+H]+= 283.2 / 285.2, [M+H]+calculated for C9H11BrF3N2= 283.0. STEP-2. TEA (0.04 mL, 0.03 mmol) and Boc2O (59.0 mg, 0.27 mmol) were sequentially added to a solution of N-((4-bromopyridin-2-yl)methyl)-3,3,3-trifluoropropan-1- amine (74.6 mg, 0.27 mmol) in DCM dry (2.0 mL) under argon at 0°C, and reaction mixture stirred for 2 hours. Upon completion of the reaction, solvent was removed under vacuum and the product was purified by silica eluting by gradient from 100 / 0 to 90 / 10 DCM / MeOH affording pure title product 37e (82.7 mg, 80% yield). LC / MS: Rt = 2.54 min (gradient 1), (ESI) m / z [M+H]+= 383.1 / 385.1, [M+H]+calculated for C14H19BrF3N2O2= 383.0.1H NMR showed the presence of two rotamers of BOC derivative.1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 5.3 Hz, 1H, rotamer a, rotamer b), 7.57 (dd, J = 5.4, 2.0 Hz, 1H, rotamer a, rotamer b), 7.49 (s, 1H, rotamer a, rotamer b), 4.48 (s, 1H, CH2 rotamer a) and 4.45 (s, 1H, CH2 rotamer b), 3.59 – 3.44 (m, 2H, rotamer a, rotamer b), 2.55 (m, 2H, rotamer a, rotamer b), 1.41 (s, 4.5 H, tBu Boc rotamer a), 1.24 (s, 4.5 H, rotamer b). Synthesis of 4-bromo-2-phenylpyridine (compound 41a, Scheme 9 (Fig. 9), equation III) Compound 41a was prepared according to General Procedure 9 using: 2,4-dibromopyridine 39 (100.0 mg, 0.42 mmol), phenyl boronic acid 40a (51.0 mg, 0.42 mmol), Pd(PPh3)4(48.0 mg, 0.042 mmol), potassium carbonate (116.0 mg, 0.84 mmol). Purification via column chromatography using 10% to 20% EtOAc in cyclohexane afford the pure title compound 41a as a white solid (52 mg, 53%). LC / MS: Rt: 2.43 min (gradient 1) (ESI) m / z: 233.8 [M+H]+. [M+H]+Calculated for C11H8BrN = 233.0.1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.3 Hz, 1H), 8.03 – 7.96 (m, 2H), 7.93 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 10.7, 7.2 Hz, 3H), 7.44 – 7.41 (m, 1H). Synthesis of 4-bromo-2-(thiophen-3-yl)pyridine (compound 41b, Scheme 9 (Fig. 9)) Compound 41b was prepared according to General Procedure 9 using: 2,4-dibromopyridine 39 (500.0 mg, 2.11 mmol), thiophen-3-ylboronic acid 40b (270.0 mg, 2.11 mmol), Pd(PPh3)4 (244.0 mg, 0.21 mmol), potassium carbonate (582.0 mg, 4.22 mmol). Purification via column chromatography using 10% to 20% EtOAc in Cyclohexane. Fractions were concentrated to dryness to yield the pure title compound 41b as a white solid (320 mg, 63%). LC / MS: Rt: 2.19 min (gradient 1) (ESI) m / z: 239.8 [M+H]+. [M+H]+Calculated for C9H6BrNS = 238.9.1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 5.3 Hz, 1H), 7.84 (dd, J = 3.0, 1.3 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 5.1, 1.3 Hz, 1H), 7.32 (dd, J = 5.1, 3.0 Hz, 1H), 7.25 (dd, J = 5.3, 1.8 Hz, 1H). tert-butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)methyl)piperazine-1-carboxylate (compound 35, Scheme 9 (Fig. 9), equation I) Compound 35 was prepared according to General Procedure 7 using: compound 34 (100.0 mg, 0.28 mmol), Bis(pinacolato)diboron (92.3 mg, 0.3648 mmol), potassium acetate (138.0 mg, 1.40 mmol), Pd(dppf)Cl2·DCM (34.4 mg, 0.04 mmol) in 2.8 mL in degassed 1,4-dioxane dry (2.8 M). Resulted crude was used as such in the next step. LC / MS: Rt = 1.46 min (gradient 1), (ESI) m / z [M+H]+= 321.9, [M+H]+calculated for C15H25BN3O4 = 322.2; While the LC / MS analysis is consistent with related boronic acid, the NMR analysis of the crude showed the presence of a major product consistent with the desired boronic ester 35.1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.8, 1.0 Hz, 1H), 7.63 (s, 1H), 7.44 (dd, J = 4.8, 1.2 Hz, 1H), 3.60 (s, 2H), 3.29 (s, 4H), 2.39 – 2.32 (m, 4H), 1.38 (s, 9H), 1.31 (s, 12H). 2-(pyrrolidin-1-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (compound 38a, Scheme 9 (Fig. 9), equation II). Compound 38a was prepared according to General Procedure 7 using: compound 37a (68.0 mg, 0.28 mmol), Bis(pinacolato)diboron (92.3 mg, 0.3648 mmol), potassium acetate (138.0 mg, 1.40 mmol), Pd(dppf)Cl2·DCM (34.4 mg, 0.04 mmol) in 2.8 mL in degassed 1,4-dioxane dry. Resulted crude was used as such in the next step. LC / MS: Rt = 0.63 min (gradient 1), (ESI) m / z [M−H]−= 205.1, [M+H]+calculated for C16H24BN2O2 = 205.1; While the LC / MS analysis is consistent with related boronic acid, the NMR analysis of the crude showed the presence of a major product consistent with the desired boronic ester 38a.1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.7 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 3.70 (s, 2H), 2.48 – 2.43 (m, 4H), 1.70 (t, J = 3.6 Hz, 4H), 1.31 (s, 12H). 2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound 38b, Scheme 9 (Fig. 9), equation II). Compound 38b was prepared according to General Procedure 7 using: compound 37b (77.6 mg, 0.28 mmol), Bis(pinacolato)diboron (92.3 mg, 0.3648 mmol), potassium acetate (138.0 mg, 1.40 mmol), Pd(dppf)Cl2·DCM (34.4 mg, 0.04 mmol) in 2.8 mL in degassed 1,4-dioxane dry. Resulted crude was used as such in the next step. LC / MS: Rt = 1.11 min (gradient 1), (ESI) m / z [M+H]+= 242.9, [M+H]+calculated for C10H14BF2N2O2= 243.1; While the LC / MS analysis is consistent with related boronic acid, the NMR analysis of the crude showed the presence of a major product consistent with the desired boronic ester 38b.1H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.9, 1.0 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 4.7, 1.1 Hz, 1H), 3.75 (s, 2H), 2.92 (t, J = 13.4 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.25 (tt, J = 14.9, 7.0 Hz, 2H), 1.31 (s, 12H). tert-butyl cyclobutyl((4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate (compound 38c, Scheme 9 (Fig. 9), equation II) Compound 38c was prepared according to General Procedure 7 using: compound 37c (100.0 mg, 0.28 mmol), Bis(pinacolato)diboron (92.3 mg, 0.3648 mmol), potassium acetate (138.0 mg, 1.40 mmol), Pd(dppf)Cl2·DCM (34.4 mg, 0.04 mmol) in 2.8 mL in degassed 1,4-dioxane dry. Resulted crude was used as such in the next step. LC / MS: Rt = 1.46 min (gradient 1), (ESI) m / z [M+H]+= 307 (mass is consistent with corresponding boronic acid), [M+H]+calculated for C21H34BN2O4 = 389.2. tert-butyl (2,2-difluoroethyl)((4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate (compound 38d, Scheme 9 (Fig. 9), equation II). Compound 38d was prepared according to General Procedure 7 using: compound 37d (88.0 mg, 0.25 mmol), Bis(pinacolato)diboron (94.5 mg, 0.32 mmol), potassium acetate (103.0 mg, 1.05 mmol), Pd(dppf)Cl2·DCM (24.5 mg, 0.03 mmol) in 2.1 mL in degassed 1,4-dioxane dry. Upon completion of reaction the mixture was filtered on a pad of celite, and concentrated under vacuum. Resulted crude was used as such in the next step. LC / MS: Rt = 1.67 min (gradient 1), (ESI) m / z [M+H]+= 317.1 (mass is consistent with corresponding boronic acid), [M+H]+calculated for C13H20BF2N2O4 = 317.1. tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)methyl)(3,3,3-trifluoropropyl)carbamate (compound 38e, Scheme 9 (Fig. 9), equation II). Compound 38e was prepared according to General Procedure 7 using: compound 37e (82.0 mg, 0.21 mmol), Bis(pinacolato)diboron (69.1 mg, 0.27 mmol), potassium acetate (103.0 mg, 1.05 mmol), Pd(dppf)Cl2·DCM (24.5 mg, 0.03 mmol) in 2.1 mL in degassed 1,4-dioxane dry. Upon completion of reaction the mixture was filtered on a pad of celite, and concentrated under vacuum. Resulted crude was used as such in the next step. LC / MS: Rt = 1.86 min (gradient 1), (ESI) m / z [M+H]+= 349.1 (mass is consistent with corresponding boronic acid), [M+H]+calculated for C14H21BF3N2O4 = 349.2. Synthesis of 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (compound 42a, Scheme 9 (Fig. 9), equation III) Compound 42a was prepared according to General Procedure 7 using: compound 41a (44.0 mg, 0.19 mmol), bis(pinacolato)diboron (56.0 mg, 0.22 mmol), Pd(dppf)Cl2 x DCM (16.0 mg, 0.02 mmol), potassium acetate (92.0 mg, 0.94 mmol), 1,4-dioxane (0.05 M). Crude mixture was used without purification. LC / MS: Rt: 1.49 min (gradient 1) (ESI) m / z: 199.8 [M+H]+. [M+H]+Calculated for C11H11BNO2 = 200.1. While the LC / MS analysis is consistent with related boronic acid, the NMR analysis of the crude showed the presence of a major product consistent with the desired boronic ester 42a.1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.7, 0.9 Hz, 1H), 8.03 (d, J = 1.0 Hz, 1H), 8.00 – 7.94 (m, 2H), 7.50 (dd, J = 4.8, 1.0 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.36 – 7.29 (m, 1H), 1.31 (s, 12H). Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2-(thiophen-3-yl)pyridine (compound 42b, Scheme 9 (Fig. 9), equation III) Compound 42b was prepared according to General Procedure 7 using: compound 41b. (100.0 mg, 0.42 mmol), bis(pinacolato)diboron (127.5 mg, 0.5 mmol), Pd(dppf)Cl2x DCM (34.0 mg, 0.042 mmol), potassium acetate (206.0 mg, 2.1 mmol), 1,4-dioxane (0.05 M). Crude mixture was used without purification. LC / MS: Rt: 1.40 min (gradient 1) (ESI) m / z: 203.9 [M-H]-. [M-H]- Calculated for C9H7BNO2S = 205.0. While the LC / MS analysis is consistent with related boronic acid, the NMR analysis of the crude showed the presence of a major product consistent with the desired boronic ester 42b.1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.7 Hz, 1H), 7.97 (s, 1H), 7.95 – 7.92 (m, 1H), 7.71 (d, J = 5.1 Hz, 1H), 7.50 (d, J = 4.6 Hz, 1H), 7.38 (dd, J = 5.0, 3.0 Hz, 1H), 1.37 (s, 12H). Synthesis of (5-chloro-N-methyl-N-(3,4,5-trimethoxyphenyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide) (compound 43, Scheme 10 (Fig. 10)) NaH (60% dispersion in mineral oil) (12.0 mg, 0.30 mmol) was added to a solution of compound 4b (75.0 mg, 0.2 mmol) in DMF dry (2 mL) under argon at 0°C followed by the addition of SemCl (0.05 mL, 0.24 mmol). Upon completion of the reaction, water was added, organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by silica eluting by gradient from100 / 0 to 50 / 50 cyclohexane / EtOAc affording pure title compound 43 (112.3 mg, 74% yield). LC / MS: Rt = 2.75 min (gradient 1), (ESI) m / z [M+H]+= 506.0 / 507.9, [M+H]+calculated for C24H33ClN3O5Si = 507.1.1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.63 (s, 2H), 6.35 (s, 1H), 5.75 (s, 2H), 3.64 (s, 6H), 3.59 (s, 3H), 3.53 (dd, J = 9.0, 7.5 Hz, 2H), 3.41 (s, 3H), 0.91 – 0.81 (m, 2H), - 0.06 (s, 9H). tert-butyl 4-((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)piperazine-1-carboxylate (compound 44a, Scheme 10 (Fig. 10)) Compound 44a was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 35 (160 mg, putative 0.39 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol) in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL). The product was purified by silica eluting by gradient from 9 / 1 DCM / Acetone to 6 / 3.8 / 0.2 DCM / Acetone / MeOH affording pure title compound 44a (65.7 mg, 44% yield). LC / MS: Rt = 1.92 min (gradient 6), (ESI) m / z [M+H]+= 747.3, [M+H]+calculated for C39H55N6O7Si = 747.4.1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.06 (bs, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 5.3, 1.7 Hz, 1H), 6.66 (s, 2H), 6.48 (s, 1H), 5.81 (s, 2H), 3.66 – 3.65 (m, 8H), 3.60 – 3.56 (m, 5H), 3.43 (s, 3H), 2.41 – 2.39 (m, 4H), 1.38 (s, 9H), 0.94 – 0.83 (m, 2H), -0.04 (s, 9H). Synthesis of compound N-methyl-5-(2-(pyrrolidin-1- ylmethyl)pyridin-4-yl)-N-(3,4,5-trimethoxyphenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b] pyridine - 2 – carboxamide (compound 44b, Scheme 10 (Fig. 10)). Compound 44b was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 38a (116.0 mg, putative 0.40 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol), KI (50.0 mg, 0.3 mmol) in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL) under microwave irradiation. The product was purified by silica eluting by gradient from 9 / 1 DCM / Acetone to 6 / 3.5 / 0.5 DCM / Acetone / MeOH affording title compound 44b (83.3 mg, 66% yield). LC / MS: Rt = 2.41 min (gradient 1), (ESI) m / z [M+H]+= 632.4, [M+H]+calculated for C34H46N5O5Si = 632.3.1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 5.3 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 5.3, 1.8 Hz, 1H), 6.66 (s, 2H), 6.48 (s, 1H), 5.80 (s, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.65 (s, 6H), 3.61 – 3.54 (m, 5H), 3.43 (s, 3H), 2.57 – 2.54 (m, 4H), 2.57 – 2.54 (m, 4H), 0.92 – 0.86 (m, 2H), -0.05 (s, 9H). Synthesis of 5-(2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridin-4-yl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-b]pyridine - 2 –carboxamide (compound 44c, Scheme 10 (Fig. 10)).

[0002] Compound 44c was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 38b (129.7 mg, putative 0.40 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL) under microwave irradiation. The product was purified by silica eluting by gradient from 8 / 2 to 6 / 4 DCM / Acetone affording pure title compound 44c (95.5 mg, 72% yield). LC / MS: Rt = 1.81 min (gradient 6), (ESI) m / z [M+H]+= 668.1, [M+H]+calculated for C34H44F2N54Si = 668.3. NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.3 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 5.3, 1.8 Hz, 1H), 6.66 (s, 2H), 6.48 (s, 1H), 5.80 (s, 2H), 3.80 (s, 2H), 3.65 (s, 6H), 3.60 – 3.53 (m, 5H), 3.43 (s, 3H), 2.96 (t, J = 13.4 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.25 (tt, J = 14.9, 7.0 Hz, 2H), 0.93 – 0.85 (m, 2H), -0.05 (s, 9H). Synthesis of tert-butyl cyclobutyl((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)carbamate (compound 44d, Scheme 10 (Fig. 10)). Compound 44d was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 38c (155.8 mg, putative 0.40 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 60 / 40 Cyclohexane / EtOAc affording title compound 44d not pure, which was used as such in the next step. LC / MS: Rt = 2.38 min (gradient 6), (ESI) m / z [M+H]+= 732, [M+H]+calculated for C39H54N5O7Si = 732.4. Synthesis of tert-butyl (2,2-difluoroethyl)((4-(2- (methyl(3,4,5-trimethoxyphenyl)carbamoyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)carbamate (compound 44e, Scheme 10 (Fig. 10)). Compound 44e was synthesized according to General Procedure 10 using: intermediate 43 (65.0 mg, 0.13 mmol), crude of compound 38d (80.0 mg, putative 0.20 mmol), Pd(PPh3)4(17.0 mg, 0.015 mmol), XPhos (7.1 mg, 0.015 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(3.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 90 / 10 DCM / MeOH affording title compound 44e not pure, which was used as such in the next step. LC / MS: Rt = 2.05 min (gradient 6), (ESI) m / z [M+H]+= 742.5, [M+H]+calculated for C37H50F2N5O7Si = 742.3. Synthesis of tert-butyl ((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)(3,3,3-trifluoropropyl)carbamate (compound 44f, Scheme 10 (Fig. 10)). Compound 44f was synthesized according to General Procedure 10 using: intermediate 43 (76.0 mg, 0.15 mmol), crude of compound 38e (90.0 mg, putative 0.21 mmol), Pd(PPh3)4 (17.0 mg, 0.015 mmol), XPhos (7.1 mg, 0.015 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(3.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 60 / 40 Cyclohexane / EtOAc affording title compound 44f not pure, which was used as such in the next step. LC / MS: Rt = 2.25 min (gradient 6), (ESI) m / z [M+H]+= 774.5, [M+H]+calculated for C38H51F3N5O7Si = 773.3. Synthesis of N-methyl-5-(2-phenylpyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (compound 44g, Scheme 10 (Fig. 10)) Compound 44g was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 42a (115.0 mg, putative 0.40 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 70 / 30 cyclohexane / EtOAc affording pure title compound 44g (68.7 mg, 56% yield). LC / MS: Rt = 2.16 min (gradient 6), no ionization.1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 5.1 Hz, 1H), 8.33 (s, 1H), 8.09 (dd, J = 7.1, 1.8 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 5.1, 1.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.3, 6.6 Hz, 2H), 7.44 – 7.38 (m, 1H), 6.48 (s, 1H), 6.44 (s, 2H), 5.84 (s, 2H), 3.79 (s, 3H), 3.72 (s, 6H), 3.68 – 3.63 (m, 2H), 3.52 (s, 3H), 0.99 – 0.90 (m, 2H). Synthesis of N-methyl-5-(2-(thiophen-3-yl)pyridin-4-yl)-N- (3,4,5-trimethoxyphenyl)- 1 -( (2 - (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide (compound 44h, Scheme 10 (Fig. 10)) Compound 44h was synthesized according to General Procedure 10 using: intermediate 43 (100.0 mg, 0.20 mmol), crude of compound 42b (114.0 mg, putative 0.40 mmol), Pd(PPh3)4(22.0 mg, 0.02 mmol), XPhos (9.0 mg, 0.02 mmol), potassium carbonate (82.0 mg, 0.60 mmol), in a degassed toluene / EtOH / H2O 4.5:4.5:0.1 mixture(4.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 70 / 30 cyclohexane / EtOAc affording pure title compound 44h (39.1 mg, 31% yield). LC / MS: Rt = 2.05 min (6), (ESI) m / z [M+H]+= 631.0, [M+H]+calculated for C33H39N4O5SSi = 631.2. NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.2 Hz, 1H), 8.23 (s, 1H), 7.99 (dd, J = 3.1, 1.2 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.76 (dd, J = 5.1, 1.3 Hz, 1H), 7.70 (m, 2H), 7.39 (dd, J = 5.1, 3.0 Hz, 1H), 7.25 (s, 2H), 6.47 (s, 1H), 6.44 (s, 2H), 5.84 (s, 2H), 3.79 (s, 3H), 3.72 (s, 6H), 3.68 – 3.62 (m, 2H), 3.52 (s, 3H), 0.97 – 0.92 (m, 2H). Synthesis of tert-butyl 4-((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)piperazine-1-carboxylate (compound 45a, Scheme 10 (Fig. 10)). Compound 45a was synthesized according to General Procedure 6 using: intermediate 44a (60.0 mg, 0.08 mmol), TBAF – 1M solution in THF (0.8 mL, 0.8 mmol) in THF dry (0.8 mL). The product was purified by silica eluting by gradient from 100 / 0 to 95 / 5 DCM / MeOH affording pure title compound (39.5 mg, 80% yield). LC / MS: Rt = 2.10 min (gradient 1), (ESI) m / z [M+H]+ = 617.0, [M+H]+calculated for C33H41N6O6= 617.3.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.53 (s, 1H), 8.04 (s, 1H), 7.92 – 7.86 (m, 3H), 6.82 (s, 2H), 5.60 (s, 1H), 3.74 (s, 9H), 3.66 (s, 2H), 3.42 (s, 3H), 3.30 (s, 12H), 3.19 – 3.12 (m, 4H), 2.41 (bs, 4H), 1.39 (s, 9H). Synthesis of N-methyl-5-(2-(pyrrolidin-1-ylmethyl)pyridin- 4-yl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine- 2-carboxamide (compound 45b, Scheme 10 (Fig. 10)). Compound 45b was synthesized according to General Procedure 6 using: intermediate 44b (63.2 mg, 0.10 mmol), TBAF – 1M solution in THF (1.0 mL, 1.0 mmol) in THF dry (1.0 mL). The product was purified by silica eluting by gradient from 100 / 0 to 85 / 15 DCM / MeOH affording pure title compound (73.9 mg, 96% yield). LC / MS: Rt = 1.99 min (gradient 1), (ESI) m / z [M+H]+= 502.3, [M+H]+calculated for C28H32N5O4= 502.2. NMR (400 MHz, DMSO-d6) δ 12.02 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.96 (dd, J = 4.7, 1.4 Hz, 1H), 7.94 – 7.90 (m, 2H), 5.59 (bs, 1H), 4.17 (s, 2H), 3.74 (s, 9H), 3.42 (s, 5H), 2.91 (bs, 4H), 1.83 (bs, 4H). Synthesis of 5-(2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridin-4-yl)-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 45c, Scheme 10 (Fig. 10))

[0003] Compound 45c was synthesized according to General Procedure 6 using: intermediate 44c (95.0 mg, 0.14 mmol), TBAF – 1M solution in THF (1.4 mL, 1.4 mmol) in THF dry (1.4 mL). The product was purified by silica eluting by gradient from 100 / 0 to 97 / 3 DCM / MeOH affording pure title compound (73.9 mg, 96% yield). LC / MS: Rt = 1.99 min (gradient 1), (ESI) m / z [M+H]+= 537.8, [M+H]+calculated for C28H30F2N5O4= 538.2.1H NMR (400 MHz, DMSO-d6) δ 11.99 (bs, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.92 – 7.88 (m, 2H), 7.88 (dd, J = 5.2, 1.8 Hz, 1H), 6.82 (s, 2H), 5.61 (s, 1H), 3.80 (s, 2H), 3.74 (d, J = 1.3 Hz, 9H), 3.42 (s, 3H), 2.96 (t, J = 13.4 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.24 (tt, J = 14.9, 6.9 Hz, 2H). Synthesis of tert-butyl cyclobutyl((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)carbamate (compound 45d, Scheme 10 (Fig. 10)). Compound 45d was synthesized according to General Procedure 6 using: intermediate 44d (102.3 mg, 0.14 mmol), TBAF – 1M solution in THF (1.4 mL, 1.4 mmol) in THF dry (1.4 mL). The product was purified by silica eluting by gradient from 100 / 0 to 95 / 5 DCM / MeOH affording pure title compound (49.1 mg, 41% yield after two steps). LC / MS: Rt = 2.38 min (gradient 1), (ESI) m / z [M+H]+= 602, [M+H]+calculated for C33H40N5O6 = 602.3.1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 5.3 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.50 (s, 2H), 5.76 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.76 (s, 6H), 3.47 (s, 3H), 2.00 (d, J = 9.4 Hz, 3H), 1.49 (d, J = 7.1 Hz, 2H), 1.41 – 1.18 (m, 9H). tert-butyl (2,2-difluoroethyl)((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)carbamate (compound 45e, Scheme 10 (Fig. 10)) Compound 45e was synthesized according to General Procedure 6 using: intermediate 44e (93.0 mg, 0.12 mmol), TBAF – 1M solution in THF (1.2 mL, 1.2 mmol) in THF dry (1.2 mL). The product was purified by silica eluting by gradient from 100 / 0 to 20 / 80 DCM / acetone affording pure title compound 45e (20.0 mg, 25% yield after two steps). LC / MS: Rt = 2.19 min (gradient 1), (ESI) m / z [M−H]−= 610.5, [M−H]−calculated for C31H34F2N5O6 = 610.3.1H showed the presence of two rotamers of Boc derivative.1H NMR δ (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.30 – 7.23 (m, 3H), 7.21 – 7.13 (m, 2H), 6.58 (s, 2H), 6.10 (t, J = 56.6 Hz, 1H), 5.88 (bs, 1H), 4.72 (s, 1H, CH2 rotamer-a), 4.67 (s, 1H, CH2 rotamer- b), 3.98 (s, 3H), 3.84 (s, 6H), 3.78 – 3.62 (m, 2H), 1.51 (s, 4.5H, tBu Boc rotamer-a), 1.40 (s, 4.5 H, tBu Boc rotamer-b). tert-butyl ((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5- yl)pyridin-2-yl)methyl)(3,3,3-trifluoropropyl)carbamate (compound 45f, Scheme 10 (Fig. 10)) Compound 45f was synthesized according to General Procedure 6 using: intermediate 44f (80.0 mg, 0.10 mmol), TBAF – 1M solution in THF (1.0 mL, 1.0 mmol) in THF dry (1.0 mL). The product was purified by silica eluting by gradient from 80 / 20 DCM / cyclohexane to 80 / 5 / 15 DCM / cyclohexane / acetone affording pure title compound 45f (25.7 mg, 40% yield after two steps). LC / MS: Rt = 1.20 min (gradient 6), (ESI) m / z [M+H]+= 644.3, [M+H]+calculated for C32H37F3N5O6 = 644.3.1H showed the presence of two rotamers of Boc derivative.1H NMR δ 11.97 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.92 – 7.87 (m, 4H), 6.82 (s, 2H), 5.59 (s, 1H), 4.54 (s, 1H, CH2rotamer a), 4.49 (s, 1H, CH2 rotamer b), 3.74 (s, 3H), 3.73 (s, 6H), 3.52 – 3.48 (m, 2H), 2.55 (d, J = 7.4 Hz, 2H), 1.42 (s, 4.5H, tBu of Boc rotamer a), 1.32 (s, 4.5H, tBu of Boc rotamer b). Synthesis of N-methyl-5-(2-phenylpyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 45g, Scheme 10 (Fig. 10))

[0004] Compound 45g was synthesized according to General Procedure 6 using: intermediate 44g (65.0 mg, 0.10 mmol), TBAF – 1M solution in THF (1.0 mL, 1.0 mmol) in THF dry (1.0 mL). The product was purified by trituration MeOH (1 mL) affording pure title compound (41.0 mg, 83%). LC / MS: Rt = 0.98 min (gradient 6), no ionization.1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.24 – 8.14 (m, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 5.1, 1.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 6.66 (s, 2H), 5.94 (s, 1H), 4.06 (s, 3H), 3.92 (s, 6H), 3.60 (s, 3H). Synthesis of N-methyl-5-(2-(thiophen-3-yl)pyridin-4-yl)-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide (compound 45h, Scheme 10 (Fig. 10)) Compound 45h was synthesized according to General Procedure 6 using: intermediate 44h (35.0 mg, 0.06 mmol), TBAF – 1M solution in THF (0.6 mL, 0.6 mmol) in THF dry (0.6 mL). The product was purified by trituration with a 9:1 DCM / Et2O mixture affording pure title compound as beige powder (18.5 mg, 62%).1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.67 (d, J = 5.3 Hz, 1H), 8.46 (s, 1H), 8.37 (dd, J = 3.0, 1.3 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.01 – 7.95 (m, 2H), 7.92 (dd, J = 5.0, 1.3 Hz, 1H), 7.71 (dd, J = 5.1, 3.0 Hz, 1H), 6.89 (s, 2H), 5.73 (s, 1H), 3.81 (s, 9H), 3.48 (s, 3H), 3.37 (s, 3H). Synthesis of N-methyl-5-(2-(piperazin-1-ylmethyl)pyridin-4- yl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide dihydrobromide (compound 46a (ARN26936), Scheme 10 (Fig. 10)) Compound 46a was prepared according to General procedure 3 using: compound 45a (40.5 mg, 0.07 mmol), BBr31M DCM solution (0.7 mL, 0.7 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46a as a yellow solid (7.0 mg, 18% yield).LC / MS: Rt: 1.09 min (gradient 1) (ESI) m / z: 475.1 [M+H]+. [M+H]+Calculated for C28H33N6O4= 475.2. NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.88 (bs, 2H), 8.76 (d, J = 5.6 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.26 (dd, J = 5.6, 1.7 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.00 – 7.92 (m, 1H), 6.31 (s, 2H), 5.65 (s, 1H), 4.50 (s, 2H), 3.32 – 3.27 (m, 8H). Synthesis of N-methyl-5-(2-(pyrrolidin-1-ylmethyl)pyridin- 4-yl)-N-(3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine- 2-carboxamide di-hydrobromide (compound 46b (ARN26975), Scheme 10 (Fig. 10)) Compound 46b was prepared according to General procedure 3 using: compound 45b (36.0 mg, 0.07 mmol), BBr31M DCM solution (0.7 mL, 0.7 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46b as a yellow solid (7.0 mg, 18% yield). LC / MS: Rt: 2.11 min (gradient 4) (ESI) m / z: 460.2 [M+H]+. [M+H]+Calculated for C25H26N5O4= 460.2.1H NMR (400 MHz, DMSO-d6) δ 12.11 (d, J = 2.2 Hz, 1H), 10.14 (s, 1H), 8.72 (d, J = 5.3 Hz, 1H), 8.31 (bs, 1H), 8.09 (dd, J = 5.3, 1.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 6.31 (s, 2H), 5.65 (s, 1H), 4.63 (d, J = 3.6 Hz, 3H), 3.36 (bs, 4H), 1.97 (bs, 5H). Synthesis of 5-(2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridin-4-yl)-N-methyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide di-hydrobromide (compound 46c (ARN26976), Scheme 10 (Fig. 10)) Compound 46c was prepared according to General procedure 3 using: compound 45c (36.7 mg, 0.07 mmol), BBr31M DCM solution (0.7 mL, 0.7 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46c as a yellow solid (3.8 mg, 11% yield). LC / MS: Rt: 2.11 min (gradient 4) (ESI) m / z: 496.1 [M+H]+. [M+H]+Calculated for C25H24F2N5O = 496.2.1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.72 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.18 (dd, J = 5.4, 1.8 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 6.31 (s, 2H), 5.64 (s, 1H), 4.66 (s, 2H), 3.83 (t, J = 12.3 Hz, 2H), 3.58 (t, J = 12.3 Hz, 2H), 3.32 (s, 3H), 2.60 (tt, J = 14.3, 7.3 Hz, 2H). Synthesis of 5-(2-((cyclobutylamino)methyl)pyridin-4-yl)-N- methyl-N-(3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide di-hydrobromide (compound 46d (ARN27043), Scheme 10 (Fig. 10)) Compound 46d was prepared according to General procedure 3 using: compound 45d (36.1 mg, 0.06 mmol), BBr31M DCM solution (0.6 mL, 0.6 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46d as a yellow solid (18.6 mg, 50% yield). LC / MS: Rt: 1.21 min (gradient 1) (ESI) m / z: 460 [M+H]+. [M+H]+Calculated for C25H26N5O4= 460.2. NMR (400 MHz, DMSO-d6) δ 12.29 – 12.00 (m, 1H), 9.33 (s, 1H), 8.74 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H), 8.12 (dd, J = 5.4, 1.7 Hz, 1H), 8.02 (s, 2H), 6.32 (s, 2H), 5.66 (s, 1H), 4.32 (s, 2H), 3.78 (t, J = 8.1 Hz, 1H), 3.33 (s, 3H), 2.20 (m, 4H), 1.86 – 1.67 (m, 2H). 5-(2-(((2,2-difluoroethyl)amino)methyl)pyridin-4-yl)-N- methyl-N-(3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide (compound 46e (ARN27103), Scheme 10 (Fig. 10)) Compound 46e was prepared according to General procedure 3 using: compound 45e (18.0 mg, 0.03 mmol), BBr31M DCM solution (0.3 mL, 0.3 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46e as a yellow solid (18.6 mg, 50% yield). LC / MS: Rt: 1.28 min (gradient 1) (ESI) m / z: 468.5 [M−H]−. [M−H]−Calculated for C23H20F2N5O4 = 468.2. (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.71 (d, J = 5.3 Hz, 1H), 8.29 (s, 1H), 8.13 – 8.06 (m, 1H), 7.98 (s, 2H), 6.44 (tt, J = 53.9, 2,9 Hz, 1H), 6.31 (s, 2H), 5.64 (s, 1H), 4.50 (s, 2H). one CH2overlaps with water signal. N-methyl-5-(2-(((3,3,3- trifluoropropyl)amino)methyl)pyridin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide (compound 46f (ARN27120), Scheme 10 (Fig. 10)). Compound 46f was prepared according to General procedure 3 using: compound 45f (22.0 mg, 0.03 mmol), BBr31M DCM solution (0.3 mL, 0.3 mmol). Crude triturated in Et2O:MeOH 9:1 (3 mL) to yield pure title compound 46f as a yellow solid (18.6 mg, 50% yield). LC / MS: Rt: 1.32 min (gradient 1) (ESI) m / z: 502.4 [M+H]+. [M+H]+Calculated for C24H23F3N5O4 = 502.2.1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.26 (s, 2H), 8.54 (bs, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.05 (s, 1H), 7.89 (s, 3H), 6.30 (s, 2H), 5.64 (s, 1H), 3.87 (s, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.47 – 2.39 (m, 2H). Synthesis of N-methyl-5-(2-phenylpyridin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 46g (ARN26907), Scheme 10 (Fig. 10)). Compound 46g was prepared according to General procedure 3 using: compound 45g (20.0 mg, 0.04 mmol), BBr31M DCM solution (0.4 mL, 0.4 mmol, 10 eq). Final trituration in water (2 mL) yielded pure pure title 46g as an ochre solid (3.0 mg, 17%). LC / MS: Rt: 1.73 min (gradient 1) (ESI) m / z: 451.0 [M-H]-. [M-H]- Calculated for C26H20N4O4 = 451.1.1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.78 (d, J = 5.6 Hz, 1H), 8.65 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.19 – 8.15 (m, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.59 (q, J = 7.5 Hz, 4H), 6.32 (s, 2H), 5.74 (s, 1H), 3.34 (s, 3H). Synthesis of 4-(2-(methyl(3,4,5- trihydroxyphenyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)- 2-(thiophen-3-yl)pyridin-1-ium (compound 46h (ARN26929), Scheme 10 (Fig. 10)). Compound 46h was prepared according to General procedure 3 using: compound 45h (30.0 mg, 0.06 mmol), BBr31M DCM solution (0.54 mL, 0.54 mmol, 9eq). Final trituration in MeOH / Et2O (2 mL) yielded pure title compound 46h as an ochre solid (18 mg, 56%). LC / MS: Rt: 1.66 min (gradient 1) (ESI) m / z: 459.2 [M+H]+. [M+H]+Calculated for C24H18N4O4S = 458.1. NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.81 – 8.70 (m, 2H), 8.68 – 8.59 (m, 1H), 8.39 (d, J = 6.5 Hz, 1H), 8.33 – 8.25 (m, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.00 – 7.93 (m, 1H), 7.85 (dt, J = 5.6, 2.7 Hz, 1H), 6.32 (s, 2H), 5.76 (s, 1H), 3.33 (d, J = 2.0 Hz, 3H). Synthesis of 5-chloro-N,1-dimethyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 47, Scheme 11 (Fig. 11), equation I). NaH (60% dispersion in mineral oil) (26.0, 0.58 mmol) and methyl iodide (0.03 mL, 0.4 mL) was added to a solution of compound 4b (100 mg, 0.29 mmol) in DMF dry (2 mL) under argon at 0°C. Reaction mixture stirred for letting it to raise to room temperature. After completion of the reaction, LiCL sat acqueous solution (3 mL) was added and the product was extracted with DCM (3 x 3 mL). Collected organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica from 100 / 0 to 80 / 20 Cyclohexane afforded title pure compound 43 (57.0 mg, 50%). LC / MS: Rt: 1.89 min (gradient 1) (ESI) m / z: 390 [M+H]+. [M+H]+Calculated for C19H21ClN3O4 = 390.1.1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.37 (s, 2H), 6.35 (s, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.76 (s, 6H), 3.50 (s, 3H). Synthesis of 5-chloro-N,1-dimethyl-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (compound 48 (ARN27079), Scheme 11 (Fig. 11), equation I). Compound 48 was prepared according to General procedure 3 using: compound 47 (17.0 mg, 0.04 mmol), BBr31M DCM solution (0.44 mL, 0.44 mmol, 9eq) in DCM (1.7 mL). Final trituration in water (2 mL) yielded pure title 48 as an ochre solid (9.0 mg, 60%). LC / MS: Rt: 1.32 min (gradient 1) (ESI) m / z: 348.0 [M+H]+. [M+H]+Calculated for C16H15ClN3O4 = 347.1.1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.18 (s, 2H), 6.15 (s, 1H), 3.87 (s, 3H), 3.31 (s, 3H). Synthesis of N-methyl-5-(pyridin-4-yl)-1-(4,4,4- trifluorobutyl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide (compound 49, Scheme 11 (Fig. 11), equation II). NaH (60% dispersion in mineral oil) (6.4 mg, 0.24 mmol) and 3,3,3, trifluorobutyl iodide (48.0 mg, 0.2 mmol) was added to a solution of compound 7bd (50 mg, 0.12 mmol) in a DMF dry (1.0 mL) under argon at 0°C. Then reaction mixture stirred at 100°C under microwave irradiation for 5 minutes. After completion of the reaction, LiCL sat aqueous solution (3 mL) was added and the product was extracted with DCM (3 x 3 mL). Collected organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica from 100 / 0 to 60 / 40 Cyclohexane afforded title pure compound 49 (36.0 mg, 57% yield). LC / MS: Rt: 2.13 min (gradient 1) (ESI) m / z: 529 [M+H]+. [M+H]+Calculated for C27H28F3N4O4 = 529.2.1H NMR (400 MHz, CDCl3) 8.65 – 8.55 (m, 2H), 7.85 – 7.75 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.41 (s, 1H), 6.32 (s, 2H), 4.61 – 4.38 (m, 2H), 3.74 (s, 3H), 3.69 (s, 6H), 3.44 (s, 3H), 2.18 – 2.09 (m, 4H). Synthesis of 4-(2-(methyl(3,4,5- trihydroxyphenyl)carbamoyl)-1-(4,4,4-trifluorobutyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-1-ium (compound 50 (ARN27071), Scheme 11 (Fig. 11), equation II). Compound 50 was prepared according to General procedure 3 using: compound 49 (44.0 mg, 0.08 mmol), BBr31M DCM solution (0.75 mL, 0.75 mmol, 9 eq). Final trituration in water (2 mL) yielded pure title compound 50 as an ochre solid (15 mg, 33%).LC / MS: Rt: 1.69 min (gradient 1) (ESI) m / z: 487.3 [M+H]+. [M+H]+Calculated for C24H22F3N4O4= 487.1.1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 6.3 Hz, 2H), 8.73 (d, J = 6.3 Hz, 2H), 8.33 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.23 (s, 2H), 4.51 (t, J = 7.5 Hz, 2H), 3.34 (s, 3H), 2.47 – 2.32 (m, 2H), 2.06 (h, J = 7.1 Hz, 2H). Synthesis of tert-butyl(2,6-dimethoxy-4- nitrophenoxy)dimethylsilane (compound 52, Scheme 12 (Fig. 12)) DIPEA (0.88 mL, 5.02 mmol) and DMAP (61.0 mg, 0.50 mmol) were added to a solution of compound 51 (500.0 mg, 2.51 mmol) in DCM dry (5 mL) under argon. After 10 minutes stirring, TBSCl (680.9 mg, 4.52 mmol) was added and reaction mixtures stirred with for 19 hours. After that, reaction mixture was washed with water (3 mL), organic layer was divided, dried over Na2SO4, filtered and concentrated under vacuum. Product was purified by silica eluting by gradient from 100 / 0 to 90 / 10 cyclohexane / EtOAc afforded pure title compound 52 (780.2 mg, 99% yield). LC / MS: Rt: 2.42 min (gradient 6) (ESI) m / z: 314.2. [M+H]+. [M+H]+Calculated for C14H24NO5Si = 313.1.1H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 2H), 3.87 (s, 6H), 0.97 (s, 9H), 0.13 (s, 6H). Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3,5- dimethoxyaniline (compound 53, Scheme 12 (Fig. 12)). Et3SiH (4.1 mL, 26 mmol) was slowly added to a suspension of compound 52 (782.5 mg, 2.50 mmol) and Pd / C (39.5 mg) in EtOH (30 mL). After completion of reaction, the mixture was filtered over a pad of celite and concentrated under vacuum. The product was purified by silica eluting by gradient from 100 / 0 to 70 / 30 cyclohexane / EtOAc affording pure title compound 53 (700.0 mg, 95% yield). LC / MS: Rt: 1.60 min (gradient 6) (ESI) m / z: 284.5. [M+H]+. [M+H]+Calculated for C14H26NO3Si = 284.2.1H NMR (400 MHz, DMSO-d6) δ 5.86 (s, 2H), 4.65 (s, 2H), 3.62 (s, 6H), 0.93 (s, 9H), 0.01 (s, 6H). 4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxy-N- methylaniline (compound 54, Scheme 12 (Fig. 12)). Aniline 53 (350.0 mg, 1.23 mmol) was dissolved in dry methanol (4 mL); MeONa (200 mg, 3.70 mmol) was added, and the suspension stirred for 5 mins under nitrogen; this slurry was added to a suspension of paraformaldehyde (111.0 mg, 3.70 mmol) in MeOH (4 mL). The resulting mixture was stirred at RT for 6 hrs under nitrogen, then NaBH4(140 mg, 3.70 mmol) was added and the mixture refluxed. Upon completion of the reaction, the mixture was concentrated to under vacuum, KOH 1M (3 mL) was added, and the mixture stirred for 5 mins. Extractions with EtOAc were performed (2 x 6 mL), the organic layers combined were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by silica eluting by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc affording pure title compound 54 (138.8 mg, 38% yield). LC / MS: Rt: 1.99 min (gradient 6) (ESI) m / z: 298.3. [M+H]+. [M+H]+Calculated for C15H28NO3Si = 298.2. Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)-3,5- dimethoxyphenyl)-5-chloro-N-methyl-1H-pyrrolo[3,2- b]pyridine-2-carboxamide (compound 55, Scheme 12 (Fig. 12)). DIPEA (0.16 mL, 0.91 mmol) was added to a solution of compounds 54 (130.0 mg, 0.44 mmol) and 3a (71.6 mg, 0.36 mmol) in a 4:1 DCM / DMF mixture (2.5 mL) under argon at room temperature. Reaction mixture stirred for 15 minutes, after that propanephosphonic acid anhydride T3P (≥50 wt. % in ethyl acetate) (1157 mg, 1.82 mmol) was slowly added and reaction mixture stirred for 1 hour. After that water (1 mL) and NH4Cl sat. aqueous solution (2 mL) were added, and the aqueous layer was extracted with EtOAc (3 x 4 mL). Collected organic layers were dried over Na2So4, filtered and concentrated under vacuum. The product was purified by silica eluting with 70 / 30 cyclohexane / EtOAc affording pure title compound 55 (105.7 mg, 61% yield). LC / MS: Rt: 2.20 min (gradient 6) (ESI) m / z: 474.4 [M−H]−. [M−H]−Calculated for C23H29ClN3O4Si = 474.0.1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.75 (s, 2H), 5.34 (s, 1H), 3.68 (s, 6H), 3.40 (s, 3H), 0.99 (s, 9H), 0.13 (s, 6H). Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)-3,5- dimethoxyphenyl)-N-methyl-5-(pyridin-4-yl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide (compound 56, Scheme 12 (Fig. 12)) General procedure 2, Method A. Amide 55 (60mg, 0.126 mmol), pyridine-4-boronic acid (38.7 mg, 0.31 mmol), K2CO3(87.0 mg, 0.63 mmol) and PdCl2(dppf)∙DCM complex (10.5 mg, 0.013 mmol), reaction time: 7 hrs. Upon completion and DCM / water work-up, collected organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by silica eluting by gradient from95 / 5 to 70 / 30 DCM / acetone affording pure title compound as white powder (54.2 mg, 83% yield) (70.0 mg, 65% yield). TLC: Rf= 0.4 (EtOAc / Cyclohexane = 7:3). LC / MS: Rt: 1.80 min (gradient 6) (ESI) m / z: 519.3 [M+H]+. [M+H]+Calculated for C28H35N4O4Si = 519.2.1H NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 8.63 – 8.57 (m, 2H), 8.03 – 7.98 (m, 2H), 7.91 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 6.79 (s, 2H), 5.45 (bs, 1H), 3.70 (s, 6H), 3.42 (s, 3H), 1.00 (s, 9H), 0.16 (s, 6H). Synthesis of N-(4-hydroxy-3,5-dimethoxyphenyl)-N-methyl-5- (pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrochloride (compound 57 (ARN27073), Scheme 12 (Fig. 12)). HCl (4M in 1,4 dioxane dry) (0.19 mL, 0.77 mmol) was slowly added to a solution of compound 56 (40.0 mg, 0.08 mmol) in 5:1 mixture MeOH / DCM (0.6 mL) at 0°C under argon at 0°C. The reaction mixture stirred for 19 hours at room temperature. Upon completion of the conversion, the mixture was concentrated under vacuum and the residue was purified with a 9:1 mixture MeOH / Et2OH (1.5 mL) affording the title pure product as pale-yellow powder (26.2 mg, 77% yield). LC / MS: Rt: 1.44 min (gradient 1) (ESI) m / z: 405.2 [M+H]+. [M+H]+Calculated for C22H21N4O4= 405.1.1H NMR (400 MHz, DMSO-d6): δ 12.21 (d, J = 2.3 Hz, 1H), 8.88 (d, J = 6.0 Hz, 2H), 8.67 (d, J = 6.3 Hz, 2H), 8.20 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 6.77 (s, 2H), 5.53 (s, 1H), 3.72 (s, 6H). Synthesis of 2-chloro-8-(3,4,5-trimethoxyphenyl)-7,8- dihydropyrido[2',3':4,5]pyrrolo[1,2-a]pyrazin-9(6H)-one (compound 58, Scheme 13, equation I (Fig. 13)) Amide 4a (120 mg, 0.33 mmol) 1,2-dibromoethane (216 mg, 0.1 mL, 1.15 mmol, 3.5 eq) and Cs2CO3(430 mg, 1.32 mmol, 4 eq) were suspended in dry DMF (3 mL) and stirred at 100 °C (closed vial). After 1 hr, the resulting solution was cooled to RT (reaction completion assessed by LC / MS); the suspension was diluted with H2O (20 mL) and extracted with EtOAc (3 x 15 mL); the organic phases combined were dried on Na2SO4, filtered and concentrated to dryness, concentrated from toluene (2 x 40 mL) to yield the crude product as a yellow solid. This material was triturated with MeOH (4 mL) to yield pure title compound 58 as a canary yellow solid (81 mg, 63 % yield). LC / MS: Rt: 1.74 min (gradient 1), (ESI) m / z: calculated for [C19H18ClN3O4 + H]+= 388.1; found: 388.1.1H- NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.17 (s, 1H), 6.80 (s, 2H), 4.56 (m, 2H), 4.28 – 4.18 (m, 2H), 3.78 (s, 6H), 3.69 (s, 3H). Synthesis of 2-chloro-8-(3,4,5-trihydroxyphenyl)-7,8- dihydropyrido[2',3':4,5]pyrrolo[1,2-a]pyrazin-9(6H)-one (compound 59, ARN27097, Scheme 13, equation I (Fig. 13)) General procedure 3. Amide 58 (30 mg, 0.08 mmol), BBr31 M solution (0.7 mL, 0.7 mmol, 9 eq) in dry DCM (1.5 mL). Crude from reaction triturated in MeOH (1.5 mL) to yield pure title compound 59 as a yellow solid (19 mg, 71 % yield).1H-NMR (400 MHz, DMSO-d6) δ 9.05 (br s, 2H), 8.14 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.12 (s, 1H), 6.35 (s, 2H), 4.54 – 4.46 (m, 2H), 4.14 – 4.07 (m, 2H).13C-NMR (101 MHz, DMSO-d6) δ 157.6 (Cq), 145.9 (Cq), 144.2 (Cq), 143.5 (Cq), 133.6 (Cq), 132.8 (Cq), 132.0 (Cq), 128.2 (Cq), 122.4 (CH), 118.8 (CH), 104.9 (CH, 2C), 103.8 (CH), 49.1 (CH2), 40.6 (CH2). Synthesis of 2-chloro-7-(3,4,5-trimethoxyphenyl)-6H- imidazo[1',5':1,5]pyrrolo[3,2-b]pyridine-6,8(7H)-dione (compound 60, Scheme 13, equation II (Fig. 13)) Acid 3a (20 mg, 0.10 mmol), aniline 1 (19 mg, 0.10 mmol) and CDI (65 mg, 0.40 mmol, 4 eq) and TEA (61 mg, 84 μL, 0.60 mmol, 6 eq) were suspended in dry CHCl3 (0.6 mL) in a microwave vial. The headspace was filled with N2, and the mixture was subjected to MW irradiation for 60 mins (100 °C, 150 W). The resulting solution was cooled to RT, diluted with Et2O (1 mL), stirred for 10 mins and the resulting suspension was filtered to obtain a yellow / beige solid, that was triturated in MeOH (1.5 mL) to obtain the pure title compound 60 as a canary yellow solid (36 mg, 93 % yield). LC / MS: Rt: 2.13 min (gradient 1), (ESI) m / z: calculated for [C18H14ClN3O5+ H]+ = 388.1; found: 388.1.1H-NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 6.88 (s, 2H), 3.77 (s, 6H), 3.73 (s, 3H). Synthesis of 2-chloro-7-(3,4,5-trihydroxyphenyl)-6H- imidazo[1',5':1,5]pyrrolo[3,2-b]pyridine- 6,8(7H)-dione compound 61, ARN27044, Scheme 13, equation II (Fig. 13)) General procedure 3. Compound 60 (36 mg, 0.09 mmol), BBr31 M solution (0.84 mL, 0.84 mmol, 9 eq) in dry DCM (1.5 mL). Crude from reaction triturated in MeOH (0.7 mL) to yield pure title compound 61 as a yellow solid (18 mg, 59 % yield). LC / MS: Rt: 2.85 min (gradient 2), (ESI) m / z: calculated for [C15H8ClN3O5+ H]+ = 346.02; found: 346.09.1H-NMR (400 MHz, DMSO-d6) δ 9.27 (br s, 2H), 8.50 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.54 (s, 1H), 6.42 (s, 2H).13C-NMR (101 MHz, DMSO-d6) δ 158.3 (Cq), 149.0 (Cq), 146.3 (Cq), 145.9 (Cq), 133.9 (Cq), 132.6 (Cq), 125.3 (Cq), 123.6 (CH), 122.6 (CH), 121.26 (Cq), 106.8 (CH, 2C), 106.4 (CH). Synthesis of methyl 2,3-dimethoxy-5-(methylamino)benzoate (compound 63, Scheme 14, (Fig.14)) Aniline 62 (62.0 mg, 0.29 mmol) was dissolved in dry methanol (2.0 mL) and reaction mixture stirred; NaOMe (48.0 mg, 0.88 mmol) was added, and the suspension stirred for 5 mins under nitrogen at 50°C; then paraformaldehyde (27.0 mg, 0.88) was added, and the resulting mixture was stirred at RT for 4 hrs under nitrogen, then NaBH4(33.0 mg, 0.88 mmol) was added and the mixture stirred for other 2 hrs. Crude preabsorbed on silica (0.6 g) and purified by column chromatography (CombiFlash system, 4g Gold cartridge) eluting with a gradient 10% to 50% EtOAc / cyclohexane over 20 C.V., to obtain pure compound 63 as a yellow oil (48 mg, 73 % yield). TLC: Rf = 0.69 (50 % EtOAc / Cyclohexane, UV dark blue 254 nm, light blue 366 nm). LC / MS: Rt: 1.61 min (gradient 1), (ESI) m / z: calculated for [C11H15NO4+ H]+= 226.1 ; found: 225.9 .1H- NMR (400 MHz, DMSO-d6) δ 6.40 (d, J = 2.7 Hz, 1H), 6.26 (d, J = 2.7 Hz, 1H), 5.66 (q, J = 5.1 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.62 (s, 3H), 2.65 (d, J = 5.1 Hz, 3H). methyl 5-(5-chloro-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamido)-2,3-dimethoxybenzoate (compound 64, Scheme 14, (Fig.14)) General procedure 1. Acid 3a (41 mg, 0.21 mmol), SOCl2 (148 mg, 90 μL, 1.25 mmol) in DCM dry (2 mL). Then aniline 63 (47 mg, 0.21 mmol), Py / DCM (1 / 1mL). Upon completion, the mixture was concentrated to dryness, and the crude brown solid was triturated in MeOH (2 mL, twice) to yield pure compound 64 as a yellow solid (60 mg, 71 % yield). LC / MS: 1.90 min (gradient 1), (ESI) m / z: calculated for [C19H18ClN3O5 + H]+= 404.1 ; found: 403.8.1H-NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.83 (dd, J = 8.6, 0.9 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 5.5, 3.1 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.41 (s, 3H). 5-(5-chloro-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamido)-2,3-dimethoxybenzoic acid (compound 65, Scheme 14, (Fig.14)) LiOH (11.9 mg, 0.50 mmol) was added to a suspension of compound 64 (50.0 mg, 0.12 mmol) in THF dry (1.3 mL). Reaction mixture stirred at room temperature for 3hrs. After that THF was removed under vacuum, and the water mixture was acidified until pH = 2 with HCl (2M)aq. Resulted precipitate was filtered affording pure compound 65 as grey solid (43.2 mg, 96% yield). LC / MS: 1.23 min (gradient 1), (ESI) m / z: calculated for [C18H16ClN3O5+ H]+= 389.8. ; found: 390.0.1H- NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 12.10 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.6, 0.9 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 5.45 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.40 (s, 4H). 5-(5-chloro-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamido)-2,3-dihydroxybenzoic acid (compound 66, ARN26004, Scheme 14 (Fig. 14)) General procedure 3. Compound 65 (30 mg, 0.08 mmol), BBr31 M DCM solution (0.46 mL, 0.46 mmol, 6 eq). Crude triturated in MeOH (2 mL) to yield pure title compound 66 as a white solid (23 mg, 82 % yield). LC / MS: Rt: 1.78 min (gradient 6) (ESI) m / z: calculated for [C16H12ClN3O5 + H]+= 362.0; found: 362.2.1H-NMR (400 MHz, DMSO-d6) δ 12.09 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.6, 0.9 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 5.38 (s, 1H), 3.34 (s, 3H).13C-NMR (101 MHz, DMSO-d6) δ 171.7 (Cq), 160.5 (Cq), 150.5 (Cq), 147.0 (Cq), 143.7 (Cq), 143.6 (Cq), 134.2 (Cq), 133.6 (Cq), 127.3 (Cq), 123.2 (CH), 120.0 (CH), 118.7 (CH, 2C), 113.5 (Cq), 104.6 (CH), 38.5 (CH3). In vitro, IC50 assay (Table 1) Table 1 reports IC50 values for in vitro tests. Data reported for activity against fungal group IIB intron (S. cerevisiae) and bacterial group IIC intron (O. iheyensis) Spliced-exon reopening reaction to determine the IC50 value of the compounds related to the inhibition of the fungal group IIB intron (S. cerevisiae). 96-well plates were filled with 10 μl of solution containing 20nM intron (D135 construct), 20nM double-labeled substrate and small-molecule inhibitor in 50mM MOPS, pH 7.0, 100mM MgCl2 and 500mM KCl. Small-molecule inhibitors were tested at 12 different concentrations ranging from 250nM to 1mM. Plates were incubated at 37 °C for 50min in qPCR system (BioRad). Each experiment was performed in triplicate. The initial rates, calculated as the tangent of the curve in the first 10 min of reaction, were used to calculate the % activity with respect to the control (DMSO). Data were fit to a 2-parameter logistic function 100 / (1+(x / a)b), where a is the IC50, b is the slope parameter, c is the minimum response and d is the maximum response (GraphPad Software). Data are reported as average±s.e.m. Splicing kinetic assays to determine the Ki value of the compounds related to the inhibition of the bacterial group IIB intron (O. iheyensis) (Table 1) Purified radiolabeled intron precursor was refolded by denaturation at 95 °C for 1 min in the presence of 40 mM Na- MOPS pH 7.5, and cooled at room temperature for 2 min. Then KCl to a final concentration of 150 mM and MgCl2 to a final concentration of 5 mM were added, and the refolded intron was incubated with various concentrations of small-molecule inhibitor. Aliquots at different time points were quenched with urea and analyzed on a 5% denaturing polyacrylamide gel. The kinetic rate constants (kobs) in presence of each compound concentration were calculated using the Prism 8 package (GraphPad Software) and plotted against the inhibitor concentration according to the following equation to determine Ki values: kobs = kmax / (1+[I] / Ki), where kobs and kmax are the rate constants measured in the presence and in the absence of the inhibitor, respectively, [I] is the concentration of the inhibitor and Ki is the inhibition constant. Experiments were performed in triplicate. Data represent average ± s.e.m. The IC50value was calculated by measuring the fraction of precursor (5e-I-3e) at the reaction time of 15 min, calculating the percentage of reacted precursor at each concentration of compound according to the following equation: %5e-I-3e= 100*(F5e-I-3e, 15min, [I]max- F5e-I-3e,15min, [I]) / (F5e-I-3e, 15min, [I]max - F5e-I-3e, 15min, DMSO), and fitting the percentage of reacted precursor as function of the compound concentration according to the following function: %5e-I-3e = 100 / (1+[I] / IC50). Data are reported as average ± s.e.m. Table 1. In vitro, IC50 assay against fungal group II intron. IC50 from SER Ki from splicing reaction on kinetics assays on Ex Compound Saccaromyces Oceanobacillus cerevisiae ai5γ iheyensis I1 group group IIB intron IIC intron 1 5a (ARN25414) 25.6 ± 6.0µM NDa2 5b (ARN25459) 3.6 ± 1.4µM 11.3 ± 9.1 µM 3 5c (ARN27074) 1.9 ± 0.9 µM NDa4 8aa (ARN25424) 8.2 ± 2.1µM NDa5 8ab (ARN25425) 7.9 ± 1.6µM NDa6 8ba (ARN25885) 2.1 ± 0.8µM NDa7 8bc (ARN26849) 14.0 ± 5.2 µM NDa8 8bd (ARN25917) 1.7 ± 0.5 µM NDa9 8be (ARN25918) 5.2± 1.9µM NDa10 8bf (ARN26715) 54.3 ± 17.5 µM NDa11 8bg (ARN25954) 6.5 ± 2.0 µM NDa12 8bk (ARN25955) 16.8± 4.4µM NDa13 8bh (ARN26717) 13.8 ± 3.7µM NDa14 8bi (ARN26958) 33.6 ± 2.7 µM NDa15 8bj (ARN26716) 9.8 ± 2.9 µM NDa16 8bl (ARN26977) 2.3 ± 2.2 µM NDa17 8bm (ARN26928) 8.2 ± 2.3 µM NDa18 8bp (ARN27072) 0.2 ± 0.0 µM NDa 19 8bn (ARN27025) 3.4 ± 1.5 µM NDa19 10a (ARN26718) 8.7 ± 1.9 µM NDa20 10b (ARN26729) 14.6 ± 3.7 µM NDa21 10c (ARN26730) 5.2 ± 1.3 µM NDa22 18a (ARN25625) 17.8 ± 5.1µM NDa23 18b (ARN25522) 24.1± 10.1µM NDa24 20a (ARN25626) 17.8 ± 5.1µM NDa25 20b (ARN25628) 18.5 ± 5.4µM NDa26 25 (ARN25497) 6.0 ± 1.8 µM NDa27 30 (ARN26974) 55.4 ± 11.2 µM NDa28 46a (ARN26936) 2.5 ± 0.2 µM NDa29 46b (ARN26975) 8.7 ± 1.7 µM NDa30 46c (ARN26976) 0.2 ± 0.08 µM 18.6 ± 16 µM 31 46d (ARN27043) 0.3 ± 0.2 µM NDa32 46e (ARN27103) 1.1 ± 0.6 µM NDa33 46f (ARN27120) 1.0 ± 0.6 µM NDa34 46g (ARN26907) 12.2 ± 6.0 µM NDa35 46h (ARN26929) 7.7 ± 0.3 µM NDa36 48 (ARN27079) 9.0 ± 1.3 µM NDa37 50 (ARN27071) 0.7 ± 0.6 µM NDa38 57 (ARN27073) 23.7 ± 6.3 µM NDa39 60 (ARN27097) 0.3 ± 0.2 µM NDa40 62 (ARN27044) 0.4 ± 0.2 µM NDaND = not determined Material and Methods for the Spliceosome-specific gene reporter assay (Table 2). Plasmids — Reporter construct II was created by a Gibson reaction in which we inserted the gene expression cassette triose-phosphate isomerase (TPI) / GFP (plasmid pLIB CMV) into the vector containing mCherry sequence and resistance to Puromycin and Hygromycin antibiotics (pMN01 is the final plasmid). In the construct II a site-directed mutagenesis was used to remove an in-frame stop codon in the intron and add a G at position 6 in TPI exon 7. Cell Culture and Generation of Stable Cell Lines — Cells were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum. To generate a host cell line expressing mCherry and GFP signal, HEK293 cells (ATCC) we used CRISPR / Cas9. The cells were co-transfected, using lipofectamine 2000 (Invitrogen), with pMN01 and a donor plasmid containing Cas9 that was able to integrate the gene cassette into the locus of ActinB (chromosome 7). Stable integrants were selected with 100µg / ml puromycin and 50µg / ml hygromycin. Positive cell clones were identified by genotyping different clones using the PCR. Phenotypic gene-reporter Assays — Cells were seeded at 0.5x105cells / well in the 24-well plates and, after 24h, treated with DMSO, as vehicle, or modulator compounds (named with the ARN number) or Pladienolide B, as positive control. The treatment lasted 48h, then the media was removed and the wells were washed with cold PBS. The cells were incubated with trypsin and collected in a tube with media in a final volume of 500 µL. The samples were analyzed using the MACSQuant® Analyzer Flow Cytometer to measure the percentage of GFP positive cells in 10000 events. The results are reported in percentages as average of triplicates ± SEM. Table 2. Activity on human spliceosome. Ex Compound Activity (% GFP positive cells) 10 µM 50 µM 100 µM 1 46d (ARN27043) 0.5 ± 0.0 0.7 ±0.2 0.9 ± 0.2 2 8bd (ARN25917) 2.5 ± 0.5 3.8 ± 0.9 8.0 ± 0.0 3 8bl (ARN26977) 7.2 ± 0.4 8.4± 0.7 9.8 ± 0.2 4 46a (ARN26936) 2.2 ± 1.0 2.5 ± 1.3 3.8 ± 0.5 5 8ba (ARN25885) 1.8 ± 0.5 3.9 ± 1.1 6.6 ± 0.6 6 5b (ARN25459) 0.9 ± 0.6 0.8 ± 0.3 0.5 ± 0.1 7 8be (ARN25918) 3.2 ± 0.4 3.4 ± 0.6 3.4 ± 0.2 8 8bg (ARN25954) 1.6 ± 0.4 1.0 ± 0.2 1.2 ± 0.2 9 46b (ARN26975) 1.5 ± 0.2 0.7 ± 0.1 2.0 ± 0.6 10 8bc (ARN26849) 0.7 ± 0.0 0.8 ± 0.0 0.9 ± 0.1 11 8bh (ARN26717) 1.1 ± 0.4 4.1 ± 3.4 3.9 ± 1.3 12 8bk (ARN25955) 1.6 ± 0.0 1.6 ± 0.1 2.7 ± 0.6 13 18b (ARN25522) 0.5 ± 0.1 0.5 ± 0.1 0.5 ± 0.0 14 8bi (ARN2958) 0.7 ± 0.0 1.0 ± 0.2 0.9 ± 0.2 15 30 (ARN26974) 1.2 ± 0.1 0.8 ± 0.1 0.6 ± 0.1 16 66 (ARN26004) 2.7 ± 0.5 4.3 ± 0.3 6.2 ± 1.2 Structural biology Crystallization The natively purified intron was mixed with a 0.5 mM spermine solution and with the crystallization buffer in a 1:1:1 volume ratio (Marcia and Pyle, 2012). The intron was crystallized in its apo form or in the presence of a substrate oligonucleotide 5’-AUUUAU-3’ 100 μM. Crystals were grown at 30°C by the hanging drop vapor diffusion method using 2 μL sample drops and 300 μL crystallization solution in a sealed chamber (EasyXtal 15-Well Tool, Qiagen). Crystals were soaked for 1–3h in a solution containing the corresponding crystallization buffers supplemented with 1 mM compound and cryo-protected with 25% ethylene glycol before flash frozen in liquid nitrogen. Crystals were harvested after 1 day or up to 2 – 3 weeks after preparing the crystallization plates. The crystallization solutions were composed of 100 mM Mg-Acetate, 150 mM KCl, 10 mM LiCl, 50 mM Na-HEPES pH 7.0, 4% PEG 8000. Structure determination Diffraction data were collected at beamlines ID30A-1 and ID30B at ESRF (Grenoble, France) and processed with the XDS suite (Kabsch, 2010). The structures were solved by molecular replacement using Phaser in CCP4 (McCoy et al., 2007) and the RNA coordinates of PDB entry 4FAR and 4E8M (without solvent atoms) as the initial model (Marcia, 2016; Marcia et al., 2013a; Marcia and Pyle, 2012). The models were improved automatically in Phenix (Adams et al., 2010; Adams et al., 2004; Adams et al., 2002) and Refmac5 (Murshudov et al., 2011) and manually in Coot (Emsley, 2004), and finally evaluated by MolProbity (Davis, 2007). Simulated annealing Fo-Fc omit maps were generated in Phenix. The figures depicting the structures were drawn using PyMOL Molecular Graphics System (Version 1.5.0.4, Schrödinger).

Claims

CLAIMS 1.- Compound of formula (I):(Ia) or its pharmaceutically acceptable salts, solvates and tautomers wherein: R1 is selected from the group consisting of: H, halogen, saturated or partially unsaturated C1-C6cycloalkyl optionally substituted with one or more R7, saturated or partially unsatured C1-C6heterocycloalkyl optionally substituted with one or more R7, a C1-C10aryl group optionally substituted with one or more R7and C1-C10heteroaryl group optionally substituted with one or more R7; R2, R3and R4are independently selected from the group consisting of –H, -OH, -COOH, -COO-C1-C6alkyl, -CONH-C1- C6alkyl, -C(=O)H, -C1-C6alkyl-OH, -O-C1-C6alkyl, provided that at least one of R2, R3and R4is not H; R5 is selected from the group consisting of hydrogen, C1- C8alkyl, halo-C1-C8alkyl, -C(=O)NH2, -C(=S)NH2, -C1-C8alkyl- NH2, -C1-C8alkyl-NH(C1-C6alkyl), -C1-C8alkyl-N(C1-C6alkyl)2, - C1-C8alkyl-NH(C1-C6cycloalkyl), -C1-C8alkyl-N(C1- C6cycloalkyl)2and -C1-C8alkyl-OH; R6 is selected from the group consisting of H, C1-C6alkyl,haloC1-C6alkyl, C1-C6alkyl-OH, C-Calkyl-NH, -C-Calkyl-NH(C-Calkyl), -C-Calkyl-N(C-Calkyl), -C-Calkyl-NH(C -Ccycloalkyl), -C-Calkyl-N(C-Ccycloalkyl); or R5 and R6 form a ring with the N atoms to which they are linked to form compounds of formula (Ic)(Ic) wherein L is selected from the group consisting of –C(=O)-, C1-C3alkylene, - C1-C3alkyleneC(=O)- R7 is selected from the group consisting of halogen, C1-C8alkyl optionally substituted with halogen, OH, amino, - NH-C3-C6 cycloalkyl, -NH-C1-C6alkyl, -NH-haloC1-C6alkyl, - N(C1-C6alkyl)(C3-C6cycloalkyl), -N(haloC1-C6alkyl)(COO C1- C6alkyl), cyclic amine having a formula selected from:OH, amino, -NH(C-Calkyl), -N(C-Calkyl), -O-C1-C8alkyl, -C(=O)R8, phenyl thiophene, –SO2NHR9, sulfonyl piperazine, sulfonylmethyl piperazine, sulfonyl piperidine,methylsulfonyl; R8is selected from the group consisting of H, OH, C1-C8alkyl, O-C1-C8 alkyl, amino, aminoC1-C8alkyl, aminodi-C1-C8alkyl, - NH-C1-C8alkyl-amino-C1-C8alkyl, -NH-C1-C8alkyl-amino-diC1- C8alkyl, -NH-C(=NH)NH2, -NH- C1-C8alkyl-OH, -NH-halo-C1- C8alkyl, piperidinyl, -NH-C1-C8alkyl- pyrrolidinyl, methylpiperazinyl; R9 is selected from the group consisting of H and C1-C6alkyl; provided that the compound of formula (Ia) is not one of the following compounds: N-(4-hydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-hydroxyphenyl)-N-methyl-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3,4-diethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3-hydroxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-[4-(aminocarbonyl)phenyl]-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, Ethyl 4[(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)amino] benzoate, N-(3-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2- carboxamide, N-(4-ethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, Methyl 4[(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)amino] benzoate. 2.- Compound according to claim 1, characterized in that R1is selected from the group consisting of H, halogen, saturated or partially unsaturated piperidine optionally substituted with one or more R7, phenyl optionally substituted with one or more R7, pyridine optionally substituted with one or more R7,quinolineoptionally substituted with one or more R7, isoquinoline optionally substituted with one or more R7, indole optionally substituted with one or more R7, benzofuran optionally substituted with one or more R7. 3.- Compound according to claim 1, characterized in that R1 has the structurewherein Z is selected from CH, CR7and NH and each of R7 is independently selected from the group consisting of H halogen, C1-C8alkyl optionally substituted with halogen, OH, amino, - NH-C3-C6 cycloalkyl, -NH-C1-C6alkyl, -NH-haloC1- C6alkyl,cyclic amine having a formula selected from:OH, amino, amino-C1-C8alkyl, amino-di-C1-C8alkyl, -O-C1-C8alkyl, -C(=O)R8,phenyl thiophene –SO2NHR9, sulfonyl piperazine, sulfonylmethyl piperazine, sulfonyl piperidine, methylsulfonyl. 4.- Compound of formula (Ia) according to claim 1, characterized that it has formula (Ic):(Ic) 5.- Compound of formula (I) according to claim 1 selected from the group consisting of: 5a 5-chloro-N-(3,4,5-trihydroxyphenyl)-1H- (ARN25414) pyrrolo[3,2-b]pyridine-2-carboxamide 5b 5-chloro-N-methyl-N-(3,4,5- (ARN25459) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 5c N-methyl-N-(3,4,5-trihydroxyphenyl)-1H- (ARN27074) pyrrolo[3,2-b]pyridine-2-carboxamide 8aa 5-(4-(dimethylamino)phenyl)-N-(3,4,5- (ARN25424) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 8ab 5-(2-hydroxyphenyl)-N-(3,4,5- (ARN25425) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8ba 5-(4-(dimethylamino)phenyl)-N-methyl-N- (ARN25885) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide8bc N-methyl-5-phenyl-N-(3,4,5- (ARN26849) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bd N-methyl-5-(pyridin-4-yl)-N-(3,4,5- (ARN25917) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide, hydrobromic salt 8be 5-(2-aminopyridin-4-yl)-N-methyl-N- (ARN25918) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bf 5-(4-(bromomethyl)phenyl)-N-methyl-N- (ARN26715) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bg N-methyl-5-(1,2,3,6-tetrahydropyridin-4- (ARN25954) yl)-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 8bk N-methyl-5-(piperidin-4-yl)-N-(3,4,5- (ARN25955) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bh 5-(4-hydroxyphenyl)-N-methyl-N-(3,4,5- (ARN26717) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bi 4-(2-(methyl(3,4,5- (ARN26958) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)benzoic acid 8bj 5-(3-carbamoylphenyl)-N-methyl-N-(3,4,5- (ARN26716) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bl 3-(2-(methyl(3,4,5- (ARN26977) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)benzoic acid8bm N-methyl-5-(pyridin-3-yl)-N-(3,4,5- (ARN26928) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 8bn 5-(isoquinolin-5-yl)-N-methyl-N-(3,4,5- (ARN27025) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 8bp N-methyl-5-(4-(piperidin-1- (ARN27072) ylmethyl)phenyl)-N-(3,4,5- trihydroxyphenyl)-1Hpyrrolo[3,2- b]pyridine-2 carboxamide dihydrobromide 10a 5-(4-((2- (ARN26718) (dimethylamino)ethyl)carbamoyl)phenyl)- N-methyl-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 10b N-methyl-5-(4-(4-methylpiperazine-1- (ARN26729) carbonyl)phenyl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrobromide 10c 5-(4-(carbamimidoylcarbamoyl)phenyl)-N- (ARN26730) methyl-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46a N-methyl-5-(2-(piperazin-1- (ARN26936) ylmethyl)pyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 46b N-methyl-5-(2-(pyrrolidin-1- (ARN26975) ylmethyl)pyridin-4-yl)-N-(3,4,5- trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide dihydrobromide 46c 5-(2-((3,3-difluoropyrrolidin-1-(ARN26976) yl)methyl)pyridin-4-yl)-N-methyl-N- (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide di-hydrobromide 46d 5-(2-((cyclobutylamino)methyl)pyridin-4- (ARN27043) yl)-N-methyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide di-hydrobromide 46e 5-(2-(((2,2- (ARN27103) difluoroethyl)amino)methyl)pyridin-4- yl)-N-methyl-N-(3,4,5-trihydroxyphenyl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46f N-methyl-5-(2-(((3,3,3- (ARN27120) trifluoropropyl)amino)methyl)pyridin-4- yl)-N-(3,4,5-trihydroxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide hydrobromide 46g N-methyl-5-(2-phenylpyridin-4-yl)-N- (ARN26907) (3,4,5-trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 46h 4-(2-(methyl(3,4,5- (ARN26929) trihydroxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)-2-(thiophen- 3-yl)pyridin-1-ium 48 5-chloro-N,1-dimethyl-N-(3,4,5- (ARN27079) trihydroxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 50 4-(2-(methyl(3,4,5- (ARN27071) trihydroxyphenyl)carbamoyl)-1-(4,4,4- trifluorobutyl)-1H-pyrrolo[3,2- b]pyridin-5-yl)pyridin-1-ium 57 N-(4-hydroxy-3,5-dimethoxyphenyl)-N-(ARN27073) methyl-5-(pyridin-4-yl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide hydrochloride 59 2-chloro-8-(3,4,5-trihydroxyphenyl)-7,8- (ARN27097) dihydropyrido[2',3':4,5]pyrrolo[1,2- a]pyrazin-9(6H)-one 61 2-chloro-7-(3,4,5-trihydroxyphenyl)-6H- (ARN27044) imidazo[1',5':1,5]pyrrolo[3,2- b]pyridine- 6,8(7H)-dione 66 5-(5-chloro-N-methyl-1H-pyrrolo[3,2- (ARN26004) b]pyridine-2-carboxamido)-2,3- dimethoxybenzoic acid 6.- Compound of formula (Ia) according to any of the preceding claims for the use as a medicament. 7.- Compound of formula (Ia) according to any of the preceding claims for the use in the treatment of a disease or disorder selected from the group consisting of viral infections, fungal infections, bacterial infections, neurological and neurodevelopmental disorders, lysosomal storage diseases (LSDs), and cancer. 8.- Compound of formula (Ia) for the use according to claim 7 wherein the neurological and neurodevelopmental disorder is selected from the group consisting of Spinal Muscular Atrophy SMA, Duchenne Muscular Distrophy (DMD), Alzheimer, Huntington, Myotonic Distrophy 1 (MD1), Familial Dysautonomia, dementia, Parkinson. 9.- Compound of formula (Ia) for the use according to claim 7 wherein the cancer is selected from the group consisting of gliomas, neuroblastoma, rhabdomyosarcoma, primary brain tumors, medulloblastoma, myelodysplastic syndrome, central nervous system cancer, skin cancer, melanoma, lung cancer, non-small cell lung cancer, bladder cancer, kidney cancer, urinary tract cancer, urothelial carcinoma, cervical cancer,ovarian cancer, liver cancer, head and neck squamous cell cancer, oral squamous cell cancer, esophageal cancer, malignant carcinoid, gastric cancer, stomach cancer, upper digestive tract cancer, colon cancer, colorectal cancer, seminoma, prostate cancer, testicular cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, malignant insulinoma, intraductal papillary mucinous neo plasm carcinoma of the pancreas, thyroid cancer, head / neck squamous cell cancer, hematopoietic cancers, lymphoid cancers, leukemias, solid tumors, sarcomas, adenocarcinomas, adrenal cortical cancer. 10.- Pharmaceutical composition comprising a compound of formula (Ia) according to any claims 1-5 and at least one pharmaceutically acceptable excipient. 11.- Method for the treatment of a disease or disorder selected from the group consisting of viral infections, fungal infections, bacterial infections, neurological and neurodevelopmental disorders, lysosomal storage diseases (LSDs), and cancer in a patient by administering a therapeutically effective amount of a compound of formula (Ia) according to any of claims 1 to 5. 12.- Intermediates for the preparation of a compound of formula (Ia) according to anyone of claims 1 to 5 selected from the group consisting of: 4a 5-chloro-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 4b 5-chloro-N-methyl-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide 4c N-methyl-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide 43 (5-chloro-N-methyl-N-(3,4,5-trimethoxyphenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide)a tert-butyl 4-((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)piperazine-1-carboxylateb N-methyl-5-(2-(pyrrolidin-1- ylmethyl)pyridin-4-yl)-N-(3,4,5- trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide c 5-(2-((3,3-difluoropyrrolidin-1- yl)methyl)pyridin-4-yl)-N-methyl-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide d tert-butyl cyclobutyl((4-(2- (methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)carbamate e tert-butyl (2,2-difluoroethyl)((4-(2- (methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)carbamate f tert-butyl ((4-(2-(methyl(3,4,5- trimethoxyphenyl)carbamoyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)pyridin-2- yl)methyl)(3,3,3- trifluoropropyl)carbamate g N-methyl-5-(2-phenylpyridin-4-yl)-N- (3,4,5-trimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide h N-methyl-5-(2-(thiophen-3-yl)pyridin-4- yl)-N-(3,4,5-trimethoxyphenyl)-1H- pyrrolo[3,2-b]pyridine-2-carboxamide methyl 5-(5-chloro-N-methyl-1H- pyrrolo[3,2-b]pyridine-2-carboxamido)- 2,3-dimethoxybenzoate 5-(5-chloro-N-methyl-1H-pyrrolo[3,2- b]pyridine-2-carboxamido)-2,3- dimethoxybenzoic acid

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