Sulfone derivatives

Abstract

The present invention provides compounds as described herein, as well as pharmaceutically acceptable salts thereof. The present invention also relates to the preparation of compounds of the formula, pharmaceutical formulations containing them, and their use as medicaments.

Description

Sulfone derivatives The present invention provides compounds that are inhibitors of human methionine adenosyltransferase 2A (Mat2A) for use in treating, preventing and / or delaying the progression of cancer. In particular, the present invention relates to compounds of formula I. in which X1 is equivalent to N or C. X2 is equivalent to N or CR4. X3 is equivalent to N or CR5. X4 is equivalent to N or CH Provided that no more than two of the cases X1, X2, and X3 represent N; The dotted lines indicate a single or double bond, to allow for the possibility of six-membered rings being aromatic provided that when X1 is N and X2 is C=O then the bond between X1 and X2, the bond between X2 and X3, bonds a and c are single bonds and the bond between X3 and CR7 and b are double bonds; and provided that when X1 is N and X2 is not C=O then the bond between X1 and X2, the bond between X3 and CR7, bonds b and c are single bonds and the bond between X2 and X3 and bond a are double bonds; R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j; R4a, R4b and R4c are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4d, R4e and R4f are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4h and R4g are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4i and R4j are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2; and its pharmaceutically acceptable salts. Unless otherwise noted, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of this invention, suitable methods and materials are described below. All publications, patent applications, patent certificates and other references cited herein are incorporated by reference in their entirety. The nomenclature used in this application is based on IUPAC systematic nomenclature, unless otherwise noted. Any open valence shown on a carbon, oxygen, sulfur, or nitrogen atom in the structures shown here indicates the presence of a hydrogen, unless otherwise specified. "Halo" or "halogen" means fluoro, chloro, bromo or iodo, especially chloro or fluoro. "Hydroxy" refers to an -OH group. "(C1-C6)alkyl" refers to a hydrocarbon chain consisting of one to six straight-chain or branched carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl. "(C1-C6)alkoxy" means a moiety of the formula -ORa, where Ra is a (C1-C6)alkyl moiety as defined herein. Examples of (C1-C6)alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The term "(C3-C6)cycloalkyl" means a monovalent, saturated, monocyclic hydrocarbon group consisting of 3 to 6 ring carbon atoms. Examples of monocyclic (C3-C6)cycloalkyl include cyclopropyl, cyclobutanyl, cyclopentyl, or cyclohexyl. A specific example of (C3-C6)cycloalkyl is cyclopropyl. "(C3-C6)cycloalkyl-(C1-C6)alkyl" refers to a (C1-C6)alkyl, as defined above, substituted with one or more (C3-C6)cycloalkyl groups, particularly with a (C3-C6)cycloalkyl group. More particularly "(C3-C6)cycloalkyl-(C1-C6)alkyl" refers to or. The term "perhalo(C1-C3)alkyl" means a (C1-C3)alkyl group as defined above in which all hydrogen atoms have been replaced by halogen atoms. More specifically, "(C1-C3)perhaloalkyl" is equivalent to (C1-C3)perfluoroalkyl, most preferably trifluoromethyl. "Halo-(C1-C6)alkyl" refers to a (C1-C6)alkyl, as defined above, substituted with one or more halogen atoms, especially with one to three halogen atoms. More specifically, halo-(C1-C6)alkyl is equivalent to chloro- and fluoro-(C1-C6)alkyl. In some specific embodiments, halo-(C1-C6)alkyl refers to perhalo(C1-C3)alkyl as defined herein. In particular, halo-(C1-C6)alkyl is equivalent to trifluoromethyl, difluoromethyl or fluoromethyl. "Halo-(C1-C6)alkoxy" refers to a (C1-C6)alkoxy, as defined above, substituted with one or more halogen atoms, especially with one to three halogen atoms. More specifically, halo-(C1-C6)alkoxy is equivalent to chloro- and fluoro-(C1-C6)alkoxy. In some specific embodiments, halo-(C1-C6)alkoxy refers to perhalo(C1-C3)alkoxy, such as trifluoromethoxy or difluoromethoxy. "Hydroxy-(C1-C6)alkyl" refers to a (C1-C6)alkyl, as defined above, substituted with one or more hydroxy groups, especially with a hydroxy group. More specifically, hydroxy-(C1-C6)alkyl refers to methyl-hydroxide or ethyl-hydroxide. "(C1-C6)alkoxy-(C1-C6)alkyl" refers to a (C1-C6)alkyl, as defined above, substituted with one or more (C1-C6)alkoxy groups as defined herein, particularly with a (C1-C6)alkoxy group. More particularly, (C1-C6)alkoxy-(C1-C6)alkyl refers to -CH2-O-CH3 or -CH2CH2-O-CH3. "Halo-(C1-C6)alkoxy" refers to an alkoxy, as defined above, substituted with one or more halogen atoms, especially with one to three halogen atoms. More specifically, halo-(C1-C6)alkoxy is equivalent to chloro- and fluoro-(C1-C6)alkoxy. "Heteroaryl" means a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms each independently selected from N, O, or S (preferably N or O), with the remainder being C ring atoms, provided that the point of attachment of the heteroaryl moiety is on an aromatic ring. More specifically, the term heteroaryl includes, but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothinyl, imidazo[‎1,2-a]-pyridinyl, imidazo[‎2,1-b]thiazolyl, and derivatives thereof. "N-Heteroaryl" refers specifically to heteroaryl as previously defined containing at least one nitrogen atom.The point of attachment of the N-heteroaryl to the rest of the molecule can be through nitrogen or a carbon ring atom. Examples of N-heteroaryl include pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl. The term "heterocycloalkyl" or "heterocyclic" means a monovalent saturated or semi-saturated monocyclic or bicyclic ring system with 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, the remaining ring atoms being carbon. Examples of heterocycloalkyl include pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thynyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azpanyl, diazpanyl, homopiperazinyl, or oxazapanyl. More specifically, heterocycloalkyl refers to dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyl, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazyl, 1,2,3,4-tetrahydropyrazyl. The term "therapeutically effective amount" refers to an amount of a compound or molecule of the present invention that, when administered to a subject, will (i) prevent or treat a particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a disease, condition, or disorder described herein. The therapeutically effective amount will depend on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and method of administration, the judgment of the treating physician or veterinarian, and other factors. The term "optional" or "optionally" means that the subsequently described event or condition may occur, but its occurrence is not necessary, and the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur. For example, "aryl group optionally substituted with an alkyl group" means that alkyl may be present but its presence is not necessary, and the description includes instances in which the aryl group is substituted with an alkyl group and instances in which the aryl group is not substituted with an alkyl group. The terms "individual" or "subject" refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., human primates and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some specific instances, the individual or subject is a human. The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to the compounds disclosed herein and the stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. While the compounds of this invention are solids, it will be apparent to those skilled in the art that these compounds, and their solutes and salts, may exist in various solid forms, particularly various crystalline forms, all of which are within the scope of the present invention and the formulae recited. The term "pharmaceutically acceptable salts" means salts that do not have undesirable biological or other properties. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, Acid, mandelic acid, ambonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid have been formed. The term "pharmaceutically acceptable base-added salt" refers to pharmaceutically acceptable salts formed from an organic or inorganic base. Examples of acceptable inorganic bases include salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins. The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical formulation that has a specific biological activity. The terms "pharmaceutical composition or formulation" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and pharmaceutically acceptable excipients for administration to a mammal, e.g., a human, in need thereof. The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable substance in a pharmaceutical formulation that lacks therapeutic activity and is non-toxic to the individual to whom it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in the formulation of pharmaceutical products. The term "treating" or "treating" a disease state includes either inhibiting the disease state, in other words, stopping the progression of the disease or its clinical symptoms, or alleviating the disease state, in other words, causing temporary or permanent regression in the disease state or its clinical symptoms. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers or spatial isomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, if a carbon atom is attached to four different groups, a pair of enantiomers is possible. The identity of an enantiomer can be determined by the absolute configuration of its asymmetric center and described by the R and S sequencing rules of Kahn, Ingold, and Prolog, or by the way in which the molecule rotates the plane of polarized light, known as dextrorotatory or levorotatory isomers (in other words, as (+) or (-) isomers, respectively). A chiral compound can exist as a single enantiomer or as a mixture of them.A mixture containing equal proportions of enantiomers is called a "racemic mixture". Compounds of formula I may have one or more asymmetric centers or axes. The description or naming of a particular compound in the specification and claims includes both the single enantiomers, atropisomers and mixtures, racemic or otherwise, as well as the single epimers, atropisomers and mixtures thereof, unless otherwise indicated. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992). Some specific compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto / enol tautomers (-C(=O)-CH- ↔ -C(-OH)=CH-), amide / imidic acid tautomers (-C(=O)-NH- ↔ -C(-OH)=N-), and amidine (-C(=NR)-NH- ↔ -C(-NHR)=N-). The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds. It has now been determined that the compounds of Formula I are inhibitors of Mat2A and may have therapeutic utility in the treatment of cancer disorders including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma. These compounds are potent inhibitors of methionine adenosyltransferase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity, thereby producing S-adenosylmethionine (SAM), the major methyl donor in cells. MAT1A is a liver-specific enzyme that produces SAM, whereas MAT2A is widely expressed elsewhere except in the liver. MAT2A is found in complex with MAT2B (methionine adenosyltransferase II beta), an allosteric regulator of MAT2A, and MAT2B acts as a rheostat for the enzymatic activity of MAT2A. When MAT2B binds to MAT2A, MAT2A undergoes a conformational change that increases its affinity for methionine and SAM. The net effect is that MAT2A, bound to MAT2B, is more active under low concentrations of methionine, but is inhibited under high concentrations of methionine. Loss-of-function mutations in tumor suppressor genes are critical in the molecular pathogenesis of cancer, however, successful targeting of tumor suppressors has been elusive, largely because the mutated proteins cannot be directly inhibited for therapeutic benefit, and restoration of mutant function (such as restoration of mutant p53 function) has not been possible to date. The recent clinical success of PARP inhibition in patients with BRCA1 / 2 deficiencies has demonstrated that targeting conditional synthetic killers (CSLs) caused by loss-of-function mutations in tumor suppressors is a clinically valid approach to treating cancers. The CSL relationship is not only valid for tumor suppressors but can also be extended to genes located in the same genetic region as the tumor suppressor and lost by deletion of that region. Methylthioadenosine phosphorylase (MTAP) is one such gene, located very close to the tumor suppressor CDKN2A, and is deleted in ~15% of all cancers.MTAP is deleted in ~53% of, but not limited to, glioblastoma multiforme (GBM), ~25% of pancreatic adenocarcinoma (PDAC), ~25% of melanoma, ~23% of squamous cell carcinoma of the lung, ~20% of head and neck squamous cell carcinoma, and ~15% of lung adenocarcinoma. In fact, this deletion occurs in several indications, many of which are areas for which there are no effective treatments and therefore an unmet need for the development of new treatments. In glioblastoma, with a median survival of 14 months, the approval of the latest treatments has not significantly increased overall survival (OS) and the standard of care (SoC) has remained unchanged for over a decade. The same is true for most patients with PDAC whose OS is less than 1 year. MTAP deletion is a somatic event that occurs early in tumor growth and can occur at all stages of tumor evolution, including metastasis.Its loss therefore represents a change that is not affected by tumor heterogeneity, genetic background, or resistance to clinically validated agents. A CSL relationship identified for MTAP deficiency is a real weakness for various tumor indications. MTAP is located in close proximity to the tumor suppressor CDKN2A on chromosome 9. When CDKN2A is deleted, MTAP is often deleted at the same time. Its loss is thought to be a bystander effect and phenotypically neutral. MTAP is a building block of the adenine and methionine salvage pathways in cells. The methionine salvage pathway drives the production of SAM, and SAM levels are a key regulator of cancer cell growth that must be carefully regulated because large changes in SAM concentrations, either increased or decreased, lead to cell cycle arrest. The importance of SAM levels for cancer development lies in its central role in methylation, DNA, RNA, and protein, acting as a checkpoint for cellular health, and decreased SAM and increased SAM lead to hypomethylation and hypermethylation, respectively. In cells lacking MTAP, methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) accumulate without negatively affecting the levels of any of the salvage products / metabolites, including SAM.This accumulation creates a new stress on the cell, in which MTA, due to its structural similarity to SAM, acts as a competitive inhibitor of SAM-dependent reactions. Loss of MTAP forces the cell to adapt to the new MTA / SAM paradigm without loss of viability, whereas a cell with MTAP does not have to make this adaptation without difficulty, and this adaptation is mediated by a strong dependence on methionine adenosyltransferase II alpha2 (MAT2A), one of the enzymes that produces SAM, in MTAP-deficient cells. This conditional synthetic lethal (CSL) relationship between MTAP loss and MAT2A dependence was identified in three large-scale shRNA screens (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016). Targeting MAT2A with a small molecule inhibitor would be beneficial for genetically defined patient populations that represent many areas of high unmet medical need. The present invention provides compounds of formula I, the use of such compounds for the preparation of medicaments for the treatment, prevention and / or delaying the progression of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly for the treatment of cancer including lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck, the production and medicaments or treatments thereof based on a compound of formula I according to the present invention. Further objects of the present invention are all forms of pure optical enantiomers, racemates or diastereomeric mixtures for compounds of formula I. In particular, the present invention relates to compounds of formula Ia in which X1 is equivalent to N or C; X3 is equivalent to N or CR5. The dotted line represents a double bond, which allows six-membered rings to be aromatic, provided that when X1 is N and R4 is exo, the bond is a single bond; R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j; R4a, R4b and R4c are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4d, R4e and R4f are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4h and R4g are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4i and R4j are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2; and its pharmaceutically acceptable salts. In particular, the present invention relates to compounds of formula Ib in which X3 is equivalent to N or CR5. R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j; R4a, R4b and R4c are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4d, R4e and R4f are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4h and R4g are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4i and R4j are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2; and its pharmaceutically acceptable salts. In another embodiment, the present invention relates to compounds of formula Ic in which R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2; and Pharmaceutically acceptable salts are derived from it. In another embodiment, the present invention provides a compound of formula Id, in which R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j; R4a, R4b and R4c are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4d, R4e and R4f are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4h and R4g are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4i and R4j are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2; and It has presented pharmaceutically acceptable salts thereof. In another embodiment, the present invention relates to compounds of formula Ie in which R1 is equivalent to -SO2R1a or -SOR1b; R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl; or R2' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R2” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3' is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R3” is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(C1-C6)alkoxy; R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j; R4a, R4b and R4c are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4d, R4e and R4f are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4h and R4g are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R4i and R4j are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl and oxanyl; R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, oxanyl or thiophenyl or -SO2R6a; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl or halo(C1-C6)alkyl; R7 is hydrogen, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, halo-(C1-C6)alkoxy or NR7'aR7'b, where one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkyl-O-(C1-C6)alkyl-NHCO-(C1-C6)alkyl, -(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NHCO-(C1-C6)alkyl or -(C1-C6)alkyl-NH2, and Pharmaceutically acceptable salts are derived from it. Also, it is apparent that any example associated with a particular X1, X2, X3, X4, R1, R1a, R1b, R1'a, R1'b, R2', R2”, R3', R3”, R4, R4a, R4b, R4c, R4d, R4e, R4f,R4h, R4g, R4i, R4j, R5, R6, R6a, R7, R7'a and R7'b disclosed herein may be combined with any other example associated with X1, X2, X3, R1, R1a, R1b, R1'a, R1'jjb, R2', R2”, R3', R3”, R4, R4a, R4b, R4c, R4d, R4e, R4f, R4h, R4g, R4i, R4j, R5, R6, R6a; R7, R7'a and R7'b are further combined as disclosed herein. A specific example of the present invention relates to a compound of formula I, wherein X4 is N. A specific embodiment of the present invention relates to a compound of formula I, wherein X1 is N or C, X2 is N or CR4, and X3 is N or CR5. A specific example of the present invention relates to a compound of formula I, wherein X1 is C. A specific example of the present invention relates to a compound of formula I, wherein X2 is CR4. A specific example of the present invention relates to a compound of formula I, wherein X3 is N. A specific embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R1 is -SO2R1a. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, NR1'aR1'b, oxtanyl, furanyl and pyranyl, wherein at least one of R1'a and R1'b is (C1-C6)alkyl and the other is H or (C1-C6)alkyl, in particular wherein R1a is selected from (C1-C3)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl-(C1-C3)alkyl, halo(C1-C3)alkyl, hydroxy(C1-C3)alkyl, (C1-C3)alkoxy-(C1-C3)alkyl, NR1'aR1'b and oxanyl are selected, wherein at least one of R1'a and R1'b is (C1-C3)alkyl and the other is H or (C1-C3)alkyl, more particularly wherein R1a is selected from methyl, ethyl, propyl, i-propyl, i-butyl, cyclopropyl, ,., fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methylamino (-NHCH3), dimethylamino (-N(CH3)2) and oxanyl, even more particularly wherein, R1a is selected from ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl and 1,2,2-trifluoroethyl, especially wherein, R1a is selected from methyl, Ethyl, cyclopropyl, and difluoromethyl are selected. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R1b is (C1-C6)alkyl, more particularly (C1-C3)alkyl, especially methyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie. If R2' is other than hydrogen as defined herein, then R3' is hydrogen, R2' is hydrogen and R3' is as defined herein, and conversely, if R2' is other than hydrogen, then R3' is hydrogen, R2' is hydrogen and R3' is as defined herein. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein one of R2' and R2" is hydrogen, halogen, -NH2, (C1-C2)alkyl, (C1-C2)alkoxy or halo(C1-C2)alkyl, while the other is hydrogen, in particular wherein R2' is hydrogen, halogen, -NH2, methyl, ethyl, methoxyfluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl or 1,2-difluoroethyl, and R2" is hydrogen, more particularly R2' is methyl, ethyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, and R2" is hydrogen, in particular R2' is methyl or is difluoromethyl and R2” is hydrogen. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein one of R3' and R3" is hydrogen, halogen, -NH2, (C1-C3)alkyl, (C1-C3)alkoxy or halo(C1-C3)alkyl, while the other is hydrogen, more particularly R3" is hydrogen, halogen or (C1-C3)alkyl and R3' is hydrogen, even more particularly R3" is hydrogen or fluorine and R3' is hydrogen, in particular both R3' and R3" are hydrogen. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Id or Ie wherein R4 is cyano, oxo, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, halo(C1-C6)alkoxy, (C1-C3)alkoxy-(C1-C3)alkyl, (C3-C4)cycloalkyl, -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R4g or -SO2(NR4i)R4j, in particular wherein R4 is cyano, oxo, hydroxy, (C1-C2)alkoxy, halo(C1-C2)alkyl, halo(C1-C2)alkoxy, (C1-C2)alkoxy-(C1-C2)alkyl, cyclopropyl, -CO‎2H, --CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, or -SO(NH)CH3, especially where R4 is cyano, oxo, hydroxy, methoxy, -CF3, -OCF3, -methyl-methoxy, cyclopropyl, -CO‎2H, --CONR4bR4c, -SO2R4d, -SOR4e, or -SR4f, especially R4 is cyano, oxo, -CONHR4c, or -SO2R4d. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Id or Ie, wherein R4a, R4b and R4c are independently selected from hydrogen, (C1-C3)alkyl, (C3-C4)cycloalkyl, and oxanyl, in particular wherein R4a, R4b and R4c are independently selected from hydrogen, (C1-C3)alkyl, cyclopropyl, and oxanyl, more particularly R4a, R4b and R4c are independently selected from hydrogen, (C1-C3)alkyl and cyclopropyl, in particular R4a and R4b are hydrogen, R4c is hydrogen or methyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Id or Ie wherein R4d, R4e and R4f are independently selected from (C1-C3)alkyl, (C3-C4)cycloalkyl, and oxanyl, in particular wherein R4d, R4e and R4f are independently selected from (C1-C3)alkyl, cyclopropyl, and oxanyl, more particularly R4d, R4e and R4f are independently selected from (C1-C3)alkyl and cyclopropyl, in particular R4d is methyl or cyclopropyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Id or Ie, wherein R4h and R4g are independently selected from hydrogen and (C1-C6)alkyl, especially hydrogen and (C1-C3)alkyl, more particularly wherein R4h is hydrogen and R4g is (C1-C3)alkyl, especially wherein R4h is hydrogen and R4g is methyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Id or Ie, wherein R4i and R4j are independently selected from hydrogen and (C1-C6)alkyl, in particular from hydrogen and (C1-C3)alkyl, more particularly wherein R4i is hydrogen and R4j is (C1-C3)alkyl, in particular wherein R4i is hydrogen and R4j is methyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic or Id, wherein R5 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl, in particular R5 is hydrogen, halogen, (C1-C2)alkyl, (C1-C2)alkoxy or (C3-C4)cycloalkyl, more particularly R5 is hydrogen, fluoro, chloro, cyclopropyl, methyl or methoxy, in particular R5 is hydrogen. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R6 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, thiophenyl, oxtanyl or -SO2R6a, wherein R6a is (C1-C6)alkyl, in particular R6 is bromo, (C1-C3)alkyl, (C1-C3)alkoxy, cyano, halo(C1-C3)alkyl, halo(C1-C3)alkoxy, (C3-C4)cycloalkyl, thiophenyl, oxtanyl or -SO2R6a, wherein R6a is (C1-C6)alkyl, in particular R6 is halo(C1-C3)alkyl, halo(C1-C3)alkoxy or (C3-C4)cycloalkyl, more particularly R6 is trifluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R6a is (C1-C6)alkyl, more particularly R6a is methyl. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein R7 is hydrogen, halogen, hydroxy or (C1-C6)alkyl, in particular R7 is hydrogen, halogen or hydroxy, more particularly R7 is hydrogen. A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Ie, wherein one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C3)alkyl-O-(C1-C3)alkyl-NHCO-(C1-C3)alkyl, -(C1-C3)alkyl-O-(C1-C3)alkyl-NH2, -(C1-C3)alkyl-NHCO-(C1-C3)alkyl or -(C1-C3)alkyl-NH2, in particular wherein one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C6)alkyl, or (C1-C6)alkoxy, more particularly wherein one of R7'a and R7'b is hydrogen and the other is hydrogen, (C1-C3)alkyl, or (C1-C3)alkoxy, Specific compounds of formula I of the present invention are those selected from the group consisting of: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine; 4-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine; 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 2-Chloro-4-(3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridin-4-yl)-‎N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[‎3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[‎4,3-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine;3-Cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine;3-Isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-4-(‎2,5-dimethyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine hydrochloride; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-‎1H-indazole-5-carbonitrile; 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine hydrochloride 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridin-7-ol 4-(3-methyl-4-(methylsulfonyl)phenyl)-‎3-(thiophen-3-yl)-‎1H-pyrazolo[‎4,3-c]pyridine; 3-Cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine; 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎4,3-c]pyridine; 3‎-(difluoromethoxy)-4-[4‎-(difluoromethylsulfonyl)-3-methyl-phenyl]-‎1H-pyrazolo[‎4,3-c]pyridine;4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-[difluoromethoxy]-4-(3-methyl-4-propylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-[difluoromethoxy]-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 3-[difluoromethoxy]-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-[3-(Difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethyl-benzenesulfonamide; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile;6-Chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-methyl-4-(oxetan-3-ylsulfonyl)phenyl]-1H-pyrazolo[4,3-c]pyridine; 2-[4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-methyl-phenyl]sulfonylethanol 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 2,2,2-trifluoroacetic acid; 3-(Difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-d]pyridazine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-‎1H-indazole; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-‎1H-indazole;3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(difluoromethoxy)-4-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine Formic acid; 5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine; 3-Cyclopropyl-‎N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine;3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3,5-Dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; N,3-Dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile; 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile; 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-‎1H-indazole 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-‎1H-indole-5-carbonitrile; 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-indazole-5-carboxamide; 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-‎1H-indazole-5-carboxamide;6-Chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1#H!-indazole-5-carbonitrile; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile; 4‎-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-‎1H-pyrazolo[‎4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-pyrrolo[‎3,2-b]pyridin-5-one; 4-[3-(Difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide; 3-[difluoromethoxy]-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;3-(Difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-(difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole; 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-‎1H-indazol-5-yl]-imino-methyl-oxo-sulfane; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-‎1H-indazol-5-yl]-methyl-methylimino-oxo-λ⁶-sulfane; 3-cyclopropyl-‎N,N-dimethyl-4-(3-methyl-4-methylsulfonylphenyl)-‎1H-indazole-5-sulfonamide;3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-indazole-5-sulfonamide; 4‎(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide; 3‎(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-‎1H-indazole; 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-‎1H-indazole; 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole; or 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide and the pharmaceutically acceptable salts thereof have been selected. Specific compounds of formula I of the present invention are those selected from the group consisting of: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; or 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide and the pharmaceutically acceptable salts thereof have been selected. In another embodiment, the present invention provides a compound according to Formula I, Ia, Ib, Ic, Id or Ie as described herein for use as a therapeutic active ingredient. In yet another embodiment, the present invention provides a compound according to Formula I, Ia, Ib, Ic, Id or Ie as described herein for the treatment, prevention and / or delaying the progression, more particularly for the treatment of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma. In another embodiment, the present invention provides the use of a compound according to formula I, Ia, Ib, Ic, Id or Ie as described herein for the preparation of a medicament for the treatment, prevention and / or delaying the progression, more particularly for the treatment of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma. In one instance, this application provides a method for treating a Mat2A disorder in a subject having a Mat2A-related disorder, said method comprising administering to the subject a therapeutically effective amount of any of the above compounds. In another embodiment, the present invention provides a method for treating, preventing and / or delaying the progression, more particularly treating cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising administering an effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, or Ie as described herein. In a specific embodiment, the present invention provides a method for treating, preventing and / or delaying the progression, more particularly treating cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising administering a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, or Ie as described herein. In particular, Mat2A disorders or Mat2A-related diseases are cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma. In one case, this application provides a pharmaceutical formulation comprising the compound recited in any of the above examples, admixed with at least one pharmaceutically acceptable carrier, such as an excipient or diluent. In another embodiment, the present invention provides the use of a compound of formula I, Ia, Ib, Ic, Id or Ie in the preparation of a medicament for treating, preventing and / or delaying the progression, more particularly for treating Mat2A-associated diseases. In another embodiment, the present invention provides medicaments comprising a compound of formula I, Ia, Ib, Ic, Id or Ie as defined herein or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for their manufacture, which comprises mixing one or more compounds of formula I, Ia, Ib, Ic, Id or Ie and / or pharmaceutically acceptable acid addition salts thereof, and, optionally, one or more other substances of therapeutic value in the form of a galenic medicament together with one or more therapeutically inert carriers. Another embodiment provides pharmaceutical formulations or medicaments comprising the compounds of this invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of this invention to prepare such formulations and medicaments. The formulations are formulated, dosed, and administered in a manner consistent with appropriate medical practice. Factors to be considered in this regard include the particular disorder to be treated, the mammal being treated, the clinical condition of the patient, the cause of the disorder, the site to which the agent is to be delivered, the route of administration, the timing of administration, and other factors known to the medical professional. For example, such a dose may be below the toxic dose to normal cells, or to the mammal as a whole. The compounds of this invention can be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, injectable, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intraspinal, epidural, and intranasal, and if desired, intralesional administration is possible for local treatment. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous injections. The compositions of the present invention may be administered in any suitable manner, including tablets, coated tablets, dragees, powders, capsules (soft and hard gelatin capsules), solutions (i.e., injectable solutions), dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, wound dressings or adhesives, eye drops, ear drops, etc. Such compositions may contain conventional ingredients in pharmaceutical preparations, for example, diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents. A typical formulation is prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers and excipients are well known to those skilled in the art and are described in detail in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier may be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.In powders, the carrier is generally a soft powdered solid in admixture with the powdered active ingredient. In tablets, the active ingredient is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted into the desired size and shape. Powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The dosage at which the compounds of the invention may be administered may vary within wide limits and will of course be tailored to the individual requirements in each particular case. In general, in the case of oral administration, a daily dose of about 0.01 to 1000 mg per person of a compound of formula I, Ia, Ib, Ic, Id or Ie should be suitable, although the above upper limit may be exceeded if necessary. An example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of a compound of the invention combined with about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powdered materials are first mixed together and then mixed with a solution of PVP. The resulting formulation can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. An example of an aerosol formulation can be prepared by dissolving, for example, 10 to 100 mg, of the compound of the invention in a suitable buffer solution, for example, a phosphate buffer, adding a tonicifier, for example, a salt such as sodium chloride, if desired. For example, the solution can be filtered, for example, using a 0.2 μm filter, to remove impurities and contaminants. Thus, one embodiment comprises a pharmaceutical formulation comprising a compound according to the invention described herein, or a stereoisomer thereof. In another embodiment comprises a pharmaceutical formulation comprising a compound according to the invention described herein, or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or excipient. The compounds of the present invention can be used, alone or in combination with other drugs, to treat, prevent and / or delay the progression of Mat2A-related diseases, particularly cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma. A particular embodiment of the present invention relates to pharmaceutical formulations comprising compounds of formula I, Ia, Ib, Ic, Id or Ie or pharmaceutically acceptable salts thereof as defined above and one or more pharmaceutically acceptable excipients for use in the treatment, prevention and / or delaying the progression of cognitive impairment associated with cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma. Another example includes a pharmaceutical formulation comprising a compound according to the invention described herein for use in the treatment, prevention and / or delaying the progression, more particularly in the treatment of Mat2A-related diseases. Another example includes a pharmaceutical formulation comprising a compound according to the invention described herein for use in the treatment, prevention and / or delaying the progression, more particularly in the treatment of Mat2A-related diseases. In another embodiment, the present invention provides for the production of compounds of formula I, Ia, Ib, Ic, Id or Ie described herein. The preparation of compounds of formula I, Ia, Ib, Ic, Id or Ie of this invention can be carried out using sequential or convergent or convergent synthetic steps. The syntheses of this invention are shown in the schematic diagram below. The skills required to carry out the reaction and purify the products obtained are known to those skilled in the art. When a mixture of enantiomers or diastereomers is produced during a reaction, these enantiomers or diastereomers can be separated by the methods described herein or by methods known to those skilled in the art, for example, such as chiral chromatography or crystallization. The compounds of the present invention can also be prepared from commercially available starting materials or by using general synthetic approaches and techniques known to those skilled in the art. The following are suitable reaction schemes for preparing such compounds. The substituents and indices used in the following description of the processes are of significance herein. Further examples can be found in the specific examples described below. General synthesis More specifically, compounds of formula I, Ia, Ib, Ic, Id or Ie and their intermediates may be prepared by Schemes 1 to 2 and by explaining specific examples. A subgroup of compounds of formula I, Ia, Ib, Ic, Id or Ie, wherein X is halo, X1 is C, X4 is CH, R2” and R3' are H, and R7 is H and X2, X3, R1a, R2', R3”, R4, R5 and R6 are as previously defined, can be prepared as outlined in Schemes 1-2 below. Plan 1 Wherein, X is halo, Rb is H or is cyclized to form a pinacol ester, and X2, X3 and R6 are as previously defined. Dihalide A was deprotonated with strong bases (e.g. n-BuLi, LDA, LiHDMS, TMPMgCl.LiCl) at reduced temperature (-78°C) in THF and then reacted with aldehydes to give alcohol II (as described in Synthesis, 1988, p. 803–805), or with appropriate esters to give ketone III directly (as described in Journal of Organic Chemistry, 2007, pp. 2501–2507). Alternatively, alcohol II could be oxidized to ketone III using common oxidizing agents (e.g., MnO2, Des-Martin periodinane, TEMPO / PhI(OAc)2) in dichloroethane. Ketone III can then be reacted with hydrazine (aqueous or monohydrate) at ambient or reduced temperatures in THF, dioxane, or ethanol to afford pyrazoles IV (as described in Journal of Medicinal Chemistry, 2019, pp. 531–551).Alternatively, ketone III can be coupled with boronic esters or acids X in a Suzuki-Miura coupling in dioxane / water mixtures at elevated temperatures (e.g. 80°C-120°C) under palladium catalysis (e.g., Pd(dppf)) in the presence of carbonate bases (e.g., K2CO3, Cs2CO3) to give ketone VII, which is similarly cyclized with hydrazine to give pyrazole VIII. Alternatively, N-pyrazole IV can be protected under standard conditions (e.g., SEM, THP, or trityl), reacted analogously with boronic acid or esters X, and then deprotected with strong acids (e.g., 4N HCl in dioxane or TFA) to give pyrazole VIII. Plan 2 Where X is halo, Rb is H or cyclizes to give the pinacol ester. Alternatively, the pyrazole core III can be prepared from the anilines A1 described in Journal of the American Chemical Society, 1954, 1176. Subsequent halogenation with halo-succinimides in polar solvents (e.g., DMF) produces halo-pyrazole IV. Protection of pyrazole IV with N (e.g., SEM, THP, or trityl) under standard conditions allows for subsequent halogenation (e.g., Suzuki coupling) to produce pyrazole VI. Halogenation of VI can be effected using halo-succinimides as before to give pyrazole VII, which is then coupled with boronic esters or acids and deprotected as described in Scheme 1. A subgroup of compounds of formula I or Ia, wherein X is halo, X1 is N, X2 is C=O, X3 is CH, R2” and R3' are H, and R7 is H, and X4, R1a, R2', R3”, R4, R5 and R6 are as previously defined, can be prepared according to Scheme 3, which is summarized below. Plan 3 Pyridone structures were first prepared by protecting the pyrazole or pyrrole nitrogens of A2 with suitable protecting groups, e.g., (THP, SEM, trityl) under standard conditions to produce II. Derivatization of halogen X (e.g., by Suzuki coupling) produced III, which could be converted to pyridone by treatment under strongly acidic conditions (e.g., hydrochloric acid in dioxane) which in some cases led to the removal of the protecting group (PG), necessitating the reinsertion of this group to obtain IV. Cham-Lam coupling of boronic acids V under the catalysis of copper(II) acetate with a mixture of pyridine and triethylamine produced derivative VI, which after standard removal of the protecting group (e.g., 4N HCl in dioxane, TFA) produced the final compounds VII. General trends Plan 4 Where X is equivalent to halo and X2, X3 and R6 are as defined previously. General process A: Aryl / heteroaryl functionalization To a cooled -78°C solution of an aryl or heteroaryl halide (eq: 1) in anhydrous THF (0.1 M) under argon was added dropwise lithium diisopropylamine or nBuLi (eq: 1.1-1.5). After stirring for a suitable period of time (10 min to 1 h), the required electrophile (aldehyde, ester or chloroformate eq: 1.5-2) was added and the reaction stirred for a longer period of time (10 min to 1 h) at the same temperature. After which the reaction was quenched at -78°C by addition of saturated aqueous ammonium chloride solution, the reaction temperature was brought to room temperature, diluted with ethyl acetate, the organic material was washed with water, brine, dried (Na2SO4) and concentrated. The crude products can be used directly in the next step or purified by flash column chromatography. Plan 5 Where, X is equivalent to halo and X2, X3, and R6 are as defined previously. General process B1: Oxidation of benzyl alcohol with Des-Martin periodinane To a solution of benzyl alcohol (equivalent: 1) in dichloromethane (0.1 M) was added Des-Martin periodinane (equivalent: 1.3) and the reaction was stirred until completion (1 h). The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. General process B2: Oxidation of benzyl alcohol with TEMPO To a solution of benzyl alcohol (1 equiv.) in dichloromethane (0.1 M) was added TEMPO (1 equiv.) followed by (diacetoxyiodo)benzene (1 equiv.) and the reaction was stirred until complete (3 h). The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. Plan 6 Where X is equivalent to halo and X2, X3 and R6 are as defined previously. General process C: Pyrazole cyclization To a solution of the ketone or ester (1 equiv.) dissolved in THF, dioxane or ethanol (0.1 M) at ambient temperature or with cooling, hydrazine (2-5 equiv.) in the presence / absence of additional base (Et3N 1.5 equiv.) was added and the reaction was stirred until complete (1 h). The reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. Overall trend D: Suzuki pairing To a solution of the halide (equivalence: 1) dissolved in dioxane:water (0.1 M, 4:1-10:1) was added potassium carbonate (equivalence: 3-6), boronic acid or the required ester (equivalence: 1-6) and the mixture was degassed by sonication while passing argon through the mixture to create bubbles. The adduct product 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (equivalence: usually 0.05, and 0.5 for difficult cases) was added and the mixture was heated under argon to 100-120°C to consume the starting material (0.5 h-16 h). The reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Alternatively, the reaction mixture can be directly adsorbed onto silica gel and concentrated. The residue is purified by flash column chromatography. General process E1: SEM protection To a solution of pyrazole (eq: 1) dissolved in anhydrous DMF or THF (0.1 M) under argon was added sodium hydride (60% dispersion in mineral oil, eq: 2), the reaction was stirred for 15 min before SEM-Cl (eq: 1.8) was added and the reaction was stirred until the initiator was completely consumed (1 h). The reaction was then diluted with ethyl acetate, extracted with water, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. General trend E2: SEM protection To a solution of pyrazole (equivalent: 1) dissolved in dichloromethane (0.1 M) under argon, DIPEA (equivalent: 1.2) and SEM-Cl (equivalent: 1.2) were added and the reaction was stirred until the starting material was completely consumed (1 h). The reaction was then concentrated and the residue was purified by flash column chromatography. Plan 7 Where, X is equivalent to halo and R1, R2', R2”, R3' and R3” are as defined previously. General process F: Conversion of aryl halides to boronates To a solution of aryl halide (eq: 1) dissolved in dioxane (0.1 M) was added bis(pinacolato)diboron (eq: 1.1), potassium acetate (eq: 3) and the mixture was degassed by sparging with argon under sonication. The adduct [‎1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (eq: 0.1) was added and the reaction was heated until complete conversion (80°C-100°C). The reaction was then diluted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. General process G: Oxidation of sulfides To an ice-cold solution of sulfide (equivalence: 1) in dichloromethane (0.1 M) was added m-chloroperbenzoic acid (equivalence: 1.5, depending on whether sulfoxide or sulfone was required), the ice bath was removed and the reaction was allowed to reach room temperature. Stirring was continued until complete conversion, after which the reaction was diluted with dichloromethane, washed with 1N NaOH, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography. General process H: Trityl deprotection The trityl-protected compound (eq: 1) was dissolved in trifluoroacetic acid (0.1 M) and triethylsilane (eq: 1.5) was added and the reaction was stirred at ambient temperature until complete. The mixture was then carefully poured into saturated aqueous sodium hydrogen carbonate solution, extracted with dichloromethane, the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography or reverse phase preparative HPLC. Overall process I1: THP deprotection The THP-protected compound (1 equiv.) was dissolved in dichloromethane (0.1 M), trifluoroacetic acid (10 equiv.) was added and the reaction was stirred at ambient temperature until complete. The mixture was then diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography or reverse phase preparative HPLC. Overall process I2: THP deprotection The THP-protected compound (equiv.: 1) was dissolved in 4N HCl in dioxane (0.1 M) and the reaction was stirred at ambient temperature until complete. The mixture was then diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography or preparative reverse phase HPLC. General trend J: SEM / MOM deprotection The SEM / MOM protected compound (equiv.: 1) was dissolved in trifluoroacetic acid (0.1 M) and the reaction was stirred at ambient temperature until complete. Evaporation of the trifluoroacetic acid followed by redissolution of the reaction in dichloromethane or dioxane (0.1 M) and addition of ethylenediamine (equiv.: 10) completed the deprotection. The equivalent mixture was then concentrated and purified by flash column chromatography or reverse-phase preparative HPLC. General process J2: SEM deprotection The SEM-protected compound (1 equiv.) was dissolved in 1 M TBAF in THF (10 equiv.) and the reaction was heated to 50°C until complete. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography or reverse phase preparative HPLC. A specific embodiment of the invention relates to a process for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof as defined herein, which comprises deprotecting a compound of formula (Ia) wherein X1, X2, X3, X4, R1, R2', R2”, R3', R3”, R4, R5, R6 and R7 are as defined herein, particularly in the presence of an organic acid (e.g., TFA) or an inorganic acid (e.g., aqueous HCl), as shown in Scheme 8. Plan 8 These compounds were investigated according to the experiment described below. Determination of Mat2A activity Mat2A inhibition measurements were performed in a 384-well format absorbance-based assay. Recombinant human Mat2a (12.5 nM) and compounds serially diluted in DMSO (concentration range from 10 μM to 508 pmol) or controls (DMSO) were incubated for 15 min at room temperature (RT) in assay buffer containing 50 mM HEPES pH 7.5, 50 mM KCl, 50 mM MgCl2, 0.01% Tween 20, and 10 mM DTT. The reaction was initiated by the addition of the combined substrates ATP and methionine, each at a final concentration of 100 μM. The final assay conditions included 12.5 nM Mat2A substrates, 100 μM ATP and methionine, and 2% DMSO. After 120 min of incubation at room temperature, the reaction was stopped by the addition of Biomol Green. The absorbance signal at λ = 635 nm was measured with a multiplate reader (BMG Pherastar reader or equivalent) after 30 min of equilibration at room temperature. The table below shows the data for the selected compounds: Example Number MAT‎2A_LECIC50 (uM)(Num) 1 0 / 048 2 0 / 37 3 0 / 15 4 0 / 24 5 0 / 17 6 0 / 17 7 0 / 046 8 0 / 37 9 0 / 24 10 <0 / 013 11 0 / 28 12 0 / 22 13 0 / 11 14 0 / 099 15 0 / 27 16 <0 / 013 17 <0 / 013 18 0 / 095 19 0 / 042 20 0 / 015 21 0 / 056 22 0 / 15 23 0 / 083 24 <0 / 013 25 0 / 013 26 <0 / 013 27 <0 / 013 28 0 / 51 29 0 / 29 30 0 / 057 31 0 / 033 32 <0 / 013 33 0 / 029 34 <0 / 013 35 0 / 12 36 0 / 051 37 0 / 10 38 0 / 021 39 <0 / 013 40 0 / 029 41 0 / 14 42 <0 / 013 43 <0 / 013 44 0 / 017 45 0 / 02 46 <0 / 013 47 0 / 017 48 0 / 13 49 <0 / 013 50 <0 / 013 51 <0 / 013 52 <0 / 013 53 0 / 062 54 0 / 015 55 <0 / 013 56 0 / 19 57 <0 / 013 58 0 / 24 59 0 / 26 60 0 / 29 61 0 / 25 62 <0 / 013 63 <0 / 013 64 0 / 2 65 0 / 52 66 0 / 13 67 0 / 025 68 <0 / 013 69 <0 / 013 70 0 / 061 71 <0 / 013 72 <0 / 013 73 <0 / 013 74 0 / 11 75 0 / 013 76 0 / 26 77 0 / 013 78 <0 / 013 79 <0 / 013 80 0 / 031 81 0 / 079 82 <0 / 013 83 0 / 5 84 <0 / 013 85 0 / 02 86 <0 / 013 87 <0 / 013 88 <0 / 013 89 0 / 035 90 <0 / 013 91 <0 / 013 92 0 / 029 93 <0 / 013 94 0 / 05 95 <0 / 013 96 <0 / 013 97 <0 / 013 98 <0 / 013 99 0 / 07 100 0 / 03 101 0 / 14 102 0 / 06 103 0 / 04 104 0 / 04 105 <0 / 013 106 <0 / 013 107 0 / 013108 0 / 015 109 <0 / 013 110 <0 / 013 111 <0 / 013 112 0 / 09 113 0 / 31 114 0 / 03 115 0 / 03 116 <0 / 013 117 <0 / 013 118 <0 / 013 119 0 / 02 120 <0 / 013 Laboratory section The following examples are provided to illustrate the invention. They should not be construed as limiting the scope of the invention but are merely illustrative and exemplifying thereof. General Analytical methods HPLC (LCMS_fastgradient method) Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2 / 1x30 mm, 1 / 8µm, part number 959731-902 Solvent A: Water 0.01% formic acid; Solvent B: Acetonitrile (MeCN) Slope: Time [minutes] Flow rate [ml / minute] %A %B Start 0 / 8 97 3 0 / 2 1 / 0 97 3 1 / 7 1 / 0 3 97 2 / 0 1 / 0 3 97 2 / 1 1 / 0 97 3 Abbreviations The following abbreviations are used in the laboratory section: Ar = argon; nBuLi = n-butyl lithium; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; DMF = dimethylformamide; EtOH = ethanol; Ex. No. = example number; HCl = hydrochloric acid; HPLC = high-performance liquid chromatography; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; mCPBA = metachloroperbenzoic acid; Mol = molecular; MOM = methoxymethyl; NMP = N-methyl-2-pyrrolidone; Prep. = product; SEM = [2-(trimethylsilyl)ethoxy)methyl]acetal; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyloxy; TBAF = tetra-n-butylammonium fluoride; TLC = thin layer chromatography; Primer materials Basic chemicals and solvents were purchased and used without further purification. Some of the intermediates are commercially available, or can be synthesized using methods known in the art. Intermediates Intermediate 1: 4-Chloro-3-cyclopropyl-‎1H-pyrazolo[‎4,3-c]pyridine The desired compound ([M+H, Cl]+194.1) was prepared as described in WO2010 / 106333 A1. Intermediate 2: 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine Step 1: 3-Ido-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine 3-Ido-5-methoxy-1H-pyrazolo[3,4-c]pyridine (76006-07-0: WO2015 / 25025 A1) was converted to the title compound ([M+H]+406.2) (with 20% regioisomers) using the general procedure E1. Step 2: 3-Cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine 3-Ido-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (Step 1) was reacted with cyclopropylboronic acid (6 equiv.), potassium carbonate (3 equiv.) under the catalysis of the adduct 1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.1 equiv.) for 4 h according to general procedure D to give the title compound ([M+H]+320.3). Step 3: 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine To a solution of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (Step 2, 20 mg, 63 µmol) in DCM (1 mL) was added N-bromosuccinimide (12 mg, 70 µmol) and the reaction was stirred for 4 h. The reaction was then adsorbed onto silica gel and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) afforded the title compound (18 mg, 65%) as a brown oil ([M+H, Br]+400.2). Intermediate 3: 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine Step 1: 4-Chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine 2,4-Dichloropyridine was deprotonated with nBuLi (1.3 equiv) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 equiv) according to general procedure A to give 1-(2,4-dichloropyridin-3-yl)-2,2,2-trifluoroethan-1-one, which was directly reacted with hydrazine hydrate (5 equiv) in THF initially at -40°C and then with increasing temperature to ambient for 16 h according to general procedure C to give the title compound ([M+H, Cl]+0.220). Step 2: 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine The title compound ([M+H, Cl]+352.2) was prepared from 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 1) using the E2 catalytic procedure. Intermediate 4: 4-Chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine Step 1: 3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine 3-Bromo-4-chloro-‎1H-pyrrolo[‎3,2-c]pyridine was converted to the desired compound ([M+H, Br, Cl]+361.1) using the general E1 procedure. Step 2: 4-Chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine 3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (Step 1) was reacted with cyclopropylboronic acid (6 equiv.), potassium carbonate (6 equiv.), catalyzed by the addition product 1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.15 equiv.) for 1 h at 100°C according to general procedure D to give the desired compound ([M+H, Cl]+2.32). Intermediate 5: 4-bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Step 1: 3-bromo-4-(cyclopropanecarbonyl)-5-fluoroquinonitrile 3-Bromo-5-fluoropicolinonitrile was treated with LDA (2 equiv) for 10 min before addition of cyclopropanecarbaldehyde according to general procedure A to give crude 3-bromo-4-(cyclopropyl(hydroxy)methyl)-5-fluoropicolinonitrile, which was then oxidized to the title compound ([MH, Br]-265.3) using general procedure E2. Step 3: 4-bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile 3-Bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile (Step 2) was reacted with hydrazine hydrate (2 equiv.) in EtOH initially at 0°C and then with increasing temperature to ambient for 1 h according to general procedure C to give the desired compound ([M+H, Br]+1.263). Intermediate 6: 4-Chloro-3-(‎1,1-difluoroethyl)-‎1H-pyrazolo[‎4,3-c]pyridine Step 1: 1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one 2-Chloro-4-fluoropyridine was deprotonated with nBuLi (1.3 equiv.) for 1 h and reacted with ethyl 2,2-difluoropropanoate (1.3 equiv.) according to general procedure A to give the title compound ([M+H, Cl]+1.224). Step 2: 4-Chloro-3-(‎1,1-difluoroethyl)-‎1H-pyrazolo[‎4,3-c]pyridine 1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one (Step 1) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature for 15 min according to general procedure C to give the title compound ([M+H, Cl]+1.218). Intermediate 7: 2-[[4-chloro-3-(difluoromethyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethylsilane Step 1: 1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoroethan-1-one 2-Chloro-4-fluoropyridine was deprotonated with LDA (2 equiv.) for 3 h and reacted with ethyl 2,2-difluoroacetate (1.3 equiv.) for 3 h according to general procedure A to give the desired compound ([MH, Cl]-1.206). Step 2: 4-Chloro-3-(difluoromethyl)-1H-pyrazolo[4,3-c]pyridine 1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoroethan-1-one (Step 1) was reacted with hydrazine hydrate (5 equiv) in THF at -40°C for 1 h according to general procedure C to give the title compound ([M+H, Cl]+0.204). Step 3: 4-Chloro-3-(‎1,1-difluoroethyl)-‎1H-pyrazolo[‎4,3-c]pyridine 4-Chloro-3-(difluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 2) was converted to the title compound ([M+H, Cl]+1.324) along with its regioisomer using the general E2 procedure. Intermediate 8: 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine Step 1: 4-Chloro-‎1H-pyrazolo[‎4,3-c]pyridin-3-ol To a solution of methyl 2-chloro-4-fluoro-pyridine-3-carboxylate (950 mg, 0.5 mmol) in dioxane (9.5 mL) was added hydrazine monohydrate (325 mg, 6.5 mmol) and triethylamine (1.4 mL, 0.10 mmol) and the mixture was heated to 70°C for 16 h. The reaction was diluted with 2-methoxy-2-methylpropane (5 mL) and the precipitate was isolated by filtration to give the title compound (900 mg, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 36.9 - 59.11 (m, 2H), 85.01 - 7.85 (m, 1H), 7.38 - 7.03 (m, 1H). Step 2: 4-Chloro-1-trityl-pyrazolo[‎4,3-c]pyridin-3-ol To a solution of 4-chloro-1H-pyrazolo[4,3-c]pyridin-3-ol (Step 1) (700 mg, 3.7 mmol), triphenylmethyl chloride (1035 mg, 3.7 mmol) in DMF (100 mL) under argon was added triethylamine (1.55 mL, 11.5 mmol) and the reaction was stirred at 30°C for 4 h, after which it was diluted with water and extracted repeatedly with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:6-3:1) afforded the title compound (620 mg, 41%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (d, J = 1.6 Hz, 1H), 7.33 - 7.27 (s, 15H), 6.13 (d, J = 1.6 Hz, 1H). Step 3: 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine A suspension of 4-chloro-1-trityl-pyrazolo[4,3-c]pyridin-3-ol (Step 2) (100 mg, 0.2 mmol), cesium carbonate (158 mg, 0.5 mmol), and 2-chloro-2,2-difluoro-acetyl)sodium oxide (74 mg, 0.45 mmol) in acetonitrile was heated to 80°C for 2 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (100 mg, 89%) as a yellow solid, which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.79 - 7.74 (d, 1H), 7.33 - 7.28 (m, 9H), 7.22 - 6.85 (m, 6H), 7.28-6.85 (t, 1H), 5.99 - 5.94 (m, 1H) Intermediate 9: 4-Chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine Step 1: (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanol 2,4-Dichloropyridine was deprotonated with LDA (1.2 equiv.) for 0.5 h and reacted with xetane-3-carbaldehyde (1.5 equiv.) for 1 h according to general procedure A to give the desired compound ([M+H, Cl]+233.8). Step 2: (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanone (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanol (Step 1) was oxidized using general procedure B1 to give the title compound. ([M+H, Cl]+231.7. Step 3: 4-Chloro-3-(oxetan-3-yl)-‎1H-pyrazolo[‎4,3-c]pyridine (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanone (Step 2) was reacted with hydrazine monohydrate (1.5 equiv.) and triethylamine (1.5 equiv.) in dioxane at 60°C for 1 h according to general procedure C to give the title compound ([M+H, Cl]+209.8). Step 4: 4-Chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine A solution of 4-chloro-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (0.200 mg, 0.95 mmol), p-toluenesulfonic acid monohydrate (18.2 mg, 0.1 mmol), and 3,4-dihydro-2H-pyran (0.44 mL, 4.77 mmol) in THF (20 mL) was heated to 60°C for 16 h. The reaction was quenched by the addition of triethylamine (0.2 mL) and concentrated to dryness. Purification by preparative TLC (n-heptane:ethyl acetate 1:1) afforded the title compound (150 mg, 53%) as a light yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.08 (d, J=0.6 Hz, 1H), 7.35 (d, J=5.9 Hz, 1H), 5.63 (dd, J=2.7, 0.9 Hz, 1H), 5.16 - 5.10 (m, 1H), 5.09 - 4.98 (m, 3H), 4.89 - 4.77 (m, 1H), 3.94 (m, 1H), 3.72 - 3.63 (m, 1H), 2.54 - 2.39 (m, 1H), 2.17 - 1.98 (m, 2H), 1 / 83 - 1 / 63 (m, 3H). Intermediate 10: 4,6-Dichloro-3-cyclopropyl-‎1H-pyrazolo[‎4,3-c]pyridine Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone 2,4,6-Trichloropyridine (300 mg, 1.64 mmol, eq:1) was deprotonated with LDA (0.9 eq) for 1 h and reacted with cyclopropanecarbaldehyde (1.5 eq) for 1.5 h according to general procedure A to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized using general procedure B1 to give the title compound. ([M+H, 2Cl]+1.250. Step 2: 4,6-Dichloro-3-cyclopropyl-‎1H-pyrazolo[‎4,3-c]pyridine Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (Step 2) was reacted with hydrazine monohydrate (5 equiv) in THF at 0°C for 2 h and then at room temperature for 2 h according to general procedure C to give the title compound ([M+H, 2Cl]+1.228). Intermediate 11: 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine Step 1: 3-Ido-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine 3-Ido-5-methoxy-1H-pyrazolo[3,4-c]pyridine (WO2015 / 25025 A1) was converted to the desired compound ([M+H]+406.2) along with its regioisomer using the general procedure E1. Step 2: 5-Methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine To a suspension of 3-iodo-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (Step 1) (70 mg, 0.17 mmol), copper(I) iodide (164 mg, 0.86 mmol) and potassium fluoride (50 mg, 0.17 mmol) in NMP (1 mL) was added (trifluoromethyl)trimethylsilane (0.13 mL, 0.86 mmol) and the mixture was heated under argon to 50°C for 1 h. The reaction was then diluted with water, filtered through Celite®, extracted with ethyl acetate and the organic fraction dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:4) afforded the title compound (32 mg, 53%) as a yellow viscous oil ([M+H]+348.3). Step 3: 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine 5-Methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (Step 2) (32 mg, 0.9 mmol) was dissolved in 1,2-dichloroethane (0.5 mL), N-bromosuccinimide (18 mg, 0.1 mmol) was added, and the mixture was heated to 70°C for 2 h. The reaction was concentrated and purified by flash column chromatography (ethyl acetate:n-heptane 1:4) to give the title compound (20 mg, 51%) as a yellow solid ([M+H, Br]+3.428). Intermediate 12: 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine Step 1: 4-Chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (CAS: 1190313-39-3) (100 mg, 0.4 mmol) and diphenyl(trifluoromethyl)sulfoniumfluoromethanesulfonate (436 mg, 1.1 mmol) were dissolved in DMF (2 mL), and copper (138 mg, 2.2 mmol) was added and the mixture was stirred in a sealed tube under argon for 6 h at 60°C. The reaction was diluted with ethyl acetate, the organic phase was washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 0:1-6:1) afforded the title compound (18 mg, 22%) as a white solid ([M+H, Cl]+0.221). Step 2: 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine 4-Chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine was converted to the title compound ([M+H,Cl]+351.2) using the general E1 procedure. Intermediate 13: 4-Bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-‎2H-pyran-2-yl)-‎1H-pyrazolo[‎3,4-c]pyridine Step 1: 4-Bromo-3-cyclopropyl-1-(tetrahydro-‎2H-pyran-2-yl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 5) (500 mg, 1.9 mmol) was suspended in water (15 mL) and sodium hydroxide (380 mg, 9.5 mmol) was added and the reaction was heated to 100°C for 15 h. The reaction was then acidified with concentrated HCl and the resulting solid was isolated by filtration to give the title compound (435 mg, 77%) as a light brown solid ([M+H, Br]+1.282). Step 2: Methyl 4-bromo-3-cyclopropyl-1-(tetrahydro-‎2H-pyran-2-yl)-‎1H-pyrazolo[‎3,4-c]pyridine-5-carboxylate 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) (300 mg, 1.1 mmol) was suspended in dichloromethane (2 mL) and 3,4-dihydro-2H-pyran (0.5 mL, 3.5 mol) and p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol) was added. The reaction was stirred for 4 h, then diluted with ethyl acetate, washed with 1N HCl, dried (Na2SO4), and concentrated. Crude 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (389 mg, 1.1 mmol) was dissolved in a mixture of DCM / MeOH (6 mL / 3 mL) and trimethylsilyldiazomethane (3.5 mL, 2 M in hexanes, 10.6 mmol) was added. The reaction was stirred for 15 h, after which it was concentrated to dryness. Flash column chromatography (ethyl acetate:n-heptane 4:6) afforded the title compound (320 mg, 90%) as a colorless gum ([M+H, Br]+380.2). Step 3: (4-Bromo-3-cyclopropyl-1-(tetrahydro-‎2H-pyran-2-yl)-‎1H-pyrazolo[‎3,4-c]pyridin-5-yl)methanol Methyl 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (Step 2) (320 mg, 0.8 mmol) was dissolved in THF (10 mL) and cooled to -78°C before adding di-isobutylaluminum hydride (37.3 mL, 1 M in THF, 3.4 mmol) and the reaction was stirred for 90 min before adding another portion of di-isobutylaluminum hydride (37.3 mL, 1 M in THF, 3.4 mmol) and the mixture was stirred for a further 3 h. The reaction was quenched by adding a few drops of water, acidified by adding 1N HCl, extracted with ethyl acetate, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) afforded the title compound (60 mg, 19%) as a light gray solid ([M+H, Br]+354.2). Step 4: 4-bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (4-Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methanol (Step 3) (60 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), triethylamine (49 µL, 0.3 mmol) was added followed by methanesulfonyl chloride (16 µL, 0.2 mmol) and the reaction was stirred for 30 min. Another portion of triethylamine (49 µL, 0.3 mmol) was added followed by methanesulfonyl chloride (16 µL, 0.2 mmol) and the reaction was stirred for an additional 3 h. The reaction was concentrated to dryness, redissolved in DCM (1 mL) and sodium methoxide (0.2 g, 9.3 mmol) was added. After 1 h, the reaction was diluted with saturated aqueous sodium hydrogen carbonate, extracted with DCM and the combined organic phase was dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) afforded the title compound (40 mg, 64%) as a colorless solid ([M+H, Br]+2.368). Intermediate 14: 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole Step 1: 1-(2-Bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one (2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.3 equiv.) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 equiv.) according to general procedure A to give crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one, which was used directly. Crude 1-(2-Bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one (1.8 g, 1.5 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0°C. mCPBA (3.5 g, 11.2 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with dichloromethane, washed repeatedly with 1N NaOH, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 7:3) afforded the title compound (0.1 g, 56%) as a yellow oil. Step 32 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole 1-(2-Bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one (Step 1) was reacted with hydrazine monohydrate (5 equiv) in THF for 1 h at ambient temperature according to general procedure C to give the title compound ([M+H, Br]+1.343). Step 3: 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole (step 3) was converted to the title compound ([M+H,Cl]+351 / 2) using the general procedure of E2. 1H NMR (CHLOROFORM-d, 300 MHz) δ 8.37 (d, 1H, J=1 / 9 Hz), 7.83 (d, 1H, J=1 / 9 Hz), 5.85 (s, 2H), 3.5-3.7 (m, 2H), 3.41 (s, 3H), 0.8-1 / 0 (m, 2H), 0.00 (s, 8H). Intermediate 15: 4-Bromo-3-cyclopropyl-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (intermediate 13, step 1) (3000 mg, 10.6 mmol), methylamine hydrochloride (1070 mg, 15.8 mmol), and diisopropylethylamine (4 mL, 42.2 mmol) in DMF (60 mL) was added TBTU (4068 mg, 12.7 mmol) and the mixture was stirred for 16 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated. Preparative reverse-phase HPLC yielded the title compound (1.6 g, 51%) as a white solid ([M+H, Br]+0.296). Intermediate 16: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole Step 1: Ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.1 equiv) for 30 min and reacted with ethyl chloroformate (1.2 equiv) according to general procedure A to give the title compound. ([M+H,Br]+3.292). Step 2: Ethyl 2-bromo-6-fluoro-3-(methylsulfonyl)-benzoate To a solution of ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (Step 1) (100 mg, 0.3 mmol) in dichloromethane (3 mL) was added mCPBA (153 mg, 0.7 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1N NaOH, dried (Na2SO4) and concentrated to give the title compound (111 mg, quant.) as a light yellow oil. ([M+H, Br]+0.325). Step 3: 4-bromo-5-(methylsulfonyl)-1,2-dihydro-3H-indazol-3-one To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(methylsulfonyl)benzoate (Step 2) (1050 mg, 3.2 mmol) in ethanol (13 mL) was added hydrazine monohydrate (157 µL, 3.2 mmol) followed by triethylamine (0.45 mL, 0.8 mmol) and the reaction was brought to ambient temperature. The reaction was heated to 80°C for 2 h, after which, upon cooling to ambient temperature, the desired product precipitated and was isolated by filtration. The title compound (192 mg, 70%) was obtained as a light yellow solid. ([M+H, Br]+290.9). Step 4: 4-bromo-5-(methylsulfonyl)-1-triethyl-1H-indazol-3-ol To an ice-cold solution of 4-bromo-5-(methylsulfonyl)-1,2-dihydro-3H-indazol-3-one (Step 3) (540 mg, 1.9 mmol) in DMF (20 mL) was added trityl chloride (517 mg, 1.9 mmol) followed by sodium hydride (89 mg, 60% dispersion in mineral oil, 2.2 mmol), the cooling bath was removed and the reaction was stirred at ambient temperature for 2 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9-1:0) afforded the title compound (460 mg, 43%) as a colorless solid. ([MH, Br]-533.3). Step 5: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole To a solution of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Step 4) (250 mg, 0.5 mmol) in DMF (7.5 mL) was added sodium chlorodifluoroacetate (143 mg, 0.9 mmol) and potassium carbonate (194 mg, 1.4 mmol) and the mixture was heated to 80°C for 30 min. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 5:95-1:0) afforded the title compound (192 mg, 70%) as a light yellow solid. ([M+H-Tr, Br]+1.339). Intermediate 17: 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile Step 1: Ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate 3-Bromo-5-fluoropicolinonitrile was deprotonated with a solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (2.5 equiv) in THF at -78°C for 1 h and then reacted with ethyl cyanoformate according to general procedure A to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.8 (s, 1H), 4.60 - 4.44 (m, 2H), 1.43 (t, J = 2.7 Hz, 3H). Step 2: 4-Bromo-3-oxo-1,2-dihydropyrazolo[‎3,4-c]pyridine-5-carbonitrile To a solution of ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate (Step 1) (0.5 g, 18.3 mmol) in ethanol (50 mL) was added hydrazine monohydrate (1.9 mL, 36.6 mmol) and the reaction was heated to 70°C for 2 h. The reaction was concentrated to dryness and the residue was purified by solid phase HPLC to give the title compound (3.5 g, 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 13.15 (s, 1H), 11.74 (s, 1H), 8.88 (s, 1H). Step 3: 4-Bromo-3-hydroxy-1-trityl-pyrazolo[‎3,4-c]pyridine-5-carbonitrile To a solution of 4-bromo-3-oxo-1,2-dihydropyrazolo[3,4-c]pyridine-5-carbonitrile (Step 2) (3500 mg, 14.6 mmol) in DMF (200 mL) was added triphenylmethyl chloride (4286 mg, 15.4 mmol) and triethylamine (1.6 mL, 43.9 mmol) and the mixture was stirred for 12 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography (ethyl acetate:n-heptane 1:9-1:3) to give the title compound (400 mg, 6%) as a yellow solid. ([MH,Br]-3.533).1H NMR (400 MHz, DMSO-d6) δ = 7.48 (s, 1H), 7.44 (t, 1H), 7.39-7.35 (m, 9H), 7.17-7.21 (m, 6H). Step 4: 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile To a solution of 4-bromo-3-hydroxy-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 3) (50 mg, 0.1 mmol) in acetonitrile (1.5 mL) was added (2-chloro-2,2-difluoro-acetyl)sodium oxide (32 mg, 0.2 mmol) and cesium carbonate (68 mg, 0.2 mmol) and the mixture was stirred at 80°C for 2 h. The reaction was diluted with ethyl acetate, filtered, and concentrated to give the title compound (50 mg, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 49.7 (s, 1H), 16.7 - 45.7 (m, 16H). Intermediate 18: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: (4-bromo-2-methylphenyl)(cyclopropyl)sulfane 4-Bromo-2-methylbenzenethiol (600 mg, 0.3 mmol) was dissolved in DMF (12 mL), the solution was purged with argon under sonication before addition of potassium tert-butoxide (398 mg, 3.6 mmol) and cyclopropylbromide (0.5 mL, 5.9 mmol) and the mixture was heated to 100°C for 26 h. The reaction was diluted with ethyl acetate, washed repeatedly with water, dried (Na2SO4) and concentrated to give the title compound (737 mg, 59%) as a light brown oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.4-7.4 (m, 1H), 7.3-7.3 (m, 1H), 7.2-7.3 (m, 1H), 2.2-2.2 (m, 3H), 2.0-2.1 (m, 1H), 1.1-1.1 (m, 2H), 0.6-0.7 (m, 2H) Step 2: 4-bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (4-Bromo-2-methylphenyl)(cyclopropyl)sulfane (Step 1) was converted to the title compound using general procedure G. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.5-7.5 (m, 2H), 2.7-2.7 (m, 3H), 2.5-2.6 (m, 1H), 1.3-1.4 (m, 2H), 1.0-1.1 (m, 2H). Step 3: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (Step 2) was converted to the title compound using general procedure F. ([M+H]+2.323). Intermediate 19: 2-(4-(cyclopropylsulfonyl)-3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (CAS: 1310947-51-3, US2011 / 237791 A1) was converted to the title compound using general procedure F. ([M+H]+343.2). Intermediate 20: 2-Chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Step 1: 4-Bromo-2-chloro-N,N-dimethyl-benzenesulfonamide To a solution of dimethylamine hydrochloride (1.2 g, 25.9 mmol) and diisopropylethylamine (6.5 mL, 17.2 mmol) in dichloromethane (40 mL) was added 4-bromo-2-chlorobenzenesulfonyl chloride (0.5 g, 17.2 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was then washed with water, brine, dried (Na2SO4) and concentrated to give the title compound (3.4 g, 84%) as a light brown solid. ([M+H, Br, Cl]+299.9). Step 2: 2-Chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide 4-Bromo-2-chloro-N,N-dimethyl-benzenesulfonamide (Step 1) was converted to the title compound using general procedure F. ([M+H]+1.346). Intermediate 21: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: (2-(difluoromethyl)phenyl)(methyl)sulfane To a degassed solution of bromo-2-(difluoromethyl)benzene (400 mg, 1.9 mmol) in DMF (6 mL) was added sodium thiomethoxide (271 mg, 3.9 mmol) and the mixture was heated to 100°C for 3 h. It was then diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated to give the title compound (0.22 g, 44%) as a yellow oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 0.8-0.8 (m, 1H), 7.61 (s, 1H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.02 (s, 1H), 2.5-2.5 (m, 3H) Step 2: 4-Bromo-2-(difluoromethyl)phenyl)(methyl)sulfane To an ice-cold solution of 2-(difluoromethyl)phenyl)(methyl)sulfane (Step 1, 224 mg, 1.3 mmol) in DCM (4.5 mL) was added bromine (93 µL, 1.8 mmol) and the reaction was warmed to ambient temperature and stirred for 4 days. The reaction was diluted with DCM, washed with aqueous sodium thiosulfate, brine, dried (Na2SO4) and concentrated to give the title compound (0.29 g, 67%) as a yellow oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.74 (br d, 1H, J=2.2 Hz), 7.55 (tdd, 1H, J=0.1, 2.2, 5.8 Hz), 7.2-7.3 (m, 2H), 6.95 (t, 1H, J=0.1 Hz), 2.48 (s, 3H) Step 3: 4-Bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene 4-Bromo-2-(difluoromethyl)phenyl)(methyl)sulfane (step 2) was converted to the title compound using general procedure G. 1H NMR (CHLOROFORM-d, 300 MHz) δ 0.8-1.8 (m, 1H), 0.8-0.8 (m, 1H), 7.8-7.9 (m, 1H), 7.4-7.8 (m, 1H), 3.1-3.1 (m, 3H) Step 4: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene (Step 3) was converted to the title compound using general procedure F. ([M+H-C6H12]+2.500). Intermediate 22: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 4-Bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene To a solution of (5-bromo-2-(methylsulfonyl)phenyl)methanol (CAS: 773134-43-3, WO2011 / 138751 A2) (780 mg, 2.9 mmol) cooled to -78°C was added diethylaminosulfurtrifluoride (0.5 mL, 3.5 mmol) and the reaction was stirred for 1 h before warming to 0°C for 2 h. The reaction was then washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) afforded the title compound (400 mg, 6%) as a yellow solid. ([MH, Br]-533.3). to give the title compound (0.62 mg, 75%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 0.9-7.8 (m, 1H), 7.7-7.8 (m, 2H), 5.64 (s, 1H), 4.9-4.9 (m, 2H), 3.25 (s, 3H) Step 2: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene (step 1) was converted to the title compound using general procedure F. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.90-8.10 (m, 3H), 5.70-6.00 (m, 2H), 3.14 (s, 3H), 1.37 (s, 12H) Intermediate 23: 4,4,5,5-Tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane Step 1: 3-((4-bromo-2-methylphenyl)thio)oxetane A degassed solution of 4-bromo-2-methylbenzenethiol (200 mg, 0.9 mmol) and 4-methylbenzenesulfonate-3-oxan-3-yl (CAS: 26272-83-3, WO2012 / 138678 A1) (275 mg, 1.1 mmol) was heated to 85°C for 1 h. The reaction was then diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) afforded the title compound (185 mg, 71%) as a colorless oil. ([M+H, Br]+0.261). Step 2: 3-((4-Bromo-2-methylphenyl)sulfonyl)extane 3-((4-Bromo-2-methylphenyl)thio)oxetane (Step 2) was converted to the title compound using general procedure G. ([M+H+ MeCN, Br]+1.334). Step 4: 4,4,5,5-Tetramethyl-2-(3-methyl-4-(oxan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane 3-((4-Bromo-2-methylphenyl)sulfonyl)extane was converted to the title compound using general procedure F. ([M+H+ MeCN]+380.3). Intermediate 24: 2-(4-Ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 4-Bromo-1-ethylsulfanyl-2-methyl-benzene To a solution of 1-ethylsulfanyl-2-methyl-benzene (CAS: 3695-36-1) (0.30 g, 0.197 mmol) in dichloromethane (300 mL) at 0°C was added bromine (0.40 g, 0.256 mmol) and the reaction was stirred at ambient temperature for 1 h. The reaction was concentrated to give the title compound (0.40 g, 87%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=34.7 Hz, 3 H) 2.23 (s, 3 H) 2.93 (q, J=34.7 Hz, 2 H) 18.7 (d, J=31.8 Hz, 1 H) 7.31 - 7.41 (m, 2 H) Step 2: 4-Bromo-1-ethylsulfonyl-2-methyl-benzene 4-Bromo-1-ethylsulfanyl-2-methyl-benzene (Step 1) was converted to the desired compound using general procedure G. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.89 - 7.82 (m, 1H), 7.55 - 7.50 (m, 2H), 3.17 - 3.11 (m, 2H), 2.67 (s, 3H), 1.27 (t, 3H) Step 3: 2-(4-ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-ethylsulfonyl-2-methyl-benzene (Step 2) was converted to the title compound using general procedure F. ([M+H]+1.229) Intermediate 25: 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 1-Bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene 1-Bromo-2-fluoro-5-methyl-4-methylsulfanyl-benzene (CAS: 1351167-83-3, WO2011 / 146335 A1) was converted to the title compound using general procedure G. ([M+H+ MeCN, Br]+0.267). Step 2: 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene (Step 1) was converted to the title compound using general procedure F at 70°C ([M+H-C6H12]+1.233). Intermediate 26: 2-(2,5-Dimethyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane #x200fStep 1: 1-Bromo-#x200f#x200e‎#x200e#x200e2,5#x200e#x200f-dimethyl-4-methylsulfonyl-benzene#x200f To a mixture of 1,4-dibromo-2,5-dimethylbenzene (0.2 g, 7.6 mmol), L-proline (0.7 g, 1.6 mmol) and copper(I) iodide (1.2 g, 1.6 mmol) in DMSO (20 mL) was added sodium hydroxide (0.2 g, 1.6 mmol) and sodium methanesulfinate (0.1 g, 9.9 mmol). The mixture was stirred at 120°C for 20 h under a nitrogen atmosphere, after which it was diluted with water and subjected to repeated extraction with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:4) afforded the title compound (627 mg, 13%) as a yellow solid ([M+H, Br]+0.263). Step 2: 2-(2,5-Dimethyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-2,5-dimethyl-4-methylsulfonyl-benzene (step 1) was converted to the title compound ([M+H]+2.311) using general procedure F at 95°C. Intermediate 27: 2-[4-(Difluoromethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 4-Bromo-1-(difluoromethylsulfanyl)-2-methyl-benzene To a solution of 1-(difluoromethylsulfanyl)-2-methylbenzene (CAS: 1450743-54-0, Organic Letters, 2013, 5036 – 5039) (0.15 g, 1.86 mmol) in heptane (162 mL) was added bromine (1.15 g, 7.94 mmol) and the mixture was stirred at ambient temperature for 12 h, after which the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (0.15 g, 69%) as a yellow liquid. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.50 (d, J=1.9 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.40 - 7.31 (m, 2H), 6.97 - 6.61 (m, 1H), 2.50 (s, 3H) Step 2: 4-Bromo-1-(difluoromethylsulfonyl)-2-methyl-benzene 4-Bromo-1-(difluoromethylsulfanyl)-2-methyl-benzene (Step 1) was converted to the title compound using general procedure G. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.89 (d, J=0.9 Hz, 1H), 7.64 - 7.58 (m, 2H), 6.37 - 6.05 (m, 1H), 2.71 (s, 3H) Step 3: 2-[4-(Difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(difluoromethylsulfonyl)-2-methyl-benzene (step 1) was converted to the title compound using general procedure F at 80°C. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.99 (d, J=7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 6.38 - 5.97 (m, 1H), 2.71 (s, 3H), 1.36 (s, 12H) Intermediate 28: 2-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 1-(cyclopropylmethylsulfanyl)-2-methyl-benzene To a solution of o-thiocresol (0.2 g, 1.16 mmol) in acetonitrile (20 mL) was added potassium carbonate (4.4 g, 32.2 mmol) and (bromomethyl)cyclopropane (1.6 mL, 1.16 mmol). The mixture was stirred at 50°C for 12 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to give the desired compound (0.3 g, quant.) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.24 - 0.30 (m, 2 H) 0.56 - 0.63 (m, 2 H) 1.01 - 1.15 (m, 1 H) 2.40 (s, 3 H) 2.84 (d, J=7.00 Hz, 2 H) 7.05 - 7.12 (m, 1 H) 7.12 - 7.20 (m, 2 H) 7.27 - 7.33 (m, 1 H) Step 2: 4-Bromo-1-(cyclopropylmethylsulfanyl)-2-methyl-benzene To a solution of 1-(cyclopropylmethylsulfanyl)-2-methyl-benzene (Step 1) (0.3 g, 16.8 mmol) in hexane (35 mL) was added bromine (2.7 g, 16.9 mmol) and the mixture was stirred at ambient temperature for 3 h, after which the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (3.7 g, 86%) as a yellow liquid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.01 - 0.07 (m, 2 H) 0.34 - 0.42 (m, 2 H) 0.76 - 0.90 (m, 1 H) 2.14 (s, 3 H) 2 / 16 - 2 / 19 (m, 1 H) 2 / 17 - 2 / 18 (m, 1 H) 2 / 59 (d, J=7.00 Hz, 2 H) 2 / 62 (d, J=7.00 Hz, 1 H) 6 / 93 (d, J=8.25 Hz, 1 H) 6 / 91 - 6 / 94 (m, 1 H) 7 / 03 - 7 / 06 (m, 1 H) 7 / 08 - 7 / 10 (m, 1 H) 7 / 09 (d, J=2.25 Hz, 1 H) Step 3: 4-Bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene 4-Bromo-1-(cyclopropylmethylsulfanyl)-2-methyl-benzene (step 2) was converted to the title compound using general procedure G. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.13 - 0.18 (m, 2 H) 0.53 - 0.58 (m, 2 H) 0.90 - 1.03 (m, 1 H) 2.65 (s, 3 H) 3.04 (d, J=7 / 25 Hz, 2 H) 7.49 - 7.54 (m, 2 H) 7.88 (d, J=8 / 25 Hz, 1 H) Step 4: 2-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (step 3) was converted to the title compound using the general procedure F at 70°C. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.12 (q, J=5 / 13 Hz, 2 H) 0.47 - 0.56 (m, 2 H) 0.95 (quint, J=7 / 65, 7 / 65, 7 / 65, 7 / 65, 4 / 85, 4 / 85 Hz, 1 H) 1.36 (s, 12 H) 2.68 (s, 3 H) 3.05 (d, J=7 / 13 Hz, 2 H) 7.74 (s, 1 H) 7.77 (d, J=7 / 88 Hz, 1 H) 8.01 (d, J=7.88 Hz, 1 H) Intermediate 29: 4,4,5,5-Tetramethyl-2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane Step 1: 1-Methyl-2-propylsulfanyl-benzene To a solution of o-thiocresol (0.2 g, 1.16 mmol) in acetonitrile (20 mL) was added potassium carbonate (4.4 g, 2.32 mmol) and 1-iodopropane (3.4 mL, 0.29 mmol). The mixture was stirred at 60°C for 12 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to give the title compound (2.5 g, 94%) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.30 - 7.26 (m, 1H), 7.19 - 7.14 (m, 2H), 7.12 - 7.07 (m, 1H), 2.90 (t, J = 7.3 Hz, 2H), 2.39 (s, 3H), 1.71 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H) Step 2: 4-Bromo-2-methyl-1-propylsulfanyl-benzene To a solution of 1-methyl-2-propylsulfanyl-benzene (Step 1) (2.5 g, 0.15 mmol) in dichloromethane (25 mL) was added bromine (2.6 g, 16.5 mmol) and the mixture was stirred at ambient temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (3.6 g, 98%) as a yellow liquid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.01 - 0.07 (m, 2 H) 0.34 - 0.42 (m, 2 H) 0.76 - 0.90 (m, 1 H) 2.14 (s, 3 H) 2.16 - 2 / 19 (m, 1 H) 2 / 17 - 2 / 18 (m, 1 H) 2 / 59 (d, J=7.00 Hz, 2 H) 2 / 62 (d, J=7.00 Hz, 1 H) 6 / 93 (d, J=25 / 8 Hz, 1 H) 6 / 91 - 6 / 94 (m, 1 H) 7 / 03 - 7 / 06 (m, 1 H) 7 / 08 - 7 / 10 (m, 1 H) 7 / 09 (d, J=2.25 Hz, 1 H) Step 3: 4-Bromo-2-methyl-1-propylsulfonyl-benzene4-Bromo-2-methyl-1-propylsulfonyl-benzene (Step 2) was converted to the desired compound using general procedure G. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.87 - 7.83 (m, 1H), 7.54 - 7.50 (m, 2H), 3.11 - 3.07 (m, 2H), 2.67 (s, 3H), 1.77 - 1.69 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H) Step 4: 4,4,5,5-Tetramethyl-2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane4-bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (Step 3) was converted to the title compound using general procedure F at 90°C. ([M+H]+311.2). Intermediate 30: 2-(4-Isopropylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 1-Isopropylsulfanyl-2-methyl-benzene To a solution of o-thiocresol (0.2 g, 1.16 mmol) in acetonitrile (20 mL) was added potassium carbonate (4.4 g, 2.32 mmol) and 2-bromopropane (1.3 mL, 0.29 mmol). The mixture was stirred at 60°C for 2 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to give the title compound (2.5 g, 94%) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.40 - 7.36 (m, 1H), 7.22 - 7.19 (m, 1H), 7.19 - 7.18 (m, 1H), 7.18 - 7.12 (m, 2H), 3.38 (td, J = 6.7, 13.3 Hz, 1H), 2.42 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H) Step 2: 4-Bromo-2-methyl-1-propylsulfanyl-benzene To a solution of 1-isopropylsulfanyl-2-methyl-benzene (Step 1) (2.5 g, 0.15 mmol) in dichloromethane (25 mL) was added bromine (2.6 g, 16.5 mmol) and the mixture was stirred at room temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (3.6 g, 98%) as a yellow liquid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.35 (d, J = 0.2 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.24 - 20 / 7 (m, 1H), 3 / 33 (td, J = 7 / 6, 3 / 13 Hz, 1H), 2 / 38 (s, 3H), 1 / 31 (s, 3H), 1 / 29 (s, 3H) Step 3: 4-Bromo-1-isopropylsulfonyl-2-methyl-benzene 4-Bromo-2-methyl-1-propylsulfanyl-benzene (step 2) was converted to the title compound using general procedure G. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.83 (d, J = 8.9 Hz, 1H), 7.54 - 7.49 (m, 2H), 3.24 (d, J = 6.8 Hz, 1H), 2.66 (s, 3H), 1.31 (s, 3H), 1.29 (s, 3H) Step 4: 2-(4-Isopropylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane4-bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (Step 3) was converted to the title compound using general procedure F at 90°C. ([M+H]+1.325). Intermediate 31: N,2-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Step 1: 4-bromo-N,2-dimethyl-benzenesulfonamide To a solution of methylamine hydrochloride (0.6 g, 8.9 mmol) in dichloromethane (30 mL) was added triethylamine (2.5 mL, 17.8 mmol) and 4-bromo-2-methylbenzene-1-sulfonyl chloride (0.2 g, 7.4 mmol) and the reaction was stirred for 1 h at ambient temperature. The reaction was diluted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to give the title compound (1.9 g, 92%) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.82 (d, J = 3.8 Hz, 1H), 7.51 - 7.45 (m, 2H), 4.68 (br s, 1H), 2.64 (s, 3H), 2.61 (s, 3H) Step 2: N,2-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide4-Bromo-N,2-dimethyl-benzenesulfonamide (Step 2) was converted to the title compound using general procedure F at 90°C. ([M+H]+1.312). Intermediate 32: tert-Butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane Step 1: tert-butyl-dimethyl-[2-(o-tolylsulfanyl)ethoxy]silane To a solution of o-thiocresol (0.2 g, 1.16 mmol) in acetonitrile (30 mL) was added potassium carbonate (4.4 g, 2.32 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (0.6 mL, 0.29 mmol). The mixture was stirred at 60°C for 2 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to give the title compound (7.5 g, 82%) as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.32 (d, J = 7.6 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.12 - 7.07 (m, 1H), 3.81 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H) Step 2: 2-(4-Bromo-2-methyl-phenyl)sulfanylethoxy-tert-butyl-dimethyl-silane To a solution of tert-butyl-dimethyl-[2-(o-tolylsulfanyl)ethoxy]silane (Step 1) (7.5 g, 13.3 mmol) in dichloromethane (50 mL) was added bromine (2.3 g, 14.6 mmol) and the mixture was stirred at room temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (0.9 g, 65%) as a yellow liquid, which was used directly in the next step. Step 3: 2-(4-Bromo-2-methyl-phenyl)sulfonylethoxy-tert-butyl-dimethyl-silane 2-(4-Bromo-2-methyl-phenyl)sulfanylethoxy-tert-butyl-dimethyl-silane (Step 2) was converted to the title compound using general procedure G. ([M+H]+0.393). Step 4: tert-butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane 2-(4-Bromo-2-methyl-phenyl)sulfonylethoxy-tert-butyl-dimethyl-silane (Step 3) was converted to the title compound using general procedure F at 90°C. ([M+H]+1.441). Intermediate 33: 4,4,5,5-Tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1,3,2-dioxaborolane Step 1: 4-Bromo-2-methyl-1-(1-methylcyclopropyl)sulfonyl-benzene To a solution of 4-bromo-1-cyclopropylsulfonyl-2-methyl-benzene (intermediate 18, step 2) (500 mg, 1.8 mmol) in THF (23 mL) under nitrogen at −78°C was added LiHMDS (18.2 mL, 1 M in THF, 18.2 mmol) and the mixture was stirred for 1 h. Then iodomethane (515 mg, 3.6 mmol) was added and the mixture was warmed to 20°C and stirred for a further 15 h. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Purification by preparative TLC (petroleum ether:ethyl acetate 5:1) gave the title compound (0.45 g, 86%) as a colorless gum. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.84 - 7.80 (m, 1H), 7.51 - 7.47 (m, 2H), 3.48 (s, 1H), 2.66 (s, 3H), 1.63 - 1.60 (m, 2H), 1.29 (s, 3H), 0.88 - 0.84 (m, 2H) Step 2: 4,4,5,5-Tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1,3,2-dioxaborolane 4-Bromo-2-methyl-1-(1-methylcyclopropyl)sulfonyl-benzene (step 2) was converted to the title compound using the general procedure F at 80°C. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.98 (d, J=7.7 Hz, 1H), 7.81 - 7.76 (m, 2H), 2.72 (s, 3H), 1.66 (br d, J=2.0 Hz, 2H), 1.42 - 1.37 (m, 15H), 0.89 - 0.84 (m, 2H) Intermediate 34: 2-[4-(Methoxymethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 4-Bromo-1-(methoxymethylsulfanyl)-2-methyl-benzene To a solution of chloromethyl methyl ether (0.28 mL, 3.7 mmol) in acetonitrile (3 mL) was added potassium carbonate (680 mg, 4.9 mmol) and 4-bromo-2-methyl-benzenethiol (500 mg, 2.5 mmol). The mixture was stirred at 50°C for 12 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated. Flash column chromatography (n-heptane) afforded the title compound (220 mg, 36%) as a light yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.34 - 7.30 (m, 1H), 7.25 (d, J=1 / 9 Hz, 1H), 7.22 - 7.18 (m, 1H), 4.87 - 4.83 (m, 2H), 3.35 (s, 3H), 2.29 (s, 3H) Step 2: 4-Bromo-1-(methoxymethylsulfonyl)-2-methyl-benzene 4-Bromo-1-(methoxymethylsulfanyl)-2-methyl-benzene (step 2) was converted to the title compound using general procedure G. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.86 (d, J=3.8 Hz, 1H), 7.56 - 7.49 (m, 2H), 4.54 (s, 2H), 3.64 (s, 3H), 2.67 (s, 3H) Step 3: 2-[4-(Methoxymethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(methoxymethylsulfonyl)-2-methyl-benzene (step 3) was converted to the desired compound using general procedure F at 70°C, and the crude material was used in the next step. Intermediate 35: 2-[5-(Difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 2-Bromo-1-(difluoromethyl)-4-methyl-benzene To a solution of 2-bromo-4-methylbenzaldehyde (0.5 g, 1.25 mmol) in dichloromethane (75 mL) was slowly added diethylaminosulfur trifluoride (1.6 g, 37.7 mmol) over 0.5 h and the reaction was stirred for 16 h. The reaction was diluted with dichloromethane, washed cautiously with saturated aqueous sodium hydrogen carbonate solution, and concentrated. Flash column chromatography (n-heptane) afforded the title compound (3.6 g, 65%) as a yellow liquid. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.53 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.04 - 6.72 (m, 1H), 2.47 - 2.29 (m, 3H) Step 2: 1-(Difluoromethyl)-4-methyl-2-methylsulfanyl-benzene To a cooled (-78°C) solution of 2-bromo-1-(difluoromethyl)-4-methyl-benzene (Step 1) (3.6 g, 16.3 mmol) in THF (67 mL) under nitrogen was added n-butyllithium (2.7 mL, 2.5 M in hexanes, 18 mmol) and the mixture was stirred for 0.5 h. (methyldisulfanyl)methane (0.2 g, 21.5 mmol) was added and the mixture was stirred for an additional 1 h. Saturated ammonium chloride was then added and the reaction was brought to ambient temperature and extracted repeatedly with ethyl acetate. The combined organic phase was concentrated to give the title compound (2.5 g, 82%) as a yellow liquid. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.50 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.16 - 6.84 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H) Step 3: 1-Bromo-5-(difluoromethyl)-2-methyl-4-methylsulfanyl-benzene To a solution of 1-(difluoromethyl)-4-methyl-2-methylsulfanyl-benzene (Step 2) (100 mg, 0.5 mmol) in n-heptane (1 mL) was added bromine (93 mg, 0.6 mmol) and the mixture was stirred at room temperature for 12 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to give the title compound (90 mg, 63%) as a yellow liquid.1H NMR (400MHz, CHLOROFORM-d) δ = 7.75 (s, 1H), 7.25 (s, 1H), 11.7 - 6.77 (m, 1H), 2.47 (s, 3H), 2 / 42 (s, 3H) Step 4: 1-Bromo-5-(difluoromethyl)-2-methyl-4-methylsulfinyl-benzene To a solution of 1-bromo-5-(difluoromethyl)-2-methyl-4-methylsulfanyl-benzene (Step 3) (0.1 g, 3.7 mmol) in dichloromethane (20 mL) was cooled to 0°C, then 3-chloro-benzenecarboperoxoic acid (0.6 g, 0.3 mmol) was added and the mixture was stirred at 0°C for 0.5 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, saturated aqueous sodium hydrogen carbonate solution, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) afforded the title compound (800 mg, 57%) as a white solid. ([M+H, Br]+0.282). Step 5: 2-[5-(Difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-5-(difluoromethyl)-2-methyl-4-methylsulfinyl-benzene (Step 4) was converted to the title compound using general procedure F at 80°C ([M+H]+2.331). Intermediate 36: 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole Step 1: Ethyl 2-bromo-6-fluoro-3-methylsulfanyl-benzoate 2-Bromo-4-fluoro-1-methylsulfanyl-benzene was deprotonated with LDA (1.2 equiv.) for 0.5 h and reacted with ethyl chloroformate (1.5 equiv.) for 1 h according to general procedure A to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.21 - 7.17 (m, 1H), 7.14 - 7.08 (m, 1H), 4.46 (q, J = 1.7 Hz, 2H), 2.48 (s, 3H), 1.41 (t, J = 2.7 Hz, 3H) Step 2: Ethyl 2-bromo-6-fluoro-3-methylsulfonyl-benzoate Ethyl 2-bromo-6-fluoro-3-methylsulfanyl-benzoate was converted to the title compound using general procedure G. ([M+H, Br]+326.9). Step 3: 4-bromo-5-methylsulfonyl-1,2-dihydroindazol-3-one To a solution of ethyl 2-bromo-6-fluoro-3-methylsulfonyl-benzoate (Step 2) (10.8 g, 33.2 mmol) in ethanol (120 mL) was added hydrazine hydrate (2.2 g, 44.4 mmol) and triethylamine (4.6 mL, 33.2 mmol) at 0°C, and the reaction was heated to 80°C for 4 h. After cooling to ambient temperature, the title compound was isolated by filtration (0.5 g, 52%) as an off-white solid. ([M+Na, Br]+314.8). Step 4: 4-bromo-5-methylsulfonyl-1-trityl-indazol-3-yl To a solution of 4-bromo-5-methylsulfonyl-1,2-dihydroindazol-3-one (Step 3) (200 mg, 0.7 mmol) in DMF (5 mL) was added sodium hydride (41 mg, 60% dispersion in mineral oil, 0.1 mmol) and triphenylmethyl chloride (211 mg, 0.8 mmol) at 0 °C under nitrogen. The cooling bath was removed and the reaction was stirred for 2 h until it reached ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) afforded the title compound (150 mg, 41%) as a white solid ([M+Na, Br]+556.9). Step 5: 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole To a solution of 4-bromo-5-methylsulfonyl-1-trityl-indazol-3-ol (Step 4) (0.1 g, 1.9 mmol) in DMF (30 mL) was added sodium chlorodifluoroacetate (0.6 g, 3.8 mmol) and potassium carbonate (0.8 g, 5.6 mmol) and the reaction was heated to 80 °C for 30 min. The reaction was filtered and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3) afforded the title compound (0.9 g, 71%) as a white solid. ([M+ Na, Br]+0.605 Intermediate 37: 4-Chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5-carbonitrile Step 1: 4-Bromo-3-chloro-2-iodoaniline was prepared as described in WO2013 / 33228 A1. Step 2: 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole A mixture of 4-bromo-3-chloro-2-iodoaniline (Step 1) (441 mg, 1.3 mmol), (cyclopropylethynyl)trimethylsilane (159 µl, 1.5 mmol), lithium chloride (56 mg, 1.33 mmol) and sodium carbonate (281 mg, 2.7 mmol) in DMF (5 mL) was purged with argon, then the adduct [1,1'-1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (49 mg, 66 µmol)] was added. The reaction was heated in a sealed tube at 100°C for 16 h, after which the reaction was diluted with ethyl acetate, washed with aqueous sodium thiosulfate, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) afforded the title compound (185 mg, 39%) as a yellow solid. ([M+H, Cl, Br]+342.2). Step 3: 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole was converted to the title compound in THF using the general E1 procedure. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.44 (d, 1H, J=8 / 7 Hz), 7.22 (d, 1H, J=8 / 9 Hz), 5.4-5.5 (m, 2H), 3.7-3 / 8 (m, 1H), 3.6-3 / 8 (m, 1H), 3.3-3 / 5 (m, 2H), 2.12 (tt, 1H, J=5 / 2, 8 / 3 Hz), 1.1-1 / 2 (m, 2H), 0.7-0 / 8 (m, 2H), 0.5-0 / 6 (m, 9H), 0.1-0 / 1 (m, 9H) Step 4: 4-Chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5-carbonitrile 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Step 3) (170 mg, 0.3 mmol) and zinc cyanide (34 mg, 0.3 mmol) were suspended in DMF (3 mL). The reaction mixture was purged with argon and the reaction was heated in a microwave at 150 ºC for 30 min. The reaction was diluted with water and repeatedly extracted with ethyl acetate several times. The combined organic layers were washed with water, brine, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) afforded the title compound (57 mg, 46%) as a yellow solid ([M+H, Cl]+301.2). Intermediate 38: 2-(Difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Step 1: 1-Benzylsulfanyl-4-bromo-2-(difluoromethyl)benzene To an ice-cold solution of benzyl mercaptan (2.4 g, 19.4 mmol) in DMF (20 mL) was added sodium hydride (0.8 g, 60% dispersion in mineral oil, 20 mmol), after 0.5 h 4-bromo-2-(difluoromethyl)-1-fluoro-benzene (0.3 g, 13.3 mmol) was added and the reaction was stirred for a further 0.5 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine and concentrated. Flash column chromatography (ethyl acetate:heptane 0:1-5:95) gave the title compound (3.8 g, 83%) as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (d, J = 1.2 Hz, 1H), 7.49 (td, J = 1.1, 3.8 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.27 - 22.7 (m, 2H), 7.18 - 7.15 (m, 2H), 07 / 07 - 6 / 75 (m, 1H), 03 / 04 (s, 2H) Step 2: 4-Bromo-2-(difluoromethyl)benzylsulfonyl chloride To an ice-cold solution of 1-benzenesulfanyl-4-bromo-2-(difluoromethyl)benzene (200 mg, 0.6 mmol) in acetonitrile (5 mL) was added acetic acid (182 mg, 0.3 mmol) and water (0.05 mL, 3 mmol) followed by N-chlorosuccinimide (243 mg, 1.8 mmol) and the mixture was stirred for 1 h. The reaction was diluted with ethyl acetate, washed with water, brine and concentrated. Flash column chromatography (ethyl acetate:heptane 1:10) gave the title compound (150 mg, 65%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.16 - 12.8 (m, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.67 - 7.38 (m, 1H) Step 3: 4-bromo-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide To an ice-cold solution of 4-bromo-2-(difluoromethyl)benzenesulfonyl chloride (Step 2) (2.6 g, 6.8 mmol) in acetonitrile (20 mL) was added dimethylamine hydrochloride (1.7 g, 20.4 mmol) followed by pyridine (1.65 mL, 20.4 mmol) and the mixture was stirred for 0.5 h. The reaction was diluted with ethyl acetate, washed with 1N HCl, brine and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5) afforded the title compound (1.6 g, 71%) as a white solid. ([M+H, Br]+315.9). Step 4: 2-(Difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide 4-Bromo-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide (step 3) was converted to the title compound using general procedure F at 80°C ([M+H]+2.362). Examples Example No. Structure Product Name Molecular Weight Determined from Intermediates Product 1 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 1.328 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (Intermediate 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D 2 3-Cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 1.344 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (Intermediate 1) and (4-Methanesulfonyl-3-methoxyphenyl)boronic acid D 3 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine [M+H, Cl]+ 1.348 4-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate 1) and (3-Chloro-4-methanesulfonylphenyl)boronic acid D 4 3-cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 1.382 4-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate 1) and [4-methanesulfonyl-3-(trifluoromethyl)phenyl]boronic acid D 5 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide [M+H]+ 1.3574-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzenesulfonamide D 6 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[‎3,4-c]pyridine [M+H]+ 344 / 1 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[‎3,4-c]pyridine (intermediate 2) and 4-(methanesulfonyl)phenylboronic acid D, J 7 3-Cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 354 / 1 4-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate 1) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 18) D 8 4-(3-Chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine [M+H]+ 374 / 1 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 2-(4-(cyclopropylsulfonyl)-3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 19) D 9 2-Chloro-4-(3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridin-4-yl)-‎N,N-dimethylbenzenesulfonamide [M+H]+ 1.3774-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 2-chloro-‎N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (intermediate 20) D 10 4‎-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[‎3,4-b]pyridine [M+H]+ 356 / 1 4-Chloro-3-(trifluoromethyl)-1-((2‎-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[‎4,3-c]pyridine (intermediate 3) and (3-Methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 11 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 342.0 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (intermediate 3) and 4-(methanesulfonyl)phenylboronic acid D, J 12 3-Cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 364.1 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 21) D 13 3-cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 1 / 3464-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 22) D 14 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[‎3,2-c]pyridine [M+H]+ 327 / 2 4-Chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[‎3,2-c]pyridine (intermediate 4) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 15 3-Cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 370 / 2 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane (intermediate 23) D 16 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile [M+H]+ 353 / 1 4-Bromo-3-cyclopropyl-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile (intermediate 5) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D 17 3‎-(‎1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 352.24-Chloro-3-(‎1,1-difluoroethyl)-1H-pyrazolo[‎4,3-c]pyridine (intermediate 6) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D 18 3‎-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 338 / 1 2‎-[[4-chloro-3-(difluoromethyl)pyrazolo[‎4,3-c]pyridin-1-yl]methoxy]ethyl-trimethylsilane (intermediate 7) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 19 3-Isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 330 / 1 4-Chloro-3-isopropyl-1H-pyrazolo[‎4,3-c]pyridine and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D 20 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 314 / 9 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 2-(4-ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 24) D 21 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 346 / 1 4-chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and2-(2-Fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 25) D 22 3-Cyclopropyl-4-(2,5-dimethyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride [M+H]+ 342 / 1 4-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate 1) and 2-(2,5-dimethyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 26) D 23 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine hydrochloride [M+H]+ 312 / 2 4-Chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and 3-methyl-4-(methylthio)phenylboronic acid D, G (1 equiv) 24 3-Cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine [M+H]+ 358 / 3 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (intermediate 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 25 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine [M+H]+ 390 / 1 4-chloro-3-(difluoromethoxy)-1-triethyl-pyrazolo[4,3-c]pyridine (intermediate8) and 2-[4-(difluoromethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 27) D, H 26 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 380 / 1 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 18) D, H 27 3-(Difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 0.368 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 2-(4-ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 24) D, H 28 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 0.344 4-Chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (intermediate 9) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, I1 29 4‌-[4‎-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 1.3944-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine (intermediate 8) and 2‎-[4‎-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 28) D, H 30 3‎-(difluoromethoxy)-4-[3‎-(difluoromethyl)-4-methylsulfonyl-phenyl]-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 382 / 2 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine (intermediate 8) and 4,4,5,5-tetramethyl-2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane (intermediate 29) D, H 31 3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 390 / 1 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 21) D, H 32 4-(3-Methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 0.382 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 2-(4-isopropylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 30) D, H 334-[3-(Difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethyl-benzenesulfonamide [M+H]+ 369.0 4-Chloro-3-(difluoromethoxy)-1-triethyl-pyrazolo[4,3-c]pyridine (intermediate 8) and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (intermediate 30) D, H 34 6-Chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine [M+H]+ 362.3 4,6-Dichloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 10) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D 35 3‎-(difluoromethoxy)-4-[3-methyl-4-(oxetan-3-ylsulfonyl)phenyl]-1H-pyrazolo[‎4,3-c]pyridine [M+H]+ 396 / 1 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine (intermediate 8) and 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane (intermediate 23) D, H 36 2-[4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-methyl-phenyl]sulfonylethanol [M+H]+ 1.384 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) andtert-Butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane (intermediate 32) D, H 37 3-(difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine [M+H]+ 394 / 1 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 4,4,5,5-Tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1,3,2-dioxaborolane (intermediate 33) D, H 38 3-(Difluoromethoxy)-4-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine [M+H]+ 384 / 1 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine (intermediate 8) and 2-(4-(methoxymethylsulfonyl)-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 34) D, H 39 5-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[‎3,4-c]pyridine [M+H]+ 386 / 3 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[‎3,4-c]pyridine (intermediate 11) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 404-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine [M+H]+ 355 / 2 4-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (intermediate 12) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 41 3-Cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine [M+H]+ 372 / 2 4-Bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-‎2H-pyran-2-yl)-1H-pyrazolo[‎3,4-c]pyridine (intermediate 13) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, I1 42 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile [M+H]+ 0.367 4-Bromo-3-cyclopropyl-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile (intermediate 5) and -(4-Ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 24) D 43 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile [M+H]+ 0.379 4-Bromo-3-cyclopropyl-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile (intermediate 5) and2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 18) D 44 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole [M+H]+ 433 / 2 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (intermediate 14) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J 45 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indole-5-carbonitrile [M+H]+ 351 / 2 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carbonitrile (intermediate 37) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, J2 46 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide [M+H]+ 411 / 2 4-Bromo-3-cyclopropyl-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide (intermediate 15) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 18) D 473-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile [M+H]+ 371 / 0 4-Bromo-3-cyclopropyl-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile (intermediate 5) and 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 25) D 48 4-[3-(difluoromethoxy)-1H-pyrazolo[‎4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide [M+H]+ 419 / 1 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[‎4,3-c]pyridine (intermediate 8) and 2‎-(difluoromethyl)-‎N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (intermediate 38) D, H 49 3‎-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole [M+H]+ 430 / 1 4-Bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole (intermediate 16) and (3-Methyl-4-(methylsulfonyl)phenyl)boronic acid D, H 50 3-Cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile [M+H]+ 0.389 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 5) and-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 27) D 51 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide [M+H]+ 421 / 2 4-Bromo-3-cyclopropyl-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide (intermediate 15) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 21) D 52 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile [M+H]+ 1 / 379 4-Bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid D, H 53 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfonyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile [M+H]+ 1 / 413 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17) and 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 35) D, H 544-[3-(Difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine [M+H]+ 422 / 2 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (intermediate 11) 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 21) D, J 55 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole [M+H]+ 1.457 4-Bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole (intermediate 36) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 18) D, J Example 56: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine Step 1: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine 4-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (CAS: 1416713-66-0, US2014 / 128374 A1) was reacted with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid (1.1 equiv) at 100°C using general procedure D. ([M+H]+372.2). Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (40 mg, 0.1 mmol) was dissolved in dioxane / DCM (0.2 / 0.5 mL) and HCl (50 µL, 4N in dioxane, 0.2 mmol) was added. The reaction was stirred for 16 h, then washed with saturated aqueous sodium hydrogen carbonate, water, brine, dried (Na2SO4) and concentrated to give the title compound (23 mg, 67%) as an off-white solid. ([M+H]+1.288). Step 3: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 2) (23 mg, 0.1 mmol) was suspended in DCM (1.5 mL) and N-bromosuccinimide (14 mg, 0.1 mmol) was added. The reaction was stirred for 2 h, then concentrated to dryness. Flash column chromatography (ethyl acetate:n-heptane 4:6-1:0) afforded the title compound (185 mg, 71%) as a white solid. ([M+H, Br]+1.366). Examples 57 and 58: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine Step 1: 4-Chloro-1,2-dihydro-3H-pyrazolo[‎4,3-c]pyridin-3-one Ethyl 2-chloro-4-fluoronicotinate was reacted with hydrazine hydrate (1 equiv.) and triethylamine (1 equiv.) in ethanol at 80°C according to general procedure C to give the title compound ([M+H,Cl]+0.170). Step 2: 4-Chloro-1-trityl-1H-pyrazolo[‎4,3-c]pyridin-3-ol 4-Chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one (20 mg, 0.1 mmol) in DMF (1 mL) was added sodium hydride (6 mg, 60% dispersion in mineral oil, 0.1 mmol) and triphenylmethyl chloride (33 mg, 0.1 mmol) at 0 °C under nitrogen. The cooling bath was removed and the reaction was stirred for 2 h until it reached ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) afforded the title compound (19 mg, 37%) as a light yellow solid ([M+H]+412.3). Step 3: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol The title compound ([M+H]+546.2) was prepared from Suzuki coupling of 4-chloro-1-trityl-1H-pyrazolo[‎4,3-c]pyridin-3-ol (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to general procedure D. Step 4: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine and 3-methoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Step 3) (51 mg, 0.1 mmol) and potassium carbonate (39 mg, 0.3 mmol) in DMF (1.5 mL) was added methyl 2-chloro-2,2-difluoroacetate (20 µL, 0.2 mmol). The reaction was sealed in a tube and stirred at 80°C for 30 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 0:1-1:4) afforded the title compounds as a mixture (4:1) (27 mg, 35%) as a white solid ([M+H]+3.596 and 3.560). Step 5: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine A mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 4) was deprotected using general procedure H to afford the desired compounds, which were separated by preparative reverse phase HPLC. ([M+H]+1.354 and 2.318). Example 59: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline Step 1: 3-Cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine The desired compound ([M+H]+1.332) was prepared from the Suzuki coupling of 4-chloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (intermediate 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to general procedure D. Step 2: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline In a pressure tube, 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (30 mg, 0.1 mmol) and concentrated ammonia (approximately 3 mL) were added at -78°C. The tube was then tightly capped and allowed to warm to ambient temperature and stirred for 8 days. Evaporation of the ammonia and flash column chromatography (ethyl acetate:n-heptane 1:1-1:0) afforded the title compound (6 mg, 21%) as a white solid. ([M+H]+1.329). Example 60: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine Step 1: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-‎2H-pyran-2-yl)-1H-pyrazolo[‎4,3-c]pyridine To a mixture of 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (product 56) (648 mg, 1.8 mmol) in THF (20 mL) was added 3,4-dihydro-2H-pyran (1.6 mL, 17.7 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.2 mmol) and the reaction mixture was stirred at 70°C for 36 h. After which it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM:MeOH 1:0-9:1) afforded the title compound (689 mg, 78%) as a yellow solid ([M+H]+1.452). Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (102 mg, 0.2 mmol) was dissolved in DMSO (2.5 mL). 2-Methyl-2-thiosudovir sulfate (63 mg, 0.2 mmol) and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction mixture was heated to 100°C for 15 h. The reaction mixture was allowed to cool to room temperature, then silica gel was added. The suspension was concentrated under high vacuum. The crude product was purified by flash column chromatography (ethyl acetate: n-heptane 0:1-1:0) to afford the title compound (40 mg, 42% yield) as a light yellow gum ([M+H]+1.418). Step 3: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 2) was oxidized to the title compound using general procedure G. ([M+H]+450.2). Step 4: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 3) was deprotected using general procedure I to give the title compound. ([M+H]+0.366). Example 61: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile Step 1: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (intermediate 60, step 1) (40 mg, 0.1 mmol), zinc cyanide (10 mg, 0.1 mmol) and tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol) were suspended in DMF (1 mL) at room temperature. The reaction mixture was heated to 150°C for 0.5 h in a microwave reactor. Silica gel was added to the reaction mixture and concentrated. The crude product was purified by flash column chromatography (ethyl acetate: n-heptane 0:1-1:0) to afford the title compound (16 mg, 44% yield) as a light yellow gum ([M+H]+2.397). Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile (Step 1) was deprotected using general procedure I to give the title compound. ([M+H]+1.313). Example 62: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 16) (20 mg, 0.1 mmol) was suspended in aqueous sodium hydroxide (0.5 mL, 6 M, 0.3 mmol). The mixture was heated to 100°C for 16 h. The reaction was cooled to ambient temperature, acidified with 37% HCl, and concentrated. Purification by preparative reverse-phase HPLC gave the title compound (8 mg, 36% yield) as a white solid. ([M+H]+ 372.2). Example 63: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile Step 1: 2-Bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile 2-Bromo-4-fluorobenzonitrile was treated with LDA (1.3 equiv.) for 10 min and then cyclopropanecarbaldehyde (1.4 equiv.) was added according to general procedure A. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.62 (dd, 1H, J=5.2, 7.8 Hz), 7.1-7.2 (m, 1H), 4.4-4.6 (m, 1H), 2.4-2.6 (m, 1H), 1.5-1.6 (m, 1H), 0.7-0.8 (m, 1H), 0.5-0.6 (m, 3H) Step 2: 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile 2-Bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile was oxidized using general procedure B1 to give the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.2-7.3 (m, 1H), 2.24 (dtt, 1H, J=1.0, 4.5, 7.8 Hz), 1.4-1.5 (m, 2H), 1.2-1.3 (m, 2H) Step 3: 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile The desired compound ([M+H]+2.358) was prepared from Suzuki coupling of 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90°C according to general procedure D. Step 4: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile 3-(Cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile (Step 3) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H]+352.3). Example 64: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-ol Step 1: 7-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine A mixture of N-bromosuccinimide (109 mg, 0.6 mmol), 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 1) (100 mg, 0.3 mmol) in DMF (2 mL) was stirred at 80 °C for 24 h. The reaction was directly purified by preparative reverse-phase HPLC to afford the title compound (30 mg, 24%) as a green solid. ([M+H, Br]+405.8). Step 2: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-ol To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (60 mg, 0.2 mmol), potassium hydroxide (33 mg, 0.6 mmol), Pd2(dba)2 (5 mg, 0.03 mmol), tBuXPhos (4 mg, 0.01 mmol, 0.060 equiv) in dioxane (1.5 mL) and water (1 mL) was added and the mixture was stirred at 90°C for 1 h under nitrogen. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC gave the title compound (6 mg, 10%) as a yellow solid. ([M+H]+343 / 9) Example 65: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine Step 1: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (intermediate 60, step 1) was reacted with thiophene-3-boronic acid equivalents using potassium carbonate as base at 90°C according to general procedure D. ([M+H]+454.2). Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) was deprotected using general procedure I2 to give the title compound ([M+H]+370.2). Example 66: 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine Step 1: 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[‎4,3-c]pyridine To a solution of 4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridin-3-ol (Example 57, Step 3) (100 mg, 0.2 mmol) in acetonitrile (2 mL) was added cesium carbonate (120 mg, 0.4 mmol) and iodoethane (0.04 mL, 0.6 mmol) and the reaction mixture was stirred at 80°C for 2 h. The reaction was filtered and concentrated. Purification by preparative TLC (heptane:ethyl acetate 3:1) afforded the title compound (60 mg, 54%) as a white solid. ([M+H]+3.574). Step 2: 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[‎4,3-c]pyridine was deprotected using general procedure H to give the title compound. ([M+H]+1.332). Example 67: 3-Cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine Step 1: 2-Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol 2-Bromo-4-chloro-5-fluoro-pyridine was reacted with LDA (1.2 equiv.) for 30 min before addition of cyclopropanecarbaldehyde (1.4 equiv.) according to general procedure A. ([M+H, Br]+0.280) Step 2: 2-Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone 2-(Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol was oxidized using general procedure B1 to give the title compound. ([M+H, Br]+0.278) Step 3: [4-Chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone The desired compound ([M+H]+1.368) was prepared from Suzuki coupling of 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to general procedure D. Step 4: 3-Cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridine 4-Chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone (Step 3) was reacted with hydrazine hydrate (5 equiv) in dioxane at 60°C according to general procedure C to give the title compound ([M+H]+1.346). Examples 68 and 69: 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile and 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile Step 1: Ethyl 2-bromo-3-cyano-6-fluorobenzoate 2-Bromo-4-fluorobenzonitrile was deprotonated with LDA (1.2 equiv.) for 0.5 h and reacted with ethyl chloroformate (1.2 equiv.) for 0.5 h according to general procedure A to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 21.8 (dd, J=8.86, 5.64 Hz, 1 H) 7.70 (t, J=8.76 Hz, 1 H) 4.44 (q, J=7.05 Hz, 2 H) 1.34 (t, J=7.05 Hz, 3 H). Step 2: 4-Bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile Ethyl 2-bromo-3-cyano-6-fluorobenzoate (Step 1) was reacted with hydrazine hydrate (1 equiv.) and triethylamine (1 equiv.) in ethanol at 80°C according to general procedure C to give the title compound ([M+H, Br]+0.240). Step 3: 4-Bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile To 4-bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile (Step 2) (180 mg, 0.8 mmol) in DMF (5 mL) was added sodium hydride (36 mg, 60% dispersion in mineral oil, 0.9 mmol) and triphenylmethyl chloride (232 mg, 0.8 mmol) at 0°C under nitrogen. The cooling bath was removed and the reaction was stirred for 2 h until it reached ambient temperature. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, brine, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 0:1-1:1) afforded the title compound (136 mg, 36%) as a white solid ([M+Na]+1.502). Step 4: 3-Hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile The desired compound ([MH]-568 / 4) was prepared by Suzuki coupling of 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to general procedure D. Step 5: 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile and 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile To a mixture of 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (Step 3) (49 mg, 0.1 mmol) and potassium carbonate (48 mg, 0.3 mmol) in DMF (1 mL) was added methyl 2-chloro-2,2-difluoroacetate (20 µL, 0.2 mmol). The reaction was stirred in a sealed tube at 80°C for 50 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated to give 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile, which was used directly as a crude mixture. A mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (step 4) was deprotected using general procedure H to afford the desired compounds, which were separated by preparative reverse phase HPLC ([M+H]+2.342 and 2.378). Example 70: 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[‎4,3-c]pyridine Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone 2,4,6-Trichloropyridine was deprotonated with LDA (0.9 equiv) for 1 h and reacted with cyclopropanecarbaldehyde (1.2 equiv) for 1.5 h according to general procedure A to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized using general procedure B1 to give the title compound. ([M+H, Cl]+1.250) Step 2: 4,6-Dichloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (Step 1) was treated with hydrazine hydrate (5 equiv) in ethanol at ambient temperature according to general procedure C to give the title compound. ([M+H, Cl]+1.228). Step 3: 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[‎4,3-c]pyridine The title compound ([M+H, Cl]+362.3) was prepared from Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to general procedure D. Step 4: 6-Chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎4,3-c]pyridine 6-Chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (50 mg, 0.1 mmol) was SEM protected using the general procedure E2. The crude product was dissolved in 2 M sodium methoxide in MeOH (2 mL) and the reaction was heated in a microwave to 130°C for 30 min. The reaction mixture was concentrated, redissolved in trifluoroacetic acid (1 mL), ethylenediamine (0.1 mL, 1.4 mmol) was added and the mixture was stirred for 1 h. The reaction was concentrated, the residue was purified by reverse phase chromatography to afford the title compound (3 mg, 5%) as a white solid. ([M+H]+358.2). Example 71: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine Step 1: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Example 57, Step 3) (45 mg, 0.1 mmol) and potassium carbonate (35 mg, 0.3 mmol) in DMF (0.8 mL) was added 1-(trifluoromethyl)-1l3-benzo[d][1,2]iodaxol-3(1H)-one (40 mg, 0.3 mmol). The reaction was allowed to proceed at ambient temperature for 16 h, after which another portion of potassium carbonate (35 mg, 0.3 mmol) and 1-(trifluoromethyl)-1l3-benzo[d][1,2]iodoxyl-3(1H)-one (40 mg, 0.3 mmol) were added and the mixture was stirred for another 16 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1-1:4) afforded the title compound (12 mg, 22%) as a colorless gum. ([M+H]+614.4). Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (Step 1) was deprotected using general procedure H to give the title compound. ([M+H]+372.2). Example 72: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide Step 1: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-‎2H-pyran-2-yl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid To a solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 62) (147 mg, 0.4 mmol) in dichloromethane (4 mL) was added 3,4-dihydro-2H-pyran (73 µL, 0.8 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.1 mmol) and the reaction was stirred for 7 h. Concentration of the reaction afforded the crude title compound (181 mg, quant.) as a brown foam. ([M+H]+3.456). Step 2: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide To 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (45 mg, 0.1 mmol) in DMF (1 mL) was added TBTU (48 mg, 0.2 mmol) followed by triethylamine (41 µL, 0.3 mmol). After 0.5 h, ammonium hydroxide (39 µL, 1 mmol) was added and the mixture was stirred for 30 min. The reaction was concentrated, redissolved in HCl (0.5 mL, 4N in dioxane, 2 mmol), and the reaction was stirred at 50°C for 6 h, after which the reaction was again concentrated to dryness. Purification by reverse phase HPLC gave the title compound (3 mg, 8%) as a grayish-white solid ([M+H]+371.3). Example 73: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+385.3) was prepared analogously to Example 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and methylamine hydrochloride. Example 74: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-d]pyridazine Step 1: Methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate To a solution of methyl 3-cyclopropyl-1H-pyrazole-5-carboxylate (300 mg, 1.8 mmol) in dichloromethane (5 mL) was added 3,4-dihydro-2H-pyran (197 µL, 2.2 mmol) and p-toluenesulfonic acid monohydrate (35 mg, 0.2 mmol) and the reaction was stirred for 1 h. Concentration of the reaction and flash column chromatography (heptane:ethyl acetate 3:7) afforded the title compound (374 mg, 82%) as a colorless oil. ([M+H]+1.251). Step 2: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol To a solution of methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (Step 1) (1.1 g, 4.6 mmol) in THF (34 mL) was cooled to -78°C under argon and diisobutylaluminum hydride (11.9 mL, 1 M in THF, 1.9 mmol) was added and the mixture was stirred at this temperature for 30 min and then warmed to room temperature. The reaction was cooled again to -78°C and water (0.3 mL) was added and the reaction was warmed to room temperature again. Addition of Na2SO4 followed by filtration and concentration afforded the title compound (670 mg, 63%) as a white solid. ([M+H]+223.2). Step 3: 3-Cyclopropyl-1-(tetrahydro-‎2H-pyran-2-yl)-5-(((tetrahydro-‎2H-pyran-2-yl)oxy)methyl)-1H-pyrazole To a solution of (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (Step 2) (300 mg, 1.4 mmol) in DCM (5 mL) was added 3,4-dihydro-2H-pyran (136 µl, 1.6 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.1 mmol) and the reaction was stirred for 16 h. Addition of a few drops of triethylamine, concentration of the reaction and flash column chromatography (heptane:ethyl acetate 1:1) afforded the title compound (354 mg, 66%) as a light yellow oil. ([M+H]+1.307). Step 4: 3-Cyclopropyl-4-iodo-1-(tetrahydro-‎2H-pyran-2-yl)-5-(((tetrahydro-‎2H-pyran-2-yl)oxy)methyl)-1H-pyrazole To a solution of 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Step 3) (402 mg, 1.3 mmol) in dichloromethane (2.5 mL) was added N-iodosuccinimide (413 mg, 1.8 mmol) and the reaction was stirred at ambient temperature for 20 h. The reaction was diluted with dichloromethane, washed with 10% aqueous sodium thiosulfate, water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3) afforded the title compound (400 mg, 68%) as a light yellow oil. ([M+H]+433.1). Step 5: (3-Cyclopropyl-1-(tetrahydro-‎2H-pyran-2-yl)-5-(((tetrahydro-‎2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol To an ice-cold solution of 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Step 4) (50 mg, 0.1 mmol) in THF (0.2 mL) under argon was added isopropylmagnesium chloride-lithium chloride complex (98 µL, 1.3 M in THF, 0.1 mmol). The reaction was warmed to ambient temperature for 5 min and then cooled back to 0°C, then quenched with a solution of 3-methyl-4-(methylsulfonyl)benzaldehyde (28 mg, 0.1 mmol), dissolved in THF (0.1 mL), and then the reaction was stirred at ambient temperature for 1 h. Stirred for 30 min. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride, water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9-4:1) afforded the title compound (40 mg, 62%) as an off-white solid. ([M+H]+505.4). Step 6: (3-Cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (3-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (Step 5) (41 mg, 0.1 mmol) was dissolved in HCl (0.1 mL, 4N in dioxane, 1.4 mmol) and water (15 µL, 0.1 mmol) was added. The reaction mixture was then stirred at 45°C for 5 min, after which it was concentrated to give the crude title compound (40 mg, quant.) as a light yellow gum. ([M+H]+2.337). Step 7: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-d]pyridazine To a solution of (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (Step 6) (30 mg, 0.1 mmol) in dichloromethane (0.4 mL) was added Des-Martin periodinane (76 mg, 0.2 mmol) and the mixture was stirred at room temperature for 10 min. Hydrazine monohydrate (48 µl, 0.5 mmol) was then added and the reaction was stirred for a further 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) afforded the title compound (3 mg, 9%) as a light yellow solid ([M+H]+2.329). Example 75: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole Step 1: (2-Bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol (2-Bromo-4-fluorophenyl)(methyl)sulfane was reacted with LDA (1 / 1 equiv) for 1 h before addition of cyclopropanecarbaldehyde (2 / 1 equiv) according to general procedure A. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.98 - 7.11 (m, 1 H) 6.91 - 6.98 (m, 1 H) 5.25 (d, J=4 / 63 Hz, 1 H) 4.15 (ddd, J=8 / 66, 4 / 53, 1 / 31 Hz, 1 H) 2.24 (s, 3 H) 1.16 - 1 / 35 (m, 1 H), 0.11 - 0.49 (m, 4 H) Step 2: (2-Bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone (2-Bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol (Step 1) was oxidized using general procedure B1 to give the title compound. ([M+H, Br]+0.291) Step 3: Cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[‎1,1'-biphenyl]-2-yl)methanone The title compound ([M+H]+379.2) was prepared from the Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[‎4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to general procedure D. Step 4: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole Cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[‎1,1'-biphenyl]-2-yl)methanone (Step 2) was reacted with hydrazine hydrate (15 equiv) in ethanol at 150°C (microwave) according to general procedure C to give the title compound ([M+H]+373.2). Example 76: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (23 mg, 0.1 mmol) in DCM (1 mL) was added a solution of m-chloroperbenzoic acid (124 µl, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate solution, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) afforded the title compound (15 mg, 59%) as a white solid. ([M+H]+2.389). Example 77: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (26 mg, 0.1 mmol) in DCM (1 mL) was added a solution of m-chloroperbenzoic acid (263 µl, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate solution, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) afforded the title compound (18 mg, 61%) as a white solid. ([M+H]+2.405). Example 78: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one Step 1: 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine To an ice-cold solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO2018 / 11628 A1) (0.1 g, 3.6 mmol) in DMF (20 mL) under argon was added triphenylmethyl chloride (12.2 g, 4.4 mmol) and sodium hydride (175 mg, 60% dispersion in mineral oil, 4.4 mmol), and the reaction mixture was warmed to ambient temperature and stirred for 3 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10) afforded the title compound (0.9 g, 46%) as a white solid ([M+Na]+0.518). Step 2: 5-Methoxy-1-trityl-pyrazolo[‎4,3-b]pyridin-3-ol A mixture of 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (Step 1) (50 mg, 0.1 mmol), potassium hydroxide (16 mg, 0.3 mmol), t-BuBrettPhos (8 mg, 0.02 mmol), t-BuBrettPhos Pd G3 (10 mg, 0.02 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 80°C for 18 h under nitrogen. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC gave the title compound (20 mg, 51%) as a white solid. ([M+Na]+1.408) Step 3: 3-(Difluoromethoxy)-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine A suspension of 5-methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol (Step 2) (400 mg, 0.1 mmol), sodium 2-chloro-2,2-difluoroacetate (224 mg, 1.5 mmol), cesium carbonate (640 mg, 0.2 mmol) in acetonitrile (20 mL) was stirred at 50°C for 2 h. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC afforded the title compound (400 mg, 89%) as a yellow solid. ([M+H]+1.458) Step 4: 3-(Difluoromethoxy)-1,3a,4,7a-tetrahydropyrazolo[4,3-b]pyridin-5-one 3-(Difluoromethoxy)-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (Step 3) (300 mg, 0.7 mmol) was dissolved in HCl (15 mL, 4N in dioxane, 60 mmol) and stirred at 80°C for 3 h. The reaction mixture was concentrated to dryness and purified by preparative reverse-phase HPLC to give the title compound (100 mg, 75%) as a gray solid. ([M+H]+1.202) Step 5: 3-(Difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one A mixture of 3-(difluoromethoxy)-1,4-dihydropyrazolo[4,3-b]pyridin-5-one (200 mg, 0.1 mmol), 3,4-dihydro-2H-pyran (0.14 mL, 1.5 mmol), p-toluenesulfonic acid monohydrate (86 mg, 0.5 mmol) in THF (5 mL) was stirred at 60°C for 12 h, after which the reaction was concentrated. Purification by preparative reverse-phase HPLC gave the title compound (150 mg, 52%) as a white solid. ([M+H]+0.286) Step 6: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (Step 5) (100 mg, 0.4 mmol) in dichloromethane (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature under air. After 12 h, another portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) were added and the mixture was stirred for another 16 h, then the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Preliminary reverse phase HPLC gave the title compound (70 mg, 44%) as a brown solid. ([M+H]+1.454). Step 5: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (Step 4) was deprotected using general procedure I1 to give the title compound ([M+H]+1.370). Example 79: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[‎3,4-c]pyridine Step 1: (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone 3-Bromo-5-fluoro-2-(trifluoromethyl)pyridine was reacted with LDA (1.1 equiv) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv) according to general procedure A to give crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was directly oxidized using general procedure B1 to give the title compound. ([M+H, Br]+1.312) Step 2: Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone The desired compound ([M+H]+402.2) was prepared from Suzuki coupling of (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone (step 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to general procedure D. Step 3: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[‎3,4-c]pyridine 3-Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone (Step 2) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H]+2.396). Example 80: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-b]pyridin-5-one Step 1: 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine To a solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO2018 / 11628 A1) (1.6 g, 5.8 mmol) in dichloromethane (40 mL) was added 3,4-dihydro-2H-pyran (0.3 g, 35.6 mmol) and p-toluenesulfonic acid monohydrate (0.100 mg, 0.6 mmol) and the mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (heptane:ethyl acetate 7:3) afforded the title compound (1.8 g, 82%) as a brown viscous oil. ([M+H]+359.9). Step 2: 3-Cyclopropyl-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridine The title compound ([M+H]+0.274) was prepared from Suzuki coupling of 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridine (step 1) and cyclopropylboronic acid (8 equiv.) with potassium carbonate (4 equiv.) at 100°C according to general procedure D. Step 3: 3-Cyclopropyl-1-tetrahydropyran-2-yl-4H-pyrazolo[‎4,3-b]pyridin-5-one To 3-cyclopropyl-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (Step 2) (270 mg, 0.1 mmol) was dissolved in HCl (30 mL, 4N in dioxane, 120 mmol) and heated to 100 °C for 15 h. The mixture was concentrated and the residue was dissolved in DCM (9 mL) and DMF (3 mL). 4-Dihydro-2H-pyran (80 mg, 0.1 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.3 mmol) were added and the reaction was stirred for 16 h. Another portion of 4-dihydro-2H-pyran (80 mg, 0.1 mmol) was added and the reaction was stirred for another 12 h. The reaction was diluted with DCM, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate) afforded the title compound (170 mg, 62%) as a colorless viscous oil. ([M+H]+3.260). Step 4: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (Step 3) (100 mg, 0.4 mmol) in DCM (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature under air. After 12 hours, another portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) was added and the mixture was stirred for another 16 hours. Then, another portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) was added and the mixture was reacted for another 16 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Purification by preparative TLC (ethyl acetate) gave the title compound (90 mg, 50%) as a brown gum. ([M+H]+428.1). Step 5: 6-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one To a solution of 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.09 mmol) (Step 4) in DMF (2.5 mL) was added N-bromosuccinimide (33 mg, 0.2 mmol). The reaction was stirred for 24 h, then diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (40 mg, 68%) as a white solid. ([M+H, Br]+0.506). Step 6: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one The title compound ([M+H]+ 1.422) was prepared from Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one (Step 5) and trimethylboroxine with potassium carbonate at 100°C according to general procedure D. Step 7: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-b]pyridin-5-one 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one (Step 6) was deprotected using general procedure I1 to give the title compound ([M+H]+1.358). Example 81: 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-b]pyridin-5-one Step 1: 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one The title compound ([M+H]+1.468) was prepared from Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one (Example 81, Step 5) and cyclopropylboronic acid (10 equiv) with potassium carbonate (4 equiv) at 100°C according to general procedure D. Step 2: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-b]pyridin-5-one was deprotected using general procedure I1 to give the title compound ([M+H]+2.384). Example 82: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine Step 1: (3-Bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol 3-Bromo-2-(difluoromethoxy)-5-fluoropyridine was reacted with LDA (1.2 equiv) for 1 h before addition of cyclopropanecarbaldehyde (3 equiv) according to general procedure A to give the title compound. ([M+H, Br]+1.312). Step 2: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (3-Bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol (Step 1) was directly oxidized using general procedure B1 to give the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 8.06 (s, 1H), 7.61 (s, 0.25 H), 7.37 (s, 0.5 H), 7.13 (s, 0.25 H), 2.23 (tt, 1H, J=4.2, 7.9 Hz), 1.4-1.5 (m, 2H), 1.24 (qd, 2H, J=3.8, 7.7 Hz) Step 3: Cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone The title compound ([M+H]+3.400) was prepared from Suzuki coupling of (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90°C according to general procedure D. Step 4: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine Cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (Step 3) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H]+4.394). Example 83: 3-Cyclopropyl-‎N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+399.3) was prepared analogously to Example 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and dimethylamine hydrochloride. Example 84: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+425.4) was prepared analogously to Example 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and 3-oxetanamine. Example 85: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide Step 1: 3-Chloro-2-cyclopropyl-5-fluoropyridine 2-Bromo-3-chloro-5-fluoropyridine (300 mg, 1.4 mmol), potassium cyclopropyltrifluoroborate (232 mg, 1.6 mmol), palladium(II) acetate (6 mg, 29 µmol), butyldi-1-adamantylphosphine (31 mg, 86 µmol), and cesium carbonate (1.4 g, 3.4 mmol) were dissolved in a mixture of toluene (10 mL) and water (1.5 mL) and purged with argon. The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered directly over Dicalite®, washed with ethyl acetate, and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9) afforded the title compound (81 mg, 31%) as a colorless oil ([M+H]+0.172). Step 2: (3-Chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone 3-Chloro-2-cyclopropyl-5-fluoropyridine was reacted with LDA (1.1 equiv) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv) according to general procedure A to give (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was oxidized using general procedure B1 to give the title compound. ([M+H, Cl]+1.240) Step 3: Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone The title compound ([M+H]+374.2) was prepared from Suzuki coupling of (3-bromo-2-(3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120°C according to general procedure D. Step 4: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (Step 3) was reacted with hydrazine hydrate (100 equiv) in THF at 170°C (microwave) according to general procedure C to give the title compound ([M+H]+2.368). Example 86: N,3-Dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+425.4) was prepared analogously to Example 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and cyclopropylamine. Example 87: 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide Step 1: 6-Chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile To a solution of 2-chloro-4,6-difluorobenzonitrile (100 mg, 0.6 mmol) dissolved in THF (2 mL) under argon and cooled to -78°C was added LDA (0.3 mL, 0.7 mmol) and the mixture was stirred for 5 min, after which chlorotrimethylsilane (0.1 mL, 0.6 mmol) was added and the reaction was stirred for a further 30 min. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, allowed to warm to ambient temperature, extracted with ethyl acetate, dried (Na2SO4) and concentrated. Flash column chromatography (heptane) gave the title compound (127 mg, 73%) as a colourless oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.03 (dd, 1H, J=1.4, 1.8 Hz), 0.9-0.1 (m, 15H) Step 2: 2-Chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile 6-Chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile (Step 1) was reacted with LDA (1.2 equiv) for 0.25 h before addition of cyclopropanecarbaldehyde (1.3 equiv) according to general procedure A to give the title compound. ([M+H, Cl]+2.381). Step 3: 2-Chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile 2-Chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 2) was oxidized using general procedure B1 to give the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 2.22 (dtt, 1H, J=1 / 3, 4 / 5, 7 / 8 Hz), 1.37 (t, 2H, J=3 / 9 Hz), 1.1-1 / 2 (m, 2H), 0.9-1 / 0 (m, 15H) Step 4: 6-(cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile The title compound ([M+H]+376.4) was prepared from Suzuki coupling of 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120°C according to general procedure D. Step 5: 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide 6-(Cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (Step 4) was reacted with hydrazine hydrate (2 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H]+370.2). Examples 88 and 89: 3-Cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide and 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile (Example 87) (20 mg, 54 µmol) was suspended in sodium hydroxide (3 mL, 3 M in water, 9 mmol) and heated to 150°C in a microwave for 4.5 h. The reaction was acidified with 6N hydrochloric acid and extracted with ethyl acetate, the combined organic phase was dried (Na2SO4) and concentrated to give a crude mixture (1:1) of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid. The reaction was prepared with methylamine hydrochloride similar to Example 72, followed by reverse phase preparative HPLC to give the two desired compounds. ([M+H]+3.402 and 2.388). Example 90: 6-Chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile Step 1: 2,6-Dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile 2,6-Dichloro-4-fluorobenzonitrile was reacted with LDA (0.1 equiv) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv) according to general procedure A to give the title compound. ([M-H2O, 2Cl]+1.242). Step 2: 2,6-Dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile 2,6-Dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile (Step 1) was oxidized using general procedure B1 to give the title compound ([M+H, 2Cl]+1.258). Step 3: 3-Chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[‎1,1'-biphenyl]-2-carbonitrile The title compound ([M+H,Cl]+392.2) was prepared from the Suzuki coupling of 2-chloro-32,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to general procedure D. Step 4: 6-Chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile 3-Chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (Step 3) was reacted with hydrazine hydrate (15 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H,Cl]+386.2). Example 91: 4-(3-Methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one #x200fStep 1: 5-Methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[#x200f#x200e‎#x200e#x200e4,3-b#x200e#x200f]pyridine#x200f To a solution of 5-methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol (Example 78, Step 2) (430 mg, 1.1 mmol) in DMF (16 mL) was added potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol). The mixture was stirred at 25°C for 16 h, after which another portion of potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol) were added and the reaction was stirred for an additional 12 h. The reaction was diluted with water and extracted repeatedly with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:10) afforded the title compound (110 mg, 21%) as a white solid. ([M+H]+1.476). Step 2: 3-(Trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one A solution of 5-methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridine (Step 1) (110 mg, 0.2 mmol) in 4 M HCl in dioxane (0.20 mL, 80 mmol) was stirred at 80°C for 24 h. The reaction was concentrated and purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (60 mg, 53%) as a white solid. ([M+H]+1.462). Step 3: 4-(3-Methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one (Step 2) (55 mg, 0.1 mmol) in DCM (4 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) and copper(II) acetate (43 mg, 0.2 mmol) and the reaction was stirred at ambient temperature under an oxygen atmosphere (balloon). After 12 h, another portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) was added and the mixture was stirred for another 12 h, then the reaction was diluted with ethyl acetate and filtered. Purification by preparative TLC afforded the title compound (90 mg, 63%) as a white solid. ([M+H]+1.630). Step 4: 4-(3-Methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one 4-(3-Methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin-5-one was deprotected using general procedure I1 to give the title compound ([M+H]+1.388). Example 92: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[‎3,2-b]pyridin-5-one Step 1: 3-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (0.1 g, 6.75 mmol, 1 equiv) in DMF (20 mL) was added N-bromosuccinimide (1.4 g, 1.7 mmol) at 25°C and the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with water and extracted repeatedly with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane = 0:1-1:8) afforded the title compound (1.2 g, 76%) as a white solid. ([M+H, Br]+0.227). Step 2: 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane 3-Bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (step 1) was converted to the title compound in THF using the general E1 procedure. ([M+H, Br]+1.357) Step 3: 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane The title compound ([M+Hl]+319.2) was prepared from the Suzuki coupling of 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (step 2) and cyclopropylboronic acid (10 equiv) with potassium carbonate (8 equiv) at 100°C according to general procedure D. Step 4: 3-Cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[‎3,2-b]pyridin-5-one A solution of 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (Step 3) (320 mg, 1 mmol) in 4 M HCl in dioxane (0.20 mL, 80 mmol) was stirred at 90°C for 5 h. The reaction was concentrated and purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (140 mg, 58%) as an off-white solid. ([M+H]+1.219). Step 5: 3-Cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[‎3,2-b]pyridin-5-one To a solution of 3-cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[‎3,2-b]pyridin-5-one (Step 4) (140 mg, 0.6 mmol) in dichloromethane (6 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (250 mg, 1.2 mmol), pyridine (0.09 mL, 1.2 mmol), triethylamine (0.16 mL, 1.2 mmol) and copper(II) acetate (212 mg, 1.2 mmol) and the reaction was stirred at ambient temperature under an oxygen atmosphere (balloon). After 2 hours, another portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (250 mg, 1.2 mmol) and triethylamine (0.16 mL, 1.2 mmol) was added and the mixture was stirred for another 2 hours, then another third similar portion of boronic acid and triethylamine was added and the reaction was stirred for another 12 hours. The reaction was then filtered and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) gave the title compound (170 mg, 68%) as a yellow solid. ([M+H]+1.387). Step 6: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[‎3,2-b]pyridin-5-one 3-Cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[‎3,2-b]pyridin-5-one (Step 5) was deprotected using general procedure J to give the title compound. ([M+H]+2.343). Example 93: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole Step 1: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol The desired compound ([MH]-621.5) was prepared by Suzuki coupling of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (intermediate 16, step 4) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to general procedure D. Step 2: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole To a solution of 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Step 1) (206 mg, 0.3 mmol) in DMF (3 mL) was added potassium carbonate (137 mg, 0.1 mmol) and 1-(trifluoromethyl)-1l3-benzo[d][1,2]iodoxyl-3(1H)-one (165 mg, 0.5 mmol) and the mixture was stirred at room temperature for 18 h. The reaction was concentrated to dryness, suspended in ethyl acetate, washed with water, dried (Na2SO4), and concentrated. Flash column chromatography (heptane:ethyl acetate 1:9-0:1) afforded the title compound (46 g, 20%) as a white solid. ([M+NH4+]+708.5) Step 3: 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole 4-(3-Methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole (Step 2) was deprotected using general procedure I1 to give the title compound. ([M+H]+2.449). Example 94: 3-Cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole Step 1: Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[‎1,1'-biphenyl]-2-yl)methanone The desired compound ([M+H]+415.2) was prepared by Suzuki coupling of (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone (Example 75, Step 2) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 21) with potassium carbonate at 100°C according to general procedure D. Step 2: Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[‎1,1'-biphenyl]-2-yl)methanone (Step 1) was converted to the title compound using general procedure G. ([M+H]+447.3). Step 3: 3-Cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone (Step 2) was reacted with hydrazine hydrate (2 equiv) in THF at ambient temperature according to general procedure C to give the title compound ([M+H]+441.2). Example 95: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in water (4 mL) was added sodium hydroxide (0.1 mL, 6N, 6 mmol) and the reaction was heated to 100°C for 10 h. The reaction mixture was cooled to 0°C and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organic phase dried (Na2SO4) and concentrated to give the title compound (100 mg, 95%) as a yellow solid. ([M+H]+0.398) Step 2: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The desired compound ([M+H]+1.411) was prepared similarly to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 4) and methylamine hydrochloride. Example 96: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide Step 1: 1-Bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene To a stirred suspension of potassium tert-butoxide (61 mg, 0.5 mmol) in DMSO (1 mL) was added 4-bromo-5-fluoro-2-methyl-benzenethiol (CAS: 1208077-77-3) (100 mg, 0.5 mmol) and cyclopropyl bromide (164 mg, 1.4 mmol) and the reaction was heated to 100°C for 12 h. The reaction was repeatedly extracted with ethyl acetate, the combined organic phase dried (Na2SO4) and concentrated, purification by preparative TLC (heptane) afforded the title compound (60 mg, 51%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.29 (d, J = 5.9 Hz, 1H), 7.27 - 7.24 (m, 1H), 2.18 (s, 3H), 2.13 - 2.06 (m, 1H), 1.19 - 1.13 (m, 2H), 0.75 - 0.67 (m, 2H) Step 2: 1-Bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene 1-Bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene (Step 1) was converted to the title compound using general procedure G. ([M+H]+0.293). Step 3: 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene (Step 2) was converted to the title compound using general procedure F. ([M+H]+258.9). Step 4: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carbonitrile The desired compound ([M+H]+2.397) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and the adduct 1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.5 equiv) at 120°C according to general procedure D. Step 5: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid To a solution of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 4) (20 mg, 0.1 mmol) in water (0.2 mL) was added sodium hydroxide (0.05 mL, 6N, 0.3 mmol) and the reaction was heated to 100°C for 38 h. The reaction mixture was cooled to 0°C and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organic phase dried (Na2SO4) and concentrated to give the title compound (20 mg, 95%). ([M+H]+1.416) Step 6: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+1.429) was prepared similarly to Example 72 from 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid (Step 5) and methylamine hydrochloride. Example 97: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide Step 1: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid To a suspension of 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 47) (50 mg, 0.1 mmol) in water (0.6 mL) was added sodium hydroxide (0.1 mL, 0.8 mmol). The reaction mixture was stirred at 100°C for 18 h. The reaction mixture was cooled to 0°C and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organics dried (Na2SO4) and concentrated. Purification by preparative reverse phase HPLC gave the title compound (20 mg, 34%) as a grey foam. ([M+H]+0.390) Step 2: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[‎3,4-c]pyridine-5-carboxamide The title compound ([M+H]+1.403) was prepared similarly to Example 72 from 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎3,4-c]pyridine-5-carboxylic acid (Step 1) and methylamine hydrochloride. Example 98: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in ethanol (4 mL) was added sodium hydroxide (0.7 mL, 6N, 0.3 mmol) and the reaction was heated to 100°C for 12 h. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to give the title compound (28 mg, 26%) as a white solid. ([M+H]+1.397) Example 99: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formic acid salt Step 1: 7-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine To a solution of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 64, Step 1) (100 mg, 0.3 mmol) in THF (1 mL) were added p-toluenesulfonic acid monohydrate (13 mg, 0.1 mmol) and dihydropyran (0.07 mL, 0.7 mmol), and the reaction solution was stirred at 60 °C for 12 h. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the combined organic phase was dried (Na2SO4) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (60 mg, 50%) as a yellow oil. ([M+H, Br]+0.490) Step 2: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (332 mg, 0.1 mmol), N-[2-(2-aminoethoxy)ethyl]acetamide (179 mg, 1.2 mmol), xanthophos (14 mg, 0.02 mmol), and Pd(OAc)2 (4.6 mg, 0.02 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC afforded the title compound (40 mg, 34%) as a yellow solid. ([M+H]+556.2) Step 3: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formic acid salt N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide (Step 2) was deprotected using general procedure I1 to give the title compound ([M+H]+472.3). Example 100: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formic acid salt Step 1: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (Example 99, Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (332 mg, 0.1 mmol), N-(3-aminopropyl)acetamide (118 mg, 0.1 mmol), xanthophos (14 mg, 0.02 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC gave the title compound (60 mg, 56%) as a yellow solid. ([M+H]+0.526) Step 2: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formic acid N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide (Step 1) was deprotected using general procedure I1 to give the title compound ([M+H]+441.9). Example 101: N-[2-(2-Aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; Formic acid Step 1: tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (Example 99, Step 1) (120 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (399 mg, 1.2 mmol), N-Boc-2-(2-amino-ethoxy)-ethylamine (150 mg, 0.7 mmol), xanthophos (17 mg, 0.03 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC afforded the title compound (98 mg, 62%) as a yellow solid. ([M+H]+614.2) Step 2: N-[2-(2-Aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formic acid salt Tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate (Step 1) was deprotected using general procedure I1 to give the title compound ([M+H]+1.430). Example 102: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-yl]butane-1,4-diamine Step 1: tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (Example 99, Step 1) (130 mg, 0.3 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (432 mg, 1.3 mmol), N-Boc-1,4-diaminobutane (150 mg, 0.8 mmol), xanthophos (18 mg, 0.03 mmol) and Pd(OAc)2 (6 mg, 0.03 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC gave the title compound (90 mg, 56%) as a yellow solid. ([M+H]+2.598) Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-yl]butane-1,4-diamine Tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate (Step 1) was deprotected using general procedure I1 to give the title compound ([M+H]+1.414). Example 103: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide Step 1: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (Example 99, Step 1) (80 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was added cesium carbonate (266 mg, 0.8 mmol), N-(4-aminobutyl)acetamide (106 mg, 0.8 mmol), xanthophos (11 mg, 0.02 mmol) and Pd(OAc)2 (4 mg, 0.02 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC afforded the title compound (60 mg, 68%) as a yellow solid. ([M+H]+1.540) Step 2: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide (Step 1) was deprotected using general procedure I1 to give the title compound ([M+H]+499.9). Example 104: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-yl]propane-1,3-diamine Step 1: Tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[‎4,3-c]pyridine (Example 99, Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (332 mg, 0.1 mmol), N-Boc-1,3-diaminopropane (107 mg, 0.6 mmol), xanthophos (14 mg, 0.02 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) and stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse-phase HPLC gave the title compound (50 mg, 42%) as a brown oil. ([M+H]+584.4) Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[‎4,3-c]pyridin-7-yl]propane-1,3-diamine Tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate (Step 1) was deprotected using general procedure I1 to give the title compound ([M+H]+399.9). Example 105: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Step 1: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile The desired compound ([M+formate]-3.701) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and the adduct 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.05 equiv) at 100°C according to general procedure D. Step 2: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile was deprotected using general procedure H to give the title compound ([M+H]+415.2) after flash column chromatography. Example 106: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 105, Step 1) (295 mg, 0.45 mmol) in dimethyl sulfoxide (3.5 mL) was added potassium carbonate (12.4 mg, 0.09 mmol) followed by dropwise addition of 35% aqueous hydrogen peroxide (153 µL, 10.23 mmol). The reaction was stirred for 16 h and then diluted with water, resulting in precipitation of the product. The suspension was settled, filtered, the filter cake was washed with water and dried to give the title compound (325 mg, quant.) as a grayish-white powder. ([M+H]+675.3) Step 2: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide was deprotected using general procedure H to give the title compound ([M+H]+ 2.433) after flash column chromatography. Example 107: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (150 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and heated to 80°C. Tert-butyl nitrite (132 µL, 1.11 mmol) was added and the mixture was stirred for 4 h, after which the mixture was evaporated to dryness to give the crude title product (208 mg) as an orange foam, which was used in the next step without further purification. ([M+H]+ 2.434) Step 2: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]+489.2) was prepared similarly to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) and oxetan-3-ylamine. Example 108: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]+1.447) was prepared similarly to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, Step 1) and methylamine hydrochloride. Example 109: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]+1.447) was prepared similarly to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, Step 1) and 2-methoxyethylamine. Example 110: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (238 mg, 0.6 mmol) was added 6N sodium hydroxide (2.5 mL) and the reaction was heated to 100°C for 2.5 h, then diluted with water (9 mL) and heated at 90°C for 36 h. The reaction was cooled to 0°C and acidified with 25% hydrochloric acid, and the product was isolated by filtration to give the title compound (92 mg, 30%) as a light brown solid. ([M+H]+2.398) Step 2: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The desired compound ([M+H]+411.3) was prepared similarly to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) and methylamine hydrochloride. Example 111: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole Step 1: 3-(2-Bromo-4-fluoro-phenyl)sulfanyloxetane To a stirred suspension of 3-iodoxetane (10.4 g, 56.5 mmol) in DMF (30 mL) was added 2-bromo-4-fluorothiophenol (3.9 g, 18.8 mmol) and potassium tert-butoxide (2.5 g, 22.6 mmol) and the reaction was heated to 100°C for 5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10-1:3) afforded the title compound (1.4 g, 83%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37 (dd, J = 7.2, 1.8 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.05 - 6.98 (m, 1H), 5.06 (t, J = 1.7 Hz, 2H), 4.68 (t, J = 6.6 Hz) 2H), 4 / 49 - 4 / 41 (m, 1H) Step 2: Ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate 3-(2-Bromo-4-fluoro-phenyl)sulfanyloxetane (Step 1) was deprotonated with LDA (1.1 equiv) for 30 min and deprotected with ethyl chloroformate (2.1 equiv) according to general procedure A to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.12 - 7.05 (m, 2H), 5.07 (t, J = 1.7 Hz, 2H), 4.67 (t, J = 6.6 Hz, 2H), 4.50 - 4.42 (m, 3H), 1.42 (t, J = 1.7 Hz, 3H) Step 3: Ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate To a solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate (Step 2) (1.4 g, 12.2 mmol) in dichloromethane (100 mL) was added mCPBA (2.6 g, 30.6 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1 saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:1-1:1) afforded the title compound (4.6 g, 87%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 31.8 (dd, J = 6.5, 9.8 Hz, 1H), 7.33 (dd, J = 6.7, 9.8 Hz, 1H), 5.03 - 4.96 (m, 3H), 4.89 - 4.83 (m, 2H), 4.49 (q, J = 1.7 Hz, 2H), 1.42 (t, J = 2.7 Hz, 3H) Step 4: 4-Bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate (Step 3) (4.6 g, 12.5 mmol) in ethanol (40 mL) was added hydrazine monohydrate (689 µL, 13.9 mmol) followed by triethylamine (1.2 mL, 0.15 mmol) and the reaction was brought to ambient temperature. The reaction was then heated to 80°C for 2 h, after which the reaction was concentrated to dryness. Preparative reverse-phase HPLC afforded the title compound (2.8 g, 67%) as a light yellow solid. ([M+H, Br]+0.335). Step 5: 4-Bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-yl To an ice-cold solution of 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one (Step 4) (2.7 g, 1.8 mmol) in DMF (30 mL) was added trityl chloride (2.5 g, 8.9 mmol) followed by sodium hydride (389 mg, 60% dispersion in mineral oil, 9.7 mmol), the cooling bath was removed and the reaction was stirred at ambient temperature for 1 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:3-1:0) afforded the title compound (1.4 g, 65%) as a colorless solid. ([M+Na+, Br]+1.599). Step 6: 4-bromo-3-(difluoromethoxy)-5-(oxan-3-ylsulfonyl)-1-trityl-indazole To a mixture of 4-bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol (Step 5) (0.4 g, 21.5 mmol) in DMF (40 mL) was added sodium chlorofluoroacetate (1.6 g, 10.4 mmol) and potassium carbonate (1.2 g, 15.6 mmol), heated to 80 °C for 0.5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3-1:0) afforded the title compound (2.8 g, 86%) as a white solid. ([M+Na]+1.649). Step 7: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole The desired compound ([M+Na+]+737.4) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.1 equiv) at 100°C according to general procedure D. Step 8: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (Step 7) was deprotected using general procedure H to give the title compound ([M+H]+ 2.495) after flash column chromatography. Example 112: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-l6-sulfanone To a solution of cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (Example 75, Step 3) (250 mg, 661 µmol) in MeOH (3 mL) was added ammonium carbonate (95 mg, 991 µmol) and (diacetoxyiodo)benzene (532 mg, 1.65 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (dichloromethane:MeOH 1:0-9:1) afforded the title compound (199 mg, 72%) as a white solid. ([M+H]+410 / 2). Step 2: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (Step 1) (15 mg, 36.6 µmol) in methanol (1 mL) was added hydrazine monohydrate (28 µL, 366 µmol) and the reaction was heated to 65°C for 16 h, after which the reaction was concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 9:1) afforded the title compound (10 mg, 67%) as a white solid. ([M+H]+1.404). Example 113: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ⁶-sulfane Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-l6-sulfanone To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (50 mg, 122 µmol) in DMF (1 mL) was added sodium hydride (3.7 mg, 183 µmol) and iodomethane (10 µl, 159 µmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Preparative reverse phase HPLC afforded the title compound (22 mg, 37%) as a white solid. ([M+H]+2.424). Step 2: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ⁶-sulfane To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-16-sulfanone (Step 1) (22 mg, 7.52 µmol) in ethanol (0.4 mL) was added hydrazine monohydrate (156 µl, 316 µmol) followed by triethylamine (11 µl, 79 µmol) and the reaction was stirred at ambient temperature for 16 h, after which the reaction was concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 9:1) afforded the title compound (19 mg, 85%) as a white solid. ([M+H]+2.418). Example 114: 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide Step 1: 2-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (0.2 g, 7.31 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.8 mL, 21.9 mmol) and dimethylamine hydrochloride (1.1 g, 14.6 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with 1 M HCl and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:10-3:1) afforded the title compound (1.8 g, 83%) as a white solid. ([M+H, Br]+0.282). Step 2: 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide 2-Bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (Step 1) was deprotonated with LDA (1.2 equiv.) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 equiv.) for 1 h according to general procedure A to give the title compound ([M+H (-OH), Br]+0.334). Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidized using general procedure B2 to give the title compound. ([M+H, Br]+0.350. Step 4: 4-Bromo-3-cyclopropyl-‎N,N-dimethyl-1H-indazole-5-sulfonamide To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide (Step 3) (60 mg, 170 µmol) in ethanol (2 mL) was added hydrazine monohydrate (170 µl, 316 µmol) followed by triethylamine (30 µl, 210 µmol) and the reaction was heated to 80°C for 16 h, after which the reaction was concentrated to dryness. Preparative reverse-phase HPLC afforded the title compound (40 mg, 67%) as a light yellow solid. ([M+H, Br]+1.346). Step 5: 3-Cyclopropyl-‎N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide The desired compound ([M+Na+]+434.2) was prepared from Suzuki coupling of 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.1 equiv) at 100°C according to general procedure D. Example 115: 3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide Step 1: 2-Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (0.2 g, 7.31 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.6 mL, 14.6 mmol) and 4-methoxy-N-methylbenzylamine (1.7 g, 0.11 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was diluted with ethyl acetate, washed with 1 M HCl, and concentrated. Flash column chromatography afforded the title compound (2.6 g, 92%) as a white solid. ([M+H, Br]+1.412). Step 2: 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide 2-Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (Step 1) was deprotonated with LDA (1.2 equiv.) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 equiv.) for 1 h according to general procedure A to give the title compound ([M+Na, Br]+1.482). Step 3: 2-Bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (Step 2) was oxidized using general procedure B2 to give the title compound. ([M+H, Br]+480.2. Step 4: 4-Bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (Step 3) (200 mg, 440 µmol) in ethanol (4 mL) was added hydrazine monohydrate (44 µl, 880 µmol) followed by triethylamine (70 µl, 530 µmol) and the reaction was heated to 80°C for 2 h, after which the reaction was concentrated to dryness. Preparative reverse-phase HPLC afforded the title compound (200 mg, quant.) as a white solid. ([M+H, Br]+0.450). Step 5: 3-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide The desired compound ([M+Na+]+540.2) was prepared from Suzuki coupling of 44-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.1 equiv) at 100°C according to general procedure D. Step 6: 3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide 3-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide (Step 5) was deprotected using general procedure H to give the title compound ([M+H]+ 0.420) after flash column chromatography. Example 116: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile The desired compound ([M+Na]+3.669) was obtained from the Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 8) with potassium carbonate and the adduct 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.05 equiv) at 100°C according to general procedure D. Step 2: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 1) (0.220 mg, 0.34 mmol) in ethanol (5 mL) was added 2N aqueous NaOH (0.85 mL, 1.7 mmol) and the reaction was heated to 100°C for 6 h. The reaction was acidified by addition of 1N HCl, extracted with ethyl acetate and concentrated. Preparative tlc (ethyl acetate:n-heptane 1:2) gave the title compound (150 mg, 66%) as a yellow solid. Step 3: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide 4-(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (step 2) was deprotected using general procedure H to afford the title compound ([M+H]+ 2.423) after flash column chromatography. Example 117: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole The desired compound ([M+Na]+1.465) can be prepared analogously to Example 49 by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole (intermediate 6) and 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 27) followed by deprotection using general procedure H. Example 118: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole Step 1: 2-Bromo-1-cyclopropylsulfanyl-4-fluoro-benzene To a stirred suspension of cyclopropyl bromide (1.6 g, 50.71 mmol) in DMF (50 mL) was added 2-bromo-4-fluorothiophenol (3.5 g, 16.9 mmol) and potassium tert-butoxide (2.2 g, 20.3 mmol) and the reaction was heated to 100°C for 12 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (n-heptane) afforded the title compound (1.7 g, 41%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 50.7 (dd, J = 6.5, 4.8 Hz, 1H), 30.7 (dd, J = 0.2, 1.8 Hz, 1H), 06.7 (dt, J = 1.9, 8.4 Hz, 1H), 2.20 - 2.11 (m, 1H), 1.16 - 1 / 10 (m, 2H), 0 / 79 - 0 / 71 (m, 2H) Step 2: Ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate 2-Bromo-1-cyclopropylsulfanyl-4-fluoro-benzene (Step 1) was deprotonated with LDA (1.1 equiv) for 30 min and reacted with ethyl chloroformate (1.2 equiv) according to general procedure A to give the desired compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.56 (dd, J = 5.5, 9.8 Hz, 1H), 7.12 (t, J = 6.8 Hz, 1H), 4.45 (q, J = 2.7 Hz, 2H), 2.14 (tt, J = 4.4, 7.3 Hz, 1H), 1.41 (t, J = 2.7 Hz, 3H), 1.18 - 1.13 (m, 2H), 0.77 - 0.71 (m, 2H) Step 3: Ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluoro-benzoate To a solution of ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluorobenzoate (Step 2) (1.9 g, 5.95 mmol) in dichloromethane (40 mL) was added mCPBA (3.6 g, 17.9 mmol) and the reaction was stirred at ambient temperature for 12 h. The reaction was then diluted with DCM, washed with 1 saturated aqueous sodium hydrogen bicarbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5-1:3) afforded the title compound (0.2 g, 84%) as a white solid. ([M+H, Br]+ 0.353) Step 4: 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one To an ice-cold solution of ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluorobenzoate (Step 3) (0.2 g, 5.69 mmol) in ethanol (20 mL) was added hydrazine monohydrate (1130 µL, 22.6 mmol) followed by triethylamine (0.79 mL, 5.69 mmol) and the reaction was brought to ambient temperature. The reaction was then heated to 80°C for 2 h, after which the reaction was concentrated to dryness. Preparative reverse-phase HPLC afforded the title compound (1.1 g, 58%) as a grayish-white solid. ([M+H, Br]+316.8). Step 5: 4-bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol To an ice-cold solution of 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one (Step 4) (0.1 g, 3.15 mmol) in DMF (20 mL) was added trityl chloride (0.97 g, 3.47 mmol) followed by sodium hydride (151 mg, 60% dispersion in mineral oil, 3.78 mmol), the cooling bath was removed and the reaction was stirred at ambient temperature for 2 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3-1:1) afforded the title compound (1.1 g, 52%) as a yellow solid. ([M+Na, Br]+1.583). Step 6: 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole To a mixture of 4-bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol (Step 5) (1.2 g, 2.06 mmol) in DMF (30 mL) was added sodium chlorofluoroacetate (0.63 g, 11.4 mmol) and potassium carbonate (0.85 g, 17.6 mmol) and heated to 80 °C for 0.5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5-1:3) afforded the title compound (1.1 g, 83%) as a light yellow solid. ([M+Na]+0.633). Step 7: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole The desired compound ([M+Na+]+1.721) was prepared from Suzuki coupling of 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.1 equiv) at 100°C according to general procedure D. Step 8: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole (Step 7) was deprotected using general procedure H to afford the title compound ([M+H]+ 2.457) after flash column chromatography. Example 119: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole Step 1: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole The desired compound ([M+Na+]+ 2.713) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole (intermediate 36), (2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 25) with potassium carbonate and SPhos Pd G3 (0.1 equiv) at 100°C according to general procedure D. Step 2: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole (step 1) was deprotected using general procedure H to give the title compound ([M+H]+ 0.448) after flash column chromatography. Example 120: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide Step 1: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (Example 116, Step 2) (0.150 mg, 0.23 mmol) in DMF (1 mL) was added NaH (4.5 mg, 0.23 mmol) at 0 °C, and after the reaction was allowed to reach ambient temperature, iodomethane (32 mg, 0.23 mmol) was added and the mixture was stirred for another 2 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated. Preparative tlc (ethyl acetate:n-heptane 1:3) gave the title compound (110 mg, 73%) as a white solid ([M+H]+679.2).